Abstract
Rationale: Baseline characteristics and management have changed over time in patients requiring mechanical ventilation; however, the impact of these changes on patient outcomes is unclear.
Objectives: To estimate whether mortality in mechanically ventilated patients has changed over time.
Methods: Prospective cohort studies conducted in 1998, 2004, and 2010, including patients receiving mechanical ventilation for more than 12 hours in a 1-month period, from 927 units in 40 countries. To examine effects over time on mortality in intensive care units, we performed generalized estimating equation models.
Measurements and Main Results: We included 18,302 patients. The reasons for initiating mechanical ventilation varied significantly among cohorts. Ventilatory management changed over time (P < 0.001), with increased use of noninvasive positive-pressure ventilation (5% in 1998 to 14% in 2010), a decrease in tidal volume (mean 8.8 ml/kg actual body weight [SD = 2.1] in 1998 to 6.9 ml/kg [SD = 1.9] in 2010), and an increase in applied positive end-expiratory pressure (mean 4.2 cm H2O [SD = 3.8] in 1998 to 7.0 cm of H2O [SD = 3.0] in 2010). Crude mortality in the intensive care unit decreased in 2010 compared with 1998 (28 versus 31%; odds ratio, 0.87; 95% confidence interval, 0.80–0.94), despite a similar complication rate. Hospital mortality decreased similarly. After adjusting for baseline and management variables, this difference remained significant (odds ratio, 0.78; 95% confidence interval, 0.67–0.92).
Conclusions: Patient characteristics and ventilation practices have changed over time, and outcomes of mechanically ventilated patients have improved.
Clinical trials registered with www.clinicaltrials.gov (NCT01093482).
Baseline characteristics and management have changed over time in patients requiring mechanical ventilation; however, the impact of these changes on patient outcomes is unclear.
The implementation of mechanical ventilation has significantly changed in the last decade. These changes have likely resulted in a significant decrease in short-term mortality.
Mechanical ventilation remains a cornerstone in the supportive management of patients with acute respiratory failure, and is one of the defining interventions of intensive care medicine as a specialty. Basic science, translational, and physiological studies have all informed clinical trials, which, in turn, have shown significant impact in areas such as avoidance of ventilator-induced lung injury (1–5), liberation from mechanical ventilation (6–10), and improved outcomes using noninvasive positive-pressure ventilation (11, 12). Little is known, however, about the impact of these interventions on mortality in a real-world setting.
In 1998 (13) and 2004 (14), we performed two observational studies on the use of mechanical ventilation and its associated outcomes. In the first, we focused on describing mortality outcomes and identifying factors that impacted survival (13). In the second, we systematically reviewed clinical trials published in the prior 6 years and examined the implementation of this published evidence (14). The main finding of this study was the increasing use of noninvasive positive-pressure ventilation, a reduction in tidal volumes for patients with acute respiratory distress syndrome (ARDS), and more pressure support and less synchronized intermittent mandatory ventilation being used for liberation from mechanical ventilation. Despite these encouraging findings, our data failed to demonstrate a significant improvement in outcomes. Possible reasons for these results include lack of statistical power, or a true lack of outcome improvements due to differences in intensive care unit (ICU) admission patterns over time, an insufficient magnitude of practice change, or a lack of efficacy of these therapies in unselected populations outside the setting of a clinical trial.
At 6 years after the last study, we have now conducted a new international study with the primary objective of estimating whether mortality in mechanically ventilated patients has changed over time. We reasoned that combining this new study with our two prior databases would give us more statistical power to demonstrate potential improvements in survival. Furthermore, allowing more time for incorporation of previous research findings into clinical practice, and performing a multivariable analysis that accounted for potential changes in case mix over time should improve the study importance. Our secondary aims were to describe the changes in the baseline and management characteristics of ventilated patients over this 12-year period.
As in previous studies (13, 14), we conducted a prospective use review of patients receiving invasive mechanical ventilation for at least 12 hours or noninvasive positive-pressure ventilation for at least 1 hour during a 1-month period starting in March 2010. National coordinators recruited local investigators (see full list of Investigators in the Third International Study on Mechanical Ventilation (2010) at the end of this article for 2010 and the online supplement for 2004 and 1998) from eligible ICUs (see Table E1 in the online supplement). Only the investigator and research coordinators at each site were aware of the exact purpose and timing of the study to minimize practice changes in response to observation. The research ethics board of each participating institution approved the protocol and waived the need for informed consent.
We collected baseline characteristics, and daily ventilator, gas exchange, clinical management, and complications data while patients were ventilated or until Day 28. Patients were followed in hospital for mortality and length-of-stay outcomes.
For this analysis, we combined these 2010 data with those from our studies in 1998 and 2004 (13, 14). Detailed descriptions of the variables collected in each study, along with their definitions, are shown in Tables E2 and E3. One notable variable not collected in 1998 was height; we therefore express tidal volume as ml/kg actual body weight for comparisons across all three studies.
Data are expressed as mean (±SD), median (interquartile range), and absolute and relative frequencies, as appropriate. ANOVA or Kruskal-Wallis tests were used to compare continuous variables, and Chi-square tests were used for categorical variables. We rejected the null hypothesis of no difference among cohorts at a nominal significance level of 0.05. These analyses were performed using SPSS 17.0 (SPSS Inc., Chicago, IL).
To estimate the effect of the year of study on ICU mortality, we used generalized estimating equation models with a binomial distribution and logit link function to measure the impact of time (by cohort year), accounting for the effects related to the clustering of patients receiving care from the same ICU (15). For the purpose of the analysis, the overall population of patients from the three studies (n = 18,302) was randomly divided into two sets: modeling group (n = 13,644) and validation group (n = 4,658). A first generalized estimating equation estimative model was derived entering the following variables: year of study (reference year, 1998), geographical area (Europe, USA–Canada, Latin American, Africa, Asia, and Oceania), age, sex, ICU characteristics (type of unit [medical, surgical, medical–surgical, neurological, other] and size of the unit [fewer than 10 beds, 10–20 beds, more than 20 beds]), severity at ICU admission (Simplified Acute Physiology Score II), and reason for mechanical ventilation. We built on this model by entering daily variables related to management over the course of ventilation: type of ventilation (invasive or noninvasive), inspired fraction of oxygen, positive end-expiratory pressure (PEEP), tidal volume (ml/kg actual body weight), prone position (yes/no), minute ventilation, use of continuous intravenous sedatives (yes/no), and use of neuromuscular blockers (yes/no). These two models were then evaluated for consistency of effects in the validation set. As a sensitivity analysis, we ran these models in the cohort of patients included from ICUs that participated in all three studies. These analyses were performed using Stata Software 11.0 (StataCorp LP, College Station, Texas).
The characteristics of the 927 participating ICUs and 18,302 patients across the studies are shown in Table 1. These include 2,913 patients from 55 ICUs that participated in all three studies. Further details regarding the ICU distribution by country across studies are shown in Table E4.
| Cohort 1998 | Cohort 2004 | Cohort 2010 | P Value* | |
|---|---|---|---|---|
| Participating units, n | 361 | 349 | 494 | |
| Medical, % | 19 | 16 | 17 | <0.001 |
| Medical–Surgical, % | 77 | 68 | 73 | |
| Surgical, % | 4 | 13.5 | 5 | |
| Neurological, % | — | 2 | 1.5 | |
| Other, % | — | 0.4 | 3 | |
| Number of beds, median (IQR) | 10 (8, 14) | 10 (8, 15) | 12 (9, 19) | <0.001 |
| Proportion of mechanically ventilated patients, % | 33% | 25% | 35% | <0.001 |
| Patients included, n | 5,183 | 4,968 | 8,151 | |
| Geographical area, n (%) | ||||
| Europe | 2,387 (46) | 2,133 (43) | 3,407 (42) | <0.001 |
| USA/Canada | 1,455 (28) | 1,341 (27) | 929 (11) | |
| Latin America | 1,222 (24) | 1,306 (26) | 1,692 (21) | |
| Africa | 119 (2) | 110 (2) | 167 (2) | |
| Asia | 0 | 78 (2) | 1,242 (15) | |
| Oceania | 0 | 0 | 714 (9) | |
| Age, mean (SD), yr | 59 (17) | 59 (17) | 61 (17) | <0.001 |
| Female sex, n (%) | 1,985 (39) | 1,967 (40) | 3,105 (38) | 0.23 |
| Weight, mean (SD), kg | 72 (17) | 76 (20) | 75 (20) | <0.001 |
| Body mass index, mean (SD), kg/m2 | n.d. | 27 (7) | 27 (6.5) | 0.122 |
| Simplified Acute Physiology Score II on admission, mean (SD), points | 44 (17) | 42 (18) | 45 (18) | <0.001 |
| Previous tracheotomy, n (%) | 102 (2) | 123 (2) | 180 (2) | 0.22 |
| Noninvasive ventilation at home, n (%) | 73 (1) | n.d. | 213 (3) | <0.001 |
| Bilevel positive airway pressure, n (%) | 38 (52) | 81 (38) | ||
| Continuous positive airway pressure, n (%) | 35 (48) | 132 (62%) | ||
| Main reason for mechanical ventilation, n (%)† | ||||
| Chronic obstructive pulmonary disease | 522 (10) | 267 (5) | 524 (6) | <0.001 |
| Asthma | 79 (2) | 63 (1) | 98 (1) | 0.26 |
| Other chronic pulmonary disease | 60 (1) | 85 (2) | 142 (2) | 0.019 |
| Neurologic disease | 864 (17) | 938 (19) | 1,574 (19) | <0.001 |
| Metabolic, n (% of neurologic) | n.d. | 129 (14) | 265 (17) | |
| Overdose/intoxication, n (% of neurologic) | n.d. | 148 (16) | 211 (13) | |
| Hemorrhagic stroke, n (% of neurologic) | n.d. | 310 (33) | 470 (30) | |
| Ischemic stroke, n (% of neurologic) | n.d. | 119 (13) | 214 (13.5) | |
| Brain trauma, n (% of neurologic) | n.d. | 228 (24) | 302 (19) | |
| Other cause, n (% of neurologic) | n.d. | 4 (0.4) | 112 (7) | |
| Neuromuscular disease | 94 (2) | 58 (1) | 74 (1) | <0.001 |
| Acute respiratory failure | ||||
| Postoperative | 1,080 (21) | 1,053 (21) | 1,750 (21) | 0.68 |
| Pneumonia | 721 (14) | 528 (11) | 819 (10) | <0.001 |
| Community acquired, n (% of pneumonia) | n.d. | 376 (71) | 539 (66) | |
| Hospital acquired, n (% of pneumonia) | n.d. | 152 (29) | 280 (34) | |
| Sepsis | 458 (9) | 449 (9) | 726 (9) | 0.93 |
| Acute respiratory distress syndrome | 231 (5) | 148 (3) | 281 (3) | <0.001 |
| Congestive heart failure | 539 (10) | 285 (6) | 617 (8) | <0.001 |
| Cardiac arrest | 100 (2) | 239 (5) | 473 (6) | <0.001 |
| Trauma | 407 (8) | 284 (6) | 367 (4.5) | <0.001 |
| Aspiration | 129 (3) | 139 (3) | 200 (2.5) | 0.44 |
| Other cause of acute respiratory failure | 367 (7) | 432 (9) | 506 (6) | <0.001 |
Variables related to management in the ICU are shown in Table 2. The use of noninvasive positive-pressure ventilation increased significantly over the 12-year period: 5% in 1998, 10% in 2004, and 14% in 2010 (P < 0.001). Meanwhile, the median duration of noninvasive positive-pressure ventilation decreased over time (3 d [interquartile range, 2–6] in 1998 versus 2 d [interquartile range, 2–4] in 2004 and 2 d [interquartile range, 1–3] in 2010; P < 0.001). The need for intubation among these patients was not higher in 2010: 32% in 1998, 40% in 2004, and 29% in 2010 (P < 0.001).
