Evolution of Mechanical Ventilation in Response to Clinical Research

Evolution of Mechanical Ventilation in Response toClinical Research

Andres Esteban1, Niall D. Ferguson2, Maureen O. Meade3, Fernando Frutos-Vivar1, Carlos Apezteguia4,Laurent Brochard5, Konstantinos Raymondos6, Nicolas Nin1, Javier Hurtado7, Vinko Tomicic8, Marco Gonzalez9,Jose Elizalde10, Peter Nightingale11, Fekri Abroug12, Paolo Pelosi13, Yaseen Arabi14, Rui Moreno15, Manuel Jibaja16,Gabriel D’Empaire17, Fredi Sandi18, Dimitros Matamis19, Ana Marıa Montanez20, and Antonio Anzueto21, for theVENTILA Group*

1CIBER Enfermedades Respiratorias, Hospital Universitario de Getafe, Madrid, Spain; 2Interdepartmental Division of Critical Care Medicine, and

Division of Respirology, Department of Medicine, University Health Network, University of Toronto, Toronto, Canada; 3Department of Clinical

Epidemiology and Biostatistics, McMaster University, Hamilton, Canada; 4Hospital Profesor A. Posadas, El Palomar, Buenos Aires, Argentina; 5AP-HP,Centre Hospitalier Albert-Chenvier–Henri Mondor, INSERM U 841, Universite Paris 12, Paris, France; 6Medizinische Hochschule, Hannover,

Germany; 7Hospital de Clınicas, Montevideo, Uruguay; 8Clınica Alemana de Santiago, Santiago, Chile; 9Clınica Medellın y Universidad Pontificia

Bolivariana, Medellın, Colombia; 10Hospital ABC, Mexico DF, Mexico; 11Wythenshawe Hospital, Manchester, United Kingdom; 12FattoumaBourguiba Monastir, Tunisia; 13Ospedale di Circolo, Universita’ degli Studi dell’Insubria, Varese, Italy; 14King Fahad National Guard Hospital, Riyadh,

Saudi Arabia; 15Hospital de Santo Antonio dos Capuchos, Lisboa, Portugal; 16Hospital Militar de Quito, Quito, Ecuador; 17Hospital de Clınicas,

Caracas, Venezuela; 18Hospital Obrero Numero 1, La Paz, Bolivia; 19Papageorgiou General Hospital, Thessaloniki, Greece; 20Sociedad Peruana de

Medicina Intensiva, Lima, Peru; and 21South Texas Veterans Health Care System and University of Texas Health Science Center, San Antonio, Texas

Rationale: Recent literature in mechanical ventilation includes strongevidence from randomized trials. Little information is availableregarding the influence of these trials on usual clinical practice.Objectives: To describe current mechanical ventilation practices andto assess the influence of interval randomized trials when comparedwith findings from a 1998 cohort.Methods: A prospective international observational cohort study,with a nested comparative study performed in 349 intensive careunits in 23 countries. We enrolled 4,968 consecutive patients re-ceiving mechanical ventilation over a 1-month period. We recordeddemographics and daily data related to mechanical ventilation forthe duration of ventilation. We systematically reviewed the litera-ture and developed 11 practice-change hypotheses for the compar-ative cohort study before seeing these results. In assessing practicechanges, we only compared data from the 107 intensive care units(1,675 patients) that also participated in the 1998 cohort (1,383patients).Measurements and Main Results: In 2004 compared with 1998, the useof noninvasive ventilation increased (11.1 vs. 4.4%, P , 0.001).Among patients with acute respiratory distress syndrome, tidalvolumes decreased (7.4 vs. 9.1 ml/kg, P , 0.001) and positive end-expiratory pressure levels increased slightly (8.7 vs. 7.7 cm H2O,P 5 0.02). More patients were successfully extubated after their firstattempt of spontaneous breathing (77 vs. 62%, P , 0.001). Use ofsynchronized intermittent mandatory ventilation fell dramatically(1.6 vs. 11%, P , 0.001). Observations confirmed 10 of our 11practice-change hypotheses.Conclusions: The strong concordance of predicted and observedpractice changes suggests that randomized trial results have ad-vanced mechanical ventilation practices internationally.

Keywords: mechanical ventilation; mortality; acute respiratory distress

syndrome; noninvasive positive-pressure ventilation; weaning

Implementation of known effective therapies is an importanttarget in the provision of quality health care (1–3). Meanwhile,delays in the translation of knowledge from clinical research toclinical practice are ubiquitous (4, 5), and the practice of criticalcare medicine is no exception to this trend (6–10).

An international, prospective, observational study of mechan-ical ventilation practices conducted in 1998 included 5,183consecutive eligible patients from 20 countries (11). Our goalswere to provide detailed natural history and prognostic data, toevaluate practice variability, and to generate ‘‘usual care’’ bench-marks for both clinicians and clinical investigators in the field ofmechanical ventilation. Among other important observations,we found that patients continue to spend, on average, 40% oftheir duration of mechanical ventilation in the process of wean-ing, and that the overall rate of mortality in the intensive care unit(ICU) was high (31%; 95% confidence interval, 29–32%) (11).

From a global perspective, the potential benefit of interven-tions shown to improve survival associated with mechanicalventilation will be large. The past decade has witnessed theconduct of numerous randomized trials related to reducing theneed for mechanical ventilation (e.g., noninvasive ventilationtrials), reducing the duration of mechanical ventilation (e.g.,weaning and extubation studies), and improving safety of me-chanical ventilation (e.g., trials of lung-protective ventilation inacute respiratory distress syndrome [ARDS]). The impact of thisbody of research on clinical practice is unknown; moreover, thecurrent relevance of 1998 data is diminishing (11, 12).

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject

There is little information about the influence of clinicaltrials on clinical practice in the field of the mechanicalventilation.

What This Study Adds to the Field

The strong concordance of predicted and observed practicechanges suggests that randomized trial results have ad-vanced mechanical ventilation practices internationally.

(Received in original form June 20, 2007; accepted in final form October 24, 2007)

Supported by Red GIRA (G03/063) and Red RESPIRA (C03/11) from Instituto de

Salud Carlos III, Spain.

*A list of the VENTILA Group members may be found at the end of this article.

Correspondence and requests for reprints should be addressed to Andres Esteban,

M.D., Ph.D., Intensive Care Unit, Hospital Universitario de Getafe, Carretera de

Toledo Km 12,500, 28905 Getafe, Madrid, Spain. E-mail: [email protected]

This article has an online supplement, which is accessible from this issue’s table of

contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 177. pp 170–177, 2008

Originally Published in Press as DOI: 10.1164/rccm.200706-893OC on October 25, 2007

Internet address: www.atsjournals.org

We therefore conducted a second international observa-tional study of mechanically ventilated patients using method-ology similar to the original study. The objectives of this studywere as follows: (1) to describe current mechanical ventilationpractices, (2) to compare current results with those of the 1998cohort study, and (3) to judge the concordance of practicechange (or lack thereof) with interval reports of randomizedtrials. Some of the results of this study have been previouslyreported in the form of abstracts (13–15).

METHODS

Observational Study

In a prospective utilization review, we enrolled consecutive patients whoreceived mechanical ventilation for at least 12 hours after admission to 1of 349 participating ICUs within 23 participating countries. BeginningMarch 1, 2004, we enrolled patients over a 1-month period at each center,and followed each patient for the duration of mechanical ventilation, upto 28 days. Only the investigative team members at each site were awareof the purpose and the precise timing of the study. The research ethicsboard of each participating institution approved the study protocol.

We followed the methodology of the original study (11). Wecollected demographic and baseline data at ICU admission, and thenrecorded ventilator settings, gas exchange variables, ICU discharge orDay 28, whichever came first. We recorded method(s) and duration ofweaning, and the need for reintubation or tracheostomy. As in theoriginal study, we calculated the duration of weaning from the first daya patient met standard criteria for weaning readiness (improvement inthe cause of respiratory failure, PaO2

/FIO2. 200 mm Hg, positive end-

expiratory pressure [PEEP] < 5 cm H2O, and no need for vasoactivedrugs), to the time of successful extubation (lasting at least 48 h);patients were classified as ‘‘difficult to wean’’ if they failed their firstspontaneous breathing trial. We recorded vital status at hospitaldischarge.

