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

Higher positive end-expiratory pressure (PEEP) levels may reduce atelectrauma, but increase over-distention lung injury. Whether higher PEEP improves clinical outcomes among patients with acute respiratory distress syndrome (ARDS) is unclear. To compare clinical outcomes of mechanical ventilation strategies using higher PEEP levels versus lower PEEP strategies in patients with ARDS. We performed a systematic review and meta-analysis of clinical trials investigating mechanical ventilation strategies using higher versus lower PEEP levels. We used random effects models to evaluate the effect of higher PEEP on 28-day mortality, organ failure, ventilator-free days, barotrauma, oxygenation, and ventilation. We identified eight randomized trials comparing higher versus lower PEEP strategies, enrolling 2,728 patients with ARDS. Patients were 55 (±16) (mean ± SD) years old and 61% were men. Mean PEEP in the higher PEEP groups was 15.1 (±3.6) cm H2O as compared with 9.1 (±2.7) cm H2O in the lower PEEP groups. Primary analysis excluding two trials that did not use lower Vt ventilation in the lower PEEP control groups did not demonstrate significantly reduced mortality for patients receiving higher PEEP as compared with a lower PEEP (six trials; 2,580 patients; relative risk, 0.91; 95% confidence interval [CI] = 0.80-1.03). A higher PEEP strategy also did not significantly decrease barotrauma, new organ failure, or ventilator-free days when compared with a lower PEEP strategy (moderate-level evidence). Quality of evidence for primary analyses was downgraded for precision, as CIs of outcomes included estimates that would result in divergent recommendations for use of higher PEEP. Secondary analysis, including trials that did not use low Vt in low-PEEP control groups, showed significant mortality reduction for high-PEEP strategies (eight trials; 2,728 patients; relative risk, 0.84; 95% CI = 0.71-0.99), with greater mortality benefit observed for high PEEP in trials that did not use lower Vts in the low-PEEP control group (P = 0.02). Analyses stratifying by use of recruitment maneuvers (P for interaction = 0.69), or use of physiological targets to set PEEP versus PEEP/FiO2 tables (P for interaction = 0.13), did not show significant effect modification. Use of higher PEEP is unlikely to improve clinical outcomes among unselected patients with ARDS.

In patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), mortality remains high. These patients require mechanical ventilation, which has been associated with ventilator-induced lung injury. High levels of positive end-expiratory pressure (PEEP) could reduce this condition and improve patient survival. This is an updated version of the review first published in 2013. To assess the benefits and harms of high versus low levels of PEEP in adults with ALI and ARDS. For our previous review, we searched databases from inception until 2013. For this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and the Web of Science from inception until May 2020. We also searched for ongoing trials (www.trialscentral.org; www.clinicaltrial.gov; www.controlled-trials.com), and we screened the reference lists of included studies. We included randomised controlled trials that compared high versus low levels of PEEP in ALI and ARDS participants who were intubated and mechanically ventilated in intensive care for at least 24 hours. Two review authors assessed risk of bias and extracted data independently. We contacted investigators to identify additional published and unpublished studies. We used standard methodological procedures expected by Cochrane. We included four new studies (1343 participants) in this review update. In total, we included 10 studies (3851 participants). We found evidence of risk of bias in six studies, and the remaining studies fulfilled all criteria for low risk of bias. In eight studies (3703 participants), a comparison was made between high and low levels of PEEP, with the same tidal volume in both groups. In the remaining two studies (148 participants), the tidal volume was different between high- and low-level groups. In the main analysis, we assessed mortality occurring before hospital discharge only in studies that compared high versus low PEEP, with the same tidal volume in both groups. Evidence suggests that high PEEP may result in little to no difference in mortality compared to low PEEP (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.90 to 1.04; I² = 15%; 7 studies, 3640 participants; moderate-certainty evidence). In addition, high PEEP may result in little to no difference in barotrauma (RR 1.00, 95% CI 0.64 to 1.57; I² = 63%; 9 studies, 3791 participants; low-certainty evidence). High PEEP may improve oxygenation in patients up to the first and third days of mechanical ventilation (first day: mean difference (MD) 51.03, 95% CI 35.86 to 66.20; I² = 85%; 6 studies, 2594 participants; low-certainty evidence; third day: MD 50.32, 95% CI 34.92 to 65.72; I² = 83%; 6 studies, 2309 participants; low-certainty evidence) and probably improves oxygenation up to the seventh day (MD 28.52, 95% CI 20.82 to 36.21; I² = 0%; 5 studies, 1611 participants; moderate-certainty evidence). Evidence suggests that high PEEP results in little to no difference in the number of ventilator-free days (MD 0.45, 95% CI -2.02 to 2.92; I² = 81%; 3 studies, 1654 participants; low-certainty evidence). Available data were insufficient to pool the evidence for length of stay in the intensive care unit. Moderate-certainty evidence shows that high levels compared to low levels of PEEP do not reduce mortality before hospital discharge. Low-certainty evidence suggests that high levels of PEEP result in little to no difference in the risk of barotrauma. Low-certainty evidence also suggests that high levels of PEEP improve oxygenation up to the first and third days of mechanical ventilation, and moderate-certainty evidence indicates that high levels of PEEP improve oxygenation up to the seventh day of mechanical ventilation. As in our previous review, we found clinical heterogeneity - mainly within participant characteristics and methods of titrating PEEP - that does not allow us to draw definitive conclusions regarding the use of high levels of PEEP in patients with ALI and ARDS. Further studies should aim to determine the appropriate method of using high levels of PEEP and the advantages and disadvantages associated with high levels of PEEP in different ARDS and ALI patient populations.

