Published ahead of print on October 25, 2007, doi:10.1164/rccm.200706-893OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200706-893OC
Evolution of Mechanical Ventilation in Response to Clinical Research1 CIBER Enfermedades Respiratorias, Hospital Universitario de Getafe, Madrid, Spain; 2 Interdepartmental Division of Critical Care Medicine, and Division of Respirology, Department of Medicine, University Health Network, University of Toronto, Toronto, Canada; 3 Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada; 4 Hospital Profesor A. Posadas, El Palomar, Buenos Aires, Argentina; 5 AP-HP, Centre Hospitalier Albert-Chenvier–Henri Mondor, INSERM U 841, Université Paris 12, Paris, France; 6 Medizinische Hochschule, Hannover, Germany; 7 Hospital de Clínicas, Montevideo, Uruguay; 8 Clínica Alemana de Santiago, Santiago, Chile; 9 Clínica Medellín y Universidad Pontificia Bolivariana, Medellín, Colombia; 10 Hospital ABC, México DF, México; 11 Wythenshawe Hospital, Manchester, United Kingdom; 12 Fattouma Bourguiba Monastir, Tunisia; 13 Ospedale di Circolo, Universita' degli Studi dell'Insubria, Varese, Italy; 14 King Fahad National Guard Hospital, Riyadh, Saudi Arabia; 15 Hospital de Santo António dos Capuchos, Lisboa, Portugal; 16 Hospital Militar de Quito, Quito, Ecuador; 17 Hospital de Clínicas, Caracas, Venezuela; 18 Hospital Obrero Número 1, La Paz, Bolivia; 19 Papageorgiou General Hospital, Thessaloniki, Greece; 20 Sociedad Peruana de Medicina Intensiva, Lima, Peru; and 21 South Texas Veterans Health Care System and University of Texas Health Science Center, San Antonio, Texas Correspondence and requests for reprints should be addressed to Andrés Esteban, M.D., Ph.D., Intensive Care Unit, Hospital Universitario de Getafe, Carretera de Toledo Km 12,500, 28905 Getafe, Madrid, Spain. E-mail: aesteban{at}ucigetafe.com
Rationale: Recent literature in mechanical ventilation includes strong evidence from randomized trials. Little information is available regarding the influence of these trials on usual clinical practice. Objectives: To describe current mechanical ventilation practices and to assess the influence of interval randomized trials when compared with findings from a 1998 cohort. Methods: A prospective international observational cohort study, with a nested comparative study performed in 349 intensive care units in 23 countries. We enrolled 4,968 consecutive patients receiving mechanical ventilation over a 1-month period. We recorded demographics and daily data related to mechanical ventilation for the duration of ventilation. We systematically reviewed the literature and developed 11 practice-change hypotheses for the comparative cohort study before seeing these results. In assessing practice changes, we only compared data from the 107 intensive care units (1,675 patients) that also participated in the 1998 cohort (1,383 patients). Measurements and Main Results: In 2004 compared with 1998, the use of noninvasive ventilation increased (11.1 vs. 4.4%, P < 0.001). Among patients with acute respiratory distress syndrome, tidal volumes 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 = 0.02). More patients were successfully extubated after their first attempt of spontaneous breathing (77 vs. 62%, P < 0.001). Use of synchronized intermittent mandatory ventilation fell dramatically (1.6 vs. 11%, P < 0.001). Observations confirmed 10 of our 11 practice-change hypotheses. Conclusions: The strong concordance of predicted and observed practice changes suggests that randomized trial results have advanced mechanical ventilation practices internationally.
Key Words: mechanical ventilation • mortality • acute respiratory distress syndrome • noninvasive positive-pressure ventilation • weaning
Implementation of known effective therapies is an important target in the provision of quality health care (1–3). Meanwhile, delays in the translation of knowledge from clinical research to clinical practice are ubiquitous (4, 5), and the practice of critical care medicine is no exception to this trend (6–10). An international, prospective, observational study of mechanical ventilation practices conducted in 1998 included 5,183 consecutive eligible patients from 20 countries (11). Our goals were to provide detailed natural history and prognostic data, to evaluate practice variability, and to generate "usual care" benchmarks for both clinicians and clinical investigators in the field of mechanical ventilation. Among other important observations, we found that patients continue to spend, on average, 40% of their duration of mechanical ventilation in the process of weaning, 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 interventions shown to improve survival associated with mechanical ventilation will be large. The past decade has witnessed the conduct of numerous randomized trials related to reducing the need for mechanical ventilation (e.g., noninvasive ventilation trials), reducing the duration of mechanical ventilation (e.g., weaning and extubation studies), and improving safety of mechanical ventilation (e.g., trials of lung-protective ventilation in acute respiratory distress syndrome [ARDS]). The impact of this body of research on clinical practice is unknown; moreover, the current relevance of 1998 data is diminishing (11, 12). We therefore conducted a second international observational study of mechanically ventilated patients using methodology similar to the original study. The objectives of this study were as follows: (1) to describe current mechanical ventilation practices, (2) to compare current results with those of the 1998 cohort study, and (3) to judge the concordance of practice change (or lack thereof) with interval reports of randomized trials. Some of the results of this study have been previously reported in the form of abstracts (13–15).
