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(Chest. 2005;128:3098-3108.)
© 2005 American College of Chest Physicians

High Tidal Volume and Positive Fluid Balance Are Associated With Worse Outcome in Acute Lung Injury*

Yasser Sakr, MB BCh, MSc; Jean-Louis Vincent, MD, PhD, FCCP; Konrad Reinhart, MD, PhD; Johan Groeneveld, MD, PhD, FCCP; Argyris Michalopoulos, MD; Charles L. Sprung, MD; Antonio Artigas, MD; V. Marco Ranieri, MD; on behalf of the Sepsis Occurrence in Acutely Ill Patients Investigators{dagger}

* From the Department of Intensive Care (Drs. Sakr and Vincent), Erasme Hospital, Free University of Brussels, Belgium; Department of Anesthesiology and Intensive Care (Dr. Reinhart), Friedrich-Schiller-University Jena, Germany; Department of Intensive Care (Dr. Groeneveld), Vrije Universiteit Medical Centre, Amsterdam, the Netherlands; Department of Intensive Care (Dr. Michalopoulos), Henry Dunant Hospital, Athens, Greece; Department of Anesthesiology and Critical Care Medicine (Dr. Sprung), Hadassah Hebrew University Medical Center, Jerusalem, Israel; Critical Care Center (Dr. Artigas), Sabadell Hospital, University Institute Parc Taulí, Autonomous University of Barcelona, Spain; and Department of Anesthesiology and Intensive Care (Dr. Ranieri), S. Giovanni Battista Hospital, University of Turin, Italy. {dagger} A complete list of participants is given in the Appendix.

Correspondence to: Jean-Louis Vincent, MD, PhD, FCCP, Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium; e-mail: jlvincen{at}ulb.ac.be


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Study objectives: Recent data have suggested that ventilatory strategy could influence outcomes from acute lung injury (ALI) and ARDS. We tested the hypothesis that infection/sepsis and use of higher tidal volumes than those applied in the ARDS Network (ARDSnet) study (> 7.4 mL/kg of predicted body weight) would worsen outcome in patients with ALI/ARDS.

Design: International cohort, observational study.

Setting: One hundred ninety-eight European ICUs participating in the Sepsis Occurrence in Acutely Ill Patients study.

Patients or participants: All 3,147 adult patients admitted to one of the participating ICUs between May 1, 2002, and May 15, 2002.

Interventions: None.

Measurements and results: Patients were followed up until death, hospital discharge, or for 60 days. Of the 3,147 patients, 393 patients (12.5%) had ALI/ARDS. ICU and hospital mortality was higher in patients with ALI/ARDS than those without ALI/ARDS (38.9% vs 15.6% and 45.5% vs 21.0%, respectively; p < 0.001). A multivariable logistic regression analysis with ICU outcome as the dependent factor showed that the independent risks for mortality were as follows: presence of cancer, use of tidal volumes higher than those used by the ARDSnet study, degree of multiorgan dysfunction, and higher mean fluid balance. Sepsis, septic shock, and oxygenation at the onset of ALI/ARDS were not independently associated with higher mortality rates.

Conclusions: In addition to comorbidities and organ dysfunction, high tidal volumes and positive fluid balance are associated with a worse outcome from ALI/ARDS.

Key Words: ARDS • fluid balance • sepsis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Acute lung injury (ALI) and ARDS are a complex response of the lung to direct or indirect insults, characterized by sudden onset severe hypoxemia, radiographic evidence of bilateral pulmonary infiltration, and absence of left-heart failure.1 Despite improvements in supportive care and sophistication of respiratory support over the last decade, ALI is still associated with mortality rates from 40 to 60%.2

