From ICU Syndromes to ICU Subphenotypes: Consensus Report and Recommendations For Developing Precision Medicine in ICU.

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. In order to impact clinical care, identified subpopulations must do more than differentiate prognosis. They must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Dyssynchronous diaphragm contractions impair diaphragm function in mechanically ventilated patients.

BACKGROUND: Pre-clinical studies suggest that dyssynchronous diaphragm contractions during mechanical ventilation may cause acute diaphragm dysfunction. We aimed to describe the variability in diaphragm contractile loading conditions during mechanical ventilation and to establish whether dyssynchronous diaphragm contractions are associated with the development of impaired diaphragm dysfunction. METHODS: In patients receiving invasive mechanical ventilation for pneumonia, septic shock, acute respiratory distress syndrome, or acute brain injury, airway flow and pressure and diaphragm electrical activity (Edi) were recorded hourly around the clock for up to 7 days. Dyssynchronous post-inspiratory diaphragm loading was defined based on the duration of neural inspiration after expiratory cycling of the ventilator. Diaphragm function was assessed on a daily basis by neuromuscular coupling (NMC, the ratio of transdiaphragmatic pressure to diaphragm electrical activity). RESULTS: A total of 4508 hourly recordings were collected in 45 patients. Edi was low or absent (≤ 5 µV) in 51% of study hours (median 71 h per patient, interquartile range 39-101 h). Dyssynchronous post-inspiratory loading was present in 13% of study hours (median 7 h per patient, interquartile range 2-22 h). The probability of dyssynchronous post-inspiratory loading was increased with reverse triggering (odds ratio 15, 95% CI 8-35) and premature cycling (odds ratio 8, 95% CI 6-10). The duration and magnitude of dyssynchronous post-inspiratory loading were associated with a progressive decline in diaphragm NMC (p < 0.01 for interaction with time). CONCLUSIONS: Dyssynchronous diaphragm contractions may impair diaphragm function during mechanical ventilation. TRIAL REGISTRATION: MYOTRAUMA, ClinicalTrials.gov NCT03108118. Registered 04 April 2017 (retrospectively registered).

Linking Acute Physiology to Outcomes in the ICU: Challenges and Solutions for Research.

ICU clinicians rely on bedside physiological measurements to inform many routine clinical decisions. Because deranged physiology is usually associated with poor clinical outcomes, it is tempting to hypothesize that manipulating and intervening on physiological parameters might improve outcomes for patients. However, testing these hypotheses through mathematical models of the relationship between physiology and outcomes presents a number of important methodological challenges. These models reflect the theories of the researcher and can therefore be heavily influenced by one's assumptions and background beliefs. Model building must therefore be approached with great care and forethought, because failure to consider relevant sources of measurement error, confounding, coupling, and time dependency or failure to assess the direction of causality for associations of interest before modeling may give rise to spurious results. This paper outlines the main challenges in analyzing and interpreting these models and offers potential solutions to address these challenges.

Lung Recruitment Assessed by Electrical Impedance Tomography (RECRUIT): A Multicenter Study of COVID-19 Acute Respiratory Distress Syndrome.

Rationale: Defining lung recruitability is needed for safe positive end-expiratory pressure (PEEP) selection in mechanically ventilated patients. However, there is no simple bedside method including both assessment of recruitability and risks of overdistension as well as personalized PEEP titration. Objectives: To describe the range of recruitability using electrical impedance tomography (EIT), effects of PEEP on recruitability, respiratory mechanics and gas exchange, and a method to select optimal EIT-based PEEP. Methods: This is the analysis of patients with coronavirus disease (COVID-19) from an ongoing multicenter prospective physiological study including patients with moderate-severe acute respiratory distress syndrome of different causes. EIT, ventilator data, hemodynamics, and arterial blood gases were obtained during PEEP titration maneuvers. EIT-based optimal PEEP was defined as the crossing point of the overdistension and collapse curves during a decremental PEEP trial. Recruitability was defined as the amount of modifiable collapse when increasing PEEP from 6 to 24 cm H2O (ΔCollapse24-6). Patients were classified as low, medium, or high recruiters on the basis of tertiles of ΔCollapse24-6. Measurements and Main Results: In 108 patients with COVID-19, recruitability varied from 0.3% to 66.9% and was unrelated to acute respiratory distress syndrome severity. Median EIT-based PEEP differed between groups: 10 versus 13.5 versus 15.5 cm H2O for low versus medium versus high recruitability (P < 0.05). This approach assigned a different PEEP level from the highest compliance approach in 81% of patients. The protocol was well tolerated; in four patients, the PEEP level did not reach 24 cm H2O because of hemodynamic instability. Conclusions: Recruitability varies widely among patients with COVID-19. EIT allows personalizing PEEP setting as a compromise between recruitability and overdistension. Clinical trial registered with www.clinicaltrials.gov (NCT04460859).

