Different ventilation intensities among various categories of patients ventilated for reasons other than ARDS--A pooled analysis of 4 observational studies.

PURPOSE: We investigated driving pressure (ΔP) and mechanical power (MP) and associations with clinical outcomes in critically ill patients ventilated for reasons other than ARDS. MATERIALS AND METHODS: Individual patient data analysis of a pooled database that included patients from four observational studies of ventilation. ΔP and MP were compared among invasively ventilated non-ARDS patients with sepsis, with pneumonia, and not having sepsis or pneumonia. The primary endpoint was ΔP; secondary endpoints included MP, ICU mortality and length of stay, and duration of ventilation. RESULTS: This analysis included 372 (11%) sepsis patients, 944 (28%) pneumonia patients, and 2040 (61%) patients ventilated for any other reason. On day 1, median ΔP was higher in sepsis (14 [11-18] cmH2O) and pneumonia patients (14 [11-18]cmH2O), as compared to patients not having sepsis or pneumonia (13 [10-16] cmH2O) (P < 0.001). Median MP was also higher in sepsis and pneumonia patients. ΔP, as opposed to MP, was associated with ICU mortality in sepsis and pneumonia patients. CONCLUSIONS: The intensity of ventilation differed between patients with sepsis or pneumonia and patients receiving ventilation for any other reason; ΔP was associated with higher mortality in sepsis and pneumonia patients. REGISTRATION: This post hoc analysis was not registered; the individual studies that were merged into the used database were registered at clinicaltrials.gov: NCT01268410 (ERICC), NCT02010073 (LUNG SAFE), NCT01868321 (PRoVENT), and NCT03188770 (PRoVENT-iMiC).

Lung Ultrasound to Determine the Effect of Lower vs. Higher PEEP on Lung Aeration in Patients without ARDS-A Substudy of a Randomized Clinical Trial.

BACKGROUND: Ventilation with lower positive end-expiratory pressure (PEEP) may cause loss of lung aeration in critically ill invasively ventilated patients. This study investigated whether a systematic lung ultrasound (LUS) scoring system can detect such changes in lung aeration in a study comparing lower versus higher PEEP in invasively ventilated patients without acute respiratory distress syndrome (ARDS). METHODS: Single center substudy of a national, multicenter, randomized clinical trial comparing lower versus higher PEEP ventilation strategy. Fifty-seven patients underwent a systematic 12-region LUS examination within 12 h and between 24 to 48 h after start of invasive ventilation, according to randomization. The primary endpoint was a change in the global LUS aeration score, where a higher value indicates a greater impairment in lung aeration. RESULTS: Thirty-three and twenty-four patients received ventilation with lower PEEP (median PEEP 1 (0-5) cm H2O) or higher PEEP (median PEEP 8 (8-8) cm H2O), respectively. Median global LUS aeration scores within 12 h and between 24 and 48 h were 8 (4 to 14) and 9 (4 to 12) (difference 1 (-2 to 3)) in the lower PEEP group, and 7 (2-11) and 6 (1-12) (difference 0 (-2 to 3)) in the higher PEEP group. Neither differences in changes over time nor differences in absolute scores reached statistical significance. CONCLUSIONS: In this substudy of a randomized clinical trial comparing lower PEEP versus higher PEEP in patients without ARDS, LUS was unable to detect changes in lung aeration.

Effect of mechanical power on mortality in invasively ventilated ICU patients without the acute respiratory distress syndrome: An analysis of three randomised clinical trials.