Several factors have been identified as being asso

ciated with increased mortality from ALI, including sepsis,345 the presence of comorbid diseases or chronic conditions,3456 the degree of associated non-respiratory organ dysfunction,167 and factors associated with management, such as fluid loading.8 More recently, lung protective ventilatory strategies have been proposed based on the large body of animal data indicating that mechanical ventilation with high tidal volumes is associated with a pulmonary injuryindistinguishable from ARDS.910 However, despite a large clinical trial, the ARDS Network (ARDSnet) trial, which showed that compared to a ventilatory strategy using a tidal volume of 12 mL/kg, a tidal volume of 6 mL/kg decreased the mortality rate by 22%11 in a wide spectrum of patients including those with sepsis.12 Weinert et al13 and Young et al14 have demonstrated that this low tidal volume approach has not been widely adopted into clinical practice. Moreover, Eichacker and colleagues,19 on the basis of a metaanalysis of the five clinical trials1115161718 testing mechanical ventilation with low tidal volumes in patients with ALI, suggested there was a parabolic relationship between tidal volume and outcome with a greater risk of mortality associated with low, as well as high, tidal volumes.

We assessed the incidence of ALI/ARDS, factors associated with mortality, and effective use of the low tidal volume ARDSnet protective ventilatory strategy in a large cohort of European ICUs,20 examining the hypothesis that sepsis, comorbid diseases, degree of organ dysfunction, fluid loading, and deviation from the ARDSnet protective ventilatory strategy could worsen outcome of patients with ALI in a large cohort of patients admitted to European ICUs.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix
 References
 
Study Design
This prospective, multicenter, observational study included all patients > 15 years old newly admitted to one of 198 ICUs participating in the Sepsis Occurrence in Acutely Ill Patients (SOAP) network in 24 European countries during a 14-day period from May 1, 2002, to May 15, 2002. Clinical sites were recruited by open invitation, and study participation was voluntary with no financial incentive. Institutional review board approval was either waived or expedited in all institutions, and informed consent was not required since the study required no deviation from routine medical practice. Patients were followed up until death, hospital discharge, or for 60 days. Patients admitted for routine postoperative observation who stayed in the ICU for < 24 h were excluded.

Data Management
Detailed instructions explaining the aim of the study, data collection, and definitions for various important items were available for all participants on-line (www.intensive.org) before starting data collection and throughout the study period. The steering committee processed all queries during data collection. Data were collected using preprinted case report forms and entered at the Erasme Hospital (Brussels) by medical personnel using statistical software (SPSS version 11.0 for Windows; SPSS; Chicago, IL). A random sample of 5% of data were reentered by a different encoder and revised by a third encoder; a consistency of > 99.5% per variable and 98.5% per file was observed during the whole process of data entry. In cases of inconsistency, data were verified and corrected. Daily frequency tables were revised for all variables, and the investigators were queried when data values were either questionable or were missing for required fields. Data collection on ICU admission included demographic data and comorbid diseases.

Clinical status on ICU admission and laboratory data (the worst value within 24 h after ICU admission) were recorded for calculation of the simplified acute physiology score (SAPS) II.21 Microbiologic and clinical infections were reported daily, as well as the antibiotics administered. A daily evaluation of respiratory, renal, cardiovascular, hepatic, coagulation, and neurologic organ function was conducted using the parameters defined by the sequential organ failure assessment (SOFA) score,22 with the most abnormal value for each of the six organ systems being collected on ICU admission and every 24 h thereafter. The daily fluid balance was calculated as the total fluid balance divided by the length of ICU stay. The total fluid balance was calculated as the sum of daily fluid balances for the length of the ICU stay. The 48-h, 72-h, and 96-h balances were the cumulative fluid balances for those periods. For single missing values, a replacement was calculated using the mean value of the results on either side of the absent result. When the first or last values were missing, the nearest values were carried backward or forward, respectively. When more than one consecutive result was missing, it was considered to be a missing value in the analysis. The mean SOFA score was calculated as the sum of the daily SOFA scores divided by the ICU length of stay, and the maximum SOFA was the highest value reached during the ICU stay.

