Safety and Feasibility of Intraoperative High PEEP Titrated to the Lowest Driving Pressure (ΔP)-Interim Analysis of DESIGNATION.

Uncertainty remains about the best level of intraoperative positive end-expiratory pressure (PEEP). An ongoing RCT ('DESIGNATION') compares an 'individualized high PEEP' strategy ('iPEEP')-titrated to the lowest driving pressure (ΔP) with recruitment maneuvers (RM), with a 'standard low PEEP' strategy ('low PEEP')-using 5 cm H2O without RMs with respect to the incidence of postoperative pulmonary complications. This report is an interim analysis of safety and feasibility. From September 2018 to July 2022, we enrolled 743 patients. Data of 698 patients were available for this analysis. Hypotension occurred more often in 'iPEEP' vs. 'low PEEP' (54.7 vs. 44.1%; RR, 1.24 (95% CI 1.07 to 1.44); p < 0.01). Investigators were compliant with the study protocol 285/344 patients (82.8%) in 'iPEEP', and 345/354 patients (97.5%) in 'low PEEP' (p < 0.01). Most frequent protocol violation was missing the final RM at the end of anesthesia before extubation; PEEP titration was performed in 99.4 vs. 0%; PEEP was set correctly in 89.8 vs. 98.9%. Compared to 'low PEEP', the 'iPEEP' group was ventilated with higher PEEP (10.0 (8.0-12.0) vs. 5.0 (5.0-5.0) cm H2O; p < 0.01). Thus, in patients undergoing general anesthesia for open abdominal surgery, an individualized high PEEP ventilation strategy is associated with hypotension. The protocol is feasible and results in clear contrast in PEEP. DESIGNATION is expected to finish in late 2023.

Intraoperative positive end-expiratory pressure and postoperative pulmonary complications: a patient-level meta-analysis of three randomised clinical trials.

BACKGROUND: High intraoperative PEEP with recruitment manoeuvres may improve perioperative outcomes. We re-examined this question by conducting a patient-level meta-analysis of three clinical trials in adult patients at increased risk for postoperative pulmonary complications who underwent non-cardiothoracic and non-neurological surgery. METHODS: The three trials enrolled patients at 128 hospitals in 24 countries from February 2011 to February 2018. All patients received volume-controlled ventilation with low tidal volume. Analyses were performed using one-stage, two-level, mixed modelling (site as a random effect; trial as a fixed effect). The primary outcome was a composite of postoperative pulmonary complications within the first week, analysed using mixed-effect logistic regression. Pre-specified subgroup analyses of nine patient characteristics and seven procedure and care-delivery characteristics were also performed. RESULTS: Complete datasets were available for 1913 participants ventilated with high PEEP and recruitment manoeuvres, compared with 1924 participants who received low PEEP. The primary outcome occurred in 562/1913 (29.4%) participants randomised to high PEEP, compared with 620/1924 (32.2%) participants randomised to low PEEP (unadjusted odds ratio [OR]=0.87; 95% confidence interval [95% CI], 0.75-1.01; P=0.06). Higher PEEP resulted in 87/1913 (4.5%) participants requiring interventions for desaturation, compared with 216/1924 (11.2%) participants randomised to low PEEP (OR=0.34; 95% CI, 0.26-0.45). Intraoperative hypotension was associated more frequently (784/1913 [41.0%]) with high PEEP, compared with low PEEP (579/1924 [30.1%]; OR=1.87; 95% CI, 1.60-2.17). CONCLUSIONS: High PEEP combined with recruitment manoeuvres during low tidal volume ventilation in patients undergoing major surgery did not reduce postoperative pulmonary complications. CLINICAL TRIAL REGISTRATION: NCT03937375 (Clinicaltrials.gov).

Geo-economic variations in epidemiology, ventilation management and outcome of patients receiving intraoperative ventilation during general anesthesia- posthoc analysis of an observational study in 29 countries.

