Effect of immediate initiation of invasive ventilation on mortality in acute hypoxemic respiratory failure: a target trial emulation.

PURPOSE: Invasive ventilation is a fundamental treatment in intensive care but its precise timing is difficult to determine. This study aims at assessing the effect of initiating invasive ventilation versus waiting, in patients with hypoxemic respiratory failure without immediate reason for intubation on one-year mortality. METHODS: Emulation of a target trial to estimate the benefit of immediately initiating invasive ventilation in hypoxemic respiratory failure, versus waiting, among patients within the first 48-h of hypoxemia. The eligible population included non-intubated patients with SpO2/FiO2 ≤ 200 and SpO2 ≤ 97%. The target trial was emulated using a single-center database (MIMIC-IV) which contains granular information about clinical status. The hourly probability to receive mechanical ventilation was continuously estimated. The hazard ratios for the primary outcome, one-year mortality, and the secondary outcome, 30-day mortality, were estimated using weighted Cox models with stabilized inverse probability weights used to adjust for measured confounding. RESULTS: 2996 Patients fulfilled the inclusion criteria of whom 792 were intubated within 48 h. Among the non-invasive support devices, the use of oxygen through facemask was the most common (75%). Compared to patients with the same probability of intubation but who were not intubated, intubation decreased the hazard of dying for the first year after ICU admission HR 0.81 (95% CI 0.68-0.96, p = 0.018). Intubation was associated with a 30-day mortality HR of 0.80 (95% CI 0.64-0.99, p = 0.046). CONCLUSION: The initiation of mechanical ventilation in patients with acute hypoxemic respiratory failure reduced the hazard of dying in this emulation of a target trial.

Effects of intubation timing in patients with COVID-19 throughout the four waves of the pandemic: a matched analysis.

BACKGROUND: The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with coronavirus disease 2019 (COVID-19)-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior noninvasive respiratory support on outcomes. METHODS: This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICUs) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of ICU admission. Propensity score matching was used to achieve a balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different time-point (48 h from ICU admission) for early and delayed intubation. RESULTS: Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After propensity score matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%; p=0.01), ICU mortality (25.7% versus 36.1%; p=0.007) and 90-day mortality (30.9% versus 40.2%; p=0.02) compared with the early intubation group. Very similar findings were observed when we used a 48-h time-point for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth waves, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (HFNC) (n=294) who were intubated earlier. The subgroup of patients undergoing noninvasive ventilation (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h. CONCLUSIONS: In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received HFNC.

Predicting ICU Mortality in Acute Respiratory Distress Syndrome Patients Using Machine Learning: The Predicting Outcome and STratifiCation of severity in ARDS (POSTCARDS) Study.

OBJECTIVES: To assess the value of machine learning approaches in the development of a multivariable model for early prediction of ICU death in patients with acute respiratory distress syndrome (ARDS). DESIGN: A development, testing, and external validation study using clinical data from four prospective, multicenter, observational cohorts. SETTING: A network of multidisciplinary ICUs. PATIENTS: A total of 1,303 patients with moderate-to-severe ARDS managed with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We developed and tested prediction models in 1,000 ARDS patients. We performed logistic regression analysis following variable selection by a genetic algorithm, random forest and extreme gradient boosting machine learning techniques. Potential predictors included demographics, comorbidities, ventilatory and oxygenation descriptors, and extrapulmonary organ failures. Risk modeling identified some major prognostic factors for ICU mortality, including age, cancer, immunosuppression, Pa o2 /F io2 , inspiratory plateau pressure, and number of extrapulmonary organ failures. Together, these characteristics contained most of the prognostic information in the first 24 hours to predict ICU mortality. Performance with machine learning methods was similar to logistic regression (area under the receiver operating characteristic curve [AUC], 0.87; 95% CI, 0.82-0.91). External validation in an independent cohort of 303 ARDS patients confirmed that the performance of the model was similar to a logistic regression model (AUC, 0.91; 95% CI, 0.87-0.94). CONCLUSIONS: Both machine learning and traditional methods lead to promising models to predict ICU death in moderate/severe ARDS patients. More research is needed to identify markers for severity beyond clinical determinants, such as demographics, comorbidities, lung mechanics, oxygenation, and extrapulmonary organ failure to guide patient management.