| Cohort 1998 (n = 5,183) | Cohort 2004 (n = 4,968) | Cohort 2010 (n = 8,151) | P Value* | |
|---|---|---|---|---|
| Noninvasive positive-pressure ventilation before admission in the ICU, n (%) | n.d. | n.d. | 429 (5) | — |
| Noninvasive positive-pressure ventilation at admission in the ICU, n (%) | 256 (5) | 479 (10) | 1,169 (14) | <0.001 |
| Mode of ventilation, days of use per 1,000 d of invasive mechanical ventilation (excluding days during weaning from mechanical ventilation process) | ||||
| Assist-control | 627 | 412 | 330 | <0.001 |
| SIMV | 66 | 21 | 34 | <0.001 |
| SIMV-PS | 132 | 132 | 94 | <0.001 |
| Pressure support | 65 | 125 | 237 | <0.001 |
| PCV | 75 | 125 | 130 | <0.001 |
| APRV/BIPAP | n.d. | 66 | 91 | <0.001 |
| PRVC | n.d. | 98 | 61 | <0.001 |
| Other mode | 35 | 21 | 23 | <0.001 |
| Ventilator settings over the course of invasive ventilation | ||||
| Tidal volume, mean (SD) | ||||
| ml/kg actual body weight | 8.8 (2.1) | 7.6 (2.1) | 6.9 (1.9) | <0.001 |
| ml/kg predicted body weight | n.d. | 9.3 (2.3) | 8.2 (2.0) | <0.001 |
| Positive end-expiratory pressure, cm H2O, mean (SD) | 4.2 (3.8) | 5.4 (4.6) | 7.0 (3.0) | <0.001 |
| Total respiratory rate, breaths per minute, mean (SD) | 18 (11) | 18 (6) | 19 (6) | <0.001 |
| Sedation, n (%) | 3,164 (61) | 3,486 (70) | 5,755 (71) | <0.001 |
| Analgesia, n (%) | 2,241 (43) | n.d. | 5,043 (62) | <0.001 |
| Neuromuscular blocking, n (%) | 686 (13) | 524 (10.5) | 890 (11) | <0.001 |
| Liberation from mechanical ventilation | ||||
| Met criteria, n/eligible patients (%)† | 3,640/5,008 (73) | 3,005/4,682 (64) | 5,111/7,323 (70) | <0.001 |
| Scheduled extubation, n/patients met criteria (%) | 2,858/3,640 (78.5) | 2,714/3,005 (90) | 4,151/5,111 (81) | <0.001 |
| Unplanned extubation, n/patients at risk (%)‡ | 179/4,906 (4) | 135/4,559 (3) | 654/7,143 (9) | <0.001 |
| Noninvasive positive-pressure ventilation after extubation, n/eligible patients (%)§ | n.d. | 308/2,849 (11) | 473/4,805 (10) | 0.17 |
| Reintubation, n/ patients at risk (%)|| | 424/3,037 (14) | 319/2,849 (11) | 643/4,805 (13) | 0.005 |
| After scheduled extubation | 350/2,858 (12) | 278/2,714 (10) | 511/4,151 (12) | 0.001 |
| After unplanned extubation | 74/179 (41) | 41/135 (30) | 132/654 (20) | <0.001 |
| Tracheotomy, n/patients at risk (%)¶ | 546/4,906 (11) | 664/4,559 (15) | 993/7,143 (14) | <0.001 |
| Percutaneous, n (%) | n.d. | 362 (54.5) | 526 (53) | 0.53 |
During invasive ventilation, volume-cycled assist-control ventilation remained the most common ventilator mode, but its use has decreased over time in favor of other modes, particularly pressure support (Table 2; see also Figure E1). Among all patients, we observed a significant decrease in tidal volume and an increase in PEEP (P < 0.001) (Table 2).
In the subgroup of patients with ARDS, tidal volume (expressed as ml/kg actual body weight) was also significantly (P < 0.001) reduced over time (Figure 1). The proportion of patients receiving a ventilation strategy with pressure/volume limitation (arbitrarily defined as tidal volume below 6 ml/kg actual body weight; or tidal volume below 8 ml/kg actual body weight and plateau or peak inspiratory pressure less than 30 cm H2O [13]) increased significantly over time: 29% in 1998, 57% in 2004, and 67.5% in 2010 (P < 0.001). In addition, PEEP levels increased significantly (P < 0.001; Figure 2). The use of adjunctive therapies, such as prone positioning, was infrequent, and remained stable: 9% in 1998, 5% in 2004, and 7% in 2010 (P = 0.07).
Figure 1. Evolution of the set tidal volume (ml/kg actual body weight) in patients with criteria of acute respiratory distress syndrome (ARDS). Left: mean (±SD); P < 0.001 for all comparisons with ANOVA test. Right: proportion of the time of mechanical ventilation in each category of tidal volume; P < 0.001 for all comparisons with chi-square test.
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Figure 2. Evolution of the applied positive end-expiratory pressure (PEEP; cm H2O) in patients with criteria of acute respiratory distress syndrome (ARDS). Left: mean (±SD); P < 0.001 for comparisons, with ANOVA, between 1998 versus 2004 and 1998 versus 2010; P = 0.05 for comparison, with ANOVA, between 2004 and 2010. Right: proportion of the time of mechanical ventilation ventilated in each category of PEEP. P < 0.001 for all comparisons with chi-square test. ZEEP = zero positive end-expiratory pressure.
[More] [Minimize]A process of weaning or liberation from mechanical ventilation began in 73% of patients in 1998, 64% in 2004, and 70% in 2010 (Table 2). The proportion of patients who successfully completed their first attempt of liberation from mechanical ventilation increased over time (49% in 1998, 55% in 2004, and 63.5% in 2010; P < 0.001). Among patients who failed their first attempt at weaning, there was a significant increase in the subsequent use of pressure support as the weaning mode, with a concomitant significant reduction in the use of synchronized intermittent mandatory ventilation with or without pressure support (Table E5). The duration of weaning in these patients, although statistically different (P < 0.001), was not clinically different among the three time periods (median, 3 [interquartile range, 2–5] d in 1998, 3 [interquartile range, 2–4] d in 2004, and 3 [interquartile range, 2–5] d in 2010).
The rate of reintubation after scheduled extubation remained similar over time, at around 12% (Table 2). This occurred most commonly within the first 12 hours after extubation (63% of reintubations in 1998, 57% in 2004, and 52% in 2010; P = 0.01).
More tracheotomies were performed in 2004 (15%) and 2010 (14%) than in 1998 (11%) (P < 0.001). Median time to tracheotomy from intubation, however, remained stable (12 [interquartile range, 7–17] d in 1998, 9 [interquartile range, 6–14] d in 2004, and 11 [interquartile range, 6–16] d in 2010 (P = 0.73).