BACKGROUND: The aim of this analysis is to determine geo-economic variations in epidemiology, ventilator settings and outcome in patients receiving general anesthesia for surgery. METHODS: Posthoc analysis of a worldwide study in 29 countries. Lower and upper middle-income countries (LMIC and UMIC), and high-income countries (HIC) were compared. The coprimary endpoint was the risk for and incidence of postoperative pulmonary complications (PPC); secondary endpoints were intraoperative ventilator settings, intraoperative complications, hospital stay and mortality. RESULTS: Of 9864 patients, 4% originated from LMIC, 11% from UMIC and 85% from HIC. The ARISCAT score was 17.5 [15.0-26.0] in LMIC, 16.0 [3.0-27.0] in UMIC and 15.0 [3.0-26.0] in HIC (P = .003). The incidence of PPC was 9.0% in LMIC, 3.2% in UMIC and 2.5% in HIC (P < .001). Median tidal volume in ml kg- 1 predicted bodyweight (PBW) was 8.6 [7.7-9.7] in LMIC, 8.4 [7.6-9.5] in UMIC and 8.1 [7.2-9.1] in HIC (P < .001). Median positive end-expiratory pressure in cmH2O was 3.3 [2.0-5.0]) in LMIC, 4.0 [3.0-5.0] in UMIC and 5.0 [3.0-5.0] in HIC (P < .001). Median driving pressure in cmH2O was 14.0 [11.5-18.0] in LMIC, 13.5 [11.0-16.0] in UMIC and 12.0 [10.0-15.0] in HIC (P < .001). Median fraction of inspired oxygen in % was 75 [50-80] in LMIC, 50 [50-63] in UMIC and 53 [45-70] in HIC (P < .001). Intraoperative complications occurred in 25.9% in LMIC, in 18.7% in UMIC and in 37.1% in HIC (P < .001). Hospital mortality was 0.0% in LMIC, 1.3% in UMIC and 0.6% in HIC (P = .009). CONCLUSION: The risk for and incidence of PPC is higher in LMIC than in UMIC and HIC. Ventilation management could be improved in LMIC and UMIC. TRIAL REGISTRATION: Clinicaltrials.gov , identifier: NCT01601223.

Effect of intraoperative PEEP with recruitment maneuvers on the occurrence of postoperative pulmonary complications during general anesthesia--protocol for Bayesian analysis of three randomized clinical trials of intraoperative ventilation.

Background: Using the frequentist approach, a recent meta-analysis of three randomized clinical trials in patients undergoing intraoperative ventilation during general anesthesia for major surgery failed to show the benefit of ventilation that uses high positive end-expiratory pressure with recruitment maneuvers when compared to ventilation that uses low positive end-expiratory pressure without recruitment maneuvers. Methods: We designed a protocol for a Bayesian analysis using the pooled dataset. The multilevel Bayesian logistic model will use the individual patient data. Prior distributions will be prespecified to represent a varying level of skepticism for the effect estimate. The primary endpoint will be a composite of postoperative pulmonary complications (PPC) within the first seven postoperative days, which reflects the primary endpoint of the original studies. We preset a range of practical equivalence to assess the futility of the intervention with an interval of odds ratio (OR) between 0.9 and 1.1 and assess how much of the 95% of highest density interval (HDI) falls between the region of practical equivalence. Ethics and dissemination: The used data derive from approved studies that were published in recent years. The findings of this current analysis will be reported in a new manuscript, drafted by the writing committee on behalf of the three research groups. All investigators listed in the original trials will serve as collaborative authors.

The Association of Intraoperative driving pressure with postoperative pulmonary complications in open versus closed abdominal surgery patients - a posthoc propensity score-weighted cohort analysis of the LAS VEGAS study.