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.

Rationale: The most beneficial positive end-expiratory pressure (PEEP) selection strategy in patients with acute respiratory distress syndrome (ARDS) is unknown, and current practice is variable. Objectives: To compare the relative effects of different PEEP selection strategies on mortality in adults with moderate to severe ARDS. Methods: We conducted a network meta-analysis using a Bayesian framework. Certainty of evidence was evaluated using grading of recommendations assessment, development and evaluation methodology. Measurements and Main Results: We included 18 randomized trials (4,646 participants). Compared with a lower PEEP strategy, the posterior probability of mortality benefit from a higher PEEP without lung recruitment maneuver (LRM) strategy was 99% (risk ratio [RR], 0.77; 95% credible interval [CrI], 0.60-0.96, high certainty), the posterior probability of benefit of the esophageal pressure-guided strategy was 87% (RR, 0.77; 95% CrI, 0.48-1.22, moderate certainty), the posterior probability of benefit of a higher PEEP with brief LRM strategy was 96% (RR, 0.83; 95% CrI, 0.67-1.02, moderate certainty), and the posterior probability of increased mortality from a higher PEEP with prolonged LRM strategy was 77% (RR, 1.06; 95% CrI, 0.89-1.22, low certainty). Compared with a higher PEEP without LRM strategy, the posterior probability of increased mortality from a higher PEEP with prolonged LRM strategy was 99% (RR, 1.37; 95% CrI, 1.04-1.81, moderate certainty). Conclusions: In patients with moderate to severe ARDS, higher PEEP without LRM is associated with a lower risk of death than lower PEEP. A higher PEEP with prolonged LRM strategy is associated with increased risk of death when compared with higher PEEP without LRM.

Strategies for lung- and diaphragm-protective ventilation in acute hypoxemic respiratory failure: a physiological trial.

BACKGROUND: Insufficient or excessive respiratory effort during acute hypoxemic respiratory failure (AHRF) increases the risk of lung and diaphragm injury. We sought to establish whether respiratory effort can be optimized to achieve lung- and diaphragm-protective (LDP) targets (esophageal pressure swing - 3 to - 8 cm H2O; dynamic transpulmonary driving pressure ≤ 15 cm H2O) during AHRF. METHODS: In patients with early AHRF, spontaneous breathing was initiated as soon as passive ventilation was not deemed mandatory. Inspiratory pressure, sedation, positive end-expiratory pressure (PEEP), and sweep gas flow (in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO)) were systematically titrated to achieve LDP targets. Additionally, partial neuromuscular blockade (pNMBA) was administered in patients with refractory excessive respiratory effort. RESULTS: Of 30 patients enrolled, most had severe AHRF; 16 required VV-ECMO. Respiratory effort was absent in all at enrolment. After initiating spontaneous breathing, most exhibited high respiratory effort and only 6/30 met LDP targets. After titrating ventilation, sedation, and sweep gas flow, LDP targets were achieved in 20/30. LDP targets were more likely to be achieved in patients on VV-ECMO (median OR 10, 95% CrI 2, 81) and at the PEEP level associated with improved dynamic compliance (median OR 33, 95% CrI 5, 898). Administration of pNMBA to patients with refractory excessive effort was well-tolerated and effectively achieved LDP targets. CONCLUSION: Respiratory effort is frequently absent  under deep sedation but becomes excessive when spontaneous breathing is permitted in patients with moderate or severe AHRF. Systematically titrating ventilation and sedation can optimize respiratory effort for lung and diaphragm protection in most patients. VV-ECMO can greatly facilitate the delivery of a LDP strategy. TRIAL REGISTRATION: This trial was registered in Clinicaltrials.gov in August 2018 (NCT03612583).