A long-lasting porcine model of ARDS caused by pneumonia and ventilator-induced lung injury.

BACKGROUND: Animal models of acute respiratory distress syndrome (ARDS) do not completely resemble human ARDS, struggling translational research. We aimed to characterize a porcine model of ARDS induced by pneumonia-the most common risk factor in humans-and analyze the additional effect of ventilator-induced lung injury (VILI). METHODS: Bronchoscopy-guided instillation of a multidrug-resistant Pseudomonas aeruginosa strain was performed in ten healthy pigs. In six animals (pneumonia-with-VILI group), pulmonary damage was further increased by VILI applied 3 h before instillation and until ARDS was diagnosed by PaO2/FiO2 < 150 mmHg. Four animals (pneumonia-without-VILI group) were protectively ventilated 3 h before inoculum and thereafter. Gas exchange, respiratory mechanics, hemodynamics, microbiological studies and inflammatory markers were analyzed during the 96-h experiment. During necropsy, lobar samples were also analyzed. RESULTS: All animals from pneumonia-with-VILI group reached Berlin criteria for ARDS diagnosis until the end of experiment. The mean duration under ARDS diagnosis was 46.8 ± 7.7 h; the lowest PaO2/FiO2 was 83 ± 5.45 mmHg. The group of pigs that were not subjected to VILI did not meet ARDS criteria, even when presenting with bilateral pneumonia. Animals developing ARDS presented hemodynamic instability as well as severe hypercapnia despite high-minute ventilation. Unlike the pneumonia-without-VILI group, the ARDS animals presented lower static compliance (p = 0.011) and increased pulmonary permeability (p = 0.013). The highest burden of P. aeruginosa was found at pneumonia diagnosis in all animals, as well as a high inflammatory response shown by a release of interleukin (IL)-6 and IL-8. At histological examination, only animals comprising the pneumonia-with-VILI group presented signs consistent with diffuse alveolar damage. CONCLUSIONS: In conclusion, we established an accurate pulmonary sepsis-induced ARDS model.

Early intubation and patient-centered outcomes in septic shock: a secondary analysis of a prospective multicenter study.

PURPOSE: Despite the benefits of mechanical ventilation, its use in critically ill patients is associated with complications and had led to the growth of noninvasive techniques. We assessed the effect of early intubation (first 8 h after vasopressor start) in septic shock patients, as compared to non-early intubated subjects (unexposed), regarding in-hospital mortality, intensive care and hospital length of stay. METHODS: This study involves secondary analysis of a multicenter prospective study. To adjust for baseline differences in potential confounders, propensity score matching was carried out. In-hospital mortality was analyzed in a time-to-event fashion, while length of stay was assessed as a median difference using bootstrapping. RESULTS: A total of 735 patients (137 intubated in the first 8 h) were evaluated. Propensity score matching identified 78 pairs with similar severity and characteristics on admission. Intubation was used in all patients in the early intubation group and in 27 (35%) subjects beyond 8 h in the unexposed group. Mortality occurred in 35 (45%) and in 26 (33%) subjects in the early intubation and unexposed groups (hazard ratio 1.44 95% CI 0.86-2.39, p = 0.16). ICU and hospital length of stay were not different among groups [9 vs. 5 (95% CI 1 to 7) and 14 vs. 16 (95% CI - 7 to 8) days]. All sensitivity analyses confirmed the robustness of our findings. CONCLUSIONS: An early approach to invasive mechanical ventilation did not improve outcomes in this matched cohort of patients. The limited number of patients included in these analyses out the total number included in the study may limit generalizability of these findings. Trial registration NCT02780466. Registered on May 19, 2016.

