Personalized mechanical ventilation in acute respiratory distress syndrome.

A personalized mechanical ventilation approach for patients with adult respiratory distress syndrome (ARDS) based on lung physiology and morphology, ARDS etiology, lung imaging, and biological phenotypes may improve ventilation practice and outcome. However, additional research is warranted before personalized mechanical ventilation strategies can be applied at the bedside. Ventilatory parameters should be titrated based on close monitoring of targeted physiologic variables and individualized goals. Although low tidal volume (VT) is a standard of care, further individualization of VT may necessitate the evaluation of lung volume reserve (e.g., inspiratory capacity). Low driving pressures provide a target for clinicians to adjust VT and possibly to optimize positive end-expiratory pressure (PEEP), while maintaining plateau pressures below safety thresholds. Esophageal pressure monitoring allows estimation of transpulmonary pressure, but its use requires technical skill and correct physiologic interpretation for clinical application at the bedside. Mechanical power considers ventilatory parameters as a whole in the optimization of ventilation setting, but further studies are necessary to assess its clinical relevance. The identification of recruitability in patients with ARDS is essential to titrate and individualize PEEP. To define gas-exchange targets for individual patients, clinicians should consider issues related to oxygen transport and dead space. In this review, we discuss the rationale for personalized approaches to mechanical ventilation for patients with ARDS, the role of lung imaging, phenotype identification, physiologically based individualized approaches to ventilation, and a future research agenda.

Lung-Protective Ventilation With Low Tidal Volumes and the Occurrence of Pulmonary Complications in Patients Without Acute Respiratory Distress Syndrome: A Systematic Review and Individual Patient Data Analysis.

OBJECTIVE: Protective mechanical ventilation with low tidal volumes is standard of care for patients with acute respiratory distress syndrome. The aim of this individual patient data analysis was to determine the association between tidal volume and the occurrence of pulmonary complications in ICU patients without acute respiratory distress syndrome and the association between occurrence of pulmonary complications and outcome in these patients. DESIGN: Individual patient data analysis. PATIENTS: ICU patients not fulfilling the consensus criteria for acute respiratory distress syndrome at the onset of ventilation. INTERVENTIONS: Mechanical ventilation with low tidal volume. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was development of a composite of acute respiratory distress syndrome and pneumonia during hospital stay. Based on the tertiles of tidal volume size in the first 2 days of ventilation, patients were assigned to a "low tidal volume group" (tidal volumes ≤ 7 mL/kg predicted body weight), an "intermediate tidal volume group" (> 7 and < 10 mL/kg predicted body weight), and a "high tidal volume group" (≥ 10 mL/kg predicted body weight). Seven investigations (2,184 patients) were included. Acute respiratory distress syndrome or pneumonia occurred in 23% of patients in the low tidal volume group, in 28% of patients in the intermediate tidal volume group, and in 31% of the patients in the high tidal volume group (adjusted odds ratio [low vs high tidal volume group], 0.72; 95% CI, 0.52-0.98; p = 0.042). Occurrence of pulmonary complications was associated with a lower number of ICU-free and hospital-free days and alive at day 28 (10.0 ± 10.9 vs 13.8 ± 11.6 d; p < 0.01 and 6.1 ± 8.1 vs 8.9 ± 9.4 d; p < 0.01) and an increased hospital mortality (49.5% vs 35.6%; p < 0.01). CONCLUSIONS: Ventilation with low tidal volumes is associated with a lower risk of development of pulmonary complications in patients without acute respiratory distress syndrome.

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.

Smart Care™ versus respiratory physiotherapy-driven manual weaning for critically ill adult patients: a randomized controlled trial.