A comparison of patient outcomes across the studies is shown in Table 3. Half of the patients included had at least one complication over the course of mechanical ventilation (50% in 1998, 48% in 2004, and 54% in 2010; P < 0.001). We note higher rates of sepsis and cardiovascular failure in 2010, and a reduction over time in ventilator-associated pneumonia. We observed significant differences in the duration of ventilatory support, ICU, and hospital length of stay.
| Cohort 1998 | Cohort 2004 | Cohort 2010 | ||
|---|---|---|---|---|
| (n = 5,183) | (n = 4,968) | (n = 8,151) | P Value* | |
| Events emerging over the course of mechanical ventilation | ||||
| Acute respiratory distress syndrome, n (%) | 218 (4) | 279 (6) | 495 (6) | <0.001 |
| Acquired ICU pneumonia, n (%) | 438 (8.5) | 265 (5) | 359 (4) | <0.001 |
| Sepsis, n (%) | 457 (9) | 400 (8) | 1,473 (18) | <0.001 |
| Barotrauma, n (%) | 154 (3) | 157 (3) | 140 (2) | <0.001 |
| Cardiovascular failure, n (%) | 1,145 (22) | 1,193 (24) | 3,145 (39) | <0.001 |
| Renal failure, n (%) | 971 (19) | 948 (19) | 1,775 (22) | <0.001 |
| Hepatic failure, n (%) | 326 (6) | 691 (14) | 555 (7) | <0.001 |
| Hematological failure, n (%) | 552 (11) | 795 (16) | 662 (8) | <0.001 |
| Outcomes | ||||
| Duration of ventilatory support†, median (IQR), days | 4 (2, 8) | 6 (3, 11) | 5 (3, 10) | <0.001 |
| Length of stay in the ICU, median (IQR), days | 7 (4, 14) | 8 (4, 15) | 7 (4, 14) | <0.001 |
| Length of stay in the hospital‡, median (IQR) days | 16 (9,29) | 17 (9,31) | 17 (9,31) | 0.002 |
| Mortality, n (% [95% confidence interval]) | ||||
| In the ICU | 1,590 (31 [29–32]) | 1,533 (31 [29–32]) | 2,269 (28 [27–29]) | <0.001 |
| At Day 28 after admission in the ICU | 1,719 (33 [32–34]) | 1,605 (32 [31–34]) | 2,445 (30 [29–31]) | <0.001 |
| In the hospital‡ | 1,876 (40 [38–41]) | 1,759 (37 [36–38]) | 2,733 (35 [34–36]) | <0.001 |
There was a decline in the crude ICU mortality, from 31% in 1998 to 28% in 2010 (odds ratio, 0.87; 95% confidence interval, 0.80–0.94; P < 0.001).
After adjustment for baseline variables, mortality in 2010 remained lower than in 1998 (odds ratio, 0.74; 95% confidence interval, 0.66–0.84; Table 4). This result was similar after management variables were added to the model (odds ratio, 0.78; 95% confidence interval, 0.67–0.92). These results were quantitatively similar in the validation group (final model odds ratio, 0.86; 95% confidence interval, 0.67–1.09; Table 4).
| Study Year | Modeling Group (n = 13,644) | Validation Group (n = 4,658) |
|---|---|---|
| Crude odds ratio | ||
| 1998 | 1 | 1 |
| 2004 | 1.01 (0.90–1.13) | 1.00 (0.82–1.20) |
| 2010 | 0.83 (0.75–0.93) | 0.90 (0.75–1.07) |
| After adjustment for ICU and baseline variables | ||
| 1998 | 1 | 1 |
| 2004 | 1.01 (0.89–1.15) | 1.05 (0.90–1.24) |
| 2010 | 0.74 (0.66–0.84) | 0.78 (0.67–0.92) |
| After adjustment for ICU and baseline variables and for daily management variables | ||
| 1998 | 1 | 1 |
| 2004 | 1.05 (0.90–1.24) | 1.06 (0.83–1.34) |
| 2010 | 0.78 (0.67–0.92) | 0.86 (0.67–1.09) |
The observed mortality in the 2,913 patients from ICUs that participated in all three studies showed a similar trend: 34% in 1998, 34% in 2004, and 27% in 2010 (P = 0.002). Sensitivity analysis of the final model showed robust results in this subgroup, with a final adjusted odds ratio for 2010 ICU mortality of 0.58 (95% confidence interval, 0.45–0.75) relative to 1998.
Our analysis of these international multicenter studies suggests that, in mechanically ventilated patients, short-term mortality has decreased over time. Although many factors may have contributed to these results, several factors related to mechanical ventilation management may have contributed, including reducing the need for invasive mechanical ventilation, and improving both mechanical ventilation safety and the process of liberation from mechanical ventilation. This study confirms our previous work showing that changes in mechanical ventilation practices continue to follow findings of positive clinical trials, and shows, for the first time, a significant association with reduced mortality.
We have observed a significant change of mortality over time after adjustment for case mix and for variables related to ventilatory settings. Despite a similar proportion of patients with complications related to mechanical ventilation and organ dysfunctions, the intensive care mortality in 2010 was lower than in previous studies. The most likely explanation is that the overall management of mechanically ventilated patients has improved over the last 12 years. The implementation of different integrated management strategies for precipitating conditions, such as sepsis (16), protocols related to ventilator management, including sedation (10, 17, 18), and incorporating bundles of care to prevent nosocomial infections (19, 20) could all possibly contribute to these findings.
Throughout our studies, we observed a significant decrease in delivered tidal volume, both in the general mechanically ventilated population and particularly among those with ARDS. This lung-protective strategy has been evaluated in several randomized clinical trials (1, 2, 21–23), the largest of which showed reduced mortality when tidal volume and plateau pressure were controlled in patients with acute lung injury (2). These data suggest that routine implementation of a pressure–volume limited ventilation strategy in clinical practice could reduce mortality in these patients. In a recent observational ARDS study (24), adherence to lung-protective ventilation was associated with a 3% decrease in the mortality risk at 2 years (hazard ratio, 0.97; 95% confidence interval, 0.95–0.99; P = 0.002). These results, like ours, suggest that these clinical trial results are robust even applied to a less selective population, as in usual clinical practice. There are also suggestions that lung-protective strategies may be important in patients who do not yet have ARDS (25–28). The fact that the odds ratio for mortality moved closer to 1 in all datasets after accounting for management variables, including tidal volume, is in keeping with the hypothesis that lung-protective ventilation is a key intervention across a broad range of mechanically ventilated patients, not just those with ARDS.
PEEP is another essential component of the ventilatory strategy in patients with ARDS. From the first report of this syndrome (29), it has been observed that PEEP can improve oxygenation by keeping recruited alveoli open and decreasing intrapulmonary shunt (30). In addition, PEEP-induced lung recruitment can decrease alveolar overdistention, because the volume of each subsequent tidal breath is shared by more open alveoli. PEEP may also decrease repetitive alveolar opening and closing during the respiratory cycle, thereby preventing lung injury (31). Observational studies have reported an independent association between zero PEEP and mortality (32) in a heterogeneous cohort of patients who were mechanically ventilated and between low values of PEEP and mortality in patients with ARDS (33). An individual patient data meta-analysis (3, 4) from randomized trials (1, 34–38) comparing higher versus lower PEEP levels while controlling tidal volume in patients with acute lung injury overall showed no statistically significant difference in hospital mortality (random effects model relative risk, 0.85; 95% confidence interval, 0.71–1.01). However, in patients with moderate to severe ARDS (39), higher levels of PEEP were associated with a significant 4% absolute mortality reduction (40). In our analysis, we observed a marked reduction in the use of zero end-expiratory pressure and a significant increase in the use of higher PEEP, especially in patients with ARDS. Nevertheless, the mean PEEP level used in the first week of ventilatory support in 2010 (9.3 ± 3.3 cm H2O) was still lower than that set in the higher PEEP groups of some randomized clinical trials.
The use of noninvasive positive-pressure ventilation at ICU admission has almost doubled every 6 years. This finding is similar to that reported by Chandra and colleagues (41), who observed a 46% increase in noninvasive positive-pressure ventilation use and a 42% decline in invasive mechanical ventilation use between 1998 and 2008 in patients with exacerbations of chronic obstructive pulmonary disease. Encouragingly, despite this increased use, the proportion of patients intubated after failing a trial of noninvasive positive-pressure ventilation has remained stable over time. An important observation is that patients who required invasive ventilation after noninvasive positive-pressure ventilation had higher mortality than patients who were directly intubated. This finding was described previously by our group (13, 14, 42) and others (43), and has several possible explanations. First, failure of noninvasive positive-pressure ventilation could identify patients who are difficult to ventilate or who have a higher severity of illness. In our study, patients who failed noninvasive positive-pressure ventilation had significantly higher Simplified Acute Physiology Score II scores (mean = 42) than successful patients (mean = 37), but they had lower scores than patients invasively ventilated from the beginning (mean = 45). Another explanation is that failing noninvasive ventilation is, in itself, harmful, and that delayed recognition of failure may exacerbate this harm (41).
Our study has several limitations. This is an analysis of prospectively collected clinical data from a wide variety of ICUs, patient conditions, and clinical practices, some of which are related to outcome (43). We have performed an analysis accounting for clustering by the ICUs, and we have included ICU type and size in the model to try to minimize the possible bias related to those variables. Although we used multivariable modeling, unmeasured confounders may remain, which could have impacted our results. We constructed an estimative model to evaluate the decreasing ICU mortality in the last 12 years, and we have outlined plausible explanations for this. This model has been validated and adjusted, and the results appear consistent. However, it is not possible to make a causal inference model from our observational data. In addition, we have no information about withdrawal and/or withholding of life support and its possible impact on our results. Another limitation is that we did not have all the same ICUs participating in all three studies. To some extent, this was unavoidable due to closure of some previously participating hospitals, changes in resources available for data collection at participating centers, and our goal to expand the generalizability of results by including ICUs from more countries.