BACKGROUND: It is uncertain whether the association of the intraoperative driving pressure (ΔP) with postoperative pulmonary complications (PPCs) depends on the surgical approach during abdominal surgery. Our primary objective was to determine and compare the association of time-weighted average ΔP (ΔPTW) with PPCs. We also tested the association of ΔPTW with intraoperative adverse events. METHODS: Posthoc retrospective propensity score-weighted cohort analysis of patients undergoing open or closed abdominal surgery in the 'Local ASsessment of Ventilatory management during General Anaesthesia for Surgery' (LAS VEGAS) study, that included patients in 146 hospitals across 29 countries. The primary endpoint was a composite of PPCs. The secondary endpoint was a composite of intraoperative adverse events. RESULTS: The analysis included 1128 and 906 patients undergoing open or closed abdominal surgery, respectively. The PPC rate was 5%. ΔP was lower in open abdominal surgery patients, but ΔPTW was not different between groups. The association of ΔPTW with PPCs was significant in both groups and had a higher risk ratio in closed compared to open abdominal surgery patients (1.11 [95%CI 1.10 to 1.20], P <  0.001 versus 1.05 [95%CI 1.05 to 1.05], P <  0.001; risk difference 0.05 [95%CI 0.04 to 0.06], P <  0.001). The association of ΔPTW with intraoperative adverse events was also significant in both groups but had higher odds ratio in closed compared to open abdominal surgery patients (1.13 [95%CI 1.12- to 1.14], P <  0.001 versus 1.07 [95%CI 1.05 to 1.10], P <  0.001; risk difference 0.05 [95%CI 0.030.07], P <  0.001). CONCLUSIONS: ΔP is associated with PPC and intraoperative adverse events in abdominal surgery, both in open and closed abdominal surgery. TRIAL REGISTRATION: LAS VEGAS was registered at clinicaltrials.gov (trial identifier NCT01601223 ).

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study.

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients. OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference. DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries. MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation. RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT. CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV. TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223.

The effects of preoperative moderate to severe anaemia on length of hospital stay: A propensity score-matched analysis in non-cardiac surgery patients.

BACKGROUND: Anaemia is frequently recorded during preoperative screening and has been suggested to affect outcomes after surgery negatively. OBJECTIVES: The objectives were to assess the frequency of moderate to severe anaemia and its association with length of hospital stay. DESIGN: Post hoc analysis of the international observational prospective 'Local ASsessment of VEntilatory management during General Anaesthesia for Surgery' (LAS VEGAS) study. PATIENTS AND SETTING: The current analysis included adult patients requiring general anaesthesia for non-cardiac surgery. Preoperative anaemia was defined as a haemoglobin concentration of 11 g dl-1 or lower, thus including moderate and severe anaemia according to World Health Organisation criteria. MAIN OUTCOME MEASURES: The primary outcome was length of hospital stay. Secondary outcomes included hospital mortality, intra-operative adverse events and postoperative pulmonary complications (PPCs). RESULTS: Haemoglobin concentrations were available for 8264 of 9864 patients. Preoperative moderate to severe anaemia was present in 7.7% of patients. Multivariable analysis showed that preoperative moderate to severe anaemia was associated with an increased length of hospital stay with a mean difference of 1.3 ((95% CI 0.8 to 1.8) days; P < .001). In the propensity-matched analysis, this association remained present, median 4.0 [IQR 1.0 to 5.0] vs. 2.0 [IQR 0.0 to 5.0] days, P = .001. Multivariable analysis showed an increased in-hospital mortality (OR 2.9 (95% CI 1.1 to 7.5); P  = .029), and higher incidences of intra-operative hypotension (36.3 vs. 25.3%; P < .001) and PPCs (17.1 vs. 10.5%; P = .001) in moderately to severely anaemic patients. However, this was not confirmed in the propensity score-matched analysis. CONCLUSIONS: In this international cohort of non-cardiac surgical patients, preoperative moderate to severe anaemia was associated with a longer duration of hospital stay but not increased intra-operative complications, PPCs or in-hospital mortality. TRIAL REGISTRATION: The LAS VEGAS study was registered at Clinicaltrials.gov, NCT01601223.

Intraoperative ventilator settings and their association with postoperative pulmonary complications in neurosurgical patients: post-hoc analysis of LAS VEGAS study.