Observational Study In a prospective utilization review, we enrolled consecutive patients who received mechanical ventilation for at least 12 hours after admission to 1 of 349 participating ICUs within 23 participating countries. Beginning March 1, 2004, we enrolled patients over a 1-month period at each center, and followed each patient for the duration of mechanical ventilation, up to 28 days. Only the investigative team members at each site were aware of the purpose and the precise timing of the study. The research ethics board of each participating institution approved the study protocol.
We followed the methodology of the original study (11). We collected demographic and baseline data at ICU admission, and then recorded ventilator settings, gas exchange variables, ICU discharge or Day 28, whichever came first. We recorded method(s) and duration of weaning, and the need for reintubation or tracheostomy. As in the original study, we calculated the duration of weaning from the first day a patient met standard criteria for weaning readiness (improvement in the cause of respiratory failure, PaO2/FIO2 > 200 mm Hg, positive end-expiratory pressure [PEEP]
Literature Review
Two investigators (N.D.F., M.O.M.) independently applied the following criteria to select publications relevant to this study: (1) randomized controlled trial or systematic review of randomized controlled trials (study design); (2) adult patients with acute or acute-on-chronic respiratory failure (study population); (3) noninvasive positive-pressure ventilation, ventilator weaning technique, ventilation mode, lung-protective ventilation (including tidal volume or PEEP interventions), prone position, or tracheostomy (study intervention); and (4) outcomes of importance to patients (including mortality, intubation, reintubation, duration of ventilation, or length of hospital stay). Agreement between the two investigators for study inclusion was excellent (chance-corrected agreement,
Generation of Practice-Change Hypotheses
Statistical Analysis
Table 1 shows the 11 practice-change hypotheses developed from the systematic review of the literature (see the online supplement).
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 contributed patients to the 1998 study. During the 1-month study period, 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 that participated in both cohort studies. Table 2 summarizes the patient characteristics and main outcomes from both cohorts.
Noninvasive Positive-Pressure Ventilation As predicted, the use of noninvasive ventilation was significantly greater in the 2004 cohort, approximately doubling for both acute exacerbations of chronic obstructive pulmonary disease (COPD) and other causes of acute respiratory failure (Table 3). The median duration of noninvasive ventilation decreased (2 [2–4] vs 3. [2–6] d, P = 0.03], although neither the need for intubation nor the mortality among these patients changed significantly (Table 3).
ARDS We identified a total of 333 patients with ARDS who were admitted to one of the ICUs participating in both studies: 135 patients in 1998 and 198 patients in 2004 (Table 4). Tidal volumes over 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 below 6 ml/kg actual body weight (19.6 vs. 4.4%, P < 0.001). A strategy of pressure/volume limitation was applied significantly more commonly in 2004 than in 1998 (Table 4). PEEP levels in the first week increased (Table 4); use of PEEP greater than 10 cm H2O increased (40 vs. 28%, P < 0.001), whereas use of levels less than 5 cm H2O was unchanged (22 vs. 26%, P = 0.42). Inspiratory pressures were slightly lower in 2004 (Table 4).
Volume assist-control remained the most common ventilator mode used in ARDS and the use of pressure-control mode did not 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 = 0.19) and pressure-controlled ventilation in 244 and 202 days, respectively (P = 0.05). We observed a decrease in the use of prone position, which was used, at any time, in 7 versus 13% of patients in 1998 (P = 0.04). Outcomes for the patients with ARDS are displayed in Table 4. ICU mortality remained above 50% and was not significantly lower compared with the 1998 cohort.
Weaning from Mechanical Ventilation
Excluding patients admitted to the ICU with a tracheostomy tube in situ, 151 patients in 1998 and 206 patients in 2004 received a tracheostomy during their course of ventilation. The rate (12.5% [2004] vs. 11% [1998], P = 0.19) and median (interquartile range) timing of tracheostomy (2004, 11 [7–15] vs., 1998, 12 [7–17] d; P = 0.10) did not change.