Lung- and Diaphragm-Protective Ventilation.

Mechanical ventilation can cause acute diaphragm atrophy and injury, and this is associated with poor clinical outcomes. Although the importance and impact of lung-protective ventilation is widely appreciated and well established, the concept of diaphragm-protective ventilation has recently emerged as a potential complementary therapeutic strategy. This Perspective, developed from discussions at a meeting of international experts convened by PLUG (the Pleural Pressure Working Group) of the European Society of Intensive Care Medicine, outlines a conceptual framework for an integrated lung- and diaphragm-protective approach to mechanical ventilation on the basis of growing evidence about mechanisms of injury. We propose targets for diaphragm protection based on respiratory effort and patient-ventilator synchrony. The potential for conflict between diaphragm protection and lung protection under certain conditions is discussed; we emphasize that when conflicts arise, lung protection must be prioritized over diaphragm protection. Monitoring respiratory effort is essential to concomitantly protect both the diaphragm and the lung during mechanical ventilation. To implement lung- and diaphragm-protective ventilation, new approaches to monitoring, to setting the ventilator, and to titrating sedation will be required. Adjunctive interventions, including extracorporeal life support techniques, phrenic nerve stimulation, and clinical decision-support systems, may also play an important role in selected patients in the future. Evaluating the clinical impact of this new paradigm will be challenging, owing to the complexity of the intervention. The concept of lung- and diaphragm-protective ventilation presents a new opportunity to potentially improve clinical outcomes for critically ill patients.

Diaphragm protection: what should we target?

PURPOSE OF REVIEW: Diaphragm weakness can impact survival and increases comorbidities in ventilated patients. Mechanical ventilation is linked to diaphragm dysfunction through several mechanisms of injury, referred to as myotrauma. By monitoring diaphragm activity and titrating ventilator settings, the critical care clinician can have a direct impact on diaphragm injury. RECENT FINDINGS: Both the absence of diaphragm activity and excessive inspiratory effort can result in diaphragm muscle weakness, and recent evidence demonstrates that a moderate level of diaphragm activity during mechanical ventilation improves ICU outcome. This supports the hypothesis that by avoiding ventilator overassistance and underassistance, the clinician can implement a diaphragm-protective ventilation strategy. Furthermore, eccentric diaphragm contractions and end-expiratory shortening could impact diaphragm strength as well. This review describes these potential targets for diaphragm protective ventilation. SUMMARY: A ventilator strategy that results in appropriate levels of diaphragm activity has the potential to be diaphragm-protective and improve clinical outcome. Monitoring respiratory effort during mechanical ventilation is becoming increasingly important.

Lung- and diaphragm-protective strategies in acute respiratory failure: an in silico trial.

BACKGROUND: Lung- and diaphragm-protective (LDP) ventilation may prevent diaphragm atrophy and patient self-inflicted lung injury in acute respiratory failure, but feasibility is uncertain. The objectives of this study were to estimate the proportion of patients achieving LDP targets in different modes of ventilation, and to identify predictors of need for extracorporeal carbon dioxide removal (ECCO2R) to achieve LDP targets. METHODS: An in silico clinical trial was conducted using a previously published mathematical model of patient-ventilator interaction in a simulated patient population (n = 5000) with clinically relevant physiological characteristics. Ventilation and sedation were titrated according to a pre-defined algorithm in pressure support ventilation (PSV) and proportional assist ventilation (PAV+) modes, with or without adjunctive ECCO2R, and using ECCO2R alone (without ventilation or sedation). Random forest modelling was employed to identify patient-level factors associated with achieving targets. RESULTS: After titration, the proportion of patients achieving targets was lower in PAV+ vs. PSV (37% vs. 43%, odds ratio 0.78, 95% CI 0.73-0.85). Adjunctive ECCO2R substantially increased the probability of achieving targets in both PSV and PAV+ (85% vs. 84%). ECCO2R alone without ventilation or sedation achieved LDP targets in 9%. The main determinants of success without ECCO2R were lung compliance, ventilatory ratio, and strong ion difference. In silico trial results corresponded closely with the results obtained in a clinical trial of the LDP titration algorithm (n = 30). CONCLUSIONS: In this in silico trial, many patients required ECCO2R in combination with mechanical ventilation and sedation to achieve LDP targets. ECCO2R increased the probability of achieving LDP targets in patients with intermediate degrees of derangement in elastance and ventilatory ratio.