BACKGROUND: Limited information is available regarding intraoperative ventilator settings and the incidence of postoperative pulmonary complications (PPCs) in patients undergoing neurosurgical procedures. The aim of this post-hoc analysis of the 'Multicentre Local ASsessment of VEntilatory management during General Anaesthesia for Surgery' (LAS VEGAS) study was to examine the ventilator settings of patients undergoing neurosurgical procedures, and to explore the association between perioperative variables and the development of PPCs in neurosurgical patients. METHODS: Post-hoc analysis of LAS VEGAS study, restricted to patients undergoing neurosurgery. Patients were stratified into groups based on the type of surgery (brain and spine), the occurrence of PPCs and the assess respiratory risk in surgical patients in Catalonia (ARISCAT) score risk for PPCs. RESULTS: Seven hundred eighty-four patients were included in the analysis; 408 patients (52%) underwent spine surgery and 376 patients (48%) brain surgery. Median tidal volume (VT) was 8 ml [Interquartile Range, IQR = 7.3-9] per predicted body weight; median positive end-expiratory pressure (PEEP) was 5 [3 to 5] cmH20. Planned recruitment manoeuvres were used in the 6.9% of patients. No differences in ventilator settings were found among the sub-groups. PPCs occurred in 81 patients (10.3%). Duration of anaesthesia (odds ratio, 1.295 [95% confidence interval 1.067 to 1.572]; p = 0.009) and higher age for the brain group (odds ratio, 0.000 [0.000 to 0.189]; p = 0.031), but not intraoperative ventilator settings were independently associated with development of PPCs. CONCLUSIONS: Neurosurgical patients are ventilated with low VT and low PEEP, while recruitment manoeuvres are seldom applied. Intraoperative ventilator settings are not associated with PPCs.

Prediction of postoperative pulmonary complications.

PURPOSE OF REVIEW: Prediction of postoperative pulmonary complications (PPCs) enables individually applied preventive measures and maybe even early treatment if a PPC eventually starts to develop. The purpose of this review is to describe crucial steps in the development and validation of prediction models, examine these steps in the current literature and describe what the future holds for PPC prediction. RECENT FINDINGS: A systematic search of the medical literature identified 21 articles reporting on prediction models for PPCs. The studies were heterogeneous with regard to design, derivation cohort and whether or not a validation cohort was used. Furthermore, as definitions for PPCs varied substantially, PPC rates were quite different. One-third of the studies had a sufficient sample size for building a prediction model. In most articles, an internal validation step was reported, suggesting a good fit. In the four articles that reported an externally validation step, in three the prognostic model performed less well in external validation. The ARISCAT risk score was the only score that kept sufficient predictive power in external validation, albeit that the sample sizes of the cohorts used may have been too small. Analysis by machine learning could help building new prediction models, as unbiased cluster analyses could uncover clusters of patients with specific underlying pathophysiological mechanisms. Adding biomarkers to the model could optimize identification of biological phenotypes of risk groups. SUMMARY: Many predictive models for PPCs have been reported on. Development of more robust PPC prediction models could be supported by machine learning.

International multicenter observational study on assessment of ventilatory management during general anaesthesia for robotic surgery and its effects on postoperative pulmonary complication (AVATaR): study protocol and statistical analysis plan.

INTRODUCTION: Robotic-assisted surgery (RAS) has emerged as an alternative minimally invasive surgical option. Despite its growing applicability, the frequent need for pneumoperitoneum and Trendelenburg position could significantly affect respiratory mechanics during RAS. AVATaR is an international multicenter observational study aiming to assess the incidence of postoperative pulmonary complications (PPC), to characterise current practices of mechanical ventilation (MV) and to evaluate a possible association between ventilatory parameters and PPC in patients undergoing RAS. METHODS AND ANALYSIS: AVATaR is an observational study of surgical patients undergoing MV for general anaesthesia for RAS. The primary outcome is the incidence of PPC during the first five postoperative days. Secondary outcomes include practice of MV, effect of surgical positioning on MV, effect of MV on clinical outcome and intraoperative complications. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board of the Hospital Israelita Albert Einstein. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT02989415; Pre-results.

The LAS VEGAS risk score for prediction of postoperative pulmonary complications: An observational study.