The main finding of this study is the high degree of concordance between observed changes in mechanical ventilation practice and changes predicted from reports of randomized controlled trials; however, we were not able to detect significant differences in clinical outcomes. The results of this international utilization review may also serve as a current benchmark on the usual care and outcomes of patients requiring mechanical ventilation for acute respiratory failure. We developed 11 practice-change hypotheses, 7 of which predicted a change in practice, the others predicting no change and serving in a way as negative controls. Ten of our hypotheses were borne out when we compared patients admitted to those ICUs that participated in both the 1998 and 2004 cohort studies. The use of noninvasive positive-pressure ventilation doubled, the use of lower tidal volumes in ARDS increased, more patients were promptly extubated after a first attempt of spontaneous breathing, and fewer patients were weaned using synchronized intermittent mandatory ventilation. Meanwhile, as predicted, there was only a minimal increase in applied PEEP, no increase in the use of pressure-control ventilation, and no change in the use or timing of tracheostomy. Although we predicted no change in the use of prone ventilation for ARDS, there was a statistically significant reduction. Despite these positive changes in mechanical ventilation practices, clinical outcomes did not improve significantly between 1998 and 2004. We can speculate on a number of reasons as to why we arrived at this seemingly inconsistent and disappointing result. First, however, we must point out that, in this utilization review, detecting differences in clinical outcomes was not the primary outcome; consistent with our chosen methodology, examining change (or lack of change) in clinical practice was our main objective. This type of before–after international observational study is methodologically ideal for describing changes in usual practice, but it is clearly not the design of choice for studying the effects of these changes on patient outcomes, and therefore our results should not be taken to overturn those of prior randomized controlled trials. We believe that we should still look to results of randomized trials in mechanical ventilation to help guide us toward what we should be doing; meanwhile, studies like ours inform us of what we are doing. Some of the reasons for a lack of improvement in outcomes may therefore be related to study design and are applicable across all patient groups. These include the possibility that differences in ICU admission patterns over time led to a patient population with a higher risk of worse outcomes in the 2004 cohort. In addition, although overall practice change may have moved in the right direction along a continuous spectrum (e.g., in reducing tidal volume in ARDS), it is possible that the magnitude of this change was insufficient to effect the same changes seen in prior trials. Importantly, we must recognize that our study is underpowered to detect clinically important reductions in mortality (again, this was not our primary outcome), especially in the smaller subpopulations where the strongest randomized trial evidence for mortality benefit exists. It is encouraging to note, however, that numerically, if not statistically significantly, ICU mortality rates were 5–6% lower in 2004 among the noninvasive ventilation and ARDS subgroups, and in the overall population hospital mortality was indeed statistically significantly lower in 2004. We note that coincident with a doubling in the use of noninvasive ventilation in subgroups with the strongest support from clinical trial data (COPD and congestive heart failure), we have observed a 50% reduction in the overall numbers of patients in the ICU whose primary reason for mechanical ventilation was COPD or heart failure. We speculate that this may be a result of increased uptake and successful use of noninvasive ventilation in these patients outside the ICU (e.g., in the emergency room, recovery room, hospital ward), which in turn could have created a form of selection bias, whereby patients with a poor clinical evolution were admitted to the ICU for ongoing ventilatory support. Finally, in the noninvasive ventilation group, and to an even greater extent in the group with ARDS, prior randomized trials were appropriately conducted in populations that were carefully selected to a maximize treatment effects. For example, in the ARDS (Acute Respiratory Distress Syndrome) Network study of low tidal volume ventilation, only 12% of all screened patients with acute lung injury were actually enrolled in the trial, with many being excluded because of comorbidities that would limit the efficacy of lung-protective ventilation in reducing mortality (19). In contrast, our observational study included all patients that were identified by their physicians as having ARDS. The presence of this dilution of effect (i.e., a lack of selection in inclusion) is supported by the fact that outcomes observed in our study in 2004 were uniformly worse than those reported in clinical trials. ARDS mortality was 56% compared with 30% or less reported in ARDS Network clinical trials (20–22), and the failure rate 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 to study and overcome potential barriers (6, 7). Implementing research findings in the ICU may be very different from an outpatient primary care setting, with many issues needing to be addressed at a system level, rather than influencing the opinion or behavior of individual physicians. Considerations such as the specialist nature of ICU practice, the fact that many ICU clinicians are focused on ventilatory care, and the relatively small number of positive clinical trials available to guide clinical practice all may have contributed to our positive findings. On the other hand, it is possible to ask whether the degree of practice change that we observed is sufficient. This is an extremely difficult question to answer, and certainly one that needs further study. The situation for general strategies of mechanical ventilation in the ICU is much more complex than, for example, the situation of drug prescription for a defined disease. In the case of mechanical ventilation, change generally involves a shift in practice along a spectrum in the application of a common technique, rather than the introduction of a new drug. Moreover, the generalizability of oftentimes single-center study results to heterogeneous ICU populations contrasts with the generalizability of results from multiple multicenter trials to a more homogeneous population, as in studies of acute myocardial infarction. All of these factors may influence clinicians' choices regarding the implementation of new evidence (10, 27). As noted above, however, it is possible that an insufficient degree of practice change contributed to our inability to detect significant reductions in ICU mortality over time. Overall, however, we are unable to comment with certainty on the adequacy of observed clinical practice change, only on the direction of this change.