Introduction: The optimal level of positive end-expiratory pressure (PEEP) in mechanically ventilated patients with acute respiratory failure remains debated. High PEEP may enhance alveolar recruitment and oxygenation but increase plateau and driving pressures, risking ventilator-induced lung injury (VILI). Conversely, low PEEP may reduce overdistension but promote alveolar collapse and hypoxemia. Understanding how PEEP strategies affect respiratory mechanics and outcomes is crucial for individualized ventilator management.Methods: A prospective observational study was conducted in the intensive care unit of Hospital Clínico Quirúrgico Miguel Enríquez, Havana, Cuba, between January 2021 and January 2022. Thirty adult patients requiring invasive mechanical ventilation for ≥48 hours were allocated to a low PEEP group (8–12 cmH₂O, n = 15) or a high PEEP group (15–18 cmH₂O, n = 15). Data collected included respiratory mechanics (PaO₂/FiO₂, static compliance, plateau and driving pressures), hemodynamics (mean arterial pressure, heart rate, vasopressor use), and clinical outcomes (duration of mechanical ventilation, ICU stay, 28-day mortality, barotrauma, ventilator-associated pneumonia).Results: Among 30 patients, high PEEP improved oxygenation compared with low PEEP (PaO₂/FiO₂ 218 ± 10 vs 170 ± 38 mmHg; p < 0.01). Plateau (28 ± 4 vs 21 ± 3 cmH₂O; p < 0.001) and driving pressures (15 ± 3 vs 11 ± 2 cmH₂O; p < 0.001) were higher in the high PEEP group, whereas static compliance was similar (36 ± 7 vs 38 ± 6 mL/cmH₂O; p = 0.34). Hemodynamics and major outcomes were comparable. Barotrauma occurred in two patients in the high PEEP group and in none in the low PEEP group.Conclusion: High PEEP improves oxygenation but increases plateau and driving pressures, highlighting the need for individualized titration to minimize VILI risk. Both low and high PEEP strategies were well tolerated, with similar hemodynamic stability and short-term mortality, supporting personalized ventilator management in ICU patients.

A prospective, multicenter, randomized study of high versus low positive end-expiratory pressure during extracorporeal membrane oxygenation