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).

Intraoperative open lung condition and postoperative pulmonary complications. A secondary analysis of iPROVE and iPROVE-O2 trials.

BACKGROUND: The preventive role of an intraoperative recruitment maneuver plus open lung approach (RM + OLA) ventilation on postoperative pulmonary complications (PPC) remains unclear. We aimed at investigating whether an intraoperative open lung condition reduces the risk of developing a composite of PPCs. METHODS: Post hoc analysis of two randomized controlled trials including patients undergoing abdominal surgery. Patients were classified according to the intraoperative lung condition as "open" (OL) or "non-open" (NOL) if PaO2 /FIO2 ratio was ≥ or <400 mmHg, respectively. We used a multivariable logistic regression model that included potential confounders selected with directed acyclic graphs (DAG) using Dagitty software built with variables that were considered clinically relevant based on biological mechanism or evidence from previously published data. PPCs included severe acute respiratory failure, acute respiratory distress syndrome, and pneumonia. RESULTS: A total of 1480 patients were included in the final analysis, with 718 (49%) classified as OL. The rate of severe PPCs during the first seven postoperative days was 6.0% (7.9% in the NOL and 4.4% in the OL group, p = .007). OL was independently associated with a lower risk for severe PPCs during the first 7 and 30 postoperative days [odds ratio of 0.58 (95% CI 0.34-0.99, p = .04) and 0.56 (95% CI 0.34-0.94, p = .03), respectively]. CONCLUSIONS: An intraoperative open lung condition was associated with a reduced risk of developing severe PPCs in intermediate-to-high risk patients undergoing abdominal surgery. TRIAL REGISTRATION: Registered at clinicaltrials.gov NCT02158923 (iPROVE), NCT02776046 (iPROVE-O2).

Implementing a Rapid Response System in a tertiary-care hospital. A cost-effectiveness study.

PURPOSE: The occurrence of adverse events (AE) in hospitalized patients substancially increases the risk of disability or death, having a major negative clinical and economic impact on public health. For early identification of patients at risk and to establish preventive measures, different healthcare systems have implemented rapid response systems (RRS). The aim of this study was to carry out a cost-effectiveness analysis of implementing a RRS in a tertiary-care hospital. METHODS: We included all the patients admitted to Hospital Clínic de Barcelona from 1 to 2016 to 31 December 2016. The cost-effectiveness analysis was summarized as the incremental cost-effectiveness ratio (incremental cost divided by the incremental effectiveness of the two alternatives, RRS versus non-RRS). The effectiveness of the RRS, defined as improvements in health outcomes (AE, cardiopulmonary arrest and mortality), was obtained from the literature and applied to the included patient cohort. A budget impact analysis on the implementation of the RRS from a hospital perspective was performed over a 5-year time horizon. RESULTS: 42,409 patients were included, and 448 (1.05%) had severe AE requiring ICU admission. The cost-effectiveness analysis showed an incremental cost (savings) of EUR - 1,471,101 of RRS versus the non-RRS. The budgetary impact showed a cost reduction of EUR 896,762.00 in the first year and EUR 1,588,579.00 from the second to the fifth year. CONCLUSIONS: The present analysis shows the RRS as a dominant, less costly and more effective structure compared to the non-RRS.

Stratification for Identification of Prognostic Categories In the Acute RESpiratory Distress Syndrome (SPIRES) Score.