INTRODUCTION: A recent meta-analysis showed that weaning with SmartCare™ (Dräger, Lübeck, Germany) significantly decreased weaning time in critically ill patients. However, its utility compared with respiratory physiotherapist-protocolized weaning is still a matter of debate. We hypothesized that weaning with SmartCare™ would be as effective as respiratory physiotherapy-driven weaning in critically ill patients. METHODS: Adult critically ill patients mechanically ventilated for more than 24 hours in the adult intensive care unit of the Albert Einstein Hospital, São Paulo, Brazil, were randomly assigned to be weaned either by progressive discontinuation of pressure support ventilation (PSV) with SmartCare™. Demographic data, respiratory function parameters, level of PSV, tidal volume (VT), positive end-expiratory pressure (PEEP), inspired oxygen fraction (FIO2), peripheral oxygen saturation (SpO2), end-tidal carbon dioxide concentration (EtCO2) and airway occlusion pressure at 0.1 second (P0.1) were recorded at the beginning of the weaning process and before extubation. Mechanical ventilation time, weaning duration and rate of extubation failure were compared. RESULTS: Seventy patients were enrolled 35 in each group. There was no difference between the two groups concerning age, sex or diagnosis at study entry. There was no difference in maximal inspiratory pressure, maximal expiratory pressure, forced vital capacity or rapid shallow breathing index at the beginning of the weaning trial. PEEP, VT, FIO2, SpO2, respiratory rate, EtCO2 and P0.1 were similar between the two groups, but PSV was not (median: 8 vs. 10 cmH2O; p =0.007). When the patients were ready for extubation, PSV (8 vs. 5 cmH2O; p =0.015) and PEEP (8 vs. 5 cmH2O; p <0.001) were significantly higher in the respiratory physiotherapy-driven weaning group. Total duration of mechanical ventilation (3.5 [2.0-7.3] days vs. 4.1 [2.7-7.1] days; p =0.467) and extubation failure (2 vs. 2; p =1.00) were similar between the two groups. Weaning duration was shorter in the respiratory physiotherapy-driven weaning group (60 [50-80] minutes vs. 110 [80-130] minutes; p <0.001). CONCLUSION: A respiratory physiotherapy-driven weaning protocol can decrease weaning time compared with an automatic system, as it takes into account individual weaning difficulties. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02122016 . Date of Registration: 27 August 2013.

Impact of distinct definitions of acute lung injury on its incidence and outcomes in Brazilian ICUs: prospective evaluation of 7,133 patients*.

OBJECTIVES: Evaluation of prevalence and outcomes of acute lung injury in a large cohort of critically ill patients in Brazil and comparison of predictive receiver operating characteristic curve mortality of American European Consensus conference definition with new Berlin definition of acute respiratory distress syndrome. DESIGN: A 15-month prospective, multicenter, observational study. SETTING: Fourteen medical ICUs in Espirito Santo, a state of Brazil. PATIENTS: Mechanically ventilated patients who fulfilled American European Consensus conference criteria of acute lung injury or Berlin definition of acute respiratory distress syndrome. INTERVENTIONS: Clinical and respiratory data were collected for 7 consecutive days and on the 14 and 28 days. Twenty-eight day mortality, hospital mortality, and predictive receiver operating characteristic curve mortality were calculated. MEASUREMENTS AND MAIN RESULTS: Of 7,133 patients, 130 patients (1.8%) fulfilled criteria for acute lung injury (American European Consensus conference) or acute respiratory distress syndrome (Berlin definition). Median time for diagnosis was 2 days (interquartile range, 0-3 d). Main risk factors were pneumonia (35.3%) and nonpulmonary sepsis (31.5%). Mean age was 44.2 ± 15.9 years, and 61.5% were men. Mean Acute Physiology and Chronic Health Evaluation II score was 20.7 ± 7.9. Mean PaO2/FIO2 was 206 ± 61.5, significantly lower in nonsurvivors on day 7 (p = 0.003). Mean mechanical ventilation time was 21 ± 15 days. Length of ICU stay was 26.4 ± 18.7 days. Twenty-eight-day mortality was 38.5% (95% CI, 30.1-46.8); hospital mortality was 49.2% (95% CI, 40.6-57.8). Predictive 28-day mortality area under the receiver operating characteristic curve for American European Consensus conference definition was 0.5625 (95% CI, 0.4783-0.6467) and for the Berlin definition 0.5664 (95% CI, 0.4759-0.6568; p = 0.9510). CONCLUSIONS: In our population, prevalence of acute lung injury was low, most cases were diagnosed 2 days after ICU admission, and Berlin definition was not different from American European Consensus conference definition in predicting mortality. There are still several problems with the global epidemiology, definition, and mortality predictive indices that should be added to the classification of this still lethal syndrome to improve its predictive mortality power in the future.