On reading our results with respect to weaning and liberation from mechanical ventilation, one might initially question how it was possible for us to detect an increased use of spontaneous breathing trials to identify extubation readiness while simultaneously documenting a reduction in the use of spontaneous breathing trials as a weaning method. This seemingly paradoxical result is explained by the fact that we, like many clinicians, made a sharp distinction between detecting readiness to liberate from the ventilator and true weaning. The increased use of spontaneous breathing trials to identify extubation readiness refers to the former, and reflects the fact that more patients underwent a trial to detect extubation readiness after meeting standard "readiness to wean" criteria (improvement in the cause of respiratory failure, PaO2/FIO2 > 200 mm Hg, PEEP To our knowledge, this is the first study to analyze the evolution of mechanical ventilation practices over time among such a large and diverse group of patients with respiratory failure. Additional strengths of this study include the following: the reasonably homogeneous study populations under comparison, the rigorous approach to identifying relevant literature, and the development of practice-change hypotheses before any knowledge of the results of the second cohort study. In an effort to limit sampling bias, our nested cohort study compared only patients admitted to ICUs that participated in both studies. Limitations of our study include the fact that we did not collect information to describe the process by which practice changed—for example, some of the study ICUs may have implemented guidelines related to the topics we evaluated in our study. As discussed above, we are unable to judge whether or not the degree of practice change we observed was appropriate. Finally, for management of ARDS, we are only able to comment on practice change among patients who have been identified by clinicians as having this condition. Previous work suggests that ARDS is underrecognized by clinicians (28), and we acknowledge that it is possible that a number of patients with this entity did not receive treatment according to the current evidence. In conclusion, our results provide a description of the current usual care and outcomes of mechanically ventilated patients across several countries and continents. As indicated by the concordance of predicted and observed practice changes, our study demonstrates that, in the field of respiratory failure and mechanical ventilation, the translation of clinical research to clinical practice is happening. Significant reductions in ICU mortality were not demonstrated; several potential mechanisms for this finding exist.
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. 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.200706-893OC on October 25, 2007
Conflict of Interest Statement: A.E. does not have a financial relationship with a 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 an interest in the subject of this manuscript. M.O.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.F.-V. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.B. received research contracts from Dräger Medical for the conduct of studies concerning a ventilation system (SmartCare) and received approximately 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. Sarasino and D. Ceraso (Hospital Dr. Juan A. Fernández, Buenos Aires), D. Pezzola and F.