OBJECTIVES: To develop a scoring model for stratifying patients with acute respiratory distress syndrome into risk categories (Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score) for early prediction of death in the ICU, independent of the underlying disease and cause of death. DESIGN: A development and validation study using clinical data from four prospective, multicenter, observational cohorts. SETTING: A network of multidisciplinary ICUs. PATIENTS: One-thousand three-hundred one patients with moderate-to-severe acute respiratory distress syndrome managed with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study followed Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines for prediction models. We performed logistic regression analysis, bootstrapping, and internal-external validation of prediction models with variables collected within 24 hours of acute respiratory distress syndrome diagnosis in 1,000 patients for model development. Primary outcome was ICU death. The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score was based on patient's age, number of extrapulmonary organ failures, values of end-inspiratory plateau pressure, and ratio of Pao2 to Fio2 assessed at 24 hours of acute respiratory distress syndrome diagnosis. The pooled area under the receiver operating characteristic curve across internal-external validations was 0.860 (95% CI, 0.831-0.890). External validation in a new cohort of 301 acute respiratory distress syndrome patients confirmed the accuracy and robustness of the scoring model (area under the receiver operating characteristic curve = 0.870; 95% CI, 0.829-0.911). The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score stratified patients in three distinct prognostic classes and achieved better prediction of ICU death than ratio of Pao2 to Fio2 at acute respiratory distress syndrome onset or at 24 hours, Acute Physiology and Chronic Health Evaluation II score, or Sequential Organ Failure Assessment scale. CONCLUSIONS: The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score represents a novel strategy for early stratification of acute respiratory distress syndrome patients into prognostic categories and for selecting patients for therapeutic trials.

Early corticosteroids are associated with lower mortality in critically ill patients with COVID-19: a cohort study.

BACKGROUND: Critically ill patients with coronavirus disease 19 (COVID-19) have a high fatality rate likely due to a dysregulated immune response. Corticosteroids could attenuate this inappropriate response, although there are still some concerns regarding its use, timing, and dose. METHODS: This is a nationwide, prospective, multicenter, observational, cohort study in critically ill adult patients with COVID-19 admitted into Intensive Care Units (ICU) in Spain from 12th March to 29th June 2020. Using a multivariable Cox model with inverse probability weighting, we compared relevant outcomes between patients treated with early corticosteroids (before or within the first 48 h of ICU admission) with those who did not receive early corticosteroids (delayed group) or any corticosteroids at all (never group). Primary endpoint was ICU mortality. Secondary endpoints included 7-day mortality, ventilator-free days, and complications. RESULTS: A total of 691 patients out of 882 (78.3%) received corticosteroid during their hospital stay. Patients treated with early-corticosteroids (n = 485) had lower ICU mortality (30.3% vs. never 36.6% and delayed 44.2%) and lower 7-day mortality (7.2% vs. never 15.2%) compared to non-early treated patients. They also had higher number of ventilator-free days, less length of ICU stay, and less secondary infections than delayed treated patients. There were no differences in medical complications between groups. Of note, early use of moderate-to-high doses was associated with better outcomes than low dose regimens. CONCLUSION: Early use of corticosteroids in critically ill patients with COVID-19 is associated with lower mortality than no or delayed use, and fewer complications than delayed use.

High-flow nasal oxygen in patients with COVID-19-associated acute respiratory failure.

PURPOSE: Whether the use of high-flow nasal oxygen in adult patients with COVID-19 associated acute respiratory failure improves clinically relevant outcomes remains unclear. We thus sought to assess the effect of high-flow nasal oxygen on ventilator-free days, compared to early initiation of invasive mechanical ventilation, on adult patients with COVID-19. METHODS: We conducted a multicentre cohort study using a prospectively collected database of patients with COVID-19 associated acute respiratory failure admitted to 36 Spanish and Andorran intensive care units (ICUs). Main exposure was the use of high-flow nasal oxygen (conservative group), while early invasive mechanical ventilation (within the first day of ICU admission; early intubation group) served as the comparator. The primary outcome was ventilator-free days at 28 days. ICU length of stay and all-cause in-hospital mortality served as secondary outcomes. We used propensity score matching to adjust for measured confounding. RESULTS: Out of 468 eligible patients, a total of 122 matched patients were included in the present analysis (61 for each group). When compared to early intubation, the use of high-flow nasal oxygen was associated with an increase in ventilator-free days (mean difference: 8.0 days; 95% confidence interval (CI): 4.4 to 11.7 days) and a reduction in ICU length of stay (mean difference: - 8.2 days; 95% CI - 12.7 to - 3.6 days). No difference was observed in all-cause in-hospital mortality between groups (odds ratio: 0.64; 95% CI: 0.25 to 1.64). CONCLUSIONS: The use of high-flow nasal oxygen upon ICU admission in adult patients with COVID-19 related acute hypoxemic respiratory failure may lead to an increase in ventilator-free days and a reduction in ICU length of stay, when compared to early initiation of invasive mechanical ventilation. Future studies should confirm our findings.