BACKGROUND: The mechanical power of ventilation (MP) has an association with outcome in invasively ventilated patients with the acute respiratory distress syndrome (ARDS). Whether a similar association exists in invasively ventilated patients without ARDS is less certain. OBJECTIVE: To investigate the association of mechanical power with mortality in ICU patients without ARDS. DESIGN: This was an individual patient data analysis that uses the data of three multicentre randomised trials. SETTING: This study was performed in academic and nonacademic ICUs in the Netherlands. PATIENTS: One thousand nine hundred and sixty-two invasively ventilated patients without ARDS were included in this analysis. The median [IQR] age was 67 [57 to 75] years, 706 (36%) were women. MAIN OUTCOME MEASURES: The primary outcome was the all-cause mortality at day 28. Secondary outcomes were the all-cause mortality at day 90, and length of stay in ICU and hospital. RESULTS: At day 28, 644 patients (33%) had died. Hazard ratios for mortality at day 28 were higher with an increasing MP, even when stratified for its individual components (driving pressure ( P  < 0.001), tidal volume ( P  < 0.001), respiratory rate ( P  < 0.001) and maximum airway pressure ( P  = 0.001). Similar associations of mechanical power (MP) were found with mortality at day 90, lengths of stay in ICU and hospital. Hazard ratios for mortality at day 28 were not significantly different if patients were stratified for MP, with increasing levels of each individual component. CONCLUSION: In ICU patients receiving invasive ventilation for reasons other than ARDS, MP had an independent association with mortality. This finding suggests that MP holds an added predictive value over its individual components, making MP an attractive measure to monitor and possibly target in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02159196, ClinicalTrials.gov Identifier: NCT02153294, ClinicalTrials.gov Identifier: NCT03167580.

Myocardial Function during Ventilation with Lower versus Higher Positive End-Expiratory Pressure in Patients without ARDS.

The aim of this study was to investigate whether lower PEEP (positive end-expiratory pressure) had beneficial effects on myocardial function among intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) compared to higher PEEP. In this pre-planned substudy of a randomized controlled trial (RELAx), comparing lower to higher PEEP, 44 patients underwent transthoracic echocardiography. The exclusion criteria were known poor left ventricular function and severe shock requiring high dosages of norepinephrine. To create contrast, we also excluded patients who received PEEP between 2 cmH2O and 7 cmH2O in the two randomization arms of the study. The primary outcome was the right ventricular myocardial performance index (MPI), a measure of systolic and diastolic function. The secondary outcomes included systolic and diastolic function parameters. A total of 20 patients were ventilated with lower PEEP (mean ± SD, 0 ± 1 cmH2O), and 24 patients, with higher PEEP (8 ± 1 cmH2O) (mean difference, -8 cmH2O; 95% CI: -8.1 to -7.9 cmH2O; p = 0.01). The tidal volume size was low in both groups (median (IQR), 7.2 (6.3 to 8.1) versus 7.0 (5.3 to 9.1) ml/kg PBW; p = 0.97). The median right ventricular MPI was 0.32 (IQR, 0.26 to 0.39) in the lower-PEEP group versus 0.38 (0.32 to 0.41) in the higher-PEEP group; the median difference was -0.03; 95% CI: -0.11 to 0.03; p = 0.33. The other systolic and diastolic parameters were similar. In patients without ARDS ventilated with a low tidal volume, a lower PEEP had no beneficial effects on the right ventricular MPI.

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies.

BACKGROUND: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. METHODS: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. FINDINGS: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H2O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p<0·0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0·80 [95% CI 0·75-0·86]; p<0·0001). INTERPRETATION: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. FUNDING: No funding.

Accuracy of the Radiographic Assessment of Lung Edema Score for the Diagnosis of ARDS.