Literature Review

We sought to identify all randomized controlled trials and systematicreviews evaluating the impact of ventilation techniques on outcomes ofimportance to patients that were likely to have influenced practice onseveral continents. We systematically searched the top five generalmedical journals (according to 2003 impact factor: New EnglandJournal of Medicine, Journal of the American Medical Association,Lancet, Annals of Internal Medicine, British Medical Journal), and thetop five general critical care journals (American Journal of Respiratoryand Critical Care Medicine, Critical Care Medicine, Intensive CareMedicine, Chest, Critical Care). We searched for studies published overthe 6 years preceding the first cohort (1992–1997), and in the 6-yearinterval between the two cohorts (1998–2003), reasoning that adoptionof research findings into clinical practice may take several years (16).We searched MEDLINE using a sensitive strategy for identifyingrandomized controlled trials (17, 18), and a combination of MeSHheadings and text words to identify relevant interventions (full searchstrategy available in the online supplement). One investigator (N.D.F.)hand-searched reference lists of included trials and systematic reviewsto identify any further studies.

Two investigators (N.D.F., M.O.M.) independently applied thefollowing criteria to select publications relevant to this study: (1)randomized controlled trial or systematic review of randomizedcontrolled trials (study design); (2) adult patients with acute or acute-on-chronic respiratory failure (study population); (3) noninvasivepositive-pressure ventilation, ventilator weaning technique, ventilationmode, lung-protective ventilation (including tidal volume or PEEPinterventions), prone position, or tracheostomy (study intervention);and (4) outcomes of importance to patients (including mortality,intubation, reintubation, duration of ventilation, or length of hospitalstay). Agreement between the two investigators for study inclusionwas excellent (chance-corrected agreement, k 5 0.97; 95% confidenceinterval, 0.91–1.0) and any differences were resolved by consensus.These two investigators independently abstracted study data andquality indicators for each included paper, and resolved disagreements

by consensus. Tables summarizing the key characteristics and findingsof each of the 48 primary studies, excluding systematic reviews andmeta-analyses, that ultimately met our inclusion criteria are available inan online supplement to this article.

Generation of Practice-Change Hypotheses

Blinded to the results from the 2004 cohort, we derived summarystatements for the major findings related to each intervention. Usingthese summary statements, two investigators (N.D.F., M.O.M.) in-dependently generated hypotheses regarding how clinical practicemight have changed between 1998 and 2004 if these research findingswere widely implemented (see the online supplement). We only con-sidered hypotheses that we could test using the data in both cohorts. Inresolving differences, we based our consensus practice-change hypoth-eses exclusively on the summary data (or lack thereof). The resultantpractice-change hypotheses, therefore, do not necessarily reflect ourpersonal beliefs or practices, and are not intended as recommendationsfor clinical care.

Statistical Analysis

Data are expressed as means (SD), medians (interquartile range), andproportions as appropriate. For comparisons between the 2004 and1998 cohorts, we considered only data from ICUs that participated in bothstudies. Student’s t or Mann-Whitney U tests were used to comparecontinuous variables and chi-squared tests were used for categoricalvariables. We rejected the null hypothesis of no difference betweencohorts at a nominal significance level of 0.05. Statistical analyses wereconducted using SPPS version 13.0 (SPSS, Inc., Chicago, IL).

RESULTS

Table 1 shows the 11 practice-change hypotheses developedfrom the systematic review of the literature (see the onlinesupplement).

General Characteristics and Outcomes

The majority of the 349 ICUs were medical-surgical (239; 69%);55 units were medical (16%), 48 units were surgical (48; 14%),and 7 units were neurological (2%); 107 (31%) had also con-tributed patients to the 1998 study. During the 1-month studyperiod, 19,505 patients were admitted to a study ICU and 4,968(25%) received mechanical ventilation for more than 12 hours.A total of 1,675 (34%) patients were admitted to an ICU thatparticipated in both cohort studies. Table 2 summarizes thepatient characteristics and main outcomes from both cohorts.

TABLE 1. PRACTICE-CHANGE HYPOTHESES (1998 vs. 2004)

Noninvasive positive-pressure ventilation

d Increased use of noninvasive positive-pressure ventilation for chronic

obstructive pulmonary disease exacerbations

d Increased use of noninvasive positive pressure ventilation for acute

hypoxemic respiratory failure

Acute respiratory distress syndrome

d Decreased tidal volumes

d Minimal increase in levels of positive end-expiratory pressure

d No change in the use of pressure-controlled modes

d No change in the use of prone position

Weaning from mechanical ventilation

d Increased use of pressure support versus T-piece in spontaneous breathing

trials

d Increased use of spontaneous breathing trials to assess extubation readiness

d Decreased use of synchronized intermittent mandatory ventilation as

a method for gradually reducing ventilatory support

d Increased use of pressure support as a method for gradually reducing

ventilatory support

d No significant change in tracheostomy use or timing

Esteban, Ferguson, Meade, et al.: Evolution of Mechanical Ventilation 171

Noninvasive Positive-Pressure Ventilation

As predicted, the use of noninvasive ventilation was signifi-cantly greater in the 2004 cohort, approximately doubling forboth acute exacerbations of chronic obstructive pulmonarydisease (COPD) and other causes of acute respiratory failure(Table 3). The median duration of noninvasive ventilationdecreased (2 [2–4] vs 3. [2–6] d, P 5 0.03], although neither theneed for intubation nor the mortality among these patientschanged significantly (Table 3).

ARDS

We identified a total of 333 patients with ARDS who wereadmitted to one of the ICUs participating in both studies: 135patients in 1998 and 198 patients in 2004 (Table 4). Tidal volumesover the first week of ARDS were significantly lower in 2004(Table 4); fewer patients received a tidal volume above 10 ml/kg(7.5 vs. 29.6%, P , 0.001) and more had tidal volumes below6 ml/kg actual body weight (19.6 vs. 4.4%, P , 0.001). A strategyof pressure/volume limitation was applied significantly morecommonly in 2004 than in 1998 (Table 4). PEEP levels in thefirst week increased (Table 4); use of PEEP greater than 10 cm

H2O increased (40 vs. 28%, P , 0.001), whereas use of levels lessthan 5 cm H2O was unchanged (22 vs. 26%, P 5 0.42). Inspi-ratory pressures were slightly lower in 2004 (Table 4).

Volume assist-control remained the most common ventilatormode used in ARDS and the use of pressure-control mode didnot increase. For each 1,000 days of ARDS, volume assist-control mode was used in 548 days in 1998 and 504 days in 2004(P 5 0.19) and pressure-controlled ventilation in 244 and 202days, respectively (P 5 0.05). We observed a decrease in the useof prone position, which was used, at any time, in 7 versus 13%of patients in 1998 (P 5 0.04).

Outcomes for the patients with ARDS are displayed inTable 4. ICU mortality remained above 50% and was notsignificantly lower compared with the 1998 cohort.

Weaning from Mechanical Ventilation

Table 5 summarizes the characteristics and outcomes of the1,649 patients who underwent a planned extubation. There wasa trend toward an increase in the use of spontaneous breathingtrials to evaluate extubation readiness (58% in 1998 vs. 62%in 2004; p 5 0.09), and the percentage of patients extubatedafter successfully completing their only attempt of spontaneous

TABLE 2. GENERAL CHARACTERISTICS AND OUTCOMES OF THE COHORTS

Patients from ICUs Participating in Both Cohorts

1998 Cohort 2004 Cohort 1998 2004

(n 5 5,183) (n 5 4,968) (n 5 1,383) (n 5 1,675) P Value

Age, mean (SD), yr 59 (17) 59 (17) 59 (18) 58 (18) 0.13

Female sex, n (%) 1,985 (39) 1,967 (40) 521 (38) 682 (41) 0.13

Simplified Acute Physiology Score II,

mean (SD), points

44 (17) 42 (18) 44 (17) 43 (18) 0.05

Medical problem, n (%) 3,428 (66) 2,921 (59) 917 (66) 1,138 (68) 0.26

Main reason for mechanical

ventilation,* n (%)

