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Purpose: Variations in clinical characteristics and management and in the mortality of mechanically ventilated patients have not been sufficiently evaluated. We hypothesized that mortality shows a variability associated with country after adjustment for clinical characteristics and management., Methods: Analysis of four studies carried out at 6-year intervals over an 18-year period. The studies included 26,024 patients (5183 in 1998, 4968 in 2004, 8108 in 2010, and 7765 in 2016) admitted to 1253 units from 38 countries. The primary outcome was 28-day mortality. We performed analyses using multilevel logistic modeling with mixed-random effects, including country as a random variable. To evaluate the effect of management strategies on mortality, a mediation analysis was performed., Results: Adjusted 28-day mortality decreased significantly over time (first study as reference): 2004: odds ratio 0.82 (95% confidence interval [CI] 0.72-0.93); 2010: 0.63 (95% CI 0.53-0.75); 2016: 0.49 (95% CI 0.39-0.61). A protective ventilatory strategy and the use of continuous sedation mediated a moderate fraction of the effect of time on mortality in patients with moderate hypoxemia and without hypoxemia, respectively. Logistic multilevel modeling showed a significant effect of country on mortality: median odds ratio (MOR) in 1998: 2.02 (95% CI 1.57-2.48); in 2004: 1.76 (95% CI 1.47-2.06); in 2010: 1.55 (95% CI 1.37-1.74), and in 2016: 1.39 (95% CI 1.25-1.54)., Conclusions: These findings suggest that country could contribute, independently of confounder variables, to outcome. The magnitude of the effect of country decreased over time. Clinical trials registered with http://www.clinicaltrials.gov (NCT02731898).

Objective: To demonstrate that among patients with acute respiratory distress syndrome (ARDS), the presence of diffuse alveolar damage (DAD) at histological examination, as compared to its absence, defines a specific subphenotype., Methods: We studied 149 patients who died in our ICU with the clinical diagnosis of ARDS according to the Berlin Definition (BD) and who had autopsy examination. We compared the change over time of different clinical variables in patients with (n = 49) and without (n = 100) DAD. A predictive model for the presence of DAD was developed and validated in an independent cohort of 57 patients with ARDS and postmortem examination (21 of them with DAD)., Results: Patients with DAD, as compared to patients without DAD, had a lower PaO₂/FiO₂ ratio and dynamic respiratory system compliance, and a higher SOFA score and INR, and were more likely to die of hypoxemia and less likely to die of shock. In multivariate analysis, variables associated with DAD [odds ratio, 95% confidence interval (CI)] were PaO₂/FiO₂ ratio [0.988 (0.981-0.995)], dynamic respiratory system compliance [0.937 (0.892-0.984)] and age [0.972 (0.946-0.999)]. Areas under the ROC curve (95 % CI) for the classification of DAD using the regression model or the BD were, respectively, 0.74 (0.65-0.82) and 0.64 (0.55-0.72) (p = 0.03). In the validation cohort, the areas under the ROC curve for the diagnosis of DAD were 0.73 (0.56-0.90) and 0.67 (0.54-0.81) for the regression model and the BD, respectively., Conclusions: The presence of DAD appears to define a specific subphenotype in patients with ARDS. Targeting patients with DAD within the population of patients with the clinical diagnosis of ARDS might be appropriate to find effective therapies for this condition.

Purpose: There are limited data available about the role of sedation and analgesia during noninvasive positive pressure ventilation (NPPV). The objective of study was to estimate the effect of analgesic or sedative drugs on the failure of NPPV., Methods: We studied patients who received at least 2 h of NPPV as first-line therapy in a prospective observational study carried out in 322 intensive care units from 30 countries. A marginal structural model (MSM) was used to analyze the association between the use of analgesic or sedative drugs and NPPV failure (defined as need for invasive mechanical ventilation)., Results: 842 patients were included in the analysis. Of these, 165 patients (19.6%) received analgesic or sedative drugs at some time during NPPV; 33 of them received both. In the adjusted analysis, the use of analgesics (odds ratio 1.8, 95% confidence interval 0.6-5.4) or sedatives (odds ratio 2.8, 95% CI 0.85-9.4) alone was not associated with NPPV failure, but their combined use was associated with failure (odds ratio 5.7, 95% CI 1.8-18.4)., Conclusions: Slightly less than 20% of patients received analgesic or sedative drugs during NPPV, with no apparent effect on outcome when used alone. However, the simultaneous use of analgesics and sedatives may be associated with failure of NPPV.