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 Eva Perón, San Martín), M. Tavella and C. Irrazábal (Hospital de Clínicas José de San Martín, Buenos Aires), L. Cardonnet and A. Diez (Hospital Provincial del Centenario, Rosario), A. Giannelli and L. Vargas (Policlínico de Neuquén), M. Bustamante (Hospital Héroes de Malvinas, Merlo), E. Turchetto (Hospital Privado de la Comunidad, Mar del Plata), J. Teves and O. Elefante (Hospital Oscar Alende, Mar del Plata), C. Sola and J. Mele (Hospital Dr. José Penna, Bahía Blanca), V. Sciuto and P. Grana (Hospital Provincial de Neuquén), G. Jannello and R. Valentini (CEMIC, Buenos Aires), S. Ilutovich (Sanatorio Mitre, Buenos Aires), L. Huespe Gardel (Hospital Escuela José F. de San Martín, Corrientes), J. Scapellato and E. Orsini (Hospital F. Santojanni, Buenos Aires), G. Agüero and Á. Sánchez (Policlínico Regional J. Perón, Mercedes), R. Fernández and L. Villalobos Castañeda (Hospital Italiano, Buenos Aires), F. González and E. Estenssoro (Hospital General San Martín, La Plata), S. Lasdica (Hospital Privado del Sur, Bahía Blanca), A. Gómez and J. Scapellato (Clínica de la Esperanza, Buenos Aires), P. Pratesi (Hospital Universitario Austral, Pilar), M. Blasco and F. Villarejo (Clínica Olivos, Olivos), G. Olarte and C. Bevilacqua (Clínica Modelo de Morón / Hospital San Juan de Dios, R.Mejía), M. Quinteros (Sanatorio San Lucas, San Isidro), P. Ripoll (Clínica La Sagrada Familia, Buenos Aires), S. Filippus (Clínica del Valle, Comodoro Rivadavia), F. Guzman Díaz and M. Deheza (Hospital B. Rivadavia, Buenos Aires), E. García and J. Arrieta (Hospital Regional de Comodoro Rivadavia), P. Pardo and J. Neira (Sanatorio de la Trinidad, Buenos Aires), J. Núñez and F. Pálizas (Clínica Bazterrica, Buenos Aires), A. Ciccolini and G. Murias (Sanatorio Santa Isabel, Buenos Aires), W. Vázquez and M. Grilli (Hospital Español, Mendoza), F. Chertcoff and E. Soloaga (Hospital Británico, Buenos Aires), D. Vargas and J. Berón (Hospital Pablo Soria, San Salvador de Jujuy), A. Maceira and P. Schoon (Hospital Prof. Luis Güemes, Haedo), D. Pina (Sanatorio Franchín, Buenos Aires), 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° 1, La Paz). A. Lavandez and C. Alfaro (Complejo Hospitalario Viedma, La Paz), J. Guerra (Instituto gastroenterológico boliviano japonés, Santa Cruz). CANADA: Coordinators: Niall D. Ferguson (Toronto Hospital Western) and Maureen O. 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 Health Sciences Centre, Toronto), B. Kashin (William Osler Health Centre, Brampton, Ontario), D. J. Cook (St. Joseph's Healthcare). CHILE: Coordinator: Vinko Tomicic (Clínica Alemana de Santiago). L. Soto (Instituto Nacional del Tórax, Santiago), C. Romero (Hospital Clínico Pontificia Universidad Católica, Santiago), M. Teresa Caballero and L. Chiang (Hospital naval almirante Nef), E. Poch (Instituto de Neurocirugía), J. Canteros Gatica (Hospital Curico), H. Ugarte (Hospital de Coquimbo), M. Calvo, C. Vargas, and M. Yacsich (Hospital Regional de Valdivia), E. Tobar (Hospital Clínico de la Universidad de Chile, Santiago), J. G. Urra (Clínica Alemana de Temuco). COLOMBIA: Coordinator: Marco A. González (Clínica Medellín y Universidad Pontificia Bolivariana, Medellín). A. Guerra (Hospital General de Medellín and Clínica SOMA, Medellín), C. Cadavid (Hospital Pablo Tobón Uribe, Medellín), R. Panesso (Clínica Las Américas, Medellín), M. Granados (Clínica Valle del Lilli, Cali), C. Dueñas (Hospital Bocagrande, Cartagena), F. Molina (Clínica Bolivariana, Medellín), R. Camargo (Clínica General del Norte de Barranquilla), G. Ortiz (Hospital de Santa Clara, Bogotá), M. Gómez (Hospital de San José). ECUADOR: Coordinator: Manuel Jibaja (Hospital Militar de Quito). G. Paredes and E. Bazantes (Hospital Enrique Garcés, Quito), P. Jiménez (Hospital Carlos Andrade Martín, Quito), J. Vergara and L. González (Hospital Luis Vernaza Valdez, Guayaquil). FRANCE: Coordinators: Laurent Brochard (Centre hospitalier Albert-Chenvier-Henri Mondor, Paris) and Arnaud Thille (Centre hospitalier Albert-Chenvier-Henri Mondor, Paris). L. Mallet (Centre Hospitalier D'Auch), P. Andrivet (Centre Médico-Chirurgical de Bligny, Bris-sous-Forges), O. Peyrouset (Hôpital