In conclusion, our analysis shows that the implementation of mechanical ventilation has significantly changed in the last decade; we speculate that these changes have resulted in the significant decrease in short-term mortality.
Investigators in the Third International Study on Mechanical Ventilation (2010):
Argentina: Coordinators: Fernando Ríos (Hospital Nacional Alejandro Posadas), Damian Violi (Hospital Hospital Interzonal General de Agudo Profesor Dr .Luis Guemes, Haedo). Marisol Rodríguez-Goñi, Roger Lamoglie and Fernando Villarejo (Hospital Nacional Profesor A. Posadas, Buenos Aires); Norberto Tiribelli and Santiago Ilutovich (Sanatorio de la Trinidad, General Mitre); Matías Brizuela and Mariana Monllau (Hospital Tránsito Cáceres de Allende, Córdoba); Fernando Saldarini and Silvina Borello (Hospital General de Agudos donación Francisco Santojanni, Buenos Aires); Alberto Marino and Norberto Tiribelli (Hospital Churruca-Visca, Buenos Aires); Mauricio Vinzio and Karina Bonasegla (Sanatorio de la Trinidad, San Isidro); Julián Hernández and María Belén Yapur (Sanatorio Nuestra Señora del Rosario, Jujuy); María Eugenia González (Hospital Privado de Comunidad, Mar del Plata); Sebastián E. Mare (Sanatorio Dr. Julio Méndez, Buenos Aires); Judith Sagardía and Marco Bezzi (Hospital General de Agudos P. Piñeiro, Buenos Aires); Cecilia Pereyra and Julian Strati (Hospital Interzonal General de Agudo Profesor Dr. Luis Guemes, Haedo); Daniel Vargas and Claudia Diaz (Hospital Pablo Soria, Jujuy); Pablo Gómez and Marcelo Palavecino (Sanatorio Juncal, Temperley); Graciela Elizabeth and Aguilera García, M. Eugenia (Hospital de San Luis); Luis Pablo Cardonnet and Lisandro Betttini (Hospital Provincial del Centenario, Rosario); Hernán Nuñez and Lucas Vallejo (Hospital General de Agudos Juan A. Fernández, Buenos Aires); Fernando Fernández and Jorge Arroyo (Hospital Central, Mendoza); Daniel Duarte and Gerardo Filippa (Hospital Regional Río Grande, Tierra del Fuego); Cayetano Galetti and Hernan Nunia (Sanatorio Allende, Córdoba); Fernando Lambert and Elisa Estenssoro (Hospital Interzonal de Agudos San Martin, La Plata); Marina Busico and Fernando Villarejo (Clínica Olivos, Vicente López); Javier Horacio Álvarez (Hospital Universitario Austral, Pilar); Alejandro Raimondi and Gustavo Badariotti (Sanatorio Mater Dei, Buenos Aires); Martín Lugaro (Sanatorio Las Lomas, San Isidro); Fernando Lipovestky (Clínica Santa Isabel; Buenos Aires); Alan Javier Zazu and Hugo Capponcelli (Clínica Privada de Especialidades de Villa María); Patricia Vogl and Cristina Orlandi (Hospital Zonal Francisco López Lima, General Roca); Alejandro Gómez and Gustavo Jannello (Sanatorio de los Arcos; Buenos Aires); Alejandro Risso (Sanatorio Otamendi y Miroli, Buenos Aires); Leticia Rapetti and Guillermo Chiappero (Hospital Universitario, Universidad Abierta Interamericana, Buenos Aires); Juan Domingo Fernández (Hospital Regional de Comodoro Rivadavia, Chubut); Rodrigo E. Gómez-Paz (Hospital Español, Buenos Aires); Marcos Juan Zec and Pascual Valdez (Hospital General de Agudos Dalmacio Vélez Sársfield, Buenos Aires); Jorgelina Guyon and Ariel Chena (Hospital Lagomaggiore, Mendoza); Sergio Lasdica (Hospital Municipal Coronel Suárez, Buenos Aires); Martin Deheza and Schimdt Alejandra (Hospital General de Agudos Bernardino Rivadavia, Buenos Aires); Francisco Criado (Hospital Naval Puerto Belgrano, Bahía Blanca); Norma Beatriz Márquez (Policlínico Atlántico del Sur, Ríos Gallegos); Pablo Desmery and José Luis Scapellato (Sanatorio Anchorena, Buenos Aires); Gonzalo Javier Ríos and Cristian Casabella (Clínica Bazterrica, Buenos Aires)
Australia: Coordinators: Jasmin Board and Andrew R. Davies (Alfred Hospital, Melbourne). Andrew Bersten, Elisha Matheson, and Amy Waters (Flinders Medical Center, Adelaide); John Santamaria and Jennifer Holmes (St. Vincent’s Hospital, Melbourne); Cartan Costello, Manoj K Saxena, and John Myburgh (St. George Hospital, Sydney); Ellen Kinkel and Forbes McGain (The Western Hospital, Melbourne); Claire Cattigan and Allison Bone (Barwon Health, Geelong Hospital, Geelong); Ian Seppelt, Leonie Weisbrodt and Cheryl Cuzner (Nepean Hospital, Sydney); Christopher MacIsaac, Deborah Barge and Tania Caf (Royal Melbourne Hospital, Melbourne); Cameron Knott and Graeme Duke (The Northern Hospital, Melbourne); Imogen Mitchell, Helen Rodgers, Rachel Whyte, and Elisha Fulton (Canberra Hospital, Canberra); Jasmin Board, Andrew Davies, and Alistair Nichol (Alfred Hospital, Melbourne); Hergen Buscher, Priya Nair, and Claire Reynolds (St. Vincent’s Hospital, Sydney); Simon J. G. Hockley, Ian Moore, and Katherine Davidson (Calvary Wakefield Hospital, Adelaide); David Milliss, Raju Pusapati, and Helen Wong (Concord Hospital, Sydney); Jason Fletcher and Julie Smith (Bendigo Hospital, Bendigo); Paul Goldrick, Dianne Stephens, and Jane Thomas (Royal Darwin Hospital, Darwin); Anders Aneman, Sutrisno Gunawan, and Tom Cowlam (Liverpool Hospital, Liverpool); George Lukas and Rick McAllister (Royal Hobart Hospital, Hobart); Minka Springham, Joanne Sutton, and Jeff Presneill (Mater Health Services, Brisbane); Tony Sutherland and Dianne Hill (Ballarat Health Services, Ballarat); Howard Connor, Jenny Dennett, and Tim Coles (Central Gippsland Hospital, Sale).
Bolivia: Coordinator: Freddy Sandy (Hospital Obrero No. 1, La Paz). Sandro Chavarria and Marcelo Choque (Hospital Obrero No. 1, La Paz); Ronald Pairumani and Juan Guerra (Instituto Gastroenterológico boliviano japonés, Santa Cruz).
Brazil: Coordinator: Marco Antônio Soares Reis (Hospital Universitário São José, Belo Horizonte). José Carlos Versiani (Hospital Madre Teresa, Belo Horizonte); Eduardo Fonseca Sad (Hospital Luxemburgo, Belo Horizonte); Maria Aparecida Braga (Hospital Dia e Maternidade Unimed-BH, Belo Horizonte); Dinalva Aparecida Gomes (Hospital Vera Cruz, Belo Horizonte); Fernando Antônio Botoni (Hospital de Pronto Socorro Risoleta Tolentino Neves, Belo Horizonte); Maurício Meireles Góes (Hospital da Baleia, Belo Horizonte); Frederico Costa Val Barros (Hospital da Polícia Militar, Belo Horizonte); Rogério de Castro Pereira (Hospital Felício Rocho, Belo Horizonte); Hugo Urbano (Hospital Vila da Serra, Belo Horizonte); Valéria de Carvalho Magela (Hospital Santa Rita, Contagem); Aline Camile Yehia (Hospital Júlia Kubitschek, Belo Horizonte); Bruno Bonaccorsi Fernandino (Hospital São Francisco-Setimig, Belo Horizonte); Marco Antônio Ribeiro Leão (Hospital São João de Deus, Divinópolis); Rovílson Lara (Hospital Arnaldo Gavazza Filho, Ponte Nova); Rovílson Lara (Hospital São João Batista, Viçosa); Rubens Altair Amaral de Pádua (Hospital Vaz Monteiro, Lavras); Janine Dias Alves (Santa Casa de Misericórdia de Ouro Preto, Ouro Preto); Aloísio Marques do Nascimento (Hospital Nossa Senhora das Graças, Sete Lagoas); Bruno do Valle Pinheiro (Hospital Universitário da Universidade Federal de Juiz de Fora, Juiz de Fora); Carlos Alberto Studart Gomes (Hospital de Messejana, Fortaleza); Marcelo Alcântara Holanda (Hospital Universitário Walter Cantídio, Fortaleza); Frederico Rodrigues Anselmo (Hospital Nossa Senhora Aparecida, Belo Horizonte).
Canada: Coordinator: Niall D. Ferguson (Mount Sinai Hospital and University Health Network, Toronto). Neill Adhikari, Damon Scales, Robert Fowler, Cheromi Sittambalam, Mehar-Un-Nisa Raja, and Nicole Marinoff (Sunnybrook Health Science Centre, Toronto); Lauralyn McIntryre, Shawna Reddie, Laura Jones, and Irene Watpool (Ottawa Hospital, Ottawa); Jeffrey Singh and Madison Dennis (Toronto Western Hospital, Toronto); Andrew Steel, Andrea Matte, Marc Lipkus, Ryan Albert, and Emily Stern (Toronto General Hospital, Toronto); Michael Miletin, Antonio Raso, and Robyn Klages (William Osler Health Science Centre, Brampton); Jan Friedrich, Orla Smith and Laura Wilson (St. Michael’s Hospital, Toronto); Deborah Cook and Mark Bailey (St. Joseph’s Hospital, Hamilton); Sangeeta Mehta, Stephen Lapinsky, Hannah Mathers, Cheryl Ethier, Stephanie Lubchansky, and Samer Haj-Bakri (Mount Sinai Hospital, Toronto); Dietrich Henzler and Lisa Julien (Queen Elizabeth II Health Sciences Centre, Halifax).