Background: To find the optimal positive end expiratory pressure (PEEP) in mechanical ventilated patients without Acute Respiratory Distress Syndrome (ARDS), we conducted a Bayesian network meta-analysis and systematic review of randomized controlled trials (RCTs) comparing different level of PEEP based on a novel classification of PEEP level: ZEEP group (PEEP = 0 cm H2O); lower PEEP group (PEEP = 1–6 cm H2O); intermediate PEEP group (PEEP = 7–10 cm H2O); higher PEEP group (PEEP > 10 cm H2O).Result: Twenty eight eligible studies with 2,712 patients were included. There were no significant differences in the duration of mechanical ventilation between higher and intermediate PEEP (MD: 0.020, 95% CI: −0.14, 0.28), higher and lower PEEP (MD: −0.010, 95% CI: −0.23, 0.22), higher PEEP and ZEEP (MD: 0.010, 95% CI: −0.40, 0.22), intermediate and lower PEEP (MD: −0.040, 95% CI: −0.18, 0.040), intermediate PEEP and ZEEP (MD: −0.010, 95% CI: −0.42, 0.10), lower PEEP and ZEEP (MD: 0.020, 95% CI: −0.32, 0.13), respectively. Higher PEEP was associated with significantly higher PaO2/FiO2 ratio(PFR) when compared to ZEEP (MD: 73.24, 95% CI: 11.03, 130.7), and higher incidence of pneumothorax when compared to intermediate PEEP, lower PEEP and ZEEP (OR: 2.91e + 12, 95% CI: 40.3, 1.76e + 39; OR: 1.85e + 12, 95% CI: 29.2, 1.18e + 39; and OR: 1.44e + 12, 95% CI: 16.9, 8.70e + 38, respectively). There was no association between PEEP levels and other secondary outcomes.Conclusion: We identified higher PEEP was associated with significantly higher PFR and higher incidence of pneumothorax. Nonetheless, in terms of other outcomes, no significant differences were detected among four levels of PEEP.Systematic Review Registration: The study had registered on an international prospective register of systematic reviews, PROSPERO, on 09 April 2021, identifier: [CRD42021241745].

IntroductionOne potential mechanism of ventilator-induced lung injury (VILI) is due to shear stresses associated with alveolar instability (recruitment/derecruitment). It has been postulated that the optimal combination of tidal volume (Vt) and positive end-expiratory pressure (PEEP) stabilizes alveoli, thus diminishing recruitment/derecruitment and reducing VILI. In this study we directly visualized the effect of Vt and PEEP on alveolar mechanics and correlated alveolar stability with lung injury.MethodsIn vivo microscopy was utilized in a surfactant deactivation porcine ARDS model to observe the effects of Vt and PEEP on alveolar mechanics. In phase I (n = 3), nine combinations of Vt and PEEP were evaluated to determine which combination resulted in the most and least alveolar instability. In phase II (n = 6), data from phase I were utilized to separate animals into two groups based on the combination of Vt and PEEP that caused the most alveolar stability (high Vt [15 cc/kg] plus low PEEP [5 cmH2O]) and least alveolar stability (low Vt [6 cc/kg] and plus PEEP [20 cmH2O]). The animals were ventilated for three hours following lung injury, with in vivo alveolar stability measured and VILI assessed by lung function, blood gases, morphometrically, and by changes in inflammatory mediators.ResultsHigh Vt/low PEEP resulted in the most alveolar instability and lung injury, as indicated by lung function and morphometric analysis of lung tissue. Low Vt/high PEEP stabilized alveoli, improved oxygenation, and reduced lung injury. There were no significant differences between groups in plasma or bronchoalveolar lavage cytokines or proteases.ConclusionA ventilatory strategy employing high Vt and low PEEP causes alveolar instability, and to our knowledge this is the first study to confirm this finding by direct visualization. These studies demonstrate that low Vt and high PEEP work synergistically to stabilize alveoli, although increased PEEP is more effective at stabilizing alveoli than reduced Vt. In this animal model of ARDS, alveolar instability results in lung injury (VILI) with minimal changes in plasma and bronchoalveolar lavage cytokines and proteases. This suggests that the mechanism of lung injury in the high Vt/low PEEP group was mechanical, not inflammatory in nature.

BackgroundMortality in patients with acute respiratory distress syndrome (ARDS) remains high. These patients require mechanical ventilation strategies that include high positive end-expiratory pressure (PEEP). It remains controversial whether high PEEP can improve outcomes for ARDS patients, especially patients who show improvement in oxygenation in response to PEEP. In this meta-analysis, we aimed to evaluate the effects of high PEEP on ARDS patients.MethodsWe electronically searched randomized controlled trials (RCTs) reported in the MEDLINE, CENTRAL, EMBASE, CINAHL and Web of Science databases from January 1990 to December 2017. Meta-analyses of the effects of PEEP on survival in adults with ARDS were conducted using the methods recommended by the Cochrane Collaboration.ResultsA total of 3612 patients from nine randomized controlled trials (RCTs) were included. There were 1794 and 1818 patients in the high and low PEEP groups, respectively. Hospital mortality showed no significant difference between the high and low PEEP groups (RR = 0.92; 95% CI, 0.79 to 1.07; P = 0.26). Similar results were found for 28-d mortality (RR = 0.88; 95% CI, 0.72 to 1.07; P = 0.19) and ICU mortality (RR = 0.83; 95% CI, 0.65 to 1.07; P = 0.15). The risk of clinically objectified barotrauma was not significantly different between the high and low PEEP groups (RR = 1.24; 95% CI, 0.74 to 2.09, P = 0.41). In the subgroup of ARDS patients who responded to increased PEEP by improved oxygenation (from 6 RCTs), high PEEP significantly reduced hospital mortality (RR = 0.83; 95% CI 0.69 to 0.98; P = 0.03), ICU mortality (RR = 0.74; 95% CI, 0.56 to 0.98; P = 0.04),but the 28-d mortality was not decreased(RR = 0.83; 95% CI, 0.67 to 1.01; P = 0.07). For ARDS patients in the low PEEP group who received a PEEP level lower than 10 cmH2O (from 6 RCTs), ICU mortality was lower in the high PEEP group than the low PEEP group (RR = 0.65; 95% CI, 0.45 to 0.94; P = 0.02).ConclusionsFor ARDS patients who responded to increased PEEP by improved oxygenation, high PEEP could reduce hospital mortality, ICU mortality and 28-d mortality. High PEEP does not increase the risk of clinically objectified barotrauma.