Withdrawal from mechanical ventilation (or weaning) is one of the most common procedures in intensive care units. Almost 20 years ago, we published one of the seminal papers on weaning in which we showed that the best method for withdrawal from mechanical ventilation in difficult-to-wean patients was a once-daily spontaneous breathing trial with a T-piece. Progress has not stood still, and in the intervening years up to the present several other studies, by our group and others, have shaped weaning into an evidence-based technique. The results of these studies have been applied progressively to routine clinical practice. Currently, withdrawal from mechanical ventilation can be summarized as the evaluation of extubation readiness based on the patient's performance during a spontaneous breathing trial. This trial can be performed with a T-piece, which is the most common approach, or with continuous positive airway pressure or low levels of pressure support. Most patients can be disconnected after passing the first spontaneous breathing trial. In patients who fail the first attempt at withdrawal, the use of a once-daily spontaneous breathing trial or a gradual reduction in pressure support are the preferred weaning methods. However, new applications of standard techniques, such as noninvasive positive pressure ventilation, or new methods of mechanical ventilation, such as automatic tube compensation, automated closed-loop systems, and automated knowledge-based weaning systems, can play a role in the management of the patients with difficult or prolonged weaning.

Purpose: To compare characteristics and clinical outcomes of patients receiving airway pressure release ventilation (APRV) or biphasic positive airway pressure (BIPAP) to assist-control ventilation (A/C) as their primary mode of ventilatory support. The objective was to estimate if patients ventilated with APRV/BIPAP have a lower mortality., Methods: Secondary analysis of an observational study in 349 intensive care units from 23 countries. A total of 234 patients were included who were ventilated only with APRV/BIPAP and 1,228 patients who were ventilated only with A/C. A case-matched analysis according to a propensity score was used to make comparisons between groups., Results: In logistic regression analysis, the most important factor associated with the use of APRV/BIPAP was the country (196 of 234 patients were from German units). Patients with coma or congestive heart failure as the reason to start mechanical ventilation, pH <7.15 prior to mechanical ventilation, and patients who developed respiratory failure (SOFA score >2) after intubation with or without criteria of acute respiratory distress syndrome were less likely to be ventilated with APRV/BIPAP. In the case-matched analysis there were no differences in outcomes, including mortality in the intensive care unit, days of mechanical ventilation or weaning, rate of reintubation, length of stay in the intensive care unit or hospital, and mortality in the hospital., Conclusions: In this study, the APRV/BIPAP ventilation mode is being used widely across many causes of respiratory failure, but only in selected geographic areas. In our patient population we could not demonstrate any improvement in outcomes with APRV/BIPAP compared with assist-control ventilation.

Purpose: To evaluate, in adults, the diagnostic accuracy of the cuff-leak test for the diagnosis of upper airway obstruction secondary to laryngeal edema and for reintubation secondary to upper airway obstruction., Methods: Systematic review without language restrictions based on electronic databases and manual review of the literature up to December 2008. When appropriate, a random-effects meta-analysis and meta-regression (Moses' method) were performed., Results: Upper airway obstruction was the outcome in nine studies with an overall incidence of 6.9%. There was significant heterogeneity among studies. The pooled sensitivity was 0.56 (95% confidence interval: 0.48-0.63), the specificity was 0.92 (95% CI: 0.90-0.93), the positive likelihood ratio was 5.90 (95% CI: 4.00-8.69), the negative likelihood ratio was 0.48 (95% CI: 0.33-0.72), and the diagnostic odds ratio was 18.78 (95% CI: 7.36-47.92). The area under the curve of the summary receiver-operator characteristic (SROC) was 0.92 (95% CI: 0.89-0.94). Only three studies have evaluated the accuracy of the cuff-leak test for reintubation secondary to upper airway obstruction. Overall incidence was 7%. The pooled sensitivity was 0.63 (95% CI: 0.38-0.84), the specificity was 0.86 (95% CI: 0.81-0.90), the positive likelihood ratio was 4.04 (95% CI: 2.21-7.40), the negative likelihood ratio was 0.46 (95% CI: 0.26-0.82), and the diagnostic odds ratio was 10.37 (95% CI: 3.70-29.13)., Conclusions: A positive cuff-leak test (absence of leak) should alert the clinician of a high risk of upper airway obstruction.