Chile: Coordinator: Luis Soto-Román (Instituto Nacional del Tórax, Santiago). Juan Carlos Maurelia (Hospital de Copiapo, Copiapo); César Antonio Maquilon (Instituto Nacional del Tórax, Santiago); Luis Soto-Germani (Hospital de Coquimbo, Coquimbo).
China: Coordinator: Bin Du (Peking Union Medical College Hospital, Beijing). Yan Kang and Bo Wang (West China Hospital, Chengdu); Fachun Zhou and Fang Xu (Chongqing Medical University 1st Hospital, Chongqing); Haibo Qiu and Yi Yang (Southeast University Zhongda Hospital, Nanjing); Qingyuan Zhan and Bing Sun (Beijing Chaoyang Hospital, Beijing); Zhenjie Hu and Bin Yu (Hebei Medical University 4th Hospital, Shijiazhuang); Xi Zhu and Yu Bai (Peking University 3rd Hospital, Beijing); Gang Li and Yi Li (Sino-Japanese Friendship Hospital, Beijing); Geng Zhang and Jianbiao Meng (Zhejiang Tongde Hospital, Hangzhou); Xiaobo Huang and Hong Pu (Sichuan Provincial Hospital, Chengdu); Bin Du and Daxing Yu (Peking Union Medical College Hospital, Beijing); Chuanyun Qian and Wei Zhang (Kunming Medical College 1st Hospital, Kunming); Yongjie Yin and Debiao Song (Jilin University 2nd Hospital, Changchun); Yunxuan Yue and Zhengxuan Lv (Kunming City 3rd People’s Hospital, Kunming); Chengmin Yu and Qunmei Yao (Yunnan Chuxiong People’s Hospital; Chuxiong); Xue Wang (Xi’an Jiaotong University 1st Hospital, Xi’an); Yuan Xu and Wei He (Beijing Tongren Hospital, Beijing); Mian Chen and Zhihua Hu (Hainan Medical College Hospital, Haikou); Dongpo Jiang and Jian Huang (Daping Hospital, Chongqing); Wei Yu (Yantai Yuhuangding Hospital, Yantai); Juanxian Gu (Zhejiang Haining People’s Hospital, Naining); Yangong Chao (Beijing Huaxin Hospital, Beijing); Zhixiang Li (Fengrun District People’s Hospital, Tangshan); Zhicheng Zhang (PLA Navy General Hospital, Beijing); Wanxia Li (Nanchang University 2nd Hospital, Nanchang); Zhenyang He (Hainan Provincial People’s Hospital, Haikou); Jianguo Li and Chang Liu (Wuhan University Zhongnan Hospital, Wuhan); Tiehe Qin and Shouhong Wang (Guangdong General Hospital, Guangzhou); Feng Li (Nantong 1st People’s Hospital, Nantong); Jun Jin and Jianhong Fu (Suzhou University 1st Hospital, Suzhou); Hongyang Xu (Wuxi Municipal People’s Hospital, Wuxi); Hongyuan Lin and Jianying Guo (PLA 304 Hospital, Beijing); Yalin Liu and Jinghua Wang (Beijing Hospital, Beijing); Maoqin Li and Jiaqiong Li (Xuzhou Central Hospital, Xuzhou); Lei Chen (Sun Yet-Sen University 6th Hospital, Guangzhou); Qing Song and Liang Pan (PLA General Hospital, Beijing); Xianyao Wan and Jiuzhi Zhang (Dalian Medical University 1st Hospital, Dalian); Weihai Yao and Yuhong Guo (Beijing TCM Hospital, Beijing); Pang Wing Yan (Prince Margaret Hospital, Hong Kong); Kelly Choy (Queen Elizabeth Hospital, Hong Kong); Kwan Ming Chit (Pamela Youde Nethersole Eastern Hospital, Hong Kong); Patricia Leung (Prince of Wales Hospital, Hong Kong); Chau Chin Man (North District Hospital, Hong Kong).
Colombia: Coordinator: Marco González (Clínica Medellín and Universidad Pontificia Bolivariana, Medellín). Ricardo Buitrago (Clínica Shaio, Bogotá); Marcela Granados (Clínica Fundación Valle Lili, Cali); Guillermo Ortiz (Hospital Santa Clara, Bogotá); Cesar Enciso (Grupo Cimca Hospital San José, Bogotá); Mario Gómez (Grupo Cimca Hospital San José and Clínica Fundadores, Bogotá); Bladimir Alejandro Gil (Clínica Las Américas, Medellín); Juan Pablo Sedano, Luis Fernando Castro (Centro Medico Imbanaco, Cali); Carlos Alberto Acosta (Hospital Federico Lleras Acosta, Ibague); Marco Gonzalez A.(Hospital San Rafael, Itagui); Francisco Molina (Clínica Universitaria Bolivariana, Medellín); Camilo Pizarro (Fundación Cardiovascular Colombiana, Bucaramanga); Mario Villabon (Grupo Cimca Hospital de Suba, Bogota); Carmelo Dueñas (Nuevo Hospital Bocagrande, Cartagena de Indias); Carlos Andrés Díaz (Hospital General de Medellín, Medellín); Nelson Fonseca (Corbic, Medellín); Rubén Camargo (Clínica General del Norte, Barranquilla); Juan David Uribe (Clínica Cardiovascular, Medellín).
Denmark: Coordinator: Hans-Henrik Bülow (Holbak). Simona Beniczky and Jens Brushoj (Naestved); Mikkel Præst and Henrik Guldager (Nykobing Falster); Birgitte Viebaek and Sine Wichman (Roskilde); Anette Mortensen (Holbak); Susanne Andi Iversen (Slagelse); Bo Broberg and Lone M. Poulsen (Koge).
Dominican Republic: Edgard Luna (Hospital Universitario José María Cabral y Báez, Santiago).
Ecuador: Coordinator: Manuel Jibaja (Hospital Eugenio Espejo, Quito). Leonardo Pazmiño, Katty Trelles, and Fabricio Picoita (Hospital Eugenio Espejo, Quito); Gustavo Paredes and Vanesa Ramírez (Hospital Enrique Garcés, Quito); Guillermo Falconí, Cristian Cevallos and Boris Villamagua (Hospital Carlos Andrade Marín, Quito); Marco Escobar and Freddy Sánchez (Hospital de la Policía, Quito); Miguel Llano and Miguel Lazcano (Hospital General de las Fuerzas Armadas, Quito); Ramiro Puetate and José Miguel Guerrero (Hospital Pablo Arturo Suárez, Quito); Mijail Játiva and Myriam Montalvo (Hospital de los Valles, Quito); Franklin Villegas (Hospital Metropolitano, Quito); Luis González Zambrano, Ronnie Mantilla, Gina Quinde, Andrea Gimenez, and Luis Gonzalez Mosquera (Hospital Luis Vernaza, Guayaquil); Henry Caballero and María Fernanda García (Hospital de SOLCA, Quito); Marcelo Ochoa, Soraya Puertas, and Jackeline Coello (Hospital José Carrasco Arteaga, Cuenca); Mario Acosta (Hospital San Vicente de Paul, Ibarra).
Egypt: Medhat Soliman (Cairo University Hospitals, Cairo).
France: Coordinator: Arnaud W. Thille (CHU Henri Mondor, Créteil). Achille Kouatchet and Alain Mercat (CHU d’Angers); Laurent Brochard (CHU Henri Mondor, Créteil); François Collet (Centre Hospitalier De Saint-Malo); Guillaume Marcotte (Hôpital Édouard Herriot, Lyon); Pascal Beuret (Centre Hospitalier De Roanne); Jean-Christophe M. Richard, Gaëtan Bedunaeu, Pierre-Gildas Guitard, Dorothée Carpentier, Benoit Veber, and Fabien Soulis (CHU Charles Nicolle, Rouen); Frédéric Bellec (Centre Hospitalier De Montauban); Philippe Berger (Centre Hospitalier de Châlons en Champagne); Salem Ould Zein, Géraldine Dessertaine (CHU De Grenoble); C. Canevet (Hôpital d’Armentières); Fabien Grelon (Centre Hospitalier Du Mans).