Impact of extended lung protection during mechanical ventilation on lung recovery in patients with COVID-19 ARDS: a phase II randomized controlled trial.

BACKGROUND: Protective ventilation seems crucial during early Acute Respiratory Distress Syndrome (ARDS), but the optimal duration of lung protection remains undefined. High driving pressures (ΔP) and excessive patient ventilatory drive may hinder lung recovery, resulting in self-inflicted lung injury. The hidden nature of the ΔP generated by patient effort complicates the situation further. Our study aimed to assess the feasibility of an extended lung protection strategy that includes a stepwise protocol to control the patient ventilatory drive, assessing its impact on lung recovery. METHODS: We conducted a single-center randomized study on patients with moderate/severe COVID-19-ARDS with low respiratory system compliance (CRS < 0.6 (mL/Kg)/cmH2O). The intervention group received a ventilation strategy guided by Electrical Impedance Tomography aimed at minimizing ΔP and patient ventilatory drive. The control group received the ARDSNet low-PEEP strategy. The primary outcome was the modified lung injury score (mLIS), a composite measure that integrated daily measurements of CRS, along with oxygen requirements, oxygenation, and X-rays up to day 28. The mLIS score was also hierarchically adjusted for survival and extubation rates. RESULTS: The study ended prematurely after three consecutive months without patient enrollment, attributed to the pandemic subsiding. The intention-to-treat analysis included 76 patients, with 37 randomized to the intervention group. The average mLIS score up to 28 days was not different between groups (P = 0.95, primary outcome). However, the intervention group showed a faster improvement in the mLIS (1.4 vs. 7.2 days to reach 63% of maximum improvement; P < 0.001), driven by oxygenation and sustained improvement of X-ray (P = 0.001). The intervention group demonstrated a sustained increase in CRS up to day 28 (P = 0.009) and also experienced a shorter time from randomization to room-air breathing (P = 0.02). Survival at 28 days and time until liberation from the ventilator were not different between groups. CONCLUSIONS: The implementation of an individualized PEEP strategy alongside extended lung protection appears viable. Promising secondary outcomes suggested a faster lung recovery, endorsing further examination of this strategy in a larger trial. Clinical trial registration This trial was registered with ClinicalTrials.gov (number NCT04497454) on August 04, 2020.

Determinants of Effect of Extracorporeal CO2 Removal in Hypoxemic Respiratory Failure.

BACKGROUND: Dead space and respiratory system elastance (Ers) may influence the clinical benefit of a ventilation strategy combining very low tidal volume (VT) with extracorporeal carbon dioxide removal (ECCO2R) in patients with acute hypoxemic respiratory failure. We sought to evaluate whether the effect of ECCO2R on mortality varies according to ventilatory ratio (VR; a composite variable reflective of dead space and shunt) and Ers. METHODS: Secondary analysis of a trial of a strategy combining very low VT and low-flow ECCO2R planned before the availability of trial results. Bayesian logistic regression was used to estimate the posterior probability of effect moderation by VR, Ers, and severity of hypoxemia (ratio of arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2:FiO2]) on 90-day mortality. Credibility of effect moderation was appraised according to the Instrument for Assessing the Credibility of Effect Modification Analyses criteria. RESULTS: A total of 405 patients were available for analysis. The effect of the intervention on mortality varied substantially with VR (posterior probability of interaction, 94%; high credibility). Benefit was more probable than harm in patients with VR 3 or higher. In patients with VR less than 3, the probability of increased mortality with intervention was high (>90%). The effect of the intervention also varied with PaO2:FiO2 (posterior probability of interaction, >99%; low credibility). Benefit was more probable than harm in patients with PaO2:FiO2 110 mm Hg or higher. The effect of the intervention did not vary substantially with Ers (posterior probability of interaction, 68%; low credibility). CONCLUSIONS: VR has a highly credible influence on the effect of a strategy combining very low VT and low-flow ECCO2R on mortality. This intervention may reduce mortality in patients with high VR. (Funded by an Early Career Investigator Award from the Canadian Institutes of Health Research to Dr. Goligher.)