COPD 522 (10) 267 (5) 133 (10) 109 (7) 0.002

Asthma 79 (2) 63 (1) 13 (1) 29 (2) 0.06

Other chronic lung disease 60 (1) 85 (2) 11 (1) 29 (2) 0.02

Coma 864 (17) 938 (19) 303 (22) 401 (24) 0.18

Neuromuscular disease 94 (2) 58 (1) 26 (2) 24 (1) 0.33

Acute respiratory failure

Postoperative 1,080 (21) 1,053 (21) 259 (19) 213 (13) ,0.001

Pneumonia 721 (14) 528 (11) 183 (13) 198 (12) 0.24

Sepsis 458 (9) 449 (9) 123 (9) 169 (10) 0.26

ARDS 231 (5) 148 (3) 67 (5) 62 (4) 0.12

Congestive heart failure 539 (10) 285 (6) 152 (11) 103 (6) ,0.001

Cardiac arrest 100 (2) 239 (5) 31 (2) 91 (5) ,0.001

Trauma 407 (8) 284 (6) 99 (7) 68 (4) ,0.001

Aspiration 129 (3) 139 (3) 24 (2) 41 (2) 0.17

Other cause of acute

respiratory failure

367 (7) 432 (9) 79 (6) 138 (8) 0.007

Days of mechanical ventilation,†

median (IQR)

3 (2, 7) 4 (2, 8) 4 (2, 7) 4 (2, 8) 0.002

Days of weaning,† median (IQR) 2 (1, 4) 1 (1, 2) 2 (1, 3) 1 (1, 3) ,0.001

Days of intubation, median (IQR) 4 (2, 8) 4 (2, 8) 4 (2, 8) 5 (2, 9) 0.32

Reintubation‡, n (%) 424/3,037 (14) 320/2,859 (11) 136/797 (17) 113/908 (12) 0.004

After planned extubation, % 350/2,858 (12) 279/2,724 (10) 127/780 (16) 105/869 (12) 0.01

After unplanned extubation, % 74/179 (41) 41/135 (30) 9/17 (53) 8/39 (20) 0.01

Length of stay in ICU, d,

median (IQR)

7 (4, 14) 8 (4, 15) 8 (4, 14) 8 (4,15) 0.91

Length of stay in hospital, d,

median (IQR)

16 (9, 29) 17 (9, 31) 18 (9, 32) 17 (9, 32) 0.57

ICU mortality, n (%) (95% CI) 1,590 (31) (29–32) 1,533 (31) (29–32) 481 (35) (32–37) 560 (33) (31–36) 0.43

Hospital mortalityx, n (%) (95% CI) 1,876/4,718 (40) (38–41) 1,759/4,757 (37) (35–38) 581/1,282 (45) (43–48) 636/1,567 (41) (38–48) 0.01

Definition of abbreviations: ARDS 5 acute respiratory distress syndrome; CI 5 confidence interval; COPD 5 chronic obstructive pulmonary disease; ICU 5 intensive care

unit; IQR 5 interquartile range.

* Because of rounding, percentages may not total 100. In 1998 more than one cause of acute respiratory failure per patient was permitted.† Days of ventilation and weaning are mutually exclusive.‡ Includes patients reintubated after either accidental or deliberate extubation.x Patients whose status at discharge from hospital was unknown were not included in the calculation.

172 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 177 2008

breathing increased significantly (62 vs. 77%, P , 0.001). Use ofa T-piece was the most common initial method for spontaneousbreathing trials (76% in 1998 vs. 71% in 2004, P 5 0.07), buttrials using low levels of pressure support trended upward overtime (10 vs. 14%, P 5 0.06). Among patients not extubatedafter the first attempt of spontaneous breathing, the medianduration of weaning was similar in the two cohorts (Table 5),but methods for gradual withdrawal differed. We observedsignificant reductions in the use of synchronized intermittentmandatory ventilation (11 vs. 1.6%, P , 0.001) and synchro-nized intermittent mandatory ventilation with pressure support(26 vs. 15%, P , 0.001), and a concomitant increase in the useof the pressure support weaning (19 vs. 55%, P , 0.001). Again,among those patients who were not extubated after their firsttrial of spontaneous breathing, the use of daily spontaneousbreathing trials as a weaning method, with T-piece, continuouspositive airway pressure, or low levels of pressure supportdecreased from 39% in 1998 to 27.7% in 2004 (P , 0.001).

Excluding patients admitted to the ICU with a tracheostomytube in situ, 151 patients in 1998 and 206 patients in 2004received a tracheostomy during their course of ventilation. Therate (12.5% [2004] vs. 11% [1998], P 5 0.19) and median(interquartile range) timing of tracheostomy (2004, 11 [7–15]vs., 1998, 12 [7–17] d; P 5 0.10) did not change.

DISCUSSION

The main finding of this study is the high degree of concordancebetween observed changes in mechanical ventilation practiceand changes predicted from reports of randomized controlledtrials; however, we were not able to detect significant differ-ences in clinical outcomes. The results of this internationalutilization review may also serve as a current benchmark on theusual care and outcomes of patients requiring mechanicalventilation for acute respiratory failure. We developed 11practice-change hypotheses, 7 of which predicted a change inpractice, the others predicting no change and serving in a way asnegative controls. Ten of our hypotheses were borne out whenwe compared patients admitted to those ICUs that participated

in both the 1998 and 2004 cohort studies. The use of noninvasivepositive-pressure ventilation doubled, the use of lower tidalvolumes in ARDS increased, more patients were promptlyextubated after a first attempt of spontaneous breathing, andfewer patients were weaned using synchronized intermittentmandatory ventilation. Meanwhile, as predicted, there was onlya minimal increase in applied PEEP, no increase in the use ofpressure-control ventilation, and no change in the use or timingof tracheostomy. Although we predicted no change in the use ofprone ventilation for ARDS, there was a statistically significantreduction.

Despite these positive changes in mechanical ventilationpractices, clinical outcomes did not improve significantly between1998 and 2004. We can speculate on a number of reasons as to whywe arrived at this seemingly inconsistent and disappointing result.

TABLE 3. CHARACTERISTICS AND OUTCOMES OF PATIENTSRECEIVING NONINVASIVE POSITIVE-PRESSURE VENTILATION

1998 Cohort 2004 Cohort

P Value(n 5 61) (n 5 186)

Age, mean (SD), yr 64 (14) 62 (17) 0.45


mean (SD) (points)

39 (14) 36 (15) 0.18

Use by reason for initiation of

ventilation, n (%)

COPD 22/133 (17) 48/109 (44) ,0.001

Asthma 1/13 (8) 9/29 (31) 0.21

Acute respiratory failure 35/897 (4) 109/1,083 (10) ,0.001

Gas exchange

Prior to noninvasive ventilation

pH, mean (SD) 7.31 (0.09) 7.32 (0.10) 0.73

PaCO2, mean (SD), mm Hg 58 (23) 53 (22) 0.23

Ratio PaO2to FIO2

, mean (SD) 172 (83) 175 (90) 0.84

Need for intubation, n (%) 19 (31) 65 (35) 0.59

ICU mortality among all noninvasive

positive-pressure ventilation

patients

18/61 (30) 44/186 (24) 0.36

Mortality in failed noninvasive

ventilation, n (%)

9/19 (47) 31/65 (47) 0.98

Mortality in successful noninvasive

ventilation, n (%)

9/42 (21) 13/121 (10) 0.08

Definition of abbreviations: COPD 5 chronic obstructive pulmonary disease;

ICU 5 intensive care unit.