Definitions
Patients were a priori selected as having ALI or ARDS if they presented all the following: (1) severe hypoxemia, defined by a PaO2/fraction of inspired oxygen (FIO2) ratio < 300 mm Hg for ALI and < 200 mm Hg for ARDS; (2) presence of bilateral lung infiltrates on the chest radiograph; (3) no clinical evidence of heart failure; (4) absence of COPD or other chronic pulmonary disorders; and (5) invasive mechanical ventilation. Due to the observational nature of this study, the management of ALI/ARDS did not follow a predefined protocol. Patients were identified as being treated with ventilator settings deviating from the ARDSnet protective ventilatory strategy if at any time during the period they matched the criteria for ALI/ARDS, and showed the following: (1) a tidal volume higher than the mean of the tidal volumes used on days 1, 3, and 7 in the low tidal volume group of the ARDSnet trial plus the mean of their SDs (ie, 7.4 mL/kg predicted body weight); (2) a plateau pressure > 30 cm H2O; (3) a positive end-expiratory pressure (PEEP) higher or lower than the level allowed in the ARDSnet trial for a given FIO2. These criteria were defined a priori. Values of tidal volume, PEEP, plateau pressure, and FIO2 were recorded at the same time each day for every 24-h period; the mode of mechanical ventilation was not recorded. The predicted body weight of male patients was calculated as equal to 50 + 0.91 (centimeters of height – 152.4); and that of female patients as equal to 45.5 + 0.91 (centimeters of height – 152.4).112324

Infection was defined as the presence of a pathogenic microorganism or clinical infection necessitating antibiotic administration. Sepsis, severe sepsis, and septic shock were defined according to the American College of Chest Physicians/Society of Critical Care Medicine consensus conference definitions,25 and pneumonia was defined according to current recommendations.26 Trauma, severe trauma, and severe pancreatitis were defined according to standard definitions.

Statistical Analysis
Values are given as mean ± SD or median with interquartile range (IQR). Normal distribution of continuous variables was verified (Kolmogorov-Smirnov test and stratified distribution plots). Difference testing between groups was performed using the two-tailed t test, Mann-Whitney U test, {chi}2 test, and Fisher Exact Test as appropriate. Multivariate forward stepwise logistic regression analysis was performed with ICU outcome as the a priori-identified dependent factor. Variables considered for the multivariable analysis included demographic variables, comorbid diseases, and SAPS II score on ICU admission; sepsis syndromes; fluid balance; procedures; and mean SOFA score as a global measure of organ failure during the ICU stay. Variables were included in the multivariate analysis if found to be significant at univariate analysis with a p value < 0.2. All variables included in the multivariate model were tested for collinearity. Hosmer and Lemeshow test was used to assess the goodness of fit of the model. Odds ratios with 95% confidence intervals were calculated for statistically significant variables. A p < 0.05 was considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Appendix
 References
 
Of the 3,147 patients included in the SOAP study, 2,025 patients (64.3%) received mechanical ventilation during the ICU stay. Three hundred ninety-three patients (12.5%) had either ALI or ARDS; 85.0% of these patients had ARDS, and 15.0% had ALI. ALI/ARDS was observed on ICU admission in 329 patients (83.5%), while ALI/ARDS developed in the rest 1 to 2 days after ICU admission. Patients with ALI/ARDS had higher ICU (38.9% vs 15.6%, p < 0.001) and hospital (45.5% vs 21.0%, p < 0.001) mortality rates. Lengths of ICU and hospital stay, and organ failure scores were higher in patients with ALI/ARDS than in those without (Table 1 ). Compared to patients without ALI/ARDS, patients with ALI/ARDS were younger, were more frequently admitted to the ICU from the hospital floor and from other hospitals, were less frequently admitted from the emergency department (ED), and had a higher incidence of hematologic cancer, severe trauma, pneumonia, shock, sepsis, severe sepsis, and septic shock (Table 2 ). Central venous, arterial, and pulmonary artery catheters were used more frequently (95% vs 68%, 95% vs 68%, and 26% vs 13%, respectively, p < 0.001) and for a longer period of time (9 days [range, 5 to 17 days] vs 4 days [range, 3 to 7 days], 7 days [range, 4 to 14 days] vs 3 days [range, 2 to 6 days], and 4 days [range, 2 to 7 days] vs 3 days [range, 2 to 4 days], respectively; p < 0.001) in patients with ALI/ARDS than in those without. Patients with ALI/ARDS had a higher cumulative fluid balance during the first 24, 48, 72, and 96 h compared with others; however, the mean daily fluid balance and the whole-stay cumulative balance were comparable between the two groups (Table 3 ). Considering only the ventilatory settings during the period when ALI/ARDS criteria were met, a total of 207 patients (52.7%) received ventilation at least once with settings other than the ARDSnet protective ventilatory strategy. Figure 1 shows the distribution of the mean (top) and the maximum (bottom) tidal volumes used during the ALI/ARDS period. One hundred seventy-three patients (44%) received ventilation with a mean tidal volume in the range of 5 to 7 mL/kg predicted body weight and 35 patients (9%) with a mean tidal volume ≥ 12 mL/kg predicted body weight; 169 patients (43%) received ventilation with a maximum tidal volume in the range of 5 to 7 mL/kg predicted body weight and 79 patients (20%) with a maximum tidal volume ≥ 12 mL/kg predicted body weight.