BACKGROUND: Currently used pre-operative prediction scores for postoperative pulmonary complications (PPCs) use patient data and expected surgery characteristics exclusively. However, intra-operative events are also associated with the development of PPCs. OBJECTIVE: We aimed to develop a new prediction score for PPCs that uses both pre-operative and intra-operative data. DESIGN: This is a secondary analysis of the LAS VEGAS study, a large international, multicentre, prospective study. SETTINGS: A total of 146 hospitals across 29 countries. PATIENTS: Adult patients requiring intra-operative ventilation during general anaesthesia for surgery. INTERVENTIONS: The cohort was randomly divided into a development subsample to construct a predictive model, and a subsample for validation. MAIN OUTCOME MEASURES: Prediction performance of developed models for PPCs. RESULTS: Of the 6063 patients analysed, 10.9% developed at least one PPC. Regression modelling identified 13 independent risk factors for PPCs: six patient characteristics [higher age, higher American Society of Anesthesiology (ASA) physical score, pre-operative anaemia, pre-operative lower SpO2 and a history of active cancer or obstructive sleep apnoea], two procedure-related features (urgent or emergency surgery and surgery lasting ≥ 1 h), and five intra-operative events [use of an airway other than a supraglottic device, the use of intravenous anaesthetic agents along with volatile agents (balanced anaesthesia), intra-operative desaturation, higher levels of positive end-expiratory pressures > 3 cmH2O and use of vasopressors]. The area under the receiver operating characteristic curve of the LAS VEGAS risk score for prediction of PPCs was 0.78 [95% confidence interval (95% CI), 0.76 to 0.80] for the development subsample and 0.72 (95% CI, 0.69 to 0.76) for the validation subsample. CONCLUSION: The LAS VEGAS risk score including 13 peri-operative characteristics has a moderate discriminative ability for prediction of PPCs. External validation is needed before use in clinical practice. TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, number NCT01601223.

Association between pre-operative biological phenotypes and postoperative pulmonary complications: An unbiased cluster analysis.

BACKGROUND: Biological phenotypes have been identified within several heterogeneous pulmonary diseases, with potential therapeutic consequences. OBJECTIVE: 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. SETTING: Operating rooms of six hospitals in Europe and USA. DESIGN: Secondary analysis of the 'PROtective Ventilation with HIgh or LOw PEEP' trial. PATIENTS: Adult patients scheduled for abdominal surgery who are at risk of PPCs. INTERVENTIONS: Measurement of pre-operative concentrations of seven plasma biomarkers associated with inflammation and lung injury. MAIN OUTCOME MEASURES: 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. RESULTS: 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). CONCLUSION: 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. TRIAL REGISTRATION: 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).

Interaction between peri-operative blood transfusion, tidal volume, airway pressure and postoperative ARDS: an individual patient data meta-analysis.

BACKGROUND: Transfusion of blood products and mechanical ventilation with injurious settings are considered risk factors for postoperative lung injury in surgical Patients. METHODS: A systematic review and individual patient data meta-analysis was done to determine the independent effects of peri-operative transfusion of blood products, intra-operative tidal volume and airway pressure in adult patients undergoing mechanical ventilation for general surgery, as well as their interactions on the occurrence of postoperative acute respiratory distress syndrome (ARDS). Observational studies and randomized trials were identified by a systematic search of MEDLINE, CINAHL, Web of Science, and CENTRAL and screened for inclusion into a meta-analysis. Individual patient data were obtained from the corresponding authors. Patients were stratified according to whether they received transfusion in the peri-operative period [red blood cell concentrates (RBC) and/or fresh frozen plasma (FFP)], tidal volume size [≤7 mL/kg predicted body weight (PBW), 7-10 and >10 mL/kg PBW] and airway pressure level used during surgery (≤15, 15-20 and >20 cmH2O). The primary outcome was development of postoperative ARDS. RESULTS: Seventeen investigations were included (3,659 patients). Postoperative ARDS occurred in 40 (7.2%) patients who received at least one blood product compared to 40 patients (2.5%) who did not [adjusted hazard ratio (HR), 2.32; 95% confidence interval (CI), 1.25-4.33; P=0.008]. Incidence of postoperative ARDS was highest in patients ventilated with tidal volumes of >10 mL/kg PBW and having airway pressures of >20 cmH2O receiving both RBC and FFP, and lowest in patients ventilated with tidal volume of ≤7 mL/kg PBW and having airway pressures of ≤15 cmH2O with no transfusion. There was a significant interaction between transfusion and airway pressure level (P=0.002) on the risk of postoperative ARDS. CONCLUSIONS: Peri-operative transfusion of blood products is associated with an increased risk of postoperative ARDS, which seems more dependent on airway pressure than tidal volume size.

Respiratory System Mechanics During Low Versus High Positive End-Expiratory Pressure in Open Abdominal Surgery: A Substudy of PROVHILO Randomized Controlled Trial.