TABLE 4. CHARACTERISTICS AND OUTCOMES OF PATIENTSWITH ACUTE RESPIRATORY DISTRESS SYNDROME


P Value(n 5 135) (n 5 198)

Age, mean (SD), yr 64 (14) 62 (17) 0.45


mean (SD), points

39 (14) 36 (15) 0.18

Reason for initiation of ventilation

when not ARDS,* n (%)

(n 5 68) (n 5 136)

COPD 3 (4) 3 (2) 0.40

Pneumonia 17 (25) 38 (28) 0.65

Postoperative 9 (13) 7 (5) 0.04

Sepsis 9 (13) 24 (18) 0.42

Trauma 13 (12) 11 (8) 0.39

Aspiration 2 (3) 10 (7) 0.21

Ventilator settings in the first week

of ARDS

Tidal volume, ml/kg actual body weight

Higher, median (SD) 10 (9, 11) 8 (7, 10) ,0.001

Lower, median (SD) 8 (7, 9) 6 (5, 8) ,0.001

PEEP,† cm H2O

Higher, median (IQR) 10 (8, 12) 12 (8, 15) ,0.001

Lower, median (IQR) 5 (0, 8) 5 (0, 8) 0.66

Peak pressure, cm H2O

Higher, median (IQR) 39 (34, 45) 37 (31, 42) 0.004

Lower, median (IQR) 29 (26, 33) 26 (21, 31) ,0.001

Plateau pressure,‡ cm H2O

Higher, median (IQR) 29 (24, 32) 29 (24, 32) 0.68

Lower, median (IQR) 22 (22, 28) 23 (18, 26) 0.11

Use of a pressure/volume limitation

strategyx

Days of utilization per 1,000 ARDS-days 206 548 ,0.001

Percentage of the days fulfilling

ARDS criteria, mean (SD)

27 (40) 54 (43) ,0.001

Duration of intubation, median (IQR), days 8 (5, 15) 10(5,16) 0.27

Length of stay in the ICU, median (IQR), d 12 (7, 23) 14 (7, 21) 0.54

ICU mortality, n (%) 82 (61) 111 (56) 0.39

Hospital mortality,k n (%) 87/126 (69) 117/185(63) 0.29

Definition of abbreviations: ARDS 5 acute respiratory distress syndrome; CI 5

confidence interval; COPD 5 chronic obstructive pulmonary disease; ICU 5

intensive care unit; IQR 5 interquartile range; PEEP 5 positive end-expiratory

pressure.

* Reason for initiation of ventilation is applicable to patients who developed

ARDS over the course of mechanical ventilation.† On the first day with criteria of ARDS, 16% of patients in 1998 and 11% in

2004 were ventilated with zero PEEP.‡ Plateau pressure was available in 90 patients in 1998 and in 144 patients in

2004. Ventilator settings (tidal volume and end-expiratory positive pressure) in

these patients were similar to patients whose plateau pressure was not available.x Pressure/volume limitation strategy was arbitrarily defined as tidal volume less

than 6 ml per kg actual body weight, or volume tidal less than 8 ml/kg actual

body weight and plateau pressure or peak inspiratory pressure less than 30 cm

H2O.k Patients whose status at discharge from hospital was unknown were not

included in the calculation.


First, however, we must point out that, in this utilization review,detecting differences in clinical outcomes was not the primaryoutcome; consistent with our chosen methodology, examiningchange (or lack of change) in clinical practice was our mainobjective. This type of before–after international observationalstudy is methodologically ideal for describing changes in usualpractice, but it is clearly not the design of choice for studying theeffects of these changes on patient outcomes, and therefore ourresults should not be taken to overturn those of prior randomizedcontrolled trials. We believe that we should still look to results ofrandomized trials in mechanical ventilation to help guide ustoward what we should be doing; meanwhile, studies like oursinform us of what we are doing.

Some of the reasons for a lack of improvement in outcomesmay therefore be related to study design and are applicableacross all patient groups. These include the possibility thatdifferences in ICU admission patterns over time led to a patientpopulation with a higher risk of worse outcomes in the 2004cohort. In addition, although overall practice change may havemoved in the right direction along a continuous spectrum (e.g.,in reducing tidal volume in ARDS), it is possible that themagnitude of this change was insufficient to effect the samechanges seen in prior trials. Importantly, we must recognize thatour study is underpowered to detect clinically important reduc-tions in mortality (again, this was not our primary outcome),especially in the smaller subpopulations where the strongestrandomized trial evidence for mortality benefit exists. It is en-couraging to note, however, that numerically, if not statisticallysignificantly, ICU mortality rates were 5–6% lower in 2004among the noninvasive ventilation and ARDS subgroups, andin the overall population hospital mortality was indeed statis-tically significantly lower in 2004.

We note that coincident with a doubling in the use of non-invasive ventilation in subgroups with the strongest support fromclinical trial data (COPD and congestive heart failure), we haveobserved a 50% reduction in the overall numbers of patients inthe ICU whose primary reason for mechanical ventilation wasCOPD or heart failure. We speculate that this may be a result ofincreased uptake and successful use of noninvasive ventilation inthese patients outside the ICU (e.g., in the emergency room,recovery room, hospital ward), which in turn could have createda form of selection bias, whereby patients with a poor clinicalevolution were admitted to the ICU for ongoing ventilatorysupport. Finally, in the noninvasive ventilation group, and to aneven greater extent in the group with ARDS, prior randomizedtrials were appropriately conducted in populations that werecarefully selected to a maximize treatment effects. For example,in the ARDS (Acute Respiratory Distress Syndrome) Networkstudy of low tidal volume ventilation, only 12% of all screenedpatients with acute lung injury were actually enrolled in the trial,with many being excluded because of comorbidities that wouldlimit the efficacy of lung-protective ventilation in reducingmortality (19). In contrast, our observational study included allpatients that were identified by their physicians as having ARDS.The presence of this dilution of effect (i.e., a lack of selection ininclusion) is supported by the fact that outcomes observed in ourstudy in 2004 were uniformly worse than those reported in clinicaltrials. ARDS mortality was 56% compared with 30% or lessreported in ARDS Network clinical trials (20–22), and the failurerate for noninvasive ventilation (need for intubation) was 35%compared with trial values of 15–30% (23–26).

Little is known about knowledge translation in the ICU,both in terms of the scope of the problem and the best way tostudy and overcome potential barriers (6, 7). Implementingresearch findings in the ICU may be very different from anoutpatient primary care setting, with many issues needing to beaddressed at a system level, rather than influencing the opinionor behavior of individual physicians. Considerations such as thespecialist nature of ICU practice, the fact that many ICUclinicians are focused on ventilatory care, and the relativelysmall number of positive clinical trials available to guide clinicalpractice all may have contributed to our positive findings.

On the other hand, it is possible to ask whether the degree ofpractice change that we observed is sufficient. This is an extremelydifficult question to answer, and certainly one that needs furtherstudy. The situation for general strategies of mechanical ventila-tion in the ICU is much more complex than, for example, thesituation of drug prescription for a defined disease. In the case ofmechanical ventilation, change generally involves a shift inpractice along a spectrum in the application of a commontechnique, rather than the introduction of a new drug. Moreover,the generalizability of oftentimes single-center study results toheterogeneous ICU populations contrasts with the generalizabil-ity of results from multiple multicenter trials to a more homoge-neous population, as in studies of acute myocardial infarction.All of these factors may influence clinicians’ choices regarding theimplementation of new evidence (10, 27). As noted above,however, it is possible that an insufficient degree of practicechange contributed to our inability to detect significant reduc-tions in ICU mortality over time. Overall, however, we are unableto comment with certainty on the adequacy of observed clinicalpractice change, only on the direction of this change.

On reading our results with respect to weaning and liberationfrom mechanical ventilation, one might initially question how itwas possible for us to detect an increased use of spontaneousbreathing trials to identify extubation readiness while simulta-neously documenting a reduction in the use of spontaneousbreathing trials as a weaning method. This seemingly paradoxical

TABLE 5. CHARACTERISTICS AND OUTCOMES OF PATIENTSWHO UNDERWENT PLANNED EXTUBATION


P Value(n 5 780) (n 5 869)

Age, mean (SD), yr 58 (19) 56 (18) 0.02


mean (SD), points

42 (16) 40 (17) 0.08

Main reason for mechanical

ventilation, n (%)

COPD 85 (11) 53 (6%) ,0.001

Asthma 10 (1) 18 (2%) 0.21

Other chronic pulmonary disease 3 (0.4) 7 (1%) 0.27

Coma 154 (20) 221 (25%) 0.006

Neuromuscular disease 11 (1) 12 (1%) 0.96

Acute respiratory failure

Postoperative 178 (23%) 163 (19%) 0.04

Pneumonia 85 (11%) 87 (10%) 0.56

Sepsis 50 (6%) 72 (8%) 0.15

ARDS 22 (3%) 24 (3%) 0.94

Congestive heart failure 96 (12%) 51 (6%) ,0.001

Cardiac arrest 14 (2%) 37 (4%) 0.004

Trauma 59 (8%) 37 (4%) 0.004

Aspiration 16 (2%) 15 (2%) 0.63

Other cause 52 (7%) 72 (8%) 0.21

Days of mechanical ventilation prior

to weaning, median (IQR)

3 (2,6) 4 (2,7) 0.004

Days of weaning in difficult-to-wean

patients median (IQR)*

3 (2, 5) 3 (2, 4) 0.94

Time devoted to weaning, median (IQR),

% of total ventilation time

50 (28, 67) 40 (25, 50) ,0.001

Reintubation within 48 h, n (%) 127 (16.3) 105 (12.1) 0.01

Definition of abbreviations: ARDS 5 acute respiratory distress syndrome; COPD

5 chronic obstructive pulmonary disease; IQR 5 interquartile range.