What is the future of acute respiratory distress syndrome after the Berlin definition?

PURPOSE OF REVIEW: To analyze recently published articles in the medical literature that studied distinct aspects of adult patients with acute respiratory distress syndrome (ARDS) after the new Berlin definition introduced in 2012. RECENT FINDINGS: The degree of ARDS severity according to this new classification correlated well with extravascular lung water index, pulmonary vascular permeability index and the finding of diffuse alveolar damage on autopsy. The new possibility of bedside echocardiographic evaluation of biventricular cardiac function is indicating the necessity of including a subgroup of severity of patients with right ventricular dysfunction. High-resolution CT evaluation showed that signs of pulmonary fibroproliferation in early ARDS predict increased ventilator dependency, multiple organ failure and mortality. The median development of ARDS 1 or 2 days after hospital admission emphasizes the need for ARDS intrahospital prevention, especially protective ventilation in non-ARDS patients. The better outcome with the use of prone position in patients with PaO2/FIO2 below 150 recently observed questioned the Berlin definition thresholds to decide the future best treatment strategies according to the proposed degree of severity of the syndrome. SUMMARY: The impact of the Berlin definition of ARDS on the incidence, better treatment stratification and mortality ratio of ARDS is still to be determined.

Impact of extended lung protection during mechanical ventilation on lung recovery in patients with COVID-19 ARDS: a phase II randomized controlled trial.

BACKGROUND: Protective ventilation seems crucial during early Acute Respiratory Distress Syndrome (ARDS), but the optimal duration of lung protection remains undefined. High driving pressures (ΔP) and excessive patient ventilatory drive may hinder lung recovery, resulting in self-inflicted lung injury. The hidden nature of the ΔP generated by patient effort complicates the situation further. Our study aimed to assess the feasibility of an extended lung protection strategy that includes a stepwise protocol to control the patient ventilatory drive, assessing its impact on lung recovery. METHODS: We conducted a single-center randomized study on patients with moderate/severe COVID-19-ARDS with low respiratory system compliance (CRS < 0.6 (mL/Kg)/cmH2O). The intervention group received a ventilation strategy guided by Electrical Impedance Tomography aimed at minimizing ΔP and patient ventilatory drive. The control group received the ARDSNet low-PEEP strategy. The primary outcome was the modified lung injury score (mLIS), a composite measure that integrated daily measurements of CRS, along with oxygen requirements, oxygenation, and X-rays up to day 28. The mLIS score was also hierarchically adjusted for survival and extubation rates. RESULTS: The study ended prematurely after three consecutive months without patient enrollment, attributed to the pandemic subsiding. The intention-to-treat analysis included 76 patients, with 37 randomized to the intervention group. The average mLIS score up to 28 days was not different between groups (P = 0.95, primary outcome). However, the intervention group showed a faster improvement in the mLIS (1.4 vs. 7.2 days to reach 63% of maximum improvement; P < 0.001), driven by oxygenation and sustained improvement of X-ray (P = 0.001). The intervention group demonstrated a sustained increase in CRS up to day 28 (P = 0.009) and also experienced a shorter time from randomization to room-air breathing (P = 0.02). Survival at 28 days and time until liberation from the ventilator were not different between groups. CONCLUSIONS: The implementation of an individualized PEEP strategy alongside extended lung protection appears viable. Promising secondary outcomes suggested a faster lung recovery, endorsing further examination of this strategy in a larger trial. Clinical trial registration This trial was registered with ClinicalTrials.gov (number NCT04497454) on August 04, 2020.

How large is the lung recruitability in early acute respiratory distress syndrome: a prospective case series of patients monitored by computed tomography.

