Meta-Analysis of Higher PEEP Strategies' Effects on Mortality Rates and Inflammatory Mediators in Patients with ARDS: A Perspective Review on Patients with Severe COVID-19-Associated ARDS

Background: Different strategies of positive end-expiratory pressure (PEEP) in mechanical ventilation are crucial for patients with coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome (ARDS). PEEP acts as a “double-edged sword” for ARDS patients. PEEP could recover pulmonary atelectasis but can induce alveolar hyperinflation. Objective: This review aimed to evaluate the effect of higher PEEP in patients with severe COVID-19-associated ARDS. Method: This meta-analysis included randomized controlled trial (RCT) studies to assess the mortality rates, barotrauma events


INTRODUCTION
Articles that can not be accessed, irrelevant themes, and non-English are also excluded.We did not limit the year of publication for our included studies but only for the supporting articles, we selectively used articles from the last 5 years of publication.

Samples
The population in this study were patients with severe ARDS or low level of PaO2/FiO2.Patients with other pulmonary diseases were excluded.

Outcomes
The outcomes provided by this review were (i) Mortality rates, (ii) barotrauma events and (iii) alteration of  indicated by an I 2 value higher than 50%.
Otherwise, we used FEM forest plot.

Sensitivity Analysis
When the authors encountered an unclear decision due to conflicting results from some of the included studies, a sensitivity analysis was planned by repeating the meta-analysis, attempting to exclude studies to identify which studies were confounders.

RESULT Study identification and selection
A

Characteristic of Included Studies
The full details of explaination or extracted data from the twelve included studies were provided in the Table 1,   Table 2, and Table 3        12.Villar J, Kacmarek RM, Pérez- mortality rates 2 .But, the mortality in mechanically ventilated patients with severe ARDS due to coronavirus disease 2019 (COVID-19) is still high in some developing countires despite many new strategies of protective lung ventilation.Those many approaches have been adopted to increase lung protection, one of which is ventilation improvement strategies, but despite these efforts, ARDS mortality remains high.Recent study from Ibarra-Estrada et al. in 2022, showed a huge benefit from the use of airway pressure release ventilation (APRV) with a relatively high Positive End-Expiratory Pressure (PEEP) in patients with severe ARDS due to COVID-19 3 .Three large studies using Randomized Controlled Trials (RCTs) study design were performed to assess whether higher PEEP could improve outcomes in patients with ARDS 4 .All those clinical trials conducted by administrating the high PEEP found no improvement in patients with ARDS.However, other studies found that higher PEEP may provide an improvement condition or survival rate of patients with severe ARDS 4better clinical outcomes with the routine use of low tidal volume but not with high ventilation PEEP in patients with ARDS.Recently, some clinical studies showed a high titrated PEEP strategies can reduce the mortality rates in patients with moderate to severe ARDS.A recent meta-analysis also showed that higher PEEP could improve survival in ARDS patients with PaO2/FiO2 less than 200mmHg.These findings suggest that a Yehuda Tri Nugroho Supranoto , I Made Putra Wira Negara Meta-Analysis of Higher PEEP Strategies' Effects on Mortality Rates and Inflammatory Mediators in Patients with ARDS: A Perspective Review on Patients with Severe COVID-19-Associated ARDS 77 Solo Journal of Anesthesi, Pain and Critical Care | Vol 3 No 2 October 202 Medical Faculty of Universitas Sebelas Maret -PERDATIN Solo higher PEEP should be used in patients who could potentially benefit from it 7,8 .Despite all the findings about the benefit of high PEEP strategies, actually, it is also a double-edged sword when used in patients with mild to moderate and also sometimes in severe ARDS.PEEP can open collapsed alveoli and can also cause hyperinflation in the lungs.Therefore, higher PEEP may improve outcomes in collapsed lungs of patients with severe ARDS only 8 .The application of PEEP prevents atelectrauma, as a result of cyclic crumble with some reopening of risky alveoli.Lamentably, PEEP can overdistend some non collapsed-alveoli, as PEEP will increase pressure inside the alveoli and therefore can make contributions to the development of ventilator associated lung injury 1,8 .Pulmonary barotrauma is a probably lifestyles-threatening trouble in sufferers on mechanical air flow.This is critical to prevent barotrauma for prolonged intervals as this can lead to sizeable morbidity and mortality in sufferers intubated within the extensive care unit.This condition mostly happened in patients with ARDS associated with severe COVID-19 3 .According to the findings from the research by Goligher, patients whose response to increased PEEP was followed by increased oxygenation, defined as a positive oxygenation response to PEEP, may have more benefit from higher PEEP levels.Thus, we speculated that PEEP could have different effects on clinical outcomes according to the nature of the clinical response to PEEP itself.We, therefore performed this systematic review and meta-analysis procedures to determine whether higher criteria were considered for study eligibility were described in