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  		Table 1.. Mortality and Morbidity in Patients With and Without ALI/ARDS*

 

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  		Table 2.. Characteristics of the Study Group on ICU Admission*

 

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  		Table 3.. Fluid Balance in Liters*

 


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  		Figure 1.. Histogram representing the mean (top) and maximum (bottom) tidal volume in milliliters per kilogram of predicted body weight during the period patients met the criteria for ALI/ARDS. The Y-axis represents the percentage of patients.

 
Patients with ALI had lower SAPS II scores (40.7 ± 15 vs 47.7 ± 17.8, p = 0.005), lower maximum SOFA scores (9.4 ± 3.8 vs 11.1 ± 4.3, p = 0.001), lower incidence of sepsis at any time (47.7% vs 77.5%, p < 0.001) and on ICU admission (30.5% vs 50.3%, p = 0.005), shorter lengths of ICU stay (5.3 days [range, 2.5 to 9.6 days] vs 10.4 days [range, 4.6 to 20.2 days], p < 0.001), and lower ICU mortality rates (20.3% vs 42.3%, p = 0.001) than patients with ARDS. There were no significant differences in hospital mortality rates between patients with ALI and those with ARDS (33.9% vs 47.6%, p = 0.065).

More nonsurvivors of ALI/ARDS were admitted from another hospital than survivors, but there were no differences in other sources of admission (ie, ED, hospital floor, operating room [OR]). Compared to patients who survived, nonsurvivors of ALI/ARDS were older, more likely to be female, and had a higher incidence of cancer, higher scores for clinical status and organ failures, and a higher incidence of severe hypoxemia. Survivors were more likely to have been admitted with a diagnosis of trauma than nonsurvivors. The occurrence of infection and sepsis were similar in survivors and nonsurvivors, although septic shock was more prevalent in nonsurvivors. Cumulative fluid balance during the first 24, 48, 72, and 96 h was higher in patients who did not survive than in patients who survived ALI/ARDS (Table 4 ).


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  		Table 4.. Characteristics of ICU Survivors and Nonsurvivors in Patients With ALI/ARDS*

 
Except for PEEP, which was higher in survivors (5.2 ± 3.5 cm H2O vs 4.1 ± 3.8 cm H2O, p = 0.018), initial ventilatory variables did not differ between survivors and nonsurvivors. During the whole ventilation period, the mean respiratory rate (25 ± 6.7 breaths/min vs 23 ± 7.2 breaths/min, p = 0.049) and the maximum respiratory rate (33 ± 10.2 breaths/min vs 30 ± 9.1 breaths/min, p = 0.004) were higher in survivors than in nonsurvivors of ALI/ARDS. The maximum PEEP (4.0 ± 3.9 cm H2O vs 3.0 ± 3.4 cm H2O, p = 0.008) was higher in nonsurvivors (Table 5 ). During the period when patients matched the criteria for ALI/ARDS, the mean respiratory rate (26.1 ± 7.1 breaths/min vs 21.7 ± 7.5 breaths/min, p = 0.005) and the maximum respiratory rate (33 ± 9.5 breaths/min vs 30 ± 9.7 breaths/min, p = 0.003) were higher in survivors than in nonsurvivors of ALI/ARDS (Table 5). Higher tidal volumes (> 7.4 mL/kg predicted body weight) were more common in nonsurvivors (44.4% vs 33.5%, p = 0.019) than in survivors (Table 6 ).