Germany: Coordinator: Konstantinos Raymondos (Medizinische Hochschule Hannover, Hannover). Rolf Dembinski and Rolf Rossaint (Universitaetsklinikum Aachen, Aachen); Steffen Weber-Carstens (Charité Universitaetsklinikum, Berlin); Christian Putensen (Universitaetsklinikum Bonn, Bonn); Maximillian Ragaller (Universitaetsklinikum Carl Gustav Carus, Dresden); Michael Quintel (Universitaetsklinikum der Georg-August-Universitaet, Goettingen); Winfried Schubert (Carl-Thiem-Klinikum Cottbus gGmbH, Cottbus); Thomas Bein and Heinrich Paulus (Klinikum der Universitaet Regensburg); Walter Brandt (Universitaetsklinikum, Magdeburg); Lutz Pfeiffer and Silke Frenzel (Hufeland Klinikum GmbH, Mühlhausen); Thoralf Kerner and P. Kruska (Allgemeines Krankenhaus Harburg, Hamburg); Leila Eckholt and Joachim Hartung (Vivantes Krankenhaus am Urban, Berlin-Kreuzberg); Harald Fritz and Monika Holler (Staedtisches Krankenhaus Martha-Maria Halle-Doelau gGmbH, Halle-Doelau); Johannes Busch and Andreas Viehöfer (Evangelisches Waldkrankenhaus Bad Godesberg gGmbH, Bonn); Jens Buettner (Evangelisches Krankenhaus Elisabethenstift gGmbH, Darmstadt); Jörn Schlechtweg and Achim Lunkeit and Roland Schneider (Klinikum Bad Salzungen GmbH, Bad Salzungen); Maria Wussow, Nils Marquardt, and Christian Frenkel (Staedtisches Klinikum Lueneburg, Lueneburg); Falk Hildebrandt (Dietrich-Bonhoeffer Klinikum Neubrandenburg, Neubrandenburg); Tumbass Volker and Thomas Lipp (Ermstalklinik Bad Urach, Bad Urach); Cezar Mihailescu and Thomas Moellhoff (Katholische Stiftung Marienhospital Aachen, Aachen); Thomas Steinke (Universitaetsklinikum der Martin-Luther-Universitaet Halle-Wittenberg, Halle-Wittenberg); Oliver Franke and Marcus Ruecker (Lungenklinik Heckeshorn, Berlin); Markus Schappacher and Steffen Appel (Ermstalklinik Staedtisches Krankenhaus Sindelfingen, Sindelfingen); Heinz Kerger (Evangelisches Diakoniekrankenhaus, Freiburg); Andreas Schwartz (Bundeswehrkrankenhaus Ulm, Ulm); Jan Dittmann and Jörg Haberkorn (Georgius-Agricola-Klinikum Zeitz, Zeitz); Wolfgang Baier (St. Nikolaus-Stiftshospital GmbH, Andernach); Walter Seyde (Staedtisches Klinikum Wolfenbuettel, Wolfenbuettel).
Greece: Coordinator: Dimitrios Matamis (Papageorgiou Hospital, Thessaloniki). Eleni Antoniadou (Gennimata Hospital, Thessaloniki); Pertsas Evangelos (Agios Pavlos General Hospital, Thessaloniki); Maria Giannakou (Ahepa Hospital, Thessaloniki).
Hungary: Zoltan Szentkereszty (Kenezy Hospital, Debrecen); Zsolt Molnar (University of Szeged, Szeged).
India: Coordinator: Pravin Amin (Bombay Hospital Institute of Medical Sciences, Mumbai). Farhad N. Kapadia (Hinduja Hospital, Mumbai); Nagarajan Ramakrishnan (Apollo Hospitals, Chennai); Deepak Govil (Artemis Health Institute, Gurgaon Haryana); Anitha Shenoy and Goneppanavar Umesh (Kasturba Medical College, Manipal); Samir Sahu, (Kalinga Hospital, Odisha); Sheila Nainan Myatra (Tata Memorial Hospital, Mumbai); Subhash Kumar Todi (AMRI Hospitals Kolkata, West Bengal); Sanjay Dhanuka (CHL Apollo Hospital, Indore); Mayur Patel (Saifee Hospital, Mumbai); P. Samaddar (Tata Main Hospital, Jamshedpur); Dhruva Chaudhry (PGIMS, Rohtak); Vivek Joshi and Srinivas Samavedam (CARE Hospitals, Surat); Ankur Devendra Bhavsar (Spandan Multispeciality Hospital, Vadodar); Prachee Sathe (Ruby Hall Clinic, Pune); Sujoy Mukherjee (Calcutta Medical Research Institute, Kolkat).
Italy: Coordinator: Salvatore Maurizio Maggiore (Policlinico “Agostino Gemelli,” Università Cattolica Del Sacro Cuore, Rome). Francesco Idone and Federica Antonicelli (Policlinico “Agostino Gemelli,” Università Cattolica Del Sacro Cuore, Rome); Paolo Navalesi, Rosanna Vaschetto, and Arianna Boggero (Ospedale Maggiore Della Carità, Università Del Piemonte Orientale “Amedeo Avogadro,” Novara); Rosalba Tufano, Michele Iannuzzi, and Edoardo De Robertis (Ospedale Policlinico “Federico II,” Università Di Napoli, Naples); Romano Tetamo and Andrea Neville Cracchiolo (Ospedale “Arnas Civico, Di Cristina, Benfratelli,” Palermo), Antonio Braschi, Francesco Mojoli, and Ilaria Currò (ICU 1, Fondazione IRCCS Policlinico “S. Matteo,” Università Di Pavia, Pavia); Mirko Belliato, Chiara Verga, and Marta Ferrari (ICU 2, Fondazione IRCCS Policlinico “S. Matteo,” Università Di Pavia, Pavia); Erika Mannelli, Valerio Mangani, and Giorgio Tulli (Ospedale “San Giovanni Di Dio,” Florence); Francesca Frigieri and Armando Pedullà (Ospedale “Santa Maria Annunziata,” Florence); Monica Rocco, Giorgia Citterio, and A. Di Russo (Policlinico “Umberto I,” Università La Sapienza, Rome); Gaetano Perchiazzi and Loredana Pitagora (Ospedale Policlinico, Università Di Bari, Bari); Antonio Pesenti and Michela Bombino (Ospedale “San Gerardo,” Università Di Milano Bicocca, Monza); Davide Chiumello, Federica Tallarini, and Serena Azzari (Fondazione IRCCS “Cà Grande” Ospedale Maggiore Policlinico, Università Di Milano, Milan); Antonina Pigna, Ivano Aprile, and Marco Adversi (Policlinico Universitario “S. Orsola-Malpighi,” Bologna); Antonio Corcione, Marianna Esposito, and Annunziata Mattei (Ospedale “V. Monaldi,” Naples); Vito Marco Ranieri, Rosario Urbino, and Ilaria Maria Mastromauro (Ospedale “San Giovanni Battista–Molinette,” Università Di Torino, Torino); Antonino Giarratano, Maurizio Raineri Santi and Ambrogio Sansone (Policlinico “P. Giaccone,” Università Di Palermo, Palermo).
Japan: Toru Katani (Tokyo Women’s Medical University, Tokyo).
Korea: Coordinator: Younsuck Koh (Asan Medical Center, University of Ulsan, Seoul). Moo Suk Park (Hospital Severance, Yonsei University Health System, Seoul); Je Hyeong Kim (Hospital Korea University of Ansan, Ansan); Kyung Chan Kim (Hospital Catholic University of Daegu, Daegu); Hye Sook Choi (Hospital Dongguk University of Gyeongju, Gyeongju); Yun Seong Kim (Hospital Pusan National University of Yangsan, Yangsan); Jin Hwa Lee (Hospital Ewha Womans University Mokdong, Seoul); Myung-Goo Lee (Hospital Chuncheon Sacred Heart Hospital, Hallym University Medical Center, Chuncheon); Won-Yeon Lee (Hospital Yonsei University Wonju Christian, Wonju); Jin Young An (Hospital Chungbuk National University, Chenogiu); Gee Young Suh (Samsung Medical Center, Sungkyunkwan University, Seoul); Ki-Suck Jung (Hallym University Medical Center, Anyang).
Mexico: Coordinator: Asisclo J Villagómez Ortiz (Hospital Regional 1°de Octubre, ISSSTE, México DF). César Cruz Lozano (Hospital Regional de Pemex, Ciudad Madero); Zalatiel Maycotte Luna (Hospital Ángeles de las Lomas, Mexico DF); José Francisco López Baca (Hospital Regional de Zona No.1 del IMSS, Mexico DF); José Elizalde (Instituto Nacional De Ciencias Médicas y Nutrición Salvador Zubirán, Mexico DF); Guillermo Cueto Robledo (Hospital General de México, Mexico DF); Mario Alonso Treviño Salinas (Hospital Universitario de Nuevo León ’Dr. Eleuterio González,’ Nuevo León); Ricardo Martinez Zubieta (Hospital Español de México, Miguel Hidalgo); Claudia Olvera-Guzman and Marco Montes De Oca (Centro Médico ABC, Mexico DF), Silvio A. Ñamendys-Silva (Instituto Nacional de Cancerología, Mexico DF); José Salvador Martínez Cano (Centenario Hospital Miguel Hidalgo, Aguascalientes); Jose Angel Baltazar Torres (Umae Hospital De Especialidades Dr. Antonio Fraga Mouret, Mexico DF); Gustavo Morales Muñoz (Hospital Regional de Alta Especialidad de la Mujer, Villahermosa); Antonio Villa Delgado (Hospital Mérida Yucatán; Mérida); Javier Ladape Martinez (Hospital Juárez de México, Mexico DF).
Morocco: Coordinator: Amine Ali Zeggwagh (Hôpital Ibn Sina, Rabat). Tarek Dendane (Hôpital Ibn Sina, Rabat); Abderrahim Azzouzi (Hôpital Ibn Sina, Rabat); Ahmed Sbihi (Hôpital Ibn Sina, Rabat); Wajdi Maazouzi and Mourad Amor (Hôpital des Specialites, Rabat); Charki Haimeur (Hôpital Militaire D’Instruction Mohamed V, Rabat).