INTRODUCTION: The benefits of higher positive end expiratory pressure (PEEP) in patients with acute respiratory distress syndrome (ARDS) have been modest, but few studies have fully tested the "open-lung hypothesis". This hypothesis states that most of the collapsed lung tissue observed in ARDS can be reversed at an acceptable clinical cost, potentially resulting in better lung protection, but requiring more intensive maneuvers. The short-/middle-term efficacy of a maximum recruitment strategy (MRS) was recently described in a small physiological study. The present study extends those results, describing a case-series of non-selected patients with early, severe ARDS submitted to MRS and followed until hospital discharge or death. METHODS: MRS guided by thoracic computed tomography (CT) included two parts: a recruitment phase to calculate opening pressures (incremental steps under pressure-controlled ventilation up to maximum inspiratory pressures of 60 cmH2O, at constant driving-pressures of 15 cmH2O); and a PEEP titration phase (decremental PEEP steps from 25 to 10 cmH2O) used to estimate the minimum PEEP to keep lungs open. During all steps, we calculated the size of the non-aerated (-100 to +100 HU) compartment and the recruitability of the lungs (the percent mass of collapsed tissue re-aerated from baseline to maximum PEEP). RESULTS: A total of 51 severe ARDS patients, with a mean age of 50.7 years (84% primary ARDS) was studied. The opening plateau-pressure was 59.6 (±5.9 cmH2O), and the mean PEEP titrated after MRS was 24.6 (±2.9 cmH2O). Mean PaO2/FiO2 ratio increased from 125 (±43) to 300 (±103; P<0.0001) after MRS and was sustained above 300 throughout seven days. Non-aerated parenchyma decreased significantly from 53.6% (interquartile range (IQR): 42.5 to 62.4) to 12.7% (IQR: 4.9 to 24.2) (P<0.0001) after MRS. The potentially recruitable lung was estimated at 45% (IQR: 25 to 53). We did not observe major barotrauma or significant clinical complications associated with the maneuver. CONCLUSIONS: MRS could efficiently reverse hypoxemia and most of the collapsed lung tissue during the course of ARDS, compatible with a high lung recruitability in non-selected patients with early, severe ARDS. This strategy should be tested in a prospective randomized clinical trial.

The effects of low and high tidal volume and pentoxifylline on intestinal blood flow and leukocyte-endothelial interactions in mechanically ventilated rats.

BACKGROUND: The combination of high PEEP and low tidal volume (V(T)) decreases some risks of mechanical ventilation, including pulmonary overdistention, damage due to cyclic opening and closing of the alveoli, and inflammatory responses that can lead to multiple-organ dysfunction. We hypothesized that high V(T) and high PEEP induce mesenteric microcirculatory disturbances and that those disturbances would be attenuated by pentoxifylline, which is anti-inflammatory. METHODS: We anesthetized (isoflurane 1.5%), tracheostomized, and mechanically ventilated 57 male Wistar rats with PEEP of 10 cm H(2)O and F(IO(2)) of 0.21 for 2 hours. One group received low V(T) (7 mL/kg), another group received high V(T) (10 mL/kg), and a third group received high V(T) plus pentoxifylline (25 mg/kg). We measured mean arterial pressure, respiratory mechanics, mesenteric blood flow, and leukocyte-endothelial interactions. RESULTS: The mean arterial pressure was similar among the groups at baseline (108 mm Hg [IQR 94-118 mm Hg]) and after 2 hours of mechanical ventilation (104 mm Hg [IQR 90-114 mm Hg]). Mesenteric blood flow was also similar between the groups: low V(T) 15.1 mL/min (IQR 12.4-17.7 mL/min), high V(T) 11.3 mL/min (IQR 8.6-13.8 mL/min), high-V(T)/pentoxifylline 12.4 mL/min (10.8-13.7 mL/min). Peak airway pressure after 2 hours was lower (P = .03) in the low-V(T) group (10.4 cm H(2)O [IQR 10.2-10.4 cm H(2)O]) than in the high-V(T) group (12.6 cm H(2)O [10.2-14.9 cm H(2)O]) or the high-V(T)/pentoxifylline group (12.8 cm H(2)O [10.7-16.0 cm H(2)O]). There were fewer adherent leukocytes (P = .005) and fewer migrated leukocytes (P = .002) in the low-V(T) group (5 cells/100 µm length [IQR 4-7 cells/100 µm length] and 1 cell/5,000 µm(2) [IQR 1-2 cells/5,000 µm(2)], respectively) and the high-V(T)/pentoxifylline group (5 cells/100 µm length [IQR 3-10 cells/100 µm length] and 1 cell/5,000 µm(2) [IQR 1-3 cells/5,000 µm(2)], respectively) than in the high-V(T) group (14 cells/100 µm length [IQR 11-16 cells/100 µm length] and 9 cells/5,000 µm(2) [IQR 8-12 cells/5,000 µm(2)], respectively). CONCLUSIONS: Low V(T) with high PEEP was lung-protective, and early pentoxifylline reduced the inflammatory response to high V(T) with high PEEP (and presumed lung overdistention) during mechanical ventilation.