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  		Table 5.. Ventilatory Settings in Survivors and Nonsurvivors*

 

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  		Table 6.. Deviations From the Ventilatory Settings of the ARDSnet Protective Ventilatory Strategy*

 
A multivariate logistic forward stepwise analysis with ICU outcome as the dependent factor (Table 7 ) showed that the only factors associated independently with a higher risk of death in patients with ALI/ARDS were the presence of cancer, use of tidal volumes (milliliters per kilogram of predicted body weight) higher than those used by the ARDSnet study, the degree of multiorgan dysfunction, and higher mean fluid balance. Similar results were obtained using hospital mortality as the dependent factor (data not shown).


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  		Table 7.. Multivariate Analysis With ICU Outcome as the Dependent Factor*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix
 References
 
The major finding of our study was that in addition to comorbidities such as cancer, positive fluid balance, and multiple organ failure, use of a tidal volume higher than the one used in the low tidal volume arm of the ARDSnet study was independently associated with a worse outcome from ALI/ARDS. Infection, sepsis, and septic shock were not associated with a higher mortality. It should be acknowledged that information regarding a number of factors potentially able to influence mortality in the studied population, such as appropriate therapy for sepsis (use of activated protein C, control of glucose level, initial antibiotic therapy, steroid administration),27 ICU organizational characteristics,28 were not included in our analysis.

ALI and its most severe form, ARDS, remain common, devastating disorders in critically ill patients, with high morbidity and mortality. In this large cohort of European ICUs, we addressed the epidemiology and aggravating factors of ALI/ARDS. The incidence of ALI/ARDS in our study is higher than that reported previously.42930 This difference can be explained by the fact that only severely ill patients were admitted to our study, as we excluded patients admitted for postoperative monitoring who stayed < 24 h; also, the long period of follow-up (60 days) could have contributed to the detection of more cases. In addition, 64.3% of our patients received mechanical ventilation during their ICU stay, reflecting the more severely ill patients admitted to our ICUs. Overestimation of ALI/ARDS in our study is unlikely since all patients were hypoxic, with bilateral infiltrates, and no clinical evidence of heart failure. Moreover, we included only patients receiving mechanical ventilation and excluded patients with COPD. In accordance with previous studies5293132 that reported an incidence of 11 to 23% of ARDS in patients receiving mechanical ventilation, of 2,025 patients receiving mechanical ventilation in the SOAP study, 393 patients (19.1%) had ALI/ARDS and 334 patients (16.5%) had ARDS.

Several experimental studies33 have shown that hyperinflation of normal alveoli and recruitment/derecruitment of atelectatic alveoli may occur when large tidal volumes and/or inappropriate levels of PEEP are used. These events may lead to stress failure due to the excessive wall tension of the hyperinflated alveoli and shear stress due to the tidal opening/closing of the collapsed alveoli, inducing the disruption of pulmonary epithelium and endothelium, thus exacerbating lung and systemic inflammation and causing multiple organ failure,3334 a major determinant of outcome from ALI/ARDS. The ARDSnet study11 compared a traditional tidal volume (12 mL/kg predicted body weight) with lower tidal volume (6 mL/kg of predicted body weight) in 861 patients. In the group receiving lower tidal volumes, plateau pressure could not exceed 30 cm H2O and a detailed protocol was used to adjust FIO2 and PEEP levels. This protocol reduced the hospital mortality rates from 39.8% in the traditional tidal volume group to 31.0% in the low tidal volume group (p = 0.007).