Background: Bilateral opacities on chest radiographs are part of the Berlin Definition for Acute Respiratory Distress Syndrome (ARDS) but have poor interobserver reliability. The "Radiographic Assessment of Lung Edema" (RALE) score was recently proposed for evaluation of the extent and density of alveolar opacities on chest radiographs of ARDS patients. The current study determined the accuracy of the RALE score for the diagnosis and the prognosis of ARDS. Methods: Post-hoc analysis of a cohort of invasively ventilated intensive care unit (ICU) patients expected to need invasive ventilation for >24 h. The Berlin Definition was used as the gold standard. The RALE score was calculated for the first available chest radiograph after start of ventilation in the ICU. The primary endpoint was the diagnostic accuracy for ARDS of the RALE score. Secondary endpoints included the prognostic value of the RALE score for ICU and hospital mortality, and the association with ARDS severity, and the PaO2/FiO2. Receiver operating characteristic (ROC) curves were constructed, and the optimal cutoff was used to determine sensitivity, specificity and the negative and positive predictive value of the RALE score for ARDS. Results: The study included 131 patients, of whom 30 had ARDS (11 mild, 15 moderate, and 4 severe ARDS). The first available chest radiograph was obtained median 0 [0 to 1] days after start of invasive ventilation in ICU. Compared to patients without ARDS, a higher RALE score was found in patients with ARDS (24 [interquartile range (IQR) 16-30] vs. 6 [IQR 3-11]; P < 0.001), with RALE scores of 20 [IQR 14-24], 26 [IQR 16-32], and 32 [IQR 19-36] for mild, moderate and severe ARDS, respectively, (P = 0.166). The area under the ROC for ARDS was excellent (0.91 [0.86-0.96]). The best cutoff for ARDS diagnosis was 10 with 100% sensitivity, 71% specificity, 51% positive predictive value and 100% negative predictive value. The RALE score was not associated with ICU or hospital mortality, and weakly correlated with the PaO2/FiO2. Conclusion: In this cohort of invasively ventilated ICU patients, the RALE score had excellent diagnostic accuracy for ARDS.

Epidemiological Characteristics, Ventilator Management, and Clinical Outcome in Patients Receiving Invasive Ventilation in Intensive Care Units from 10 Asian Middle-Income Countries (PRoVENT-iMiC): An International, Multicenter, Prospective Study.

Epidemiology, ventilator management, and outcome in patients receiving invasive ventilation in intensive care units (ICUs) in middle-income countries are largely unknown. PRactice of VENTilation in Middle-income Countries is an international multicenter 4-week observational study of invasively ventilated adult patients in 54 ICUs from 10 Asian countries conducted in 2017/18. Study outcomes included major ventilator settings (including tidal volume [V T ] and positive end-expiratory pressure [PEEP]); the proportion of patients at risk for acute respiratory distress syndrome (ARDS), according to the lung injury prediction score (LIPS), or with ARDS; the incidence of pulmonary complications; and ICU mortality. In 1,315 patients included, median V T was similar in patients with LIPS < 4 and patients with LIPS ≥ 4, but lower in patients with ARDS (7.90 [6.8-8.9], 8.0 [6.8-9.2], and 7.0 [5.8-8.4] mL/kg Predicted body weight; P = 0.0001). Median PEEP was similar in patients with LIPS < 4 and LIPS ≥ 4, but higher in patients with ARDS (five [5-7], five [5-8], and 10 [5-12] cmH2O; P < 0.0001). The proportions of patients with LIPS ≥ 4 or with ARDS were 68% (95% CI: 66-71) and 7% (95% CI: 6-8), respectively. Pulmonary complications increased stepwise from patients with LIPS < 4 to patients with LIPS ≥ 4 and patients with ARDS (19%, 21%, and 38% respectively; P = 0.0002), with a similar trend in ICU mortality (17%, 34%, and 45% respectively; P < 0.0001). The capacity of the LIPS to predict development of ARDS was poor (receiver operating characteristic [ROC] area under the curve [AUC] of 0.62, 95% CI: 0.54-0.70). In Asian middle-income countries, where two-thirds of ventilated patients are at risk for ARDS according to the LIPS and pulmonary complications are frequent, setting of V T is globally in line with current recommendations.

Ventilation management and clinical outcomes in invasively ventilated patients with COVID-19 (PRoVENT-COVID): a national, multicentre, observational cohort study.