Dynamic Relative Regional Lung Strain Estimated by Electrical Impedance Tomography in an Experimental Model of ARDS.

BACKGROUND: To analyze the role of PEEP on dynamic relative regional strain (DRRS) in a model of ARDS, respective maps were generated by electrical impedance tomography (EIT). METHODS: Eight ARDS pigs submitted to PEEP steps of 0, 5, 10, and 15 cm H2O at fixed ventilation were evaluated by EIT images. DRRS was calculated as (VT-EIT/EELI)/(VT-EIT[15PEEP]/EELI[15PEEP]), where the tidal volume (VT)-EIT and end-expiratory lung impedance (EELI) are the tidal and end-expiratory change in lung impedance, respectively. The measurement at 15 PEEP was taken as reference (end-expiratory transpulmonary pressure > 0 cm H2O). The relationship between EIT variables (center of ventilation, EELI, and DRRS) and airway pressures was assessed with mixed-effects models using EIT measurements as dependent variables and PEEP as fixed-effect variable. RESULTS: At constant ventilation, respiratory compliance increased progressively with PEEP (lowest value at zero PEEP 10 ± 3 mL/cm H2O and highest value at 15 PEEP 16 ± 6 mL/cm H2O; P < .001), whereas driving pressure decreased with PEEP (highest value at zero PEEP 34 ± 6 cm H2O and lowest value at 15 PEEP 21 ± 4 cm H2O; P < .001). The mixed-effect regression models showed that the center of ventilation moved to dorsal lung areas with a slope of 1.81 (1.44-2.18) % points by each cm H2O of PEEP; P < .001. EELI increased with a slope of 0.05 (0.02-0.07) (arbitrary units) for each cm H2O of PEEP; P < .001. DRRS maps showed that local strain in ventral lung areas decreased with a slope of -0.02 (-0.24 to 0.15) with each cm H2O increase of PEEP; P < .001. CONCLUSIONS: EIT-derived DRRS maps showed high strain in ventral lung zones at low levels of PEEP. The findings suggest overdistention of the baby lung.

Validity of Empirical Estimates of the Ratio of Dead Space to Tidal Volume in ARDS.

BACKGROUND: The ratio of dead space to tidal volume (VD/VT) is a clinically relevant parameter in ARDS; it has been shown to predict mortality, and it determines the extent to which extracorporeal CO2 removal reduces tidal volume (VT) and driving pressure (ΔP). VD/VT can be estimated with volumetric capnography, but empirical formulas using demographic and physiological information have been proposed to estimate VD/VT without the need of additional equipment. It is unknown whether estimated and measured VD/VT produce similar estimates of the predicted effect of extracorporeal CO2 removal on ΔP. METHODS: We performed a secondary analysis of data from a previous clinical trial including subjects with ARDS in whom VD/VT and CO2 production ([Formula: see text]) were measured with volumetric capnography. The estimated ratio of dead space to tidal volume (VD,est/VT) was calculated using standard empiric formulas. Agreement between measured and estimated values was evaluated with Bland-Altman analysis. Agreement between the predicted change in ΔP with extracorporeal CO2 removal as computed using the measured ratio of alveolar dead space to tidal volume (VDalv/VT) or estimated VDalv/VT (VDalv,est/VT) was also evaluated. RESULTS: VD,est/VT was higher than measured VD/VT, and agreement between them was low (bias 0.05, limits of agreement -0.21 to 0.31). Differences between measured and estimated [Formula: see text] accounted for 57% of the error in VD,est/VT. The predicted reduction in ΔP with extracorporeal CO2 removal computed using VDalv,est/VT was in reasonable agreement with the expected reduction using VDalv/VT (bias -0.7 cm H2O, limits of agreement -1.87 to 0.47 cm H2O). In multivariable regression, measured VD/VT was associated with mortality (odds ratio 1.9, 95% CI 1.2-3.1, P = .01), but VD,est/VT was not (odds ratio 1.2, 95% CI 0.8-1.8, P = .3). CONCLUSIONS: VD/VT and VD,est/VT showed low levels of agreement and cannot be used interchangeably in clinical practice. Nevertheless, the predicted decrease in ΔP due to extracorporeal CO2 removal was similar when computed from either estimated or measured VDalv/VT.