Eichacker and coworkers19 evaluated the basis for recommending low tidal volume ventilation in ALI and ARDS and, from a metaanalysis of the five clinical trials1115161718 testing mechanical ventilation with low tidal volumes, suggested that the relationship between tidal volume and outcome is parabolic with a greater risk of mortality associated with low, as well as high, tidal volumes, and raised concerns regarding whether the control group of the ARDSnet was representative of the standard of care. This study generated great controversy regarding the use of a tidal volume of 6 mL/kg ideal body weight as routine treatment for patients with ALI/ARDS.3536373839

The average tidal volume used during the period when the ALI/ARDS criteria were met ranged from 5 to 15 mL/kg predicted body weight (Table 5); 173 patients (44%) received mechanical ventilation with a mean tidal volume in the range of 5 to 7 mL/kg of predicted body weight, while 35 patients (9%) received ventilation with a mean tidal volume ≥ 12 mL/kg of predicted body weight (Fig 1, top). Young et al14 recently noted in three US hospitals that although the tidal volumes used in patients with ALI/ARDS had fallen since publication of the ARDSnet study, tidal volumes in the range of 6 to 8 mL/kg of predicted body weight were used in < 10% of the patients, while > 30% of the studied patients still received tidal volumes ≥ 12 mL/kg of predicted body weight. These data confirm that the 6 mL/kg tidal volume approach has not been widely adopted into clinical practice,1314 although lower tidal volumes were more widely used in our study than in that by Young et al.14

We found that tidal volumes higher than those used by the protective ventilatory strategy of the ARDSnet study11 were independently associated with higher mortality rates. Weinert and coworkers13 and Ricard40 concluded that while there is no doubt that tidal volumes > 12 mL/kg are detrimental, it is still unknown whether clinicians should apply a principle of precaution and maintain plateau pressure < 30 cm H2O,41 rather than continuing to titrate tidal volume on the basis of body weight and reduce tidal volume < 8 mL/kg.11 Within the limits of an observational study, these data first confirm that the use of tidal volumes higher than the mean of the tidal volumes used on days 1, 3, and 7 in the low tidal volume group of the ARDSnet trial (7.4 mL/kg) is associated with an increased risk of death. We should note that the latter finding is not contradictory with the fact that initial and mean tidal volumes were similar in survivors and nonsurvivors. Initial and mean tidal volumes are global estimates of all patients in each group, so contamination is possible, with higher values masking the lower ones.

Adequate fluid administration is the mainstay in the management of critically ill patients. The optimal fluid management for patients with ALI/ARDS is always challenged by the underlying pathophysiology with increased capillary permeability842 and associated disorders such as sepsis and circulatory failure, with a dry lung and adequate tissue perfusion on either side of the balance. Simmons et al8 reported that a higher cumulative fluid balance during the first 14 days was independently associated with mortality in a group of 111 patients with ARDS. Humphrey at al43 found that reducing microvascular pressures by fluid management improved outcome in patients with ARDS. In accordance with these observations, we found that patients with ALI/ARDS received more fluids during the first 4 days than patients without ARDS; however, the mean ICU stay balance and the cumulative balance were comparable. Nonsurvivors of ALI/ARDS had a higher fluid balance during the first 4 days as well as a higher mean ICU stay and cumulative fluid balance than survivors. Higher mean fluid balance during the ICU stay was independently associated with a higher risk of mortality, although our results could be limited by the absence of insensible water loss in our calculation of fluid balance. In addition, the degree of renal dysfunction could have contributed to the higher fluid balance observed in nonsurvivors. Finally, more severely ill patients with higher mortality might be expected to have a greater fluid balance and, although the degree of organ dysfunction as assessed by the SOFA score was included in the multivariate analysis, this may not have controlled for all aspects of disease severity.

Sepsis was an important associate with ALI/ARDS in our population, occurring in 47.5% of patients, with more than a twofold increase in incidence compared with patients without ALI/ARDS; septic shock also was more prevalent in patients with ALI/ARDS. However, although septic shock was more prevalent in nonsurvivors than survivors, multiple organ failure, but not infection, sepsis, or septic shock, was associated with a higher mortality in patients with ALI/ARDS. These data challenge the concept that sepsis per se is a leading cause of death from ARDS34445 and suggest that the association between sepsis, in its severe forms, and multiple organ failure is most probably the cause.