Biological phenotypes have been identified within several heterogeneous pulmonary diseases, with potential therapeutic consequences. To assess whether distinct biological phenotypes exist within surgical patients, and whether development of postoperative pulmonary complications (PPCs) and subsequent dependence of intra-operative positive end-expiratory pressure (PEEP) differ between such phenotypes. Operating rooms of six hospitals in Europe and USA. Secondary analysis of the 'PROtective Ventilation with HIgh or LOw PEEP' trial. Adult patients scheduled for abdominal surgery who are at risk of PPCs. Measurement of pre-operative concentrations of seven plasma biomarkers associated with inflammation and lung injury. We applied unbiased cluster analysis to identify biological phenotypes. We then compared the proportion of patients developing PPCs within each phenotype, and associations between intra-operative PEEP levels and development of PPCs among phenotypes. In total, 242 patients were included. Unbiased cluster analysis clustered the patients within two biological phenotypes. Patients with phenotype 1 had lower plasma concentrations of TNF-α (3.8 [2.4 to 5.9] vs. 10.2 [8.0 to 12.1] pg ml; P < 0.001), IL-6 (2.3 [1.5 to 4.0] vs. 4.0 [2.9 to 6.5] pg ml; P < 0.001) and IL-8 (4.7 [3.1 to 8.1] vs. 8.1 [6.0 to 13.9] pg ml; P < 0.001). Phenotype 2 patients had the highest incidence of PPC (69.8 vs. 34.2% in type 1; P < 0.001). There was no interaction between phenotype and PEEP level for the development of PPCs (43.2% in high PEEP vs. 25.6% in low PEEP in phenotype 1, and 73.6% in high PEEP and 65.7% in low PEEP in phenotype 2; P for interaction = 0.503). Patients at risk of PPCs and undergoing open abdominal surgery can be clustered based on pre-operative plasma biomarker concentrations. The two identified phenotypes have different incidences of PPCs. Biologic phenotyping could be useful in future randomised controlled trials of intra-operative ventilation. The PROtective Ventilation with HIgh or LOw PEEP trial, including the substudy from which data were used for the present analysis, was registered at ClinicalTrials.gov (NCT01441791).

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Positive End-Expiratory Pressure Levels in Adult Patients With Acute Lung Injury and Acute Respiratory Distress Syndrome

To compare the effects of high and low positive end-expiratory pressure (PEEP) levels on prognosis of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). The data in PubMed, EMbase, Cochrane Library, CBM and CNKI were retrieved. All randomized controlled trials (RCTs) of treatment of ALI/ARDS with PEEP with high or low level were included. Study selection and assessment, data collection and analyses were undertaken by two independent reviewers. Meta-analyses were done using Cochrane Collaboration's RevMan 5.0 software. Six RCTs, involving a total of 2 484 patients of ALI/ARDS were included in the review. According to ventilation strategy, all trials were divided into subgroup A (high PEEP+low tidal volume of 6 ml/kg vs. low PEEP+low tidal volume) and subgroup B (high PEEP+low tidal volume vs. low PEEP+traditional tidal volume). In subgroup B, there were three RCTs, and high PEEP was found to be associated with a lower 28-day mortality [odds ratio (OR)=0.40, 95% confidence interval (95%CI) 0.22-0.72, P=0.003] and a lower barotraumas (OR=0.20, 95%CI 0.05-0.82, P=0.02) in patients with ALI/ARDS. In subgroup A, there were three RCTs, and it was found that the differences in 28-day mortality (OR=0.86, 95%CI 0.72-1.02, P=0.08) and barotraumas (OR=1.19, 95%CI 0.89-1.58, P=0.25) were not significant . As compared with conventional ventilation, high PEEP and low tidal volume ventilation are associated with improved survival and a lower rate of barotrauma in patients with ALI/ARDS. It is necessary to further confirm the role of high PEEP only in the ventilation strategy in patients with ALI/ARDS.

