Effect of High Positive End-Expiratory Pressure on Perioperative Atelectasis in Neonates and Small Infants (0-6 months) with Healthy Lungs: A Randomized Controlled Trial.

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.

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.

Intraoperative Positive End-expiratory Pressure for Obese Patients: A Step Forward, a Long Road Still Ahead.

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.

To evaluate the effect of intraoperative positive end-expiratory pressure and driving pressure on the development of postoperative pulmonary complications. The prospective study included 83 patients undergoing abdominal surgery and receiving general anaesthesia. Patients were divided into two groups: with low intraoperative positive end-expiratory pressure (0-2cm H2O) and with high intraoperative positive end-expiratory pressure (8-10cm H2O). The primary endpoint is the development of postoperative pulmonary complications during follow-up. The incidence of postoperative pulmonary complications in the group of low intraoperative positive end-expiratory pressure was 9.8%, while in the group of high positive end-expiratory pressure was 7.1% (p = 0.6), demonstrating that high positive end-expiratory pressure used during general anaesthesia does not affect the frequency of complications (odds ratio = 0.71, p = 0.6). In the multivariate analysis that controls for all confounders, driving pressure resulted in a significant and independent risk factor for complications. High intraoperative positive end-expiratory pressure does not affect the frequency of postoperative pulmonary complications. The increase in driving pressure is a risk factor for complications. Positive end-expiratory pressure is easily implemented, and its use does not result in significant economic costs.

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).

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.

Helium/Oxygen Breathing Improved Hypoxemia After Cardiac Surgery

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

Positive end-expiratory pressure (PEEP) and prone positioning may induce lung recruitment and affect alveolar dynamics in acute respiratory distress syndrome (ARDS). Whether there is interdependence between the effects of PEEP and prone positioning on these variables is unknown. To determine the effects of high PEEP and prone positioning on lung recruitment, cyclic recruitment/derecruitment, and tidal hyperinflation and how these effects are influenced by lung recruitability. Mechanically ventilated patients (Vt 6 ml/kg ideal body weight) underwent whole-lung computed tomography (CT) during breath-holding sessions at airway pressures of 5, 15, and 45 cm H2O and Cine-CTs on a fixed thoracic transverse slice at PEEP 5 and 15 cm H2O. CT images were repeated in supine and prone positioning. A recruitment maneuver at 45 cm H2O was performed before each PEEP change. Lung recruitability was defined as the difference in percentage of nonaerated tissue between 5 and 45 cm H2O. Cyclic recruitment/de-recruitment and tidal hyperinflation were determined as tidal changes in percentage of nonaerated and hyperinflated tissue, respectively. Twenty-four patients with ARDS were included. Increasing PEEP from 5 to 15 cm H2O decreased nonaerated tissue (501 ± 201 to 322 ± 132 grams; P < 0.001) and increased tidal-hyperinflation (0.41 ± 0.26 to 0.57 ± 0.30%; P = 0.004) in supine. Prone positioning further decreased nonaerated tissue (322 ± 132 to 290 ± 141 grams; P = 0.028) and reduced tidal hyperinflation observed at PEEP 15 in supine patients (0.57 ± 0.30 to 0.41 ± 0.22%). Cyclic recruitment/de-recruitment only decreased when high PEEP and prone positioning were applied together (4.1 ± 1.9 to 2.9 ± 0.9%; P = 0.003), particularly in patients with high lung recruitability. Prone positioning enhances lung recruitment and decreases alveolar instability and hyperinflation observed at high PEEP in patients with ARDS.

Acute Renal Failure and Mechanical Ventilation: Reality or Myth?

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 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.