Despite increased understanding of the pathophysiology of ALI/ARDS and apparent advances in respiratory support technology, there has been no clear decrease in the mortality rate from ARDS over time.46 Mortality rates from ARDS are cited within the range of 40 to 60%.2 Only Ullrich et al47 reported a very low mortality rate of 20%. We found a 39% ICU mortality in patients with ALI/ARDS, and 42% in patients with ARDS only. Preexisting comorbid diseases can be associated with increased mortality due to acute respiratory failure. In our study, only the presence of cancer was independently associated with mortality in patients with ALI/ARDS. Likewise, chronic liver disease has been associated with mortality from ARDS in several studies.345 Zilberberg and Epstein48 identified organ transplantation, HIV infection, cirrhosis, active malignancy, and sepsis as independent factors for hospital mortality in patients with ALI. Monchi et al4 reported that the length of mechanical ventilation prior to ARDS, cirrhosis, and the occurrence of right ventricular failure were associated with an elevated risk of death.

The degree of respiratory failure represented by the PaO2/FIO2 ratio on ICU admission or on the first day of ALI/ARDS was not independently associated with ICU mortality in our patients, confirming the observations of Montgomery et al49 and Ferring and Vincent,45 who showed that only 16% of deaths in patients with ARDS were due to respiratory failure. Recently, Bersten et al30 reported that respiratory failure contributed to death in only 24% of ARDS patients and was the only cause of death in 9% of patients. Likewise, Luhr et al5 emphasized that the degree of hypoxemia was unimportant in terms of mortality prediction, and Valta et al50 reported that the PaO2/FIO2 ratio at the onset of ARDS was similar in survivors and nonsurvivors. However, we found that organ dysfunction, as evident by higher SOFA scores, was an independent risk factor for death in our patients, an observation previously reported by several authors.67225152

In summary, this large, observational, multicenter study addresses the high incidence of ALI/ARDS in European ICUs (12.5% of admissions) and the high mortality associated with these conditions (approximately 40%). In multivariate analysis, cancer, tidal volumes higher than that proposed by the ARDSnet protective ventilatory strategy, degree of multiorgan dysfunction, and mean ICU fluid balance were independently associated with a high risk of ICU mortality. Sepsis and the PaO2/FIO2 ratio at the onset of ALI/ARDS were not independently associated with higher mortality rates.