Ambroise Paré, Boulogne Billancourt), I. Mohammedi (Hôpital Edouard Herriot, Lyon), E. Guerot (Hôpital Européen Georges Pompidou, Paris), N. Deye (Hôpital Lariboisière, Paris), S. Monsel and F. Bouvet (Hôpital Pitié Salpétrière, Paris), M. Darmon (Hôpital Saint Louis, Paris), M. Fartoukh and A. Harb (Hôpital Tenon, Paris), N. Anguel (Hôpital de Bicêtre, Kremlin-Bicêtre). GERMANY: Coordinator: Konstantinos Raymondos (Medizinische Hochschule Hannover). A. Nowak, T. Pahlitzsch, and K. F. Rothe (Krankenhaus Dresden-Friedrichstadt), M. Ragaller and T. Koch (Universitaetsklinikum Carl Gustav Carus Dresden), G. Sterzel (Kreiskrankenhaus Loebau, Ebersbach), R. Wittich (Carl-Thiem-Klinikum Cottbus GmbH), K. Rudolph and J. Raumanns (St. Elisabeth GmbH, Leipzig), U. Grueneisen and F. Stupacher (Bundeswehrkrankenhaus Leipzig), H. Bromber, G. Leonhardt, and J. Soukup (Universitaetsklinikum der Martin-Luther-Universitaet Halle-Wittenberg), C. Wuttke (Krankenhaus St. Elisabeth 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 (Zeisigwaldkliniken 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 (Charité 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 (Kreiskrankenhaus Hameln), J. Kleideiter and P. Palomino (Staedtische Kliniken Bielefeld GmbH), A. Lunkeit and Schlechtweg (Klinikum Bad Salzungen GmbH), M. Quintel (Universitaetsklinikum der Georg-August-Universitaet Goettingen), K. Schild and C. P. Criée (Evangelisches Krankenhaus Goettingen-Weende e.V., Bovenden-Lenglern), 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 (Universitaetsklinikum 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. Keller and S. Scieszka (Krankenhaus Neuwerk, Moenchengladbach), E. Schroeder and F. L. Deres (Kreiskrankenhaus Dormagen), M. Burrichter, T. Bernhardt, and W. Wilhelm (St.-Marien-Hospital, Luenen), M. Beiderlinden (Universitaetklinikum Essen), H. Steiniger and V. Weißkopf (Ruhrlandklinik, Essen), H. Militzer (Evangelisches und Johanniter Klinikum, Dinslaken), K. Eicker and F. Hinder (Universitaetsklinikum Muenster), C. Weilbach and M. Raab (St. Josefs-Stift Cloppenburg), 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 der Barmherzigen Brueder, Trier), W. Baier (St. Nikolaus-Stiftshospital GmbH, Andernach), Eller (Staedt. Hellmig-Krankenhaus, Kamen), K. Schwarke (Evang. Krankenhaus Schwerte GmbH), Buettner (Evangelisches Krankenhaus Elisabethenstift GmbH, Darmstadt), K. P. Wresch and K. Steidel (St.-Vincentius-Krankenhaus Speyer), J. F. Meyer (Universitaetsklinikum der Ruprecht-Karls-Universitaet Heidelberg), M. Layer (Thoraxklinik Heidelberg GmbH), G. Meinhardt (Robert-Bosch-Krankenhaus, Stuttgart), J. Fritschi and P. Zaar (Ermstalklinik Staedtisches Krankenhaus Sindelfingen), H. P. Stegbauer (Kreiskrankenhaus Leonberg), Tumbass and S. Hahn (Ermstalklinik Bad Urach), H. Mende, M. Fischer, J. Martin, and A. Assmann (Klinik am Eichert Goeppingen), V. Schoeffel, K. van Deyk, and S. Seyboth (Stadtklinik Baden-Baden), H. Kerger and Ernst (Evangelisches Diakoniekrankenhaus, Freiburg), H. F. Ginz (Kreiskrankenhaus Loerrach), F. Brettner (Krankenhaus der Barmherzigen Brueder, Muenchen), O. Karg (ASKLEPIOS Fachkliniken Muenchen-Gauting), M. Glaser and T. P. Zucker (Klinikum Traunstein), J. Jahn and A. Schneider (Fachkliniken Wangen), M. Burkert (Bundeswehrkrankenhaus Ulm), H. Kuenzig and T. Bein (Klinikum der Universitaet Regensburg), A. Speicher (Krankenhaus der Barmherzigen Brueder, Regensburg), J. Brederlau, E. Kaufmann, F. Schuster, and C. Soellmann (Universitaetsklinik Wuerzburg), S. Frenzel and L. Pfeiffer (Unstrut-Hainich Kreiskrankenhaus Muehlhausen), S. Weber-Carstens, K. Haid, C. Melzer-Gartzke, C. von Heymann, and B. Temmesfeld (Charité Universitaetsklinikum, Campus Mitte, Berlin). GREECE: Coordinator: Dimitrios Matamis (Papageorgiou General Hospital, Thessaloniki). 