* Difficult-to-wean patients were those who failed their first spontaneous

breathing trial.


result is explained by the fact that we, like many clinicians, madea sharp distinction between detecting readiness to liberate fromthe ventilator and true weaning. The increased use of spontane-ous breathing trials to identify extubation readiness refers to theformer, and reflects the fact that more patients underwent a trialto detect extubation readiness after meeting standard ‘‘readinessto wean’’ criteria (improvement in the cause of respiratoryfailure, PaO2

/FIO2. 200 mm Hg, PEEP < 5 cm H2O, and stable

cardiovascular function with no vasoactive drugs). The majority(77%) of these patients were successfully extubated after this firsttrial and did not need any true weaning. In contrast, the reductionin the use of spontaneous breathing trials as a method for weaningrefers only to patients who had already failed their first trial andhad thus demonstrated their need for weaning. In this situation,we saw an increase in the use of gradual reductions in pressuresupport, and a moderate decrease in the use of daily spontaneousbreathing trials as weaning methods (along with a marked reductionin the use of synchronized intermittent mandatory ventilation).

To our knowledge, this is the first study to analyze theevolution of mechanical ventilation practices over time amongsuch a large and diverse group of patients with respiratoryfailure. Additional strengths of this study include the following:the reasonably homogeneous study populations under compar-ison, the rigorous approach to identifying relevant literature,and the development of practice-change hypotheses before anyknowledge of the results of the second cohort study. In an effortto limit sampling bias, our nested cohort study compared onlypatients admitted to ICUs that participated in both studies.Limitations of our study include the fact that we did not collectinformation to describe the process by which practice changed—for example, some of the study ICUs may have implementedguidelines related to the topics we evaluated in our study. Asdiscussed above, we are unable to judge whether or not thedegree of practice change we observed was appropriate. Finally,for management of ARDS, we are only able to comment onpractice change among patients who have been identified byclinicians as having this condition. Previous work suggests thatARDS is underrecognized by clinicians (28), and we acknowl-edge that it is possible that a number of patients with this entitydid not receive treatment according to the current evidence.

In conclusion, our results provide a description of the currentusual care and outcomes of mechanically ventilated patientsacross several countries and continents. As indicated by theconcordance of predicted and observed practice changes, ourstudy demonstrates that, in the field of respiratory failure andmechanical ventilation, the translation of clinical research toclinical practice is happening. Significant reductions in ICUmortality were not demonstrated; several potential mechanismsfor this finding exist.

Conflict of Interest Statement: A.E. does not have a financial relationship witha commercial entity that has an interest in the subject of this manuscript. N.D.F.does not have a financial relationship with a commercial entity that has aninterest in the subject of this manuscript. M.O.M. does not have a financialrelationship with a commercial entity that has an interest in the subject of thismanuscript. F.F.-V. does not have a financial relationship with a commercialentity that has an interest in the subject of this manuscript. C.A. does not havea financial relationship with a commercial entity that has an interest in the subjectof this manuscript. L.B. received research contracts from Drager Medical for theconduct of studies concerning a ventilation system (SmartCare) and receivedapproximately V15,000 per year from 2001 to 2004 and approximately V10,000in 2006 in royalties from Drager. K.R. does not have a financial relationship witha commercial entity that has an interest in the subject of this manuscript. N.N.does not have a financial relationship with a commercial entity that has aninterest in the subject of this manuscript. J.H. does not have a financial relation-ship with a commercial entity that has an interest in the subject of thismanuscript. V.T. does not have a financial relationship with a commercial entitythat has an interest in the subject of this manuscript. M.G. does not havea financial relationship with a commercial entity that has an interest in the subjectof this manuscript. J.E. does not have a financial relationship with a commercialentity that has an interest in the subject of this manuscript. P.N. does not have

a financial relationship with a commercial entity that has an interest in the subjectof this manuscript. F.A. does not have a financial relationship with a commercialentity that has an interest in the subject of this manuscript. P.P. does not havea financial relationship with a commercial entity that has an interest in the subjectof this manuscript. Y.A. does not have a financial relationship with a commercialentity that has an interest in the subject of this manuscript. R.M. does not havea financial relationship with a commercial entity that has an interest in the subjectof this manuscript. M.J. does not have a financial relationship with a commercialentity that has an interest in the subject of this manuscript. G.D. does not havea financial relationship with a commercial entity that has an interest in the subjectof this manuscript. F.S. does not have a financial relationship with a commercialentity that has an interest in the subject of this manuscript. D.M. does not havea financial relationship with a commercial entity that has an interest in the subjectof this manuscript. A.M.M. does not have a financial relationship with a com-mercial entity that has an interest in the subject of this manuscript. A.A. has beena consultant for Boehringer Ingelheim, Bayer Pharma, Pfizer, GlaxoSmithKline,Sanofi-Aventis, Sepracor, and Schering Plough Corporation (all in 2006);participated as a speaker in scientific meetings or courses organized and financedby Boehringer Ingelheim, Bayer Pharma, Pfizer, GlaxoSmithKline, Sanofi-Aventis,Altana, and Schering Plough Corporation; and has been the principal investigatorfor participating in multicenter clinical trials sponsored by Boehringer Ingelheim($50,000), Bayer Pharma ($30,000), BARD ($60,000), Lilly, and GlaxoSmithKline($200,000).

The VENTILA group members include the following:*

ARGENTINA: Coordinators: Carlos Apezteguia (Hospital Prof. A. Posadas, El Palomar,Buenos Aires) and Pablo Desmery (Sanatorio Mitre, Buenos Aires). A. Sarasinoand D. Ceraso (Hospital Dr. Juan A. Fernandez, Buenos Aires), D. Pezzola andF.Villarejo (Hospital Prof. A. Posadas, El Palomar), C. Cozzani and M. Torres Boden(Hospital Dr. C. Argerich, Buenos Aires), C. Santos and E. Capparelli (Hospital EvaPeron, San Martın), M. Tavella and C. Irrazabal (Hospital de Clınicas Jose de SanMartın, Buenos Aires), L. Cardonnet and A. Diez (Hospital Provincial del Centenario,Rosario), A. Giannelli and L. Vargas (Policlınico de Neuquen), M. Bustamante(Hospital Heroes de Malvinas, Merlo), E. Turchetto (Hospital Privado de laComunidad, Mar del Plata), J. Teves and O. Elefante (Hospital Oscar Alende,Mar del Plata), C. Sola and J. Mele (Hospital Dr. Jose Penna, Bahıa Blanca), V.Sciuto and P. Grana (Hospital Provincial de Neuquen), G. Jannello and R.Valentini (CEMIC, Buenos Aires), S. Ilutovich (Sanatorio Mitre, Buenos Aires), L.Huespe Gardel (Hospital Escuela Jose F. de San Martın, Corrientes), J. Scapellatoand E. Orsini (Hospital F. Santojanni, Buenos Aires), G. Aguero and A. Sanchez(Policlınico Regional J. Peron, Mercedes), R. Fernandez and L. Villalobos Casta-neda (Hospital Italiano, Buenos Aires), F. Gonzalez and E. Estenssoro (HospitalGeneral San Martın, La Plata), S. Lasdica (Hospital Privado del Sur, Bahıa Blanca), A.Gomez and J. Scapellato (Clınica de la Esperanza, Buenos Aires), P. Pratesi(Hospital Universitario Austral, Pilar), M. Blasco and F. Villarejo (Clınica Olivos,Olivos), G. Olarte and C. Bevilacqua (Clınica Modelo de Moron / Hospital San Juande Dios, R.Mejıa), M. Quinteros (Sanatorio San Lucas, San Isidro), P. Ripoll(Clınica La Sagrada Familia, Buenos Aires), S. Filippus (Clınica del Valle,Comodoro Rivadavia), F. Guzman Dıaz and M. Deheza (Hospital B. Rivadavia,Buenos Aires), E. Garcıa and J. Arrieta (Hospital Regional de ComodoroRivadavia), P. Pardo and J. Neira (Sanatorio de la Trinidad, Buenos Aires), J. Nunezand F. Palizas (Clınica Bazterrica, Buenos Aires), A. Ciccolini and G. Murias(Sanatorio Santa Isabel, Buenos Aires), W. Vazquez and M. Grilli (Hospital Espanol,Mendoza), F. Chertcoff and E. Soloaga (Hospital Britanico, Buenos Aires), D.Vargas and J. Beron (Hospital Pablo Soria, San Salvador de Jujuy), A. Maceira and P.Schoon (Hospital Prof. Luis Guemes, Haedo), D. Pina (Sanatorio Franchın, BuenosAires), E. Sobrino and A. Raimondi (Sanatorio Mater Dei, Buenos Aires), E. De Vito(Instituto Alfredo Lanari, Buenos Aires).