Awake prone positioning does not reduce the risk of intubation in COVID-19 treated with high-flow nasal oxygen therapy: a multicenter, adjusted cohort study.

BACKGROUND: Awake prone positioning (awake-PP) in non-intubated coronavirus disease 2019 (COVID-19) patients could avoid endotracheal intubation, reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNO) with awake-PP prevents the need for intubation when compared to HFNO alone. METHODS: Prospective, multicenter, adjusted observational cohort study in consecutive COVID-19 patients with acute respiratory failure (ARF) receiving respiratory support with HFNO from 12 March to 9 June 2020. Patients were classified as HFNO with or without awake-PP. Logistic models were fitted to predict treatment at baseline using the following variables: age, sex, obesity, non-respiratory Sequential Organ Failure Assessment score, APACHE-II, C-reactive protein, days from symptoms onset to HFNO initiation, respiratory rate, and peripheral oxyhemoglobin saturation. We compared data on demographics, vital signs, laboratory markers, need for invasive mechanical ventilation, days to intubation, ICU length of stay, and ICU mortality between HFNO patients with and without awake-PP. RESULTS: A total of 1076 patients with COVID-19 ARF were admitted, of which 199 patients received HFNO and were analyzed. Fifty-five (27.6%) were pronated during HFNO; 60 (41%) and 22 (40%) patients from the HFNO and HFNO + awake-PP groups were intubated. The use of awake-PP as an adjunctive therapy to HFNO did not reduce the risk of intubation [RR 0.87 (95% CI 0.53-1.43), p = 0.60]. Patients treated with HFNO + awake-PP showed a trend for delay in intubation compared to HFNO alone [median 1 (interquartile range, IQR 1.0-2.5) vs 2 IQR 1.0-3.0] days (p = 0.055), but awake-PP did not affect 28-day mortality [RR 1.04 (95% CI 0.40-2.72), p = 0.92]. CONCLUSION: In patients with COVID-19 ARF treated with HFNO, the use of awake-PP did not reduce the need for intubation or affect mortality.

Effects of oxygen on post-surgical infections during an individualised perioperative open-lung ventilatory strategy: a randomised controlled trial.

BACKGROUND: We aimed to examine whether using a high fraction of inspired oxygen (FIO2) in the context of an individualised intra- and postoperative open-lung ventilation approach could decrease surgical site infection (SSI) in patients scheduled for abdominal surgery. METHODS: We performed a multicentre, randomised controlled clinical trial in a network of 21 university hospitals from June 6, 2017 to July 19, 2018. Patients undergoing abdominal surgery were randomly assigned to receive a high (0.80) or conventional (0.3) FIO2 during the intraoperative period and during the first 3 postoperative hours. All patients were mechanically ventilated with an open-lung strategy, which included recruitment manoeuvres and individualised positive end-expiratory pressure for the best respiratory-system compliance, and individualised continuous postoperative airway pressure for adequate peripheral oxyhaemoglobin saturation. The primary outcome was the prevalence of SSI within the first 7 postoperative days. The secondary outcomes were composites of systemic complications, length of intensive care and hospital stay, and 6-month mortality. RESULTS: We enrolled 740 subjects: 371 in the high FIO2 group and 369 in the low FIO2 group. Data from 717 subjects were available for final analysis. The rate of SSI during the first postoperative week did not differ between high (8.9%) and low (9.4%) FIO2 groups (relative risk [RR]: 0.94; 95% confidence interval [CI]: 0.59-1.50; P=0.90]). Secondary outcomes, such as atelectasis (7.7% vs 9.8%; RR: 0.77; 95% CI: 0.48-1.25; P=0.38) and myocardial ischaemia (0.6% [n=2] vs 0% [n=0]; P=0.47) did not differ between groups. CONCLUSIONS: An oxygenation strategy using high FIO2 compared with conventional FIO2 did not reduce postoperative SSIs in abdominal surgery. No differences in secondary outcomes or adverse events were found. CLINICAL TRIAL REGISTRATION: NCT02776046.