BACKGROUND: In the 2014 PROtective Ventilation using HIgh versus LOw positive end-expiratory pressure (PROVHILO) trial, intraoperative low tidal volume ventilation with high positive end-expiratory pressure (PEEP = 12 cm H2O) and lung recruitment maneuvers did not decrease postoperative pulmonary complications when compared to low PEEP (0-2 cm H2O) approach without recruitment breaths. However, effects of intraoperative PEEP on lung compliance remain poorly understood. We hypothesized that higher PEEP leads to a dominance of intratidal overdistension, whereas lower PEEP results in intratidal recruitment/derecruitment (R/D). To test our hypothesis, we used the volume-dependent elastance index %E2, a respiratory parameter that allows for noninvasive and radiation-free assessment of dominant overdistension and intratidal R/D. We compared the incidence of intratidal R/D, linear expansion, and overdistension by means of %E2 in a subset of the PROVHILO cohort. METHODS: In 36 patients from 2 participating centers of the PROVHILO trial, we calculated respiratory system elastance (E), resistance (R), and %E2, a surrogate parameter for intratidal overdistension (%E2 > 30%) and R/D (%E2 < 0%). To test the main hypothesis, we compared the incidence of intratidal overdistension (primary end point) and R/D in higher and lower PEEP groups, as measured by %E2. RESULTS: E was increased in the lower compared to higher PEEP group (18.6 [16…22] vs 13.4 [11.0…17.0] cm H2O·L; P < .01). %E2 was reduced in the lower PEEP group compared to higher PEEP (-15.4 [-28.0…6.5] vs 6.2 [-0.8…14.0] %; P < .05). Intratidal R/D was increased in the lower PEEP group (61% vs 22%; P = .037). The incidence of intratidal overdistension did not differ significantly between groups (6%). CONCLUSIONS: During mechanical ventilation with protective tidal volumes in patients undergoing open abdominal surgery, lung recruitment followed by PEEP of 12 cm H2O decreased the incidence of intratidal R/D and did not worsen overdistension, when compared to PEEP ≤2 cm H2O.

Kinetics of plasma biomarkers of inflammation and lung injury in surgical patients with or without postoperative pulmonary complications.

BACKGROUND: Postoperative pulmonary complications (PPCs) are common after major abdominal surgery. The kinetics of plasma biomarkers could improve identification of patients developing PPCs, but the kinetics may depend on intraoperative ventilator settings. OBJECTIVE: To test whether the kinetics of plasma biomarkers are capable of identifying patients who will develop PPCs, and whether the kinetics depend on the intraoperative level of positive end-expiratory pressure (PEEP). DESIGN: A preplanned substudy of a randomised controlled trial. SETTING: Operation room of five centres. PATIENTS: Two hundred and forty-two adult patients scheduled for abdominal surgery at risk of developing PPCs. INTERVENTIONS: High (12 cmH2O) versus low (≤2 cmH2O) levels of PEEP. MAIN OUTCOME MEASURES: Individual PPCs were combined as a composite endpoint. Plasma samples were collected before surgery, directly after surgery and on the fifth postoperative day. The levels of the following were measured: tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8, the soluble form of the Receptor for Advanced Glycation End-products (sRAGE), Surfactant Protein (SP)-D, Clara Cell protein (CC)-16 and Krebs von den Lungen 6 (KL6). RESULTS: Blood sampling was complete in 242 patients: 120 patients in the high PEEP group and 122 patients in the low PEEP group. Increases in plasma levels of TNF- IL-6, IL-8 and CC-16, and a decrease in plasma levels of SP-D were greater in patients who developed PPCs; however, the area under the receiver operating characteristic curve was low for all biomarkers. CC-16 was the only biomarker whose level increased more in patients who had received high levels of PEEP. CONCLUSION: In patients undergoing abdominal surgery and at risk of developing PPCs, plasma levels of biomarkers for inflammation or lung injury showed distinct kinetics with development of PPCs, but none of the biomarkers showed sufficient prognostic value. The use of high levels of PEEP was associated with increased levels of CC-16, suggesting lung overdistension. TRIAL REGISTRATION: The PROVHILO trial, including this substudy, was registered at clinicaltrials.gov (NCT01441791).

Association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anaesthesia: a meta-analysis of individual patient data.