BACKGROUND: Little is known about the practice of ventilation management in patients with COVID-19. We aimed to describe the practice of ventilation management and to establish outcomes in invasively ventilated patients with COVID-19 in a single country during the first month of the outbreak. METHODS: PRoVENT-COVID is a national, multicentre, retrospective observational study done at 18 intensive care units (ICUs) in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The primary outcome was a combination of ventilator variables and parameters over the first 4 calendar days of ventilation: tidal volume, positive end-expiratory pressure (PEEP), respiratory system compliance, and driving pressure. Secondary outcomes included the use of adjunctive treatments for refractory hypoxaemia and ICU complications. Patient-centred outcomes were ventilator-free days at day 28, duration of ventilation, duration of ICU and hospital stay, and mortality. PRoVENT-COVID is registered at ClinicalTrials.gov (NCT04346342). FINDINGS: Between March 1 and April 1, 2020, 553 patients were included in the study. Median tidal volume was 6·3 mL/kg predicted bodyweight (IQR 5·7-7·1), PEEP was 14·0 cm H2O (IQR 11·0-15·0), and driving pressure was 14·0 cm H2O (11·2-16·0). Median respiratory system compliance was 31·9 mL/cm H2O (26·0-39·9). Of the adjunctive treatments for refractory hypoxaemia, prone positioning was most often used in the first 4 days of ventilation (283 [53%] of 530 patients). The median number of ventilator-free days at day 28 was 0 (IQR 0-15); 186 (35%) of 530 patients had died by day 28. Predictors of 28-day mortality were gender, age, tidal volume, respiratory system compliance, arterial pH, and heart rate on the first day of invasive ventilation. INTERPRETATION: In patients with COVID-19 who were invasively ventilated during the first month of the outbreak in the Netherlands, lung-protective ventilation with low tidal volume and low driving pressure was broadly applied and prone positioning was often used. The applied PEEP varied widely, despite an invariably low respiratory system compliance. The findings of this national study provide a basis for new hypotheses and sample size calculations for future trials of invasive ventilation for COVID-19. These data could also help in the interpretation of findings from other studies of ventilation practice and outcomes in invasively ventilated patients with COVID-19. FUNDING: Amsterdam University Medical Centers, location Academic Medical Center.

Effect of a Lower vs Higher Positive End-Expiratory Pressure Strategy on Ventilator-Free Days in ICU Patients Without ARDS: A Randomized Clinical Trial.

Importance: It is uncertain whether invasive ventilation can use lower positive end-expiratory pressure (PEEP) in critically ill patients without acute respiratory distress syndrome (ARDS). Objective: To determine whether a lower PEEP strategy is noninferior to a higher PEEP strategy regarding duration of mechanical ventilation at 28 days. Design, Setting, and Participants: Noninferiority randomized clinical trial conducted from October 26, 2017, through December 17, 2019, in 8 intensive care units (ICUs) in the Netherlands among 980 patients without ARDS expected not to be extubated within 24 hours after start of ventilation. Final follow-up was conducted in March 2020. Interventions: Participants were randomized to receive invasive ventilation using either lower PEEP, consisting of the lowest PEEP level between 0 and 5 cm H2O (n = 476), or higher PEEP, consisting of a PEEP level of 8 cm H2O (n = 493). Main Outcomes and Measures: The primary outcome was the number of ventilator-free days at day 28, with a noninferiority margin for the difference in ventilator-free days at day 28 of -10%. Secondary outcomes included ICU and hospital lengths of stay; ICU, hospital, and 28- and 90-day mortality; development of ARDS, pneumonia, pneumothorax, severe atelectasis, severe hypoxemia, or need for rescue therapies for hypoxemia; and days with use of vasopressors or sedation. Results: Among 980 patients who were randomized, 969 (99%) completed the trial (median age, 66 [interquartile range {IQR}, 56-74] years; 246 [36%] women). At day 28, 476 patients in the lower PEEP group had a median of 18 ventilator-free days (IQR, 0-27 days) and 493 patients in the higher PEEP group had a median of 17 ventilator-free days (IQR, 0-27 days) (mean ratio, 1.04; 95% CI, 0.95-∞; P = .007 for noninferiority), and the lower boundary of the 95% CI was within the noninferiority margin. Occurrence of severe hypoxemia was 20.6% vs 17.6% (risk ratio, 1.17; 95% CI, 0.90-1.51; P = .99) and need for rescue strategy was 19.7% vs 14.6% (risk ratio, 1.35; 95% CI, 1.02-1.79; adjusted P = .54) in patients in the lower and higher PEEP groups, respectively. Mortality at 28 days was 38.4% vs 42.0% (hazard ratio, 0.89; 95% CI, 0.73-1.09; P = .99) in patients in the lower and higher PEEP groups, respectively. There were no statistically significant differences in other secondary outcomes. Conclusions and Relevance: Among patients in the ICU without ARDS who were expected not to be extubated within 24 hours, a lower PEEP strategy was noninferior to a higher PEEP strategy with regard to the number of ventilator-free days at day 28. These findings support the use of lower PEEP in patients without ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT03167580.