Spontaneous recovery of neuromuscular blockade is an independent risk factor for postoperative pulmonary complications after abdominal surgery: A secondary analysis.

BACKGROUND: In intermediate-to-high-risk patients, major abdominal surgery is associated with a high incidence of postoperative complications, mainly pulmonary. Neuromuscular blocking drugs have been suggested as a contributing factor, but this remains unproven. OBJECTIVE: To define the relationship of neuromuscular blockade management (reversal) with postoperative pulmonary complications (PPCs). DESIGN: The individualised PeRioperative Open-lung approach Versus standard protectivE ventilation in abdominal surgery study was a prospective, multicentre, four-arm, randomised controlled trial. This is a secondary analysis of the data. SETTING: Twenty-one teaching hospitals in Spain. The study was conducted between 2 January 2015, and 18 May 2016. PATIENTS: Age more than 18 years with an intermediate-to-high risk for PPCs, scheduled for major abdominal surgery lasting more than 2 h. Exclusion criteria included pregnancy or breastfeeding, and moderate-to-severe organ diseases. INTERVENTIONS: The mode of reversal of neuromuscular blockade determined two patient groups: pharmacological reversal versus spontaneous recovery. MAIN OUTCOME MEASURES: The primary outcome was a composite of PPCs during the first 30 postoperative days. The association between categorical variables and PPCs within 30 days was studied. Univariate and multivariable logistic regression modelling and propensity score analyses were performed. RESULTS: From the 923 patients included, 596 (64.6%) presented with PPCs within 30 days after surgery. Patients who developed these complications were older with a higher BMI, a lower pre-operative SpO2, a higher ASA physical status score and a higher incidence of arterial hypertension, diabetes mellitus or chronic obstructive pulmonary disease. Pharmacological neuromuscular blockade reversal was associated with a lower incidence of PPCs (odds ratio 0.62, 95% CI 0.47 to 0.82). CONCLUSION: Spontaneous recovery of neuromuscular blockade was an independent risk factor for PPCs in patients with intermediate-to-high risk, undergoing abdominal surgery. We suggest this factor should be included in future studies on PPCs. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02158923.

Multimodal non-invasive monitoring to apply an open lung approach strategy in morbidly obese patients during bariatric surgery.

To evaluate the use of non-invasive variables for monitoring an open-lung approach (OLA) strategy in bariatric surgery. Twelve morbidly obese patients undergoing bariatric surgery received a baseline protective ventilation with 8 cmH2O of positive-end expiratory pressure (PEEP). Then, the OLA strategy was applied consisting in lung recruitment followed by a decremental PEEP trial, from 20 to 8 cmH2O, in steps of 2 cmH2O to find the lung's closing pressure. Baseline ventilation was then resumed setting open lung PEEP (OL-PEEP) at 2 cmH2O above this pressure. The multimodal non-invasive variables used for monitoring OLA consisted in pulse oximetry (SpO2), respiratory compliance (Crs), end-expiratory lung volume measured by a capnodynamic method (EELVCO2), and esophageal manometry. OL-PEEP was detected at 15.9 ± 1.7 cmH2O corresponding to a positive end-expiratory transpulmonary pressure (PL,ee) of 0.9 ± 1.1 cmH2O. ROC analysis showed that SpO2 was more accurate (AUC 0.92, IC95% 0.87-0.97) than Crs (AUC 0.76, IC95% 0.87-0.97) and EELVCO2 (AUC 0.73, IC95% 0.64-0.82) to detect the lung's closing pressure according to the change of PL,ee from positive to negative values. Compared to baseline ventilation with 8 cmH2O of PEEP, OLA increased EELVCO2 (1309 ± 517 vs. 2177 ± 679 mL) and decreased driving pressure (18.3 ± 2.2 vs. 10.1 ± 1.7 cmH2O), estimated shunt (17.7 ± 3.4 vs. 4.2 ± 1.4%), lung strain (0.39 ± 0.07 vs. 0.22 ± 0.06) and lung elastance (28.4 ± 5.8 vs. 15.3 ± 4.3 cmH2O/L), respectively; all p < 0.0001. The OLA strategy can be monitored using noninvasive variables during bariatric surgery. This strategy decreased lung strain, elastance and driving pressure compared with standard protective ventilatory settings.Clinical trial number NTC03694665.