BACKGROUND: Protective mechanical ventilation strategies using low tidal volume or high levels of positive end-expiratory pressure (PEEP) improve outcomes for patients who have had surgery. The role of the driving pressure, which is the difference between the plateau pressure and the level of positive end-expiratory pressure is not known. We investigated the association of tidal volume, the level of PEEP, and driving pressure during intraoperative ventilation with the development of postoperative pulmonary complications. METHODS: We did a meta-analysis of individual patient data from randomised controlled trials of protective ventilation during general anesthaesia for surgery published up to July 30, 2015. The main outcome was development of postoperative pulmonary complications (postoperative lung injury, pulmonary infection, or barotrauma). FINDINGS: We included data from 17 randomised controlled trials, including 2250 patients. Multivariate analysis suggested that driving pressure was associated with the development of postoperative pulmonary complications (odds ratio [OR] for one unit increase of driving pressure 1·16, 95% CI 1·13-1·19; p<0·0001), whereas we detected no association for tidal volume (1·05, 0·98-1·13; p=0·179). PEEP did not have a large enough effect in univariate analysis to warrant inclusion in the multivariate analysis. In a mediator analysis, driving pressure was the only significant mediator of the effects of protective ventilation on development of pulmonary complications (p=0·027). In two studies that compared low with high PEEP during low tidal volume ventilation, an increase in the level of PEEP that resulted in an increase in driving pressure was associated with more postoperative pulmonary complications (OR 3·11, 95% CI 1·39-6·96; p=0·006). INTERPRETATION: In patients having surgery, intraoperative high driving pressure and changes in the level of PEEP that result in an increase of driving pressure are associated with more postoperative pulmonary complications. However, a randomised controlled trial comparing ventilation based on driving pressure with usual care is needed to confirm these findings. FUNDING: None.

Intraoperative protective mechanical ventilation for prevention of postoperative pulmonary complications: a comprehensive review of the role of tidal volume, positive end-expiratory pressure, and lung recruitment maneuvers.

Postoperative pulmonary complications are associated with increased morbidity, length of hospital stay, and mortality after major surgery. Intraoperative lung-protective mechanical ventilation has the potential to reduce the incidence of postoperative pulmonary complications. This review discusses the relevant literature on definition and methods to predict the occurrence of postoperative pulmonary complication, the pathophysiology of ventilator-induced lung injury with emphasis on the noninjured lung, and protective ventilation strategies, including the respective roles of tidal volumes, positive end-expiratory pressure, and recruitment maneuvers. The authors propose an algorithm for protective intraoperative mechanical ventilation based on evidence from recent randomized controlled trials.

Protective versus Conventional Ventilation for Surgery: A Systematic Review and Individual Patient Data Meta-analysis.

BACKGROUND: Recent studies show that intraoperative mechanical ventilation using low tidal volumes (VT) can prevent postoperative pulmonary complications (PPCs). The aim of this individual patient data meta-analysis is to evaluate the individual associations between VT size and positive end-expiratory pressure (PEEP) level and occurrence of PPC. METHODS: Randomized controlled trials comparing protective ventilation (low VT with or without high levels of PEEP) and conventional ventilation (high VT with low PEEP) in patients undergoing general surgery. The primary outcome was development of PPC. Predefined prognostic factors were tested using multivariate logistic regression. RESULTS: Fifteen randomized controlled trials were included (2,127 patients). There were 97 cases of PPC in 1,118 patients (8.7%) assigned to protective ventilation and 148 cases in 1,009 patients (14.7%) assigned to conventional ventilation (adjusted relative risk, 0.64; 95% CI, 0.46 to 0.88; P < 0.01). There were 85 cases of PPC in 957 patients (8.9%) assigned to ventilation with low VT and high PEEP levels and 63 cases in 525 patients (12%) assigned to ventilation with low VT and low PEEP levels (adjusted relative risk, 0.93; 95% CI, 0.64 to 1.37; P = 0.72). A dose-response relationship was found between the appearance of PPC and VT size (R2 = 0.39) but not between the appearance of PPC and PEEP level (R2 = 0.08). CONCLUSIONS: These data support the beneficial effects of ventilation with use of low VT in patients undergoing surgery. Further trials are necessary to define the role of intraoperative higher PEEP to prevent PPC during nonopen abdominal surgery.