Sir, We read with interest the article written by Sehgal et al[1] and want to raise certain issues pertaining to the important topic: In Case 1, an end-expiratory transpulmonary pressure of 0–10 cm of H2O and end-inspiratory transpulmonary pressure of <25 cm of H2O were targeted. As a result, the patient received positive end expiratory pressure (PEEP) of 13 [transpulmonary pressure (Ptp) PEEP of 3 or 4] though his FiO2 was 1 throughout the hospital course. Should a higher PEEP and hence a higher Ptp PEEP been targeted in this case (though the patient had hypotension)? Talmor et al.[2] had studied application of esophageal pressure values for titration of ventilator strategies in acute respiratory distress syndrome (ARDS) patients and had used an algorithm to determine the Plexp (end-expiratory pleural pressure) and PEEP (targeting a minimum PaO2 of 55 mm of Hg) which is provided in Table 1. Trials such as ALVEOLI have also suggested a higher PEEP at a FiO2 of 1. Table 2 portrays the PEEP–FIO2 combination used in the said trial (in the lower PEEP group). Thus, it seems that the authors have measured the esophageal pressures but have not used them for appropriate PEEP titration Table 1 FiO2 and Plexp combination used by Talmor et al2 Table 2 FiO2 and PEEP combination used in ARDSNet trial The authors have attempted to tailor the ventilator strategy based on the esophageal pressure monitoring, but they have not indicated how the strategy should be altered based on the subtype, namely, ARDSp versus ARDSexp. It is seen that application of PEEP results in increased recruitment and decreased elastance of the respiratory system in ARDSexp as compared to the ARDSp as suggested by Gattinoni et al.[3] However, whether the above findings should dissuade intensivists to apply PEEP in cases of ARDSp can be ardently debated due to lack of evidence in its favor. ARDSNet and ALVEOLI had consistently used PEEP in all ARDS patients (both ARDSp and ARDSexp) based on Table 2. Talmor et al.[2] had around 23% patients having ARDSp in the esophageal pressure group for which they had used the same strategy as in ARDSexp Of the two cases described by the authors, poor chest wall compliance in Case 2 appears to be predominantly due to increased abdominal pressures (as a result of hemoperitoneum). This, however, might not be true for all extrapulmonary ARDS patients, as also highlighted in a study by Pelosi et al,[4] indicating that ARDSexp may not be a homogenous group by itself Finally, a few caveats about using esophageal pressure for titrating PEEP – the esophageal pressure may not represent the pleural pressures in normal individuals as also in critically ill patients. Arbitrarily, correction factors (Talmor et al. had subtracted 5 cm of H2O from the esophageal pressure value to correct for the effects of mediastinal weight and balloon air volume on the observed pressures) have been used which can be variable and can make the interpretation difficult.[5] Furthermore, esophageal pressures can lead to increased PEEP administration and better oxygenation parameters in subjects but its effect on mortality, ventilator-free days, etc., is still unclear.[5] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

The effect of positive end expiratory pressure (PEEP) on postoperative pulmonary complications (PPCs) in obese patients remains controversial. To test, whether intra-operative PEEP or PPCs are associated with plasma levels of biomarkers of lung injury. A prospective substudy of a multicentre randomised controlled trial (PROBESE). Operating rooms of six tertiary care centres in the United States and Europe. Obese patients at risk for PPCs undergoing abdominal surgery. Intra-operative low tidal volume ventilation with high PEEP (12 cmH 2 O) and recruitment manoeuvres, or low PEEP (4 cmH 2 O). The primary endpoint was the association between absolute postoperative plasma levels of receptor for advanced glycation end-products (RAGE) and intra-operative PEEP; secondary endpoints included pre and postoperative plasma concentrations as well as the relative changes of interleukin-6, IL-8, tumour necrosis factor-α, surfactant protein D, mucin-1, clara cell protein-16, intercellular adhesion molecule-1 and vascular cell adhesion molecule. PPCs were assessed as a 'collapsed composite' of adverse pulmonary events. The predictive ability of biomarkers for PPCs was assessed with the receiver operating curve-area under the curve (ROC-AUC). A total of 96 patients received low PEEP, and 95 patients high PEEP. Postoperative plasma concentrations of RAGE and other biomarkers did not differ between groups. The relative increase of RAGE during surgery was more pronounced with low than high PEEP; median [IQR], 1.2 [1.0 to 1.6] vs. 1.1 [0.9 to 1.3], P = 0.012. Patients who developed PPCs showed higher postoperative plasma levels and relative increase of IL-6; 26.3 [12.6 to 139.5] vs. 15.1 [3.7 to 38.7] fold change. The ROC-AUC was less than 0.7 for all biomarkers. In this subgroup, choice of PEEP did not affect postoperative biomarkers of lung injury. Irrespective of PEEP, PPCs were associated with an increase in plasma levels of these biomarkers, but their predictive capability was poor. Clinicaltrials.gov, identifier: NCT02148692.