A new integrative weaning index of discontinuation from mechanical ventilation.

INTRODUCTION: Indexes predicting weaning outcome are frequently inaccurate. We developed a new integrative weaning index aimed at improving the accuracy of the traditional indexes. METHODS: Three hundred and thirty-one patients mechanically-ventilated for more than 24 hours were evaluated. Initially, the threshold values of each index that best discriminate between a successful and an unsuccessful weaning outcome were determined in 115 patients. In the second phase, the predictive performance of these values was tested prospectively in the other 216 patients. Frequency/tidal volume ratio (f/Vt ratio), tidal volume (Vt), tracheal airway occlusion pressure 0.1 s (P 0.1), the product of P 0.1 and f/Vt (P 0.1 x f/Vt), respiratory rate (f), static compliance of the respiratory system (Cst,rs), ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2 ratio) and the new integrative weaning index IWI (Cst,rs x arterial oxygen saturation/f/Vt ratio) were evaluated in all patients. The readiness for weaning and the decision to return to mechanical ventilation was made by the physician in charge, based on the signs of poor tolerance. The receiver operating characteristic (ROC) curves were calculated in order to evaluate the predictive performance of each index. The Bayes' theorem was used to assess the probability of each test of predicting weaning. RESULTS: In the prospective-validation set, successful weaning was observed in 183 patients (84.7%) and weaning failure in 33 (15.27%). IWI presented the highest accuracy, with the area under the ROC curves larger than that under the curves for the f/Vt ratio (0.96 x 0.85 respectively; P = 0.003), and also larger than that under the curves for the other indexes. IWI presented a higher probability of successful weaning when the test was positive (0.99) and a lower probability when the test was negative (0.14). Measurement of Cst,rs during the weaning process was considered one of the study limitations. CONCLUSIONS: IWI was the best predictive performance index of weaning outcome and can be used in the intensive care unit setting. TRIAL REGISTRATION: controlled-trials.com ISRCTN92117906.

Potentially modifiable respiratory variables contributing to outcome in ICU patients without ARDS: a secondary analysis of PRoVENT.

BACKGROUND: The majority of critically ill patients do not suffer from acute respiratory distress syndrome (ARDS). To improve the treatment of these patients, we aimed to identify potentially modifiable factors associated with outcome of these patients. METHODS: The PRoVENT was an international, multicenter, prospective cohort study of consecutive patients under invasive mechanical ventilatory support. A predefined secondary analysis was to examine factors associated with mortality. The primary endpoint was all-cause in-hospital mortality. RESULTS: 935 Patients were included. In-hospital mortality was 21%. Compared to patients who died, patients who survived had a lower risk of ARDS according to the 'Lung Injury Prediction Score' and received lower maximum airway pressure (Pmax), driving pressure (ΔP), positive end-expiratory pressure, and FiO2 levels. Tidal volume size was similar between the groups. Higher Pmax was a potentially modifiable ventilatory variable associated with in-hospital mortality in multivariable analyses. ΔP was not independently associated with in-hospital mortality, but reliable values for ΔP were available for 343 patients only. Non-modifiable factors associated with in-hospital mortality were older age, presence of immunosuppression, higher non-pulmonary sequential organ failure assessment scores, lower pulse oximetry readings, higher heart rates, and functional dependence. CONCLUSIONS: Higher Pmax was independently associated with higher in-hospital mortality in mechanically ventilated critically ill patients under mechanical ventilatory support for reasons other than ARDS. Trial Registration ClinicalTrials.gov (NCT01868321).

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.

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.

Epidemiological characteristics, practice of ventilation, and clinical outcome in patients at risk of acute respiratory distress syndrome in intensive care units from 16 countries (PRoVENT): an international, multicentre, prospective study.