Netherlands: Coordinator: Michael A. Kuiper (Medical Center Leeuwarden (MCL), Leeuwarden). Matty Koopmans (MCL, Leeuwarden); Uli Strauch, Dennis Bergmans, and Serge Heines (Universitair Medisch Centrum Maastricht, Maastricht); Sylvia den Boer (Spaarneziekenhuis, Hoofddorp); Bas M. Kors (Kennemer Gasthuis, Haarlem); Peter van der Voort (Onze Lieve Vrouwe Gasthuis, Amsterdam); Paul J. Dennesen (Medisch Centrum Haaglanden, Den Haag); Bert Beishuizen, Ingrid van den Hul, Erna Alberts, Harry PPM Gelissen, and Eduard Bootsma (Vrije Universiteit Medisch Centrum, Amsterdam); Auke Reidinga (Tjongerschans Ziekenhuis, Heerenveen).
New Zealand: Coordinators: Jasmin Board and Andrew R. Davies (Alfred Hospital, Melbourne). Kim Heus, Diane Mackle, and Paul Young (Wellington Hospital, Wellington); Rachael Parke, Eileen Gilder, and Jodi Brown (CVICU Auckland City Hospital, Auckland); Lynette Newby and Catherine Simmonds (DCCM Auckland City Hospital, Auckland); Jan Mehrtens and Seton Henderson (Christchurch Hospital, Christchurch); Tony Williams, Judi Tai, and Chantal Hogan (Middlemore, Auckland); Mary La Pine, John Durning, and Sheree Gare (Waikato, Hamilton); Troy Browne, Shirley Nelson, and Jennifer Goodson (Tauranga Hospital, Tauranga).
Panama: Julio Osorio (Hospital Rafael Hernández, Chiriquí).
Peru: Coordinator: Isabel Coronado Campos (Hospital Guillermo Almenara Irigoyen, Lima). Rollin Roldán Mori (Hospital Edgardo Rebagliatti Martins, Lima); Rosa Luz López Martínez (Hospital Guillermo Almenara Irigoyen, Lima).
Poland: Adam Mikstacki and Barbara Tamowicz (Karol Marcinkowski University of Medical Sciences, Poznan).
Portugal: Coordinator: Rui Moreno (UCINC, Hospital de São José, Centro Hospitalar de Lisboa Central, E.P.E., Lisbon). Eduardo Almeida (Hospital Garcia de Orta, Almada); Joana Silvestre (Centro Hospitalar de Lisboa Central, Lisbon); Heloisa Castro, Irene Aragão, and Susana Alves Ferreira (Centro Hospitalar Do Porto–Hospital Geral De Santo António, Porto); Nelson Barros (Centro Hospitalar Trás-Os-Montes E Alto Douro, Vila-Real); Filomena Faria (Instituto Portugues de Oncologia, Porto); Carlos André Correia Casado (Hospital Da Luz, Lisboa); Fausto Fialho Moura (Hospital de Cascais, Cascais); Paulo Marcal (Hospital De São Sebastião, São Sebastião); Ricardo Matos (Hospital de Santo Antonio dos Capuchos, Centro Hospitalar de Lisboa Central, E.P.E., Lisbon); António Alvarez (Centro Hospitalar de Lisboa Norte, Lisbon).
Russian Federation: Coordinator: Edward Nicolayenko (Hospital No.1, Moscow). Mikhail Kirov (Hospital No. 1, Arkhangelsk); Andrey Yaroshetskiy (Hospital No.7, Moscow); Andrei Piontek (Hospital No.14, Ekaterinburg); Valery Subbotin (National Institute of Surgery Named After A. V. Vishnevskij, Moscow).
Saudi Arabia: Yaseen Arabi, Olivia Dulfo, Charina Marie Olay, Edgardo E. Tabhan (King Saud Bin Abdulaziz University for Health Sciences, Riyadh).
Spain: Coordinator: Nicolas Nin (Hospital Universitario de Getafe, Madrid). Alfonso Muñoz and César Aragón (Hospital Carlos Haya, Málaga); Ana Villagrá (Corporación Sanitaria y Universitaria Parc Taulí, Sabadell); Ainhoa Rosselló and Joan Maria Raurich (Hospital Universitario Son Espasses, Mallorca); María Garitacelaya, Miguel Ángel González-Gallego, and Francisco Ortuño (Hospital Clínico Universitario San Carlos, Madrid); Miguel Fernández-Vivas (Hospital Virgen de la Arrixaca, Murcia); David Freire (Hospital Juan Canalejo, A Coruña); Francisco Guerrero and Francisco Manzano (Hospital Virgen de las Nieves, Granada); Juan Carlos Sotillo (Hospital Universitario Gregorio Marañón, Madrid); Alejandra Bustos (Hospital de Torrevieja, Torrevieja); Alfredo Padrón, Pedro Rosas, Rafael Morales, and Liliana Caipe (Hospital Doctor Negrín, Las Palmas de Gran Canaria); Maurizio Bottiroli (Hospital de la Santa Creu i Sant Pau, Barcelona); José María Nicolás (Hospital Clinic-IDIBAPS, Barcelona); Marta Ugalde (Hospital de Cruces, Barakaldo); Javier Ruiz (Hospital Sagrado Corazón, Barcelona); Lucia Capilla (Hospital Morales Meseguer, Murcia); Guillermo Muñiz (Hospital Central de Asturias, Oviedo); Jesús Sánchez-Ruiz (Hospital General de Jerez de la Frontera, Jerez de la Frontera); Javier Cebrián, Begoña Balerdi, Elena Parreño, and Alvaro van Bommel (Hospital Universitario La Fe, Valencia); César Pérez-Calvo (Fundación Jiménez Díaz, Madrid); Irene Dot (Hospital del Mar, Barcelona); Javier Blanco (Complejo Hospitalario de Ciudad Real, Ciudad Real); Raquel Manzanedo and José J. Blanco (Hospital Insular de Gran Canaria, Gran Canaria); Daniel Fontaneda, Raúl González, and Javier Díaz Domínguez (Complejo Hospitalario de León, León); Alfonso Moreno (Hospital San Pedro, Logroño); Antonio Reyes and Ian Carrasco (Hospital de la Princesa, Madrid); Itziar Mintegui, Rosa Sebastián, and Javier García-Alonso, (Complejo Hospitalario de Donostia, Donostia); Carolina Lorencio and Josep Maria Sirvent (Hospital Universitario Dr.Josep Trueta, Girona); Patricia Jimeno (Hospital General de Segovia, Segovia); Miguel León (Hospital Arnau de Vilanova, Lleida); Pedro Galdos (Hospital Universitario Puerta de Hierro, Majadahonda); Nuria Alonso (Hospital Universitario Nuestra Santa María del Rosell, Cartagena); Julia López-Díaz (Hospital Universitario La Paz, Madrid); María Victoria de la Torre, Jorge Vidal Hernández, and Nicolás Zamboschi (Hospital Universitario Virgen de la Victoria, Málaga); Francisco Lucena (Hospital Universitario de Valme, Seville); Gemma Rialp (Hospital Son Llatzer, Mallorca); Raquel Montoiro (Hospital Clínico Lozano Blesa, Zaragoza); Victoria Goñi, María Ángeles Pena, and Antonio Maestre (Hospital Virgen del Rocío, Seville); Marc Fabra, Jacinto Baena and Eva Benveniste (Hospital Germans Trias I Pujol, Badalona); Susana Temprano (Hospital 12 de Octubre, Madrid); Jesús Sánchez (Hospital de Rio Hortega, Valladolid); Carmen Campos (Hospital Universitario Dr.Peset, Valencia); Sara Cabañes (Hospital Santiago Apóstol, Vitoria); María Elena Pérez-Losada, Javier González-Robledo, and José Claudio Leo (Complejo Hospitalario de Salamanca, Salamanca); Enrique Piacentini (Hospital Mutua de Terrassa, Terrassa); María del Carmen de la Torre (Hospital de Mataró, Mataró); Laura Álvarez-Montero and Fernando Sánchez (Hospital Xeral Calde, Lugo); Antonio Viñuales (Hospital Lluis Alcanyis, Xàtiva); Bernabé Álvarez (Hospital General de Alicante, Alicante); Javier Castañeda (Hospital Clínico de Valladolid, Valladolid); Ángela Alonso (Hospital de Fuenlabrada, Fuenlabrada); María Isabel Ruiz (Complejo Hospitalario de Jaén, Jaén); Pedro Jesús Domínguez (Hospital Juan Ramón Jiménez, Huelva); Marcos Delgado (Complejo Hospitalari de Manresa, Manresa); Eugenio Palazón (Hospital Universitario Reina Sofía, Murcia); Antonio García-Jiménez (Hospital Arquitecto Marcide, Ferrol); Rosa Álvaro (Hospital de La Plana, Castellón); Clara Laplaza, Eva Regidor and Enrique Maraví (Complejo Hospitalario de Navarra, Pamplona); José María Quiroga (Hospital de Cabueñes, Gijón); Amalia Martínez de la Gandara (Hospital Infanta Leonor, Madrid); Cecilia Carbayo (Hospital Torrecárdenas, Almería); María Luisa Navarrete (Hospital San Juan, Alicante); Manuel Valledor and Raquel Yano (Hospital San Agustín, Avilés); José María Gutiérrez (Hospital General de Albacete, Albacete); Amparo Ferrandiz, Alberto Belenguer, and Lidón Mateu (Hospital General de Castellón, Castellón); Laura Sayagues (Complejo Hospitalario de Santiago de Compostela, Compostela); María José Tolón (Hospital Royo Vilanova, Zaragoza); Nieves Franco (Hospital de Móstoles, Móstoles); Elena Gallego (Hospital San Pedro de Alcántara, Cáceres); Félix Lacoma (Hospital Quirón, Madrid); Patricia Albert (Hospital del Sureste, Arganda); Vicente Arraez (Hospital Universitario General, Elche); Mar Gobernado (Hospital General de Soria, Soria); Susana Moradillo (Hospital Río Carrión, Palencia); Carolina Gímenez-Esparza (Hospital de la Vega Baja, Orihuela); Teresa Sánchez de Dios (Complejo Hospitalario Montecelo, Pontevedra); Carlos Marian Crespo (Hospital General de Guadalajara, Guadalajara); Cecilia Hermosa and Federico Gordo (Hospital del Henares, Coslada); Genis Carrasco (Hospital SCIAS, Barcelona); María Ángeles Alonso (Trauma ICU, Hospital 12 de Octubre, Madrid); Alejandro Algora (Fundación Hospital Universitario de Alcorcón, Madrid); Raúl de Pablo (Hospital Príncipe de Asturias, Alcalá de Henares); Sofía García (Hospital del Poniente, El Ejido); Ana Carolina Caballero (Hospital de Zamora, Zamora); José María Montón (Hospital Obispo Polanco, Teruel); Teresa Mut (Hospital Provincial de Castellón, Castellón); Eva Manteiga (Hospital Infanta Cristina, Parla); Alejandro de la Serna (Hospital de Galdakao, Galdakao); Ana Esther Trujillo (Hospital General de La Palma, La Palma); Rafael Blancas (Hospital del Tajo, Aranjuez); Inmaculada Vallverdú (Hospital Universitario San Juan, Reus); José Manuel Serrano (Hospital Universitario Reina Sofía, Córdoba); Miquel Ferrer (Hospital Clinic-IDIBAPS, Barcelona); Juan Diego Jiménez (Hospital de Don Benito, Don Benito); Carlos Gallego (Hospital Infanta Elena, Valdemoro); Luis Marina (Complejo Hospitalario de Toledo, Toledo).