BELGIUM: M. Malbrain (Ziekenhuis Netwerk, Antwerpen).

BOLIVIA: Coordinator: Freddy Sandi Lora (Hospital obrero N 8 1, La Paz). A.Lavandez and C. Alfaro (Complejo Hospitalario Viedma, La Paz), J. Guerra(Instituto gastroenterologico boliviano japones, Santa Cruz).

CANADA: Coordinators: Niall D. Ferguson (Toronto Hospital Western) and MaureenO. Meade (McMaster University). J. T. Granton (Toronto General Hospital), S. E.Lapinsky (Mount Sinai Hospital, Toronto), J. Meyer (St. Joseph’s Hospital, Toronto),D. C. Scales (St. Michael’s Hospital, Toronto), R. A. Fowler (Sunnybrook HealthSciences Centre, Toronto), B. Kashin (William Osler Health Centre, Brampton,Ontario), D. J. Cook (St. Joseph’s Healthcare).

CHILE: Coordinator: Vinko Tomicic (Clınica Alemana de Santiago). L. Soto(Instituto Nacional del Torax, Santiago), C. Romero (Hospital Clınico PontificiaUniversidad Catolica, Santiago), M. Teresa Caballero and L. Chiang (Hospital navalalmirante Nef), E. Poch (Instituto de Neurocirugıa), J. Canteros Gatica (HospitalCurico), H. Ugarte (Hospital de Coquimbo), M. Calvo, C. Vargas, and M. Yacsich(Hospital Regional de Valdivia), E. Tobar (Hospital Clınico de la Universidad deChile, Santiago), J. G. Urra (Clınica Alemana de Temuco).

COLOMBIA: Coordinator: Marco A. Gonzalez (Clınica Medellın y UniversidadPontificia Bolivariana, Medellın). A. Guerra (Hospital General de Medellın andClınica SOMA, Medellın), C. Cadavid (Hospital Pablo Tobon Uribe, Medellın), R.Panesso (Clınica Las Americas, Medellın), M. Granados (Clınica Valle del Lilli, Cali),


C. Duenas (Hospital Bocagrande, Cartagena), F. Molina (Clınica Bolivariana,Medellın), R. Camargo (Clınica General del Norte de Barranquilla), G. Ortiz(Hospital de Santa Clara, Bogota), M. Gomez (Hospital de San Jose).

ECUADOR: Coordinator: Manuel Jibaja (Hospital Militar de Quito). G. Paredes and E.Bazantes (Hospital Enrique Garces, Quito), P. Jimenez (Hospital Carlos AndradeMartın, Quito), J. Vergara and L. Gonzalez (Hospital Luis Vernaza Valdez,Guayaquil).

FRANCE: Coordinators: Laurent Brochard (Centre hospitalier Albert-Chenvier-HenriMondor, Paris) and Arnaud Thille (Centre hospitalier Albert-Chenvier-Henri Mondor,Paris). L. Mallet (Centre Hospitalier D’Auch), P. Andrivet (Centre Medico-Chirur-gical de Bligny, Bris-sous-Forges), O. Peyrouset (Hopital Ambroise Pare, BoulogneBillancourt), I. Mohammedi (Hopital Edouard Herriot, Lyon), E. Guerot (HopitalEuropeen Georges Pompidou, Paris), N. Deye (Hopital Lariboisiere, Paris), S.Monsel and F. Bouvet (Hopital Pitie Salpetriere, Paris), M. Darmon (Hopital SaintLouis, Paris), M. Fartoukh and A. Harb (Hopital Tenon, Paris), N. Anguel (Hopital deBicetre, Kremlin-Bicetre).