BACKGROUND: Scant information exists about the epidemiological characteristics and outcome of patients in the intensive care unit (ICU) at risk of acute respiratory distress syndrome (ARDS) and how ventilation is managed in these individuals. We aimed to establish the epidemiological characteristics of patients at risk of ARDS, describe ventilation management in this population, and assess outcomes compared with people at no risk of ARDS. METHODS: PRoVENT (PRactice of VENTilation in critically ill patients without ARDS at onset of ventilation) is an international, multicentre, prospective study undertaken at 119 ICUs in 16 countries worldwide. All patients aged 18 years or older who were receiving mechanical ventilation in participating ICUs during a 1-week period between January, 2014, and January, 2015, were enrolled into the study. The Lung Injury Prediction Score (LIPS) was used to stratify risk of ARDS, with a score of 4 or higher defining those at risk of ARDS. The primary outcome was the proportion of patients at risk of ARDS. Secondary outcomes included ventilatory management (including tidal volume [VT] expressed as mL/kg predicted bodyweight [PBW], and positive end-expiratory pressure [PEEP] expressed as cm H2O), development of pulmonary complications, and clinical outcomes. The PRoVENT study is registered at ClinicalTrials.gov, NCT01868321. The study has been completed. FINDINGS: Of 3023 patients screened for the study, 935 individuals fulfilled the inclusion criteria. Of these critically ill patients, 282 were at risk of ARDS (30%, 95% CI 27-33), representing 0·14 cases per ICU bed over a 1-week period. VT was similar for patients at risk and not at risk of ARDS (median 7·6 mL/kg PBW [IQR 6·7-9·1] vs 7·9 mL/kg PBW [6·8-9·1]; p=0·346). PEEP was higher in patients at risk of ARDS compared with those not at risk (median 6·0 cm H2O [IQR 5·0-8·0] vs 5·0 cm H2O [5·0-7·0]; p<0·0001). The prevalence of ARDS in patients at risk of ARDS was higher than in individuals not at risk of ARDS (19/260 [7%] vs 17/556 [3%]; p=0·004). Compared with individuals not at risk of ARDS, patients at risk of ARDS had higher in-hospital mortality (86/543 [16%] vs 74/232 [32%]; p<0·0001), ICU mortality (62/533 [12%] vs 66/227 [29%]; p<0·0001), and 90-day mortality (109/653 [17%] vs 88/282 [31%]; p<0·0001). VT did not differ between patients who did and did not develop ARDS (p=0·471 for those at risk of ARDS; p=0·323 for those not at risk). INTERPRETATION: Around a third of patients receiving mechanical ventilation in the ICU were at risk of ARDS. Pulmonary complications occur frequently in patients at risk of ARDS and their clinical outcome is worse compared with those not at risk of ARDS. There is potential for improvement in the management of patients without ARDS. Further refinements are needed for prediction of ARDS. FUNDING: None.

Acute remodeling of parenchyma in pulmonary and extrapulmonary ARDS. An autopsy study of collagen-elastic system fibers.

This study aimed at evaluating acute pulmonary remodeling, focusing on alterations of fibers of the collagenous and elastic systems in ARDS in the exudative phase according to the etiology of the disease. ARDS patients (n = 23), who died in our institution between 1989 and 1997, were retrospectively studied. Ten patients who died in accidents, without any pathological changes in the lung, and ten patients with Congestive Heart Failure (CHF), submitted to mechanical ventilation, were used as control groups. Histological slides were sampled from the autopsied lungs and stained by the Picrosirius and Weigert's resorcin-fuchsin methods. The fiber content of the collagenous and elastic systems of the alveolar septum was measured by image analysis. All patients were in the early ARDS phase (n = 23), 10 pulmonary and 13 extra-pulmonary diseases. Collagen content was greater in pulmonary (1.23+/-0.27) than in extra-pulmonary (0.92+/-0.39) ARDS in the early phase of the disease (p = 0.05). No differences were observed concerning the elastic fibers' content. Extracellular matrix (ECM) remodeling occurs early in the development of acute lung injury and appears to depend on the site of initial insult (pulmonary or extrapulmonary). The present study provides the basis for a prospective, controlled investigation.