Comparing the Effects of Tidal Volume, Driving Pressure, and Mechanical Power on Mortality in Trials of Lung-Protective Mechanical Ventilation.

BACKGROUND: The unifying goal of lung-protective ventilation strategies in ARDS is to minimize the strain and stress applied by mechanical ventilation to the lung to reduce ventilator-induced lung injury (VILI). The relative contributions of the magnitude and frequency of mechanical stress and the end-expiratory pressure to the development of VILI is unknown. Consequently, it is uncertain whether the risk of VILI is best quantified in terms of tidal volume (VT), driving pressure (ΔP), or mechanical power. METHODS: The correlation between differences in VT, ΔP, and mechanical power and the magnitude of mortality benefit in trials of lung-protective ventilation strategies in adult subjects with ARDS was assessed by meta-regression. Modified mechanical power was computed including PEEP (Powerelastic), excluding PEEP (Powerdynamic), and using ΔP (Powerdriving). The primary analysis incorporated all included trials. A secondary subgroup analysis was restricted to trials of lower versus higher PEEP strategies. RESULTS: We included 9 trials involving 4,731 subjects in the analysis. Odds ratios for moderation derived from meta-regression showed that variations in VT, ΔP, and Powerdynamic were associated with increased mortality with odds ratios of 1.24 (95% CI 1.03-1.49), 1.31 (95% CI 1.03-1.66), and 1.37 (95% CI 1.05-1.78), respectively. In trials comparing higher versus lower PEEP strategies, Powerelastic was increased in the higher PEEP arm (24 ± 1.7 vs 20 ± 1.5 J/min, respectively), whereas the other parameters were not affected on average by a higher PEEP ventilation strategy. CONCLUSIONS: In trials of lung-protective ventilation strategies, VT, ΔP, Powerelastic, Powerdynamic, and Powerdriving exhibited similar moderation of treatment effect on mortality. In this study, modified mechanical power did not add important information on the risk of death from VILI in comparison to VT or ΔP.

Association of different positive end-expiratory pressure selection strategies with all-cause mortality in adult patients with acute respiratory distress syndrome.

BACKGROUND: The acute respiratory distress syndrome (ARDS) has high morbidity and mortality. Positive end-expiratory pressure (PEEP) is commonly used in patients with ARDS but the best method to select the optimal PEEP level and reduce all-cause mortality is unclear. The primary objective of this network meta-analysis is to summarize the available evidence and to compare the effect of different PEEP selection strategies on all-cause mortality in adult patients with ARDS. METHODS: We will search MEDLINE, Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and LILACS from inception onwards for randomized controlled trials assessing the effect of PEEP selection strategies in adult patients with moderate to severe ARDS. We will exclude studies that did not use a lung-protective ventilation approach as part of the comparator or intervention strategy. The primary outcome will be all-cause mortality (at the longest available follow-up and up to 90 days). Secondary outcomes will include barotrauma, ventilator-free days, intensive care unit and hospital length of stay, and changes in oxygenation. Two reviewers will independently screen all citations, full-text articles, and extract study-data. We will assess the risk of bias for each of the outcomes using version 2 of the Cochrane risk of bias tool for randomized controlled trials. If feasible, Bayesian network meta-analyses will be conducted to obtain pooled estimates of all potential head-to-head comparisons. We will report pairwise and network meta-analysis treatment effect estimates as risk ratios and risk differences, together with the associated 95% credible intervals. We will assess certainty in effect estimates using GRADE methodology. DISCUSSION: The present study will inform clinical decision-making for adult patients with ARDS and will improve our understanding of the limitations of the available literature assessing PEEP selection strategies. Finally, this information may also inform the design of future randomized trials, including the selection of interventions, comparators, and predictive enrichment strategies. TRIAL REGISTRATION: PROSPERO 2020 CRD42020193302 .