GERMANY: Coordinator: Konstantinos Raymondos (Medizinische HochschuleHannover). A. Nowak, T. Pahlitzsch, and K. F. Rothe (Krankenhaus Dresden-Friedrichstadt), M. Ragaller and T. Koch (Universitaetsklinikum Carl Gustav CarusDresden), G. Sterzel (Kreiskrankenhaus Loebau, Ebersbach), R. Wittich (Carl-Thiem-Klinikum Cottbus GmbH), K. Rudolph and J. Raumanns (St. ElisabethGmbH, Leipzig), U. Grueneisen and F. Stupacher (BundeswehrkrankenhausLeipzig), H. Bromber, G. Leonhardt, and J. Soukup (Universitaetsklinikum derMartin-Luther-Universitaet Halle-Wittenberg), C. Wuttke (Krankenhaus St. Elisa-beth und St. Barbara Halle, Saale), M. Holler (Staedtisches Krankenhaus Martha-Maria Halle-Doelau GmbH), J. Haberkorn (Georgius-Agricola-Klinikum Zeitz), P.Jehle (Paul-Gerhard-Stiftung, Lutherstadt Wittenberg), B. Albrecht (Zeisigwald-kliniken Bethanien Chemnitz), Klut (Kreiskrankenhaus Rochlitz), H. J. Hartung(Vivantes Krankenhaus am Urban, Berlin-Kreuzberg), H. Gerlach (Vivantes-Klinikum Neukoelln, Berlin), T. Henneberg, S. Weber-Carstens, K. Haid, C.Melzer-Gartzke, and M. Oppert (Charite Universitaetsklinikum, Campus Virchow,Berlin), M. Reffenberg (Lungenklinik Heckeshorn, Berlin), Ch. Werel and A.Kopietz (Klinikum Barnim GmbH, Werner Forßmann Krankenhaus, Eberswalde),T. Nippraschk and D. Hoffmeister (Ruppiner Klinikum GmbH, Neuruppin), M.Schneider (Dietrich-Bonhoeffer-Klinikum-Neubrandenburg), D. A. Vagts and G.Noeldge-Schomburg (Medizinische Fakultaet der Universitaet Rostock), G.Savinski and T. Kloess (Allgemeines Krankenhaus Harburg, Hamburg), C. Frenkel,D. Yakisan, H. Schroeder, and C. Daniels (Staedtisches Klinikum Lueneburg), B.Sedemund-Adib (Universitaetsklinikum Schleswig Holstein–Campus Luebeck), S.Krueper (Klinikum Hannover Nordstadt), J. Ahrens, U. Molitoris, and K. Johanning(Medizinische Hochschule Hannover), D. Korth and W. Seitz (KreiskrankenhausHameln), J. Kleideiter and P. Palomino (Staedtische Kliniken Bielefeld GmbH), A.Lunkeit and Schlechtweg (Klinikum Bad Salzungen GmbH), M. Quintel (Uni-versitaetsklinikum der Georg-August-Universitaet Goettingen), K. Schild and C. P.Criee (Evangelisches Krankenhaus Goettingen-Weende e.V., Bovenden-Len-glern), M. Bund (Albert-Schweitzer-Krankenhaus Northeim), M. Hundt, U.Schulze, and J. Kolle (Kreiskrankenhaus Charlottenstift, Stadtoldendorf), J.Offensand, S. Youssef, and J. P. Juvana (Klinikum Salzgitter GmbH), W. Seyde(Staedtisches Klinikum Wolfenbuettel), T. Luecke and A. Gruener (Universitaets-klinikum Mannheim), E. Calzia (Universitaetsklinikum fur Anasthesiologie, Ulm),J. Heine, M. Borth, U. von Leitner and M. Hoffmann (Dr. Herbert-Nieper-Krankenhaus-Goslar), W. Brandt (Universitaetsklinikum Magdeburg), A. Kellerand S. Scieszka (Krankenhaus Neuwerk, Moenchengladbach), E. Schroeder andF. L. Deres (Kreiskrankenhaus Dormagen), M. Burrichter, T. Bernhardt, and W.Wilhelm (St.-Marien-Hospital, Luenen), M. Beiderlinden (UniversitaetklinikumEssen), H. Steiniger and V. Weißkopf (Ruhrlandklinik, Essen), H. Militzer (Evan-gelisches und Johanniter Klinikum, Dinslaken), K. Eicker and F. Hinder (Uni-versitaetsklinikum Muenster), C. Weilbach and M. Raab (St. Josefs-StiftCloppenburg), Ragaymutu (Kliniken der Stadt Koeln Krankenhaus Holweide),T. Moellhoff and K. Tsompanidis (Katholische Stiftung Marienhospital Aachen),D. Henzler and R. Kuhlen (Universitaetsklinikum Aachen), H. Wrigge, C.Putensen, and F. L. Dumoulin (Universitaetsklinikum Bonn), M. Foedisch and J.Busch (Evangelisches Waldkrankenhaus Bad Godesberg GmbH, Bonn), W.Theelen (St. Johannes-Krankenhaus Troisdorf), A. Deller (Krankenhaus derBarmherzigen Brueder, Trier), W. Baier (St. Nikolaus-Stiftshospital GmbH, Ander-nach), Eller (Staedt. Hellmig-Krankenhaus, Kamen), K. Schwarke (Evang. Kran-kenhaus Schwerte GmbH), Buettner (Evangelisches Krankenhaus ElisabethenstiftGmbH, Darmstadt), K. P. Wresch and K. Steidel (St.-Vincentius-KrankenhausSpeyer), J. F. Meyer (Universitaetsklinikum der Ruprecht-Karls-Universitaet Hei-delberg), M. Layer (Thoraxklinik Heidelberg GmbH), G. Meinhardt (Robert-Bosch-Krankenhaus, Stuttgart), J. Fritschi and P. Zaar (Ermstalklinik StaedtischesKrankenhaus Sindelfingen), H. P. Stegbauer (Kreiskrankenhaus Leonberg), Tum-bass and S. Hahn (Ermstalklinik Bad Urach), H. Mende, M. Fischer, J. Martin, andA. Assmann (Klinik am Eichert Goeppingen), V. Schoeffel, K. van Deyk, and S.Seyboth (Stadtklinik Baden-Baden), H. Kerger and Ernst (Evangelisches Diako-niekrankenhaus, Freiburg), H. F. Ginz (Kreiskrankenhaus Loerrach), F. Brettner(Krankenhaus der Barmherzigen Brueder, Muenchen), O. Karg (ASKLEPIOSFachkliniken Muenchen-Gauting), M. Glaser and T. P. Zucker (Klinikum Traun-stein), J. Jahn and A. Schneider (Fachkliniken Wangen), M. Burkert (Bundes-wehrkrankenhaus Ulm), H. Kuenzig and T. Bein (Klinikum der UniversitaetRegensburg), A. Speicher (Krankenhaus der Barmherzigen Brueder, Regensburg),J. Brederlau, E. Kaufmann, F. Schuster, and C. Soellmann (UniversitaetsklinikWuerzburg), S. Frenzel and L. Pfeiffer (Unstrut-Hainich Kreiskrankenhaus Muehl-

hausen), S. Weber-Carstens, K. Haid, C. Melzer-Gartzke, C. von Heymann, and B.

Temmesfeld (Charite Universitaetsklinikum, Campus Mitte, Berlin).

GREECE: Coordinator: Dimitrios Matamis (Papageorgiou General Hospital, Thessa-

loniki). H. Mouloudi (Ippokration General Hospital, Athens).

ITALY: Coordinator: Paolo Pelosi (Ospedale di Circolo di Varese). A. Pesenti and N.Rossi (Ospedale San Gerardo, Monza), D. Chiumello and L. Gattinoni (OspedaleMaggiore Policlinico, Milano), P. Severgnini (Ospedale di Circolo di Varese), R.Fumagalli and A. Nikiforov (Ospedali Riuniti di Bergamo), S.Grasso (Ospedale diVenere, Bari).

MEXICO: Coordinator: Jose Elizalde (Hospital ABC, Mexico DF). P. Cerda (CentroMedico de las Americas, Merida), R. Mercado (Hospital Universitario de Mon-terrey), J. Albe Castanon (Instituto mexicano del seguro social HECMNS XXI,Mexico DF).

THE NETHERLANDS: Michael Kuiper (Medical Center Leeuwarden). P. H. M. Egbersand M. Koopmans (Medical Center Leeuwarden).

PERU: Coordinator: Ana Marıa Montanez. M. Contardo, J. Cerna, and R. Roldan(Hospital Edgardo Rebagliati Martins, Lima), J. Zevallos and S. Alcabes (Hospital

Guillermo Almenara Irigoyen, Lima), C. Salcedo and D. Bruzone (Hospital Nacional

Daniel Alcides Carrion, Callao), J. Quinones (Hospital de Emergencias Grau,

Lima), M. Suarez Lazo (Hospital Nacional Hipolito Unanue, Lima), A. Cifuentes

(Hospital de Emergencias Jose Casimiro Ulloa, Lima), M. Mayorga (Clınica San

Pablo, Lima).

PORTUGAL: Coordinator: Rui Moreno (Hospital de Santo Antonio dos Capuchos,

Lisboa). P.Casanova (Hospitais da Universidade de Coimbra), R. Matos and A. L.

Jardim (Hospital de Santo Antonio dos Capuchos, UCIP, Lisboa), A. Godinho

(Hospital dos SAMS, UCI, Lisboa), P. Povoa (Hospital Sao Francisco Xavier, UCIM,

Lisboa), P. Coutinho (Centro Hospitalar de Coimbra), L. Reis (Hospital de Sao

Jose, Unidade de Urgencia Medica, Lisboa).

SAUDI ARABIA: Coordinator: Yaseen Arabi (King Fahad National Guard Hospital). N.

Abouchala (King Faisal Hospital), F. Hameed (King Khalid National Guard

Hospital).

SPAIN: Coordinators: Nicolas Nin and Eva Tejerina (Hospital Universitario deGetafe). F. Gordo (Fundacion Hospital de Alcorcon), R. Fernandez (ComplejoHospitalario Parc Taulı, Sabadell), R. de Pablo (Hospital Universitario Prıncipe deAsturias, Alcala de Henares), J. Ibanez (Hospital Son Dureta, Palma de Mallorca), E.Fernandez Mondejar (Hospital Virgen de las Nieves, Granada), F. del Nogal(Hospital Severo Ochoa, Leganes), F. Taboada (Hospital Central de Asturias,Oviedo), A. Garcıa Jimenez (Hospital Arquitecto Marcide, El Ferrol), L. Cabre andJ. Morillas (Hospital de Barcelona-SCIAS), S. Macias (Hospital General de Segovia),R. de Celis (Hospital de Galdakao), J. M. Anon (Hospital Virgen de la Luz, Cuenca),P. Ugarte (Hospital Marques de Valdecilla, Santander), T. Mut (Hospital de la Plana,Vila-Real), J. Diarte (Complejo Hospitalario de Ciudad Real), V. Sagredo (HospitalClınico de Salamanca), M. Valledor (Hospital San Agustın, Aviles), G. Gonzalez andL. Rodrıguez (Hospital Morales Meseguer, Murcia), V. Parra and E. Gomez (Hospitalde Sagunto), F. Jara (Hospital Mutua de Terrassa), J. M. Quiroga (Hospital deCabuenes, Gijon), L. Arnaiz (Hospital Clınico Universitario de San Carlos, Madrid), A.Ayensa (Hospital Virgen de la Salud, Toledo), F. Suarez Sippman (FundacionJimenez Dıaz), F. Carrizosa (Hospital General de Jerez de la Frontera), J. A.Rodrıguez Sarrıa (Hospital de Elda), C. Homs (Hospital San Jorge, Huesca), A. DıazLamas (Hospital Cristal Pinor, Ourense), M. Leon (Hospital Arnau de Vilanova,Lleida), J. Allegue (Hospital Nuestra Senora del Rosell, Cartagena), M. Ruano

(Hospital La Fe, Valencia).