Solo
Journal of Anesthesi, Pain and Critical Care | Vol 3 No 2 October 2023 Medical Faculty of Universitas Sebelas Maret -PERDATIN Solo 80 Yehuda Tri Nugroho Supranoto , I Made Putra Wira Negara Meta-Analysis of Higher PEEP Strategies' Effects on Mortality Rates and Inflammatory Mediators in Patients with ARDS: A Perspective Review on Patients with Severe COVID-19-Associated ARDS Quantitative Data Synthesis (Metaanalysis) Risk ratio (RR) with the confidence interval (CI) of 95% were calculated in this study.To determine the pooled effect size, either random-effect model (REM) or fixed-effect model (FEM) of forest plot was used based on the heterogeneity level.REM was used when the included studies were considered heterogenous (high variability in studies' outcome results), v5.3.The asymmetric shape of the funnel plot indicates the presence of publication bias, while the symmetrical shape of the funnel plot indicates the absence of publication bias.
PRISMA 2020 flow chart presenting the overall studies selection processes is demonstrated in Figure 1.PRISMA 2020 is the main checklist and guideline used for this systematic review and meta-analysis.Of 927 articles compiled during the initial search from four databases, 56 articles were duplications, 814 articles were excluded due to irrelevant topics or did not describe the use of PEEP for ARDS and ARDS associated severe COVID-19.From all 57 articles included from the first screening, 42 articles were excluded since those were not retrieved due to meet the exclusion criterias of study design.Those articles are not randomized controlled trials type of studies.In addition, from 15 articles included in the second screening, three articles were excluded because they were described as unaccessible full-text articles.As a final decision, twelve studies were eligible enough to be used and analyzed in qualitative and quantitative way in the systematic review and meta-analysis methods.Yehuda Tri Nugroho Supranoto , I Made Putra Wira Negara Meta-Analysis of Higher PEEP Strategies' Effects on Mortality Rates and Inflammatory Mediators in Patients with ARDS: A Perspective Review on Patients with Severe COVID-19-Associated ARDS 81 Solo Journal of Anesthesi, Pain and Critical Care | Vol 3 No 2 October 202 Medical Faculty of Universitas Sebelas Maret -PERDATIN Solo

Figure 1 .
Figure 1.PRISMA Flow Diagram Figure 2. Risk of Bias Assessment based on Risk of Bias 2 (RoB 2) Tools (Recommended by Cochrane Handbook for Systematic Review of Intervention)

Figure 4 .
Figure 4. Forest Plot for Mortality Rates-Based on Location Between Higher PEEP Group and Lower PEEP Group

Figure 5 .Figure 7 .
Figure 5. Forest Plot for Mortality Rates-Based on Time of Follow Up with Positive Response to PEEP

Figure 8 .Figure 9 .
Figure 8. Forest Plot and Funnel Plot for Mortality Rates-Based on location, without Positive Response to PEEP

Figure 10 .
Figure 10.(A) Forest Plot for Overall Barotrauma Events.(B) Forest Plot for Barotrauma Events in Patients with Positive Response of Oxygenation to PEEP.(C) Forest Plot for barotrauma Events in patients without Positive Oxygenation to PEEP

Description of PICOS Targeted by the Systematic Review and Meta- Analysis. Type of Studies
Solo Journal of Anesthesi, Pain and Critical Care | Vol 3 No 2 October 2023 Medical Faculty of Universitas Sebelas Maret -PERDATIN Solo 78 Yehuda Tri Nugroho Supranoto , I Made Putra Wira Negara Meta-Analysis of Higher PEEP Strategies' Effects on Mortality Rates and Inflammatory Mediators in Patients with ARDS: A Perspective Review on Patients with Severe COVID-19-Associated ARDS Tabel 1.
Analysis of Higher PEEP Strategies' Effects on Mortality Rates and Inflammatory Mediators in Patients with ARDS: A Perspective Review on Patients with Severe COVID-19-Associated ARDS 79 Solo Journal of Anesthesi, Pain and Critical Care | Vol 3 No 2 October 202 Medical Faculty of Universitas Sebelas Maret -PERDATIN Solo

Table 2 . Characteristics of Included Studies
Yehuda Tri Nugroho Supranoto , I Made Putra Wira Negara Meta-Analysis of Higher PEEP Strategies' Effects on Mortality Rates and Inflammatory Mediators in Patients with ARDS: A Perspective Review on Patients with Severe COVID-19-Associated ARDS 84 Solo Journal of Anesthesi, Pain and Critical Care | Vol 3 No 2 October 202 Medical Faculty of Universitas Sebelas Maret -PERDATIN Solo Yehuda Tri Nugroho Supranoto , I Made Putra Wira Negara Meta-Analysis of Higher PEEP Strategies' Effects on Mortality Rates and Inflammatory Mediators in Patients with ARDS: A Perspective Review on Patients with Severe COVID-19-Associated ARDS 85 Solo Journal of Anesthesi, Pain and Critical Care | Vol 3 No 2 October 202 Medical Faculty of Universitas Sebelas Maret -PERDATIN Solo HP, Higher PEEP group; LP, Lower PEEP group; VT, Tidal Volume; Plat, Plateu of Pressure; Pflex, Pressure inflection point

Table 3 . Mortality and Barotrauma Outcomes After PEEP Intervention
Yehuda Tri Nugroho Supranoto , I Made Putra Wira Negara Meta-Analysis of Higher PEEP Strategies' Effects on Mortality Rates and Inflammatory Mediators in Patients with ARDS: A Perspective Review on Patients with Severe COVID-19-Associated ARDS 87 Solo Journal of Anesthesi, Pain and Critical Care | Vol 3 No 2 October 202 Medical Faculty of Universitas Sebelas Maret -PERDATIN Solo