Incidence of mortality and morbidity related to postoperative lung injury in patients who have undergone abdominal or thoracic surgery: a systematic review and meta-analysis.

BACKGROUND: Lung injury is a serious complication of surgery. We did a systematic review and meta-analysis to assess whether incidence, morbidity, and in-hospital mortality associated with postoperative lung injury are affected by type of surgery and whether outcomes are dependent on type of ventilation. METHODS: We searched MEDLINE, CINAHL, Web of Science, and Cochrane Central Register of Controlled Trials for observational studies and randomised controlled trials published up to April, 2014, comparing lung-protective mechanical ventilation with conventional mechanical ventilation during abdominal or thoracic surgery in adults. Individual patients' data were assessed. Attributable mortality was calculated by subtracting the in-hospital mortality of patients without postoperative lung injury from that of patients with postoperative lung injury. FINDINGS: We identified 12 investigations involving 3365 patients. The total incidence of postoperative lung injury was similar for abdominal and thoracic surgery (3·4% vs 4·3%, p=0·198). Patients who developed postoperative lung injury were older, had higher American Society of Anesthesiology scores and prevalence of sepsis or pneumonia, more frequently had received blood transfusions during surgery, and received ventilation with higher tidal volumes, lower positive end-expiratory pressure levels, or both, than patients who did not. Patients with postoperative lung injury spent longer in intensive care (8·0 [SD 12·4] vs 1·1 [3·7] days, p<0·0001) and hospital (20·9 [18·1] vs 14·7 [14·3] days, p<0·0001) and had higher in-hospital mortality (20·3% vs 1·4% p<0·0001) than those without injury. Overall attributable mortality for postoperative lung injury was 19% (95% CI 18-19), and differed significantly between abdominal and thoracic surgery patients (12·2%, 95% CI 12·0-12·6 vs 26·5%, 26·2-27·0, p=0·0008). The risk of in-hospital mortality was independent of ventilation strategy (adjusted HR 0·71, 95% CI 0·41-1·22). INTERPRETATION: Postoperative lung injury is associated with increases in in-hospital mortality and durations of stay in intensive care and hospital. Attributable mortality due to postoperative lung injury is higher after thoracic surgery than after abdominal surgery. Lung-protective mechanical ventilation strategies reduce incidence of postoperative lung injury but does not improve mortality. FUNDING: None.

Association between tidal volume size, duration of ventilation, and sedation needs in patients without acute respiratory distress syndrome: an individual patient data meta-analysis.

PURPOSE: Mechanical ventilation with lower tidal volumes (≤6 ml/kg of predicted body weight, PBW) could benefit patients without acute respiratory distress syndrome (ARDS). However, tidal volume reduction could be associated with increased patient discomfort and sedation needs, and consequent longer duration of ventilation. The aim of this individual patient data meta-analysis was to assess the associations between tidal volume size, duration of mechanical ventilation, and sedation needs in patients without ARDS. METHODS: Studies comparing ventilation with different tidal volume sizes in patients without ARDS were screened for inclusion. Corresponding authors were asked to provide individual participant data. Patients were assigned to three groups based on tidal volume size (≤6 ml/kg PBW, 6-10 ml/kg PBW, or ≥10 ml/kg PBW). Ventilator-free days, alive at day 28, and dose and duration of sedation (propofol and midazolam), analgesia (fentanyl and morphine), and neuromuscular blockade (NMB) were compared. RESULTS: Seven investigations (2,184 patients) were included in the analysis. The number of patients breathing without assistance by day 28 was higher in the group ventilated with tidal volume ≤6 ml/kg PBW compared to those ventilated with tidal volume ≥10 ml/kg PBW (93.1 vs. 88.6%; p = 0.027, respectively). Only two investigations (187 patients) could be included in the meta-analysis of sedation needs. There were neither differences in the percentage of study days that patients received sedatives, opioids, or NMBA nor in the total dose of benzodiazepines, propofol, opioids, and NMBA. CONCLUSIONS: This meta-analysis suggests that use of lower tidal volumes in patients without ARDS at the onset of mechanical ventilation could be associated with shorter duration of ventilation. Use of lower tidal volumes seems not to affect sedation or analgesia needs, but this must be confirmed in a robust, well-powered randomized controlled trial.