Taiwan: Chen Chin-Ming and Ai-Chin Cheng (Chi Mei Medical Center, Tainan City).
Tunisia: Coordinator: Fekri Abroug (Hospital Fattouma Bourguina, Monastir). Besbes Mohamed (Hospital Abderrahmane Mami, Ariana); Imed Chouchene (Hospital Universitarie Farhat Hached, Sousse); Mounir Bouaziz (CHU Habib Bourguiba, Sfax); Stambouli Neji and Islem Ouanes (Hospital Fattouma Bourguina, Monastir); Ayed Samia (Hospital Taher Sfar City, Mahdia).
Turkey: Coordinator: Nahit Cakar (Istanbul Medical Faculty, Istanbul). Ismail Kati (Medical Faculty of Yuzuncu Yil University, Van) Ali Aydım Altunkan (Faculty of Medicine, Mersin University, Mersin); Remzi Iscimen (Uludag University Faculty of Medicine, Bursa); Zafer Dogan (Sutcu İmam University, Kahramanmaras); Bilge Çetin (Erciye Üniversity, Kayseri); Tayfun Adanir (Atatürk Hospital, Izmir); Sabriye Guvenc (Anadolu Medical Center Istanbul, Istanbul); Unase Büyükkoçak (Kirikkale University, Kirikkale).
United States: Coordinator: Antonio Anzueto (University Hospital San Antonio and South Texas Veterans Health Care System, San Antonio, TX). Ashley Ellis and Gary Kinasewitz (Oklahoma University Health Science Center and VA medical Center, Oklahoma City, OK); Allan Walkey and Phil Alkana (Boston Medical Center, Boston, MA); Gregory A. Schmidt, Susan Gillen, Kathleen Lilli, Jennifer Twombley, Denice Wells, and Larry Welder; (University of Iowa Hospitals and Clinics, Iowa City, IA); Alejandro Arroliga, Alfredo Vasquez-Sandoval, Vincent John Scott, Craig Cernosek, and Christopher Spradley (Temple Clinic, Scott and White Healthcare, Temple, TX); Dimple Tejwani, Sindhaghatta Venkatram, and Gilda Diaz-Fuentes (Bronx Lebanon Hospital Center, New York, NY); Amber Monson, Anthony Saleh, Madhav Gudi, and George Liziamma (New York Methodist Hospital, New York, NY); Mohamed A. Saad, Crissie De Spirito, Bryan Beatty, Samir Vermani, and Crissie Despirito (University of Louisville School of Medicine Hospital, Louisville, KY); Zaza Cohen, Amee Patrawalla, Samir Abdelhadi, Rupesh Vakil, and Steven Y. Chang (UMDNJ–New Jersey Medical School, Newark, NJ); Brian Sherman, Rosanna Del Giudice, and John Oropell (Mount Sinai Medical Center, New York, NY); Timothy D Girard, Cayce Strength, Joyce Okahashi, Leanne Boehm, and Matthew Kirchner (Vanderbilt University School of Medicine, Nashville, TN); Ashley Ellis and Gary Kinasewitz (Oklahoma City VA Medical Center, Oklahoma City, OK); Erwin J. Oei, Sebastian Circo, Nelson Medina, and Mohammed Al-Jagbeer (Morristown Medical Center, Morristown, NJ); V. J. Cardenas, Jr. and Smyth Smith (University of Texas Medical Branch at Galveston, Galveston, TX); Shelby Sutton, Marcela Canola-Mazo, Tim Houlihan, Yogeet Kaur, and Travis Parry (University Hospital San Antonio and South Texas Veterans Health Care System, San Antonio, TX); Craig A. Piquette and Kerry Canady (Omaha VA Medical Center, Omaha, NE); Rahul Nanchal and Dana K. Soetaert (Medical College of Wisconsin, Milwaukee, WI); Maria del Mar Torres-Perez, Carlos Robles-Arias, and William Rodriguez-Cintron (VA Caribbean Health Care System, San Juan, Puerto Rico); Mark Tidswell, Jennifer Germain, Lori-Ann Kozikowski, and Erin Braden (Baystate Medical Center, Springfield, MA); Geneva Tatem (Henry Ford Hospital, Detroit, MI).
Uruguay: Coordinator: Javier Hurtado (Hospital Español and CUDAM, Montevideo). Alberto Deicas (CASMU No. 2, Montevideo); Daniel Weiss (Hospital Pasteur, Montevideo); Marta Beron (Hospital Maciel, Montevideo); Román Garrido (Hospital Evangélico, Montevideo); Cristina Santos and Mario Cancela (Hospital de Clínicas, Montevideo); Raúl Lombardi (Impasa, Montevideo); Pedro Alzugaray (CAAMOC, Carmelo, Sanatorio Americano, Montevideo and Orameco, Colonia); Jorge Gerez (Hospital Policial, Montevideo); Silvia Mareque (Sanatorio CAMS, Mercedes); Graciela Franca (Circulo Católico, Montevideo); Oscar Cluzet (Sanatorio Americano, Montevideo); Edgardo Nuñez (Sanatorio Mautone and Hospital de Maldonado, Maldonado); Julio Pontet (Hospital de Florida, Florida); Sergio Cáceres (Centro Cardiológico Sanatorio Americano, Montevideo); Elia Caragna (CRAMI, Las Piedras); Alberto Soler (COMEPA and Hospital Escuela del Litoral, Paysandú); Frank Torres (Sanatorio Cantegril, Punta del Este); Gustavo Pittini (CAAMEPA, Pando).
Venezuela: Coordinator: Gabriel d`Empaire (Hospital de Clínicas de Caracas, Caracas). Stevens Salva and Fernando Pérez (Hospital de Clínicas de Caracas, Caracas); Clara Pacheco and Zoraida Parra (Hospital Clínico Universitario de Caracas, Caracas); Ingrid Von der Osten (Hospital Miguel Pérez Carreño, Caracas); Luis Williams and José Salinas (Hospital Centro de Especialidades de Anzoategui, Lechería).
Vietnam: Do Danh Quynh, Pham Thi Van Anh, Nguyen Huu Hoang, and Nghuyen ba Tuan (Viet Duc Hospital, Hanoi).
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Supported by Centro de Investigación Biomédica en red Enfermedades Respiratorias, CIBER en Epidemiología y Salud Pública. Instituto de Salud Carlos III, Madrid, Spain, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain, and by a Canadian Institutes of Health Research (Ottawa, ON, Canada) New Investigator Award (N.D.F.).
Author Contributions: A.E., as principal investigator, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: A.E., F.F.-V., O.P., N.D.F., A.A. Coordination of data acquisition: N.D.F., K.R., F.R., N.N., C.A., D.A.V., A.W.T., L.B., A.J.V., J.H., M.G., A.R.D., B.D., S.M.M., P.P., L.S., V.T., G.D., D.M., F.A., R.P.M., M.A.S., Y.A., F.S., M.J., P.A., Y.K., M.A.K., H.-H.B., A.A.Z., A.A. Analysis and interpretation of data: F.F.-V., O.P. Drafting of the manuscript: F.F.-V., O.P., N.D.F. Critical revision of manuscript: A.E., K.R., F.R., N.N., C.A., D.A.V., A.W.T., L.B., A.J.V., J.H., M.G., A.R.D., B.D., S.M.M., P.P., L.S., V.T., G.D., D.M., F.A., R.P.M., M.A.S., Y.A., F.S., M.J., P.A., Y.K., M.A.K., H.-H.B., A.A.Z., A.A. Statistical analysis: A.M., V.A.
The funding organizations had no role in the design or conduct of the study, collection, management, analysis, or interpretation of the data, or preparation, review, or approval of the manuscript.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201212-2169OC on April 30, 2013
Author disclosures are available with the text of this article at www.atsjournals.org.