Objective: A single-center retrospective study initial recently identified ventilator settings as a major risk factor for the development of acute respiratory distress syndrome (ARDS) in mechanically ventilated patients who do not have ARDS from the outset. We tested this hypothesis in a larger sample of patients prospectively enrolled in a multicenter study on mechanical ventilation., Design and Setting: From a large international mechanical ventilation study database we identified patients who required mechanical ventilation for 48 h or more but did not have ARDS at the onset of mechanical ventilation. We extracted information on demographics, initial severity of illness, ventilator settings and major underlying ARDS risk factors. Primary outcome was development of ARDS after the onset of mechanical ventilation., Measurements and Results: Of 3,261 mechanically ventilated patients who did not have ARDS at the outset 205 (6.2%) developed ARDS 48 h or more after the onset of mechanical ventilation. Multivariate logistic regression analysis adjusted for baseline patient characteristics (age, gender, Simplified Acute Physiology Score, hypoxemia) and underlying ARDS risk factors (sepsis, trauma, pneumonia) found the development of ARDS to be associated with the initial ventilator settings: high tidal volume (odds ratio 2.6 for tidal volume>700 ml), high peak airway pressure (odds ratio 1.6 for peak airway pressure>30 cmH2O), and high positive end-expiratory pressure (odds ratio 1.7 for end-expiratory pressure>5 cmH2O)., Conclusions: The association with the potentially injurious initial ventilator settings, in particular large tidal volumes, suggests that ARDS in mechanically ventilated patients is in part a preventable complication. This hypothesis needs to be tested in a prospective study.

Objective: To determine the threshold of age that best discriminates the survival of mechanically ventilated patients and to estimate the outcome of mechanically ventilated older patients., Design: International prospective cohort study., Setting: Three hundred sixty-one intensive care units from 20 countries. PATIENTS AND PARTICIPANTS. Five thousand one hundred eighty-three patients mechanically ventilated for more than 12 h., Interventions: None., Measurements and Results: Recursive partitioning and logistic regression were used and an outcome model was derived and validated using independent subgroups of the cohort. Two age thresholds (43 and 70 years) were found, by partitioning recursive analysis, to be associated with outcome. This study focuses on the analysis of patients older than 43 years of age, divided in two subgroups: between 43 and 70 years (middle age group) and older than 70 years (elderly group). Survival in hospital was 45% (95% C.I.: 43-48) for the elderly group and 55% (53-57) for the middle age group ( p<0.001). Advanced age was not associated with prolongation of mechanical ventilation, weaning or length of stay in the ICU and in hospital ( p>0.05). Variables associated with mortality in the elderly were: acute renal failure, shock, Simplified Acute Physiology Score II and a ratio of PaO(2) to FIO(2) more than 150., Conclusions: Older mechanically ventilated patients (age >70 years) had a lower ICU and hospital survival, but the duration of mechanical ventilation, ICU and hospital stay were similar to younger patients. Factors associated with the highest risk of mortality in patients older than 70 were the development of complications during the course of mechanical ventilation, such as acute renal failure and shock.

Objective: To determine the incidence, risk factors, and outcome of barotrauma in a cohort of mechanically ventilated patients where limited tidal volumes and airway pressures were used., Design and Setting: Prospective cohort of 361 intensive care units from 20 countries., Patients and Participants: A total of 5183 patients mechanically ventilated for more than 12 h., Measurements and Results: Baseline demographic data, primary indication for mechanical ventilation, daily ventilator settings, multiple-organ failure over the course of mechanical ventilation and outcome were collected. Barotrauma was present in 154 patients (2.9%). The incidence varied according to the reason for mechanical ventilation: 2.9% of patients with chronic obstructive pulmonary disease; 6.3% of patients with asthma; 10.0% of patients with chronic interstitial lung disease (ILD); 6.5% of patients with acute respiratory distress syndrome (ARDS); and 4.2% of patients with pneumonia. Patients with and without barotrauma did not differ in any ventilator parameter. Logistic regression analysis identified as factors independently associated with barotrauma: asthma [RR 2.58 (1.05-6.50)], ILD [RR 4.23 (95%CI 1.78-10.03)]; ARDS as primary reason for mechanical ventilation [RR 2.70 (95%CI 1.55-4.70)]; and ARDS as a complication during the course of mechanical ventilation [RR 2.53 (95%CI 1.40-4.57)]. Case-control analysis showed increased mortality in patients with barotrauma (51.4 vs 39.2%; p=0.04) and prolonged ICU stay., Conclusions: In a cohort of patients in whom airway pressures and tidal volume are limited, barotrauma is more likely in patients ventilated due to underlying lung disease (acute or chronic). Barotrauma was also associated with a significant increase in the ICU length of stay and mortality.