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 (Ospedale Maggiore Policlinico, Milano), P. Severgnini (Ospedale di Circolo di Varese), R. Fumagalli and A. Nikiforov (Ospedali Riuniti di Bergamo), S.Grasso (Ospedale di Venere, Bari). MEXICO: Coordinator: José Elizalde (Hospital ABC, México DF). P. Cerda (Centro Médico de las Américas, Mérida), R. Mercado (Hospital Universitario de Monterrey), J. Albe Castañón (Instituto mexicano del seguro social HECMNS XXI, México DF). THE NETHERLANDS: Michael Kuiper (Medical Center Leeuwarden). P. H. M. Egbers and M. Koopmans (Medical Center Leeuwarden). PERU: Coordinator: Ana María Montañez. M. Contardo, J. Cerna, and R. Roldán (Hospital Edgardo Rebagliati Martins, Lima), J. Zevallos and S. Alcabes (Hospital Guillermo Almenara Irigoyen, Lima), C. Salcedo and D. Bruzone (Hospital Nacional Daniel Alcides Carrión, Callao), J. Quiñones (Hospital de Emergencias Grau, Lima), M. Suárez Lazo (Hospital Nacional Hipólito Unanue, Lima), A. Cifuentes (Hospital de Emergencias José Casimiro Ulloa, Lima), M. Mayorga (Clínica San Pablo, Lima). PORTUGAL: Coordinator: Rui Moreno (Hospital de Santo António dos Capuchos, Lisboa). P.Casanova (Hospitais da Universidade de Coimbra), R. Matos and A. L. Jardim (Hospital de Santo António dos Capuchos, UCIP, Lisboa), A. Godinho (Hospital dos SAMS, UCI, Lisboa), P. Póvoa (Hospital São Francisco Xavier, UCIM, Lisboa), P. Coutinho (Centro Hospitalar de Coimbra), L. Reis (Hospital de São José, Unidade de Urgência Médica, 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 de Getafe). F. Gordo (Fundación Hospital de Alcorcón), R. Fernandez (Complejo Hospitalario Parc Taulí, Sabadell), R. de Pablo (Hospital Universitario Príncipe de Asturias, Alcalá de Henares), J. Ibañez (Hospital Son Dureta, Palma de Mallorca), E. Fernández Mondejar (Hospital Virgen de las Nieves, Granada), F. del Nogal (Hospital Severo Ochoa, Leganés), F. Taboada (Hospital Central de Asturias, Oviedo), A. García Jiménez (Hospital Arquitecto Marcide, El Ferrol), L. Cabré and J. Morillas (Hospital de Barcelona-SCIAS), S. Macias (Hospital General de Segovia), R. de Celis (Hospital de Galdakao), J. M. Añón (Hospital Virgen de la Luz, Cuenca), P. Ugarte (Hospital Marqués de Valdecilla, Santander), T. Mut (Hospital de la Plana, Vila-Real), J. Diarte (Complejo Hospitalario de Ciudad Real), V. Sagredo (Hospital Clínico de Salamanca), M. Valledor (Hospital San Agustín, Avilés), G. González and L. Rodríguez (Hospital Morales Meseguer, Murcia), V. Parra and E. Gómez (Hospital de Sagunto), F. Jara (Hospital Mutua de Terrassa), J. M. Quiroga (Hospital de Cabueñes, Gijón), L. Arnaiz (Hospital Clínico Universitario de San Carlos, Madrid), Á. Ayensa (Hospital Virgen de la Salud, Toledo), F. Suárez Sippman (Fundación Jiménez Díaz), F. Carrizosa (Hospital General de Jerez de la Frontera), J. A. Rodríguez Sarría (Hospital de Elda), C. Homs (Hospital San Jorge, Huesca), A. Díaz Lamas (Hospital Cristal Piñor, Ourense), M. León (Hospital Arnau de Vilanova, Lleida), J. Allegue (Hospital Nuestra Señora 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 (Fattouma Bourguiba, Monastir), M. Bouaziz, H. Kallel, and M. Bahloul (Habib Bourguiba Sfax), 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 of medicine, Ataturk University, Erzurum), B. Yelken (Osmangazi University, Eskisemir), I. Kati (Medical Faculty of Yuzuncu Yil University, Van), T. Guldem (Haydarpasa Numune Teaching and Research Hospital, Istambul), U. Koca (Dokuz Eylun University, Istanbul), M. Cicek (Inonu University of Medical Faculty, Malatya), H. Sungurtekin (Pamukkale University Medical Faculty). UNITED KINGDOM: Coordinator: Peter Nightingale (Wythenshawe Hospital, Manchester). J. Hunter (Macclesfield District General Hospital, Macclesfield), I. Grant (Rotherham District General Hospital, Rotherham), S. Mousdale (Blackburn Royal Infimary, 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 Science Center, 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, New York, NY), J. S. Steingrub, M. A. Tidswell and K. Kozikowski (Baystate Medical Center, Springfield, MN), C. A. Piquette and L. Morrow (Creighton University Medical Center, Omaha, NE), P. Scheinberg and J. Green (Saint Joseph's Hospital, Atlanta, GA), L. Penogreen and K. Kannady (Georgia State University, Kennestone, GA), M. Moss, M. Mealer, and R. D. Restrepo (Grady Hospital Georgia, Atlanta, GA), H. E. Fessler, R. Brower, D. Hager, and A. Scully (Johns Hopkins 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 Health University, Chicago, IL), G. T. Kinasewitz and G. L. Lee (University of Oklahoma Health Sciences Center, Oklahoma City, OK), J. Walls and V. Zimmer (Presbyterian Healthcare, 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 MU Healthcare, 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 Baptist Hospital Medical Center, Winston-Salem, NC), P. J. McShane and K. N. Olivier (Wilford Hall Medical Center, Lackland, Texas), K. W. Presberg (Froedtert and Medical College, Milwaukee, WI). URUGUAY: Coordinator: Javier Hurtado (Cudam Sanatorio Colón, Sanatorio IMPASA and Hospital de Clínicas, Montevideo). M. Borde, E. Echavarría, S. Gómez, and M. Berón (Hospital Maciel, Montevideo), F. Villalba (Sanatorio Casa de Galicia, Montevideo), I. Porras (Sanatorio CASMU 2, Montevideo), P. Cardinal, C. Surraco, and V. Navarrete (Sanatorio CASMU 4, Montevideo), F. Rodríguez and J. C. Bagattini (Hospital Británico, Montevideo), R. Garrido (Hospital Evangélico and Sanatorio IMPASA, Montevideo), S. Infanzón and J. Caraballo (Hospital Militar and CTI-SMI, Montevideo), C. Santos and A. García (Hospital de Clínicas, Montevideo), R. Cal (CTI-SMI, Montevideo), G. Pittini and J. Cabrera (Centro Nacional de Quemados, Montevideo), F. Bazzano and F. Domínguez (Hospital Pasteur, Colonia), P. Alzugaray, D. González, and M. Machado (Sanatorio CAMOC, Carmelo), F. Torres (Sanatorio Mautone and Asistencial 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, Tacuarembó), J. Baraibar (Hospital Regional de Tacuarembó), A. Soler (Sanatorio COMEPA, Paysandú), M. Rodríguez Verde (Hospital Paysandú), M. Díaz (Hospital de Salto and Sanatorio Uruguay, Salto), J. Martínez Ramos (Sanatorio Uruguay, Salto), I. Iturralde, W. González, and E. Cubas (Sanatorio CAMDEL, Minas), A. Cataldo (Sanatorio CAMEDUR, Durazno), O. Rocha (Sanatorio GREMEDA, Artigas), A. Deicas (Sanatorio CASMU 2 and Sanatorio CASMU 4). VENEZUELA: Coordinator: Gabriel D'Empaire (Hospital de Clínicas, Caracas). R. Zerpa (Hospital Militar de Caracas), M. Narvez (Hospital Domingo Luciani, Caracas), F. Pérez (Hospital de Clínicas, Caracas), J. España (Hospital Universitario de Caracas).
* ICUs that participated in both studies are shown in italics. Received in original form June 20, 2007; accepted in final form October 24, 2007
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ABSTRACT
AT A GLANCE COMMENTARY
5 cm H2O, and no need for vasoactive drugs), to the time of successful extubation (lasting at least 48 h); patients were classified as "difficult to wean" if they failed their first spontaneous breathing trial. We recorded vital status at hospital discharge. 
= 0.97; 95% confidence interval, 0.91–1.0) and any differences were resolved by consensus. These two investigators independently abstracted study data and quality indicators for each included paper, and resolved disagreements by consensus. Tables summarizing the key characteristics and findings of each of the 48 primary studies, excluding systematic reviews and meta-analyses, that ultimately met our inclusion criteria are available in an online supplement to this article. 
15,000 per year from 2001 to 2004 and approximately 