A Prognostic Enrichment Strategy for Selection of Patients With Acute Respiratory Distress Syndrome in Clinical Trials.

OBJECTIVES: Incomplete or ambiguous evidence for identifying high-risk patients with acute respiratory distress syndrome for enrollment into randomized controlled trials has come at the cost of an unreasonable number of negative trials. We examined a set of selected variables early in acute respiratory distress syndrome to determine accurate prognostic predictors for selecting high-risk patients for randomized controlled trials. DESIGN: A training and testing study using a secondary analysis of data from four prospective, multicenter, observational studies. SETTING: A network of multidisciplinary ICUs. PATIENTS: We studied 1,200 patients with moderate-to-severe acute respiratory distress syndrome managed with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated different thresholds for patient's age, PaO2/FIO2, plateau pressure, and number of extrapulmonary organ failures to predict ICU outcome at 24 hours of acute respiratory distress syndrome diagnosis. We generated 1,000 random scenarios as training (n = 900, 75% of population) and testing (n = 300, 25% of population) datasets and averaged the logistic coefficients for each scenario. Thresholds for age (< 50, 50-70, > 70 yr), PaO2/FIO2 (≤ 100, 101-150, > 150 mm Hg), plateau pressure (< 29, 29-30, > 30 cm H2O), and number of extrapulmonary organ failure (< 2, 2, > 2) stratified accurately acute respiratory distress syndrome patients into categories of risk. The model that included all four variables proved best to identify patients with the highest or lowest risk of death (area under the receiver operating characteristic curve, 0.86; 95% CI, 0.84-0.88). Decision tree analyses confirmed the accuracy and robustness of this enrichment model. CONCLUSIONS: Combined thresholds for patient's age, PaO2/FIO2, plateau pressure, and extrapulmonary organ failure provides prognostic enrichment accuracy for stratifying and selecting acute respiratory distress syndrome patients for randomized controlled trials.

Rationale and Study Design for an Individualized Perioperative Open Lung Ventilatory Strategy in Patients on One-Lung Ventilation (iPROVE-OLV).

OBJECTIVE: The aim of this clinical trial is to examine whether it is possible to reduce postoperative complications using an individualized perioperative ventilatory strategy versus using a standard lung-protective ventilation strategy in patients scheduled for thoracic surgery requiring one-lung ventilation. DESIGN: International, multicenter, prospective, randomized controlled clinical trial. SETTING: A network of university hospitals. PARTICIPANTS: The study comprises 1,380 patients scheduled for thoracic surgery. INTERVENTIONS: The individualized group will receive intraoperative recruitment maneuvers followed by individualized positive end-expiratory pressure (open lung approach) during the intraoperative period plus postoperative ventilatory support with high-flow nasal cannula, whereas the control group will be managed with conventional lung-protective ventilation. MEASUREMENTS AND MAIN RESULTS: Individual and total number of postoperative complications, including atelectasis, pneumothorax, pleural effusion, pneumonia, acute lung injury; unplanned readmission and reintubation; length of stay and death in the critical care unit and in the hospital will be analyzed for both groups. The authors hypothesize that the intraoperative application of an open lung approach followed by an individual indication of high-flow nasal cannula in the postoperative period will reduce pulmonary complications and length of hospital stay in high-risk surgical patients.