PRactice of VENTilation in Patients with Novel Coronavirus Disease (PRoVENT-COVID): rationale and protocol for a national multicenter observational study in The Netherlands.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is rapidly expanding across the world, with more than 100,000 new cases each day as of end-June 2020. Healthcare workers are struggling to provide the best care for COVID-19 patients. Approaches for invasive ventilation vary widely between and within countries and new insights are acquired rapidly. We aim to investigate invasive ventilation practices and outcome in COVID-19 patients in the Netherlands. METHODS: PRoVENT-COVID ('study of PRactice of VENTilation in COVID-19') is an investigator-initiated national, multicenter observational study to be undertaken in intensive care units (ICUs) in The Netherlands. Consecutive COVID-19 patients aged 18 years or older, who are receiving invasive ventilation in the participating ICUs, are to be enrolled during a 10-week period, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cmH2O) during the first 3 days of ventilation. Secondary outcomes include other ventilatory variables, use of rescue therapies for refractory hypoxemia such as prone positioning and extracorporeal membrane oxygenation, use of sedatives, vasopressors and inotropes; daily cumulative fluid balances; acute kidney injury; ventilator-free days and alive at day 28 (VFD-28), duration of ICU and hospital stay, and ICU, hospital and 90-day mortality. DISCUSSION: PRoVENT-COVID will be the largest observational study to date, with high density ventilatory data and major outcomes. There is urgent need for a better understanding of ventilation practices, and the effects of ventilator settings on outcomes in COVID-19 patients. The results of PRoVENT-COVID will be rapidly disseminated through electronic presentations, such as webinars and electronic conferences, and publications in international peer-reviewed journals. Access to source data will be made available through local, regional and national anonymized datasets on request, and after agreement of the PRoVENT-COVID steering committee. TRIAL REGISTRATION: PRoVENT-COVID is registered at clinicaltrials.gov (identifier NCT04346342).

RELAx - REstricted versus Liberal positive end-expiratory pressure in patients without ARDS: protocol for a randomized controlled trial.

BACKGROUND: Evidence for benefit of high positive end-expiratory pressure (PEEP) is largely lacking for invasively ventilated, critically ill patients with uninjured lungs. We hypothesize that ventilation with low PEEP is noninferior to ventilation with high PEEP with regard to the number of ventilator-free days and being alive at day 28 in this population.  METHODS/DESIGN: The "REstricted versus Liberal positive end-expiratory pressure in patients without ARDS" trial (RELAx) is a national, multicenter, randomized controlled, noninferiority trial in adult intensive care unit (ICU) patients with uninjured lungs who are expected not to be extubated within 24 h. RELAx will run in 13 ICUs in the Netherlands to enroll 980 patients under invasive ventilation. In all patients, low tidal volumes are used. Patients assigned to ventilation with low PEEP will receive the lowest possible PEEP between 0 and 5 cm H2O, while patients assigned to ventilation with high PEEP will receive PEEP of 8 cm H2O. The primary endpoint is the number of ventilator-free days and being alive at day 28, a composite endpoint for liberation from the ventilator and mortality until day 28, with a noninferiority margin for a difference between groups of 0.5 days. Secondary endpoints are length of stay (LOS), mortality, and occurrence of pulmonary complications, including severe hypoxemia, major atelectasis, need for rescue therapies, pneumonia, pneumothorax, and development of acute respiratory distress syndrome (ARDS). Hemodynamic support and sedation needs will be collected and compared. DISCUSSION: RELAx will be the first sufficiently sized randomized controlled trial in invasively ventilated, critically ill patients with uninjured lungs using a clinically relevant and objective endpoint to determine whether invasive, low-tidal-volume ventilation with low PEEP is noninferior to ventilation with high PEEP. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT03167580 . Registered on 23 May 2017.