The win ratio analysis method might provide new insight on the impact of positive end-expiratory pressure (PEEP) on clinical outcomes. The aim is to re-analyse the results of the 'Re-evaluation of the effects of high PEEP with recruitment manoeuvres vs. low PEEP without recruitment manoeuvres during general anaesthesia for surgery' (REPEAT) study using the win ratio analysis. Individual patient data meta-analysis. Three international multicentre randomised trials. Patients undergoing general anaesthesia for surgery. High vs. low PEEP. Hierarchical composite endpoint of: all-cause hospital mortality; hospital length of stay; need for postoperative mechanical ventilation; severe pulmonary complications; and mild pulmonary complications. A total of 3774 patients undergoing general anaesthesia for surgery were included in this analysis. The median (interquartile range [IQR]) age was 57 [45 to 68] years and 2077 (55%) were women. A total of 3 560 720 comparison pairs were produced. The high PEEP group had a higher percentage of losses than wins in hospital mortality (1.1 vs. 0.9%) and hospital length of stay (33.8 vs. 33.2%), comparable percentages of losses and wins in postoperative invasive mechanical ventilation (0.2 vs. 0.2%), a higher percentage of wins in severe complications (2.5 vs. 2.1%) and a higher percentage of ties in mild complications (18.7 vs. 3.9% wins vs. 3.3% losses). The win ratio for high PEEP compared with low PEEP group was 1.00 (95% CI 0.92 to 1.09). No beneficial effects of high PEEP compared with low PEEP were found in this win ratio analysis. Clinicaltrials.gov (study identifier NCT03937375).

The optimal strategy for setting positive end-expiratory pressure (PEEP) has not been established. This review examines different approaches for setting PEEP to achieve lung-protective ventilation. PEEP titration strategies commonly focus either on achieving adequate arterial oxygenation or reducing ventilator-induced lung injury from repetitive alveolar opening and closing, referred to as the open lung approach. Five recent trials of higher versus lower PEEP have not shown benefit with higher PEEP, and one of the five trials showed increased harm for patients treated with the open lung strategy. Evidence suggests that some patients may respond beneficially to higher PEEP by recruiting lung, whereas other patients do not recruit lung and merely overdistend previously open alveoli when higher PEEP is applied. A PEEP titration approach that differentiates PEEP responders from nonresponders and provides higher or lower PEEP accordingly has not been prospectively tested. When compared, no method for setting PEEP has been proven superior to another. Based on recent studies, higher compared with lower PEEP has not improved clinical outcomes and worsened mortality in one study. Future research should focus on identifying feasible methods for assessing lung recruitability in response to PEEP to enrich future trials of PEEP strategies.

Different levels of positive end-expiratory pressure (PEEP) with and without a recruitment maneuver (RM) may have a significant impact on ventilator-induced lung injury but this issue has not been well addressed. Anesthetized rats received hydrochloric acid (HCl, pH 1.5) aspiration, followed by mechanical ventilation with a tidal volume of 6 ml/kg. The animals were randomized into four groups of 10 each: (1) high PEEP at 6 cm H(2)O with an RM by applying peak airway pressure at 30 cm H(2)O for 10 s every 15 min; (2) low PEEP at 2 cm H(2)O with RM; (3) high PEEP alone; and (4) low PEEP alone. The mean arterial pressure and the amounts of fluid infused were similar in the four groups. Application of the higher PEEP improved oxygenation compared with the lower PEEP groups (P<0.05). The lung compliance was better reserved, and the systemic cytokine responses and lung wet to dry ratio were lower in the high PEEP than in the low PEEP group for a given RM (P<0.05). The use of a combination of periodic RM and the higher PEEP had an additive effect in improving oxygenation and pulmonary mechanics and attenuation of inflammation.

High versus low PEEP in non-recruitable collapsed lung tissue: possible implications for patients with COVID-19