Is Overall Mortality the Right Composite Endpoint in Clinical Trials of Acute Respiratory Distress Syndrome?

OBJECTIVES: Overall mortality in patients with acute respiratory distress syndrome is a composite endpoint because it includes death from multiple causes. In most acute respiratory distress syndrome trials, it is unknown whether reported deaths are due to acute respiratory distress syndrome or the underlying disease, unrelated to the specific intervention tested. We investigated the causes of death after contracting acute respiratory distress syndrome in a large cohort. DESIGN: A secondary analysis from three prospective, multicenter, observational studies. SETTING: A network of multidisciplinary ICUs. PATIENTS: We studied 778 patients with moderate-to-severe acute respiratory distress syndrome treated with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We examined death in the ICU from individual causes. Overall ICU mortality was 38.8% (95% CI, 35.4-42.3). Causes of acute respiratory distress syndrome modified the risk of death. Twenty-three percent of deaths occurred from refractory hypoxemia due to nonresolving acute respiratory distress syndrome. Most patients died from causes unrelated to acute respiratory distress syndrome: 48.7% of nonsurvivors died from multisystem organ failure, and cancer or brain injury was involved in 37.1% of deaths. When quantifying the true burden of acute respiratory distress syndrome outcome, we identified 506 patients (65.0%) with one or more exclusion criteria for enrollment into current interventional trials. Overall ICU mortality of the "trial cohort" (21.3%) was markedly lower than the parent cohort (relative risk, 0.55; 95% CI, 0.43-0.70; p < 0.000001). CONCLUSIONS: Most deaths in acute respiratory distress syndrome patients are not directly related to lung damage but to extrapulmonary multisystem organ failure. It would be challenging to prove that specific lung-directed therapies have an effect on overall survival.

The Effects of an Open-Lung Approach During One-Lung Ventilation on Postoperative Pulmonary Complications and Driving Pressure: A Descriptive, Multicenter National Study.

OBJECTIVE: Thoracic surgical procedures are associated with an increased risk of postoperative pulmonary complications (PPCs), which seem to be related directly to intraoperative driving pressure. The authors conducted this study to describe the incidence of PPCs in patients in whom an individualized open-lung approach was applied during one-lung ventilation. DESIGN: This was a prospective, multicenter, national descriptive study. SETTING: Thoracic surgery patients undergoing one-lung ventilation. PARTICIPANTS: Eligible participants were included consecutively from October 1, 2016, to September 30, 2017. A total of 690 patients were included. INTERVENTIONS: An individualized open-lung approach that consisted of an alveolar recruitment maneuver followed by a positive end-expiratory pressure adjusted to best respiratory system compliance was performed in all patients. MEASUREMENTS AND MAIN RESULTS: Preoperative and intraoperative data were recorded; the primary outcome was a description of the incidence of PPCs in these patients during the first 7 postoperative days. The patients were mainly male, and half of them had a high risk of PPCs (ARISCAT score exceeding 44). Eleven percent of participants developed a PPC within the first postoperative week. The mean open lung positive end-expiratory pressure was 8 ± 3 cmH2O. When compared with pre-open lung approach values, the open-lung approach significantly decreased the driving pressure (14 ± 4 cmH2O v 11 ± 3 cmH2O; p < 0.001) and increased dynamic compliance (30 ± 10 mL/cmH2O v 43 ±15 mL/cmH2O; p < 0.001). CONCLUSIONS: The low incidence of PPCs in patients who underwent an open-lung approach during one-lung ventilation compared with that reported for other thoracic surgery series and the decrease in the driving pressure in these patients justify an additional randomized controlled trial to compare the open-lung approach with the standard protective strategy of low tidal volume and low positive end-expiratory pressure.