PRactice of VENTilation in Middle-Income Countries (PRoVENT-iMIC): rationale and protocol for a prospective international multicentre observational study in intensive care units in Asia.

INTRODUCTION: Current evidence on epidemiology and outcomes of invasively mechanically ventilated intensive care unit (ICU) patients is predominantly gathered in resource-rich settings. Patient casemix and patterns of critical illnesses, and probably also ventilation practices are likely to be different in resource-limited settings. We aim to investigate the epidemiological characteristics, ventilation practices and clinical outcomes of patients receiving mechanical ventilation in ICUs in Asia. METHODS AND ANALYSIS: PRoVENT-iMIC (study of PRactice of VENTilation in Middle-Income Countries) is an international multicentre observational study to be undertaken in approximately 60 ICUs in 11 Asian countries. Consecutive patients aged 18 years or older who are receiving invasive ventilation in participating ICUs during a predefined 28-day period are to be enrolled, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cm H2O) during the first 3 days of mechanical ventilation-compared between patients at no risk for acute respiratory distress syndrome (ARDS), patients at risk for ARDS and in patients with ARDS (in case the diagnosis of ARDS can be made on admission). Secondary outcomes include occurrence of pulmonary complications and all-cause ICU mortality. ETHICS AND DISSEMINATION: PRoVENT-iMIC will be the first international study that prospectively assesses ventilation practices, outcomes and epidemiology of invasively ventilated patients in ICUs in Asia. The results of this large study, to be disseminated through conference presentations and publications in international peer-reviewed journals, are of ultimate importance when designing trials of invasive ventilation in resource-limited ICUs. Access to source data will be made available through national or international anonymised datasets on request and after agreement of the PRoVENT-iMIC steering committee. TRIAL REGISTRATION NUMBER: NCT03188770; Pre-results.

Effects of peep on lung injury, pulmonary function, systemic circulation and mortality in animals with uninjured lungs-a systematic review.

It is well-known that positive end-expiratory pressure (PEEP) can prevent ventilator-induced lung injury (VILI) and improve pulmonary physiology in animals with injured lungs. It's uncertain whether PEEP has similar effects in animals with uninjured lungs. A systematic review of randomized controlled trials (RCTs) comparing different PEEP levels in animals with uninjured lungs was performed. Trials in animals with injured lungs were excluded, as were trials that compared ventilation strategies that also differed with respect to other ventilation settings, e.g., tidal volume size. The search identified ten eligible trials in 284 animals, including rodents and small as well as large mammals. Duration of ventilation was highly variable, from 1 to 6 hours and tidal volume size varied from 7 to 60 mL/kg. PEEP ranged from 3 to 20 cmH2O, and from 0 to 5 cmH2O, in the 'high PEEP' or 'PEEP' arms, and in the 'low PEEP' or 'no PEEP' arms, respectively. Definitions used for lung injury were quite diverse, as were other outcome measures. The effects of PEEP, at any level, on lung injury was not straightforward, with some trials showing less injury with 'high PEEP' or 'PEEP' and other trials showing no benefit. In most trials, 'high PEEP' or 'PEEP' was associated with improved respiratory system compliance, and better oxygen parameters. However, 'high PEEP' or 'PEEP' was also associated with occurrence of hypotension, a reduction in cardiac output, or development of hyperlactatemia. There were no differences in mortality. The number of trials comparing 'high PEEP' or 'PEEP' with 'low PEEP' or 'no PEEP' in animals with uninjured lungs is limited, and results are difficult to compare. Based on findings of this systematic review it's uncertain whether PEEP, at any level, truly prevents lung injury, while most trials suggest potential harmful effects on the systemic circulation.