TUNISIA: Coordinator: Fekri Abroug (Fattouma Bourguiba, Monastir). M. Besbes, J.Ben Khelil, K. Belkhouja, and K. BenRomdhane (Hospital Abderrahmane Mami,Ariana), S. Ben Lakhal, S. Abdellatif and K. Bousselmi (Hospital Rabta, Tunis), M.Amamou and H. Thabet (CAMUR, Tunis), L. Besbes and N. Nciri (FattoumaBourguiba, Monastir), M. Bouaziz, H. Kallel, and M. Bahloul (Habib BourguibaSfax), S. El Atrous, S. Merghli, and M. Feki Hassen (Tahar Sfar Mahdia).

TURKEY: Coordinator: Nahit Cakar (Istanbul Medical Facility, Istanbul). R. Iscimen(Uludag University School of Medicine, Bursa), M. Kyzylkaya (College ofmedicine, Ataturk University, Erzurum), B. Yelken (Osmangazi University, Eskise-mir), I. Kati (Medical Faculty of Yuzuncu Yil University, Van), T. Guldem (Hay-darpasa Numune Teaching and Research Hospital, Istambul), U. Koca (DokuzEylun University, Istanbul), M. Cicek (Inonu University of Medical Faculty,Malatya), H. Sungurtekin (Pamukkale University Medical Faculty).

UNITED KINGDOM: Coordinator: Peter Nightingale (Wythenshawe Hospital, Man-chester). J. Hunter (Macclesfield District General Hospital, Macclesfield), I. Grant(Rotherham District General Hospital, Rotherham), S. Mousdale (Blackburn RoyalInfimary, Blackburn), J. Harper (Royal Liverpool University Hospital, Liverpool),A. Conn (Wansbeck General Hospital, Ashington), D. Higgins (Southend Hospital,Westcliffe-on-Sea), D. Jayson (Southport and Formby District General Hospital,Southport), D. Hawkins (North Staffordshire Hospital, Stoke on Trent).


UNITED STATES: Coordinator: Antonio Anzueto (University of Texas Health ScienceCenter, San Antonio). A. C. Arroliga (Cleveland Clinic, Cleveland, OH), O. Gajic,Ch. Burger, and L. Gambino (Mayo Clinic, Rochester, MN), D. Ost, A. Fein, A.Kyprianou, L. Shulman, and S. Chang (North Shore University Hospital, NewYork, NY), J. S. Steingrub, M. A. Tidswell and K. Kozikowski (Baystate MedicalCenter, Springfield, MN), C. A. Piquette and L. Morrow (Creighton UniversityMedical Center, Omaha, NE), P. Scheinberg and J. Green (Saint Joseph’sHospital, Atlanta, GA), L. Penogreen and K. Kannady (Georgia State University,Kennestone, GA), M. Moss, M. Mealer, and R. D. Restrepo (Grady HospitalGeorgia, Atlanta, GA), H. E. Fessler, R. Brower, D. Hager, and A. Scully (JohnsHopkins University Hospital, Baltimore, MD), J. Beamis, D. E. Craven, and W.Miner (Lahey Clinic Medical Center, Burlington, MA), S. Blosser, K. Miller, L.Cornman, and J. Breidinger (Penn State Hershey Medical Center, Hershey, PA), J.T. Huggins and Ch. Strange (Medical University of South Carolina, Charleston, SC),N. S. Hill and L. Lawler (Tufts–New England Medical Center, Boston), M. Rembert(Newark Beth Israel Medical Center, Newark, NJ), H. K. Donnelly, J. D. D’Amico, R.G. Wunderink, N. Queseda, and J. Topin (Northwestern Memorial Home HealthUniversity, Chicago, IL), G. T. Kinasewitz and G. L. Lee (University of OklahomaHealth Sciences Center, Oklahoma City, OK), J. Walls and V. Zimmer (PresbyterianHealthcare, Charlotte, NC), A. X. Freire (Regional Medical Center, Memphis, TN),C. Steven and L. Caskey (Louisiana State University Health Sciences Center,Shreveport, LA), R. Dhand and L. A. Despins (University Hospital and Clinics MUHealthcare, Columbia, MD), R. Hyzy, R. E. Dechert, Carl Haas, D. Fickle(University of Michigan Medical Center, MD), D. Marks and S. Benslimane(University of Texas Health Science Center, San Antonio, TX), V. J. Cardenas, Jr.(University of Texas Medical Branch, Galveston, Ann Arbor, MI), M. J. Wing and P.Krumpe (VA Sierra Nevada Health Care System, Reno, NV), J. Truwit and M.Marshall (University of Virginia Health System, Charlottesville, VA), D. L. Herr(Washington Hospital Center, Washington, DC), R. D. Hite (Wake Forest BaptistHospital Medical Center, Winston-Salem, NC), P. J. McShane and K. N. Olivier(Wilford Hall Medical Center, Lackland, Texas), K. W. Presberg (Froedtert andMedical College, Milwaukee, WI).

URUGUAY: Coordinator: Javier Hurtado (Cudam Sanatorio Colon, SanatorioIMPASA and Hospital de Clınicas, Montevideo). M. Borde, E. Echavarrıa, S.Gomez, and M. Beron (Hospital Maciel, Montevideo), F. Villalba (Sanatorio Casade Galicia, Montevideo), I. Porras (Sanatorio CASMU 2, Montevideo), P.Cardinal, C. Surraco, and V. Navarrete (Sanatorio CASMU 4, Montevideo), F.Rodrıguez and J. C. Bagattini (Hospital Britanico, Montevideo), R. Garrido(Hospital Evangelico and Sanatorio IMPASA, Montevideo), S. Infanzon and J.Caraballo (Hospital Militar and CTI-SMI, Montevideo), C. Santos and A. Garcıa(Hospital de Clınicas, Montevideo), R. Cal (CTI-SMI, Montevideo), G. Pittini and J.Cabrera (Centro Nacional de Quemados, Montevideo), F. Bazzano and F.Domınguez (Hospital Pasteur, Colonia), P. Alzugaray, D. Gonzalez, and M.Machado (Sanatorio CAMOC, Carmelo), F. Torres (Sanatorio Mautone andAsistencial Medica de Maldonado, Maldonado), S. Mareque, M. Korintan,F.Mora, E. Altieri, E. Gianoni, C. Fregosi, A. Crossi, G. Larrarte (Sanatorio CAAMS,Soriano), O. Pereira (Sanatorio COMTA, Tacuarembo), J. Baraibar (HospitalRegional de Tacuarembo), A. Soler (Sanatorio COMEPA, Paysandu), M. Rodrı-guez Verde (Hospital Paysandu), M. Dıaz (Hospital de Salto and SanatorioUruguay, Salto), J. Martınez Ramos (Sanatorio Uruguay, Salto), I. Iturralde, W.Gonzalez, and E. Cubas (Sanatorio CAMDEL, Minas), A. Cataldo (SanatorioCAMEDUR, Durazno), O. Rocha (Sanatorio GREMEDA, Artigas), A. Deicas(Sanatorio CASMU 2 and Sanatorio CASMU 4).

VENEZUELA: Coordinator: Gabriel D’Empaire (Hospital de Clınicas, Caracas). R. Zerpa(Hospital Militar de Caracas), M. Narvez (Hospital Domingo Luciani, Caracas), F.Perez (Hospital de Clınicas, Caracas), J. Espana (Hospital Universitario de Caracas).

* ICUs that participated in both studies are shown in italics.

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Evolution of Mechanical Ventilation in Response to Clinical Research

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