   Appendix
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
References
 
SOAP Investigators
Austria: University Hospital of Vienna (G. Delle Karth); LKH Steyr (V. Draxler); LKH-Deutschlandsberg (G. Filzwieser); Otto Wagner Spital of Vienna (W. Heindl); Krems of Donau (G. Kellner, T. Bauer); Barmherzige Bruede of Linz (K. Lenz); KH Floridsdorf of Vienna (E. Rossmann); University Hospital of Innsbruck (C. Wiedermann); Belgium: CHU of Charleroi (P. Biston); Hôpitaux Iris Sud of Brussels (D. Chochrad); Clinique Europe Site St Michel of Brussels (V. Collin); C.H.U. of Liège (P. Damas); University Hospital Ghent (J. Decruyenaere, E. Hoste); CHU Brugmann of Brussels (J. Devriendt); Centre Hospitalier Jolimont-Lobbes of Haine St Paul (B. Espeel); CHR Citadelle of Liege (V. Fraipont); UCL Mont-Godinne of Yvoir (E. Installe); ACZA Campus Stuivenberg (M. Malbrain); OLV Ziekenhuis Aalst (G. Nollet); RHMS Ath-Baudour-Tournai (J.C. Preiser); AZ St Augustinus of Wilrijk (J. Raemaekers); CHU Saint-Pierre of Brussels (A. Roman); Cliniques du Sud-Luxembourg of Arlon (M. Simon); Academic Hospital Vrije Universiteit Brussels (H. Spapen); AZ Sint-Blasius of Dendermonde (W. Swinnen); Clinique Notre-Dame of Tournai (F. Vallot); Erasme University Hospital of Brussels (J.L. Vincent); Czech Republic: University Hospital of Plzen (I. Chytra); U SV.Anny of Brno (L. Dadak); Klaudians of Mlada Boleslav (I. Herold); General Faculty Hospital of Prague (F. Polak); City Hospital of Ostrava (M. Sterba); Denmark : Gentofte Hospital, University of Copenhagen (M. Bestle); Rigshospitalet of Copenhagen (K. Espersen); Amager Hospital of Copenhagen (H. Guldager); Rigshospitalet, University of Copenhagen (K-L. Welling); Finland: Aland Central Hospital of Mariehamn (D. Nyman); Kuopio University Hospital (E. Ruokonen); Seinajoki Central Hospital (K. Saarinen); France: Raymond Poincare of Garches (D. Annane); Institut Gustave Roussy of Villejuif (P. Catogni); Jacques Monod of Le Havre (G. Colas); CH Victor Jousselin of Dreux (F. Coulomb); Hôpital St. Joseph & St. Luc of Lyon (R. Dorne); Saint Joseph of Paris (M. Garrouste); Hôpital Pasteur of Nice (C. Isetta); CHU Brabois of Vandoeuvre Les Nancy (J. Larché); Saint Louis of Paris (J-R. LeGall); CHU de Grenoble (H. Lessire); CHU Pontchaillou of Rennes (Y. Malledant); Hôpital des Hauts Clos of Troyes (P. Mateu); CHU of Amiens (M. Ossart); Hôpital Lariboisière of Paris (D. Payen); CHD Félix Gyuon of Saint Denis La Reunion (P. Schlossmacher); Hôpital Bichat of Paris (J-F. Timsit); Hôpital Saint Andre of Bordeaux (S. Winnock); Hôpital Victor Dupouy of Argentueil (J-P. Sollet); CH Auch (L. Mallet); CHU Nancy-Brabois of Vandoeuvre (P. Maurer); CH William Morey of Chalon (J-M. Sab); Victor Dupouy of Argenteuil (J-P. Sollet); Germany: University Hospital Heidelberg (G. Aykut); Friedrich Schiller University Jena (F. Brunkhorst); University Clinic Hamburg-Eppendorf (A. Nierhaus); University Hospital Mainz (M. Lauterbach); University Hospital Carl Gustav Carus of Dresden (M. Ragaller); Hans Sushemihl Krankenhaus of Emden (R. Gatz); Vivantes-Klinikum Neukoelln of Berlin (H. Gerlach); University Hospital RWTH Aachen (D. Henzler); Kreisklinik Langen-Seligenstadt (H-B Hopf); GKH Bonn (H. Hueneburg); Zentralklinik Bad Berka (W. Karzai); Neuwerk of Moenchengladbach (A. Keller); Philipps University of Marburg (U. Kuhlmann); University Hospital Regensburg (J. Langgartner); ZKH Links der Weser of Bremen (C. Manhold); University Hospital of Dresden (M. Ragaller); Universtiy of Wuerzburg (B. Reith); Hannover Medical School (T. Schuerholz); Universitätsklinikum Charité Campus Mitte of Berlin (C. Spies); Bethanien Hospital of Moers (R. Stögbauer); KhgmbH Schongau (J. Unterburger); Greece: Thriassio Hospital of Athens (P-M. Clouva-Molyvdas); Sismanoglion General Hospital of Athens (G. Giokas); KAT General Hospital of Athens (E. Ioannidou); G. Papanikolaou General Hospital of Thessaloniki (A. Lahana); Agios Demetrios of Thessaloniki (A. Liolios); Onassis Cardiac Surgery Center of Athens (K. Marathias); University Hospital of Ioannina (G. Nakos); Tzanio Hospital of Athens (A. Tasiou); Athens General Hospital Gennimatas (H. Tsangaris); Hungary: Peterfy Hospital of Budapest (P. Tamasi); Ireland: Mater Hospital of Dublin (B. Marsh); Beaumont Hospital of Dublin (M. Power); Israel: Hadassah Hebrew University Medical Centre (C. Sprung); Italy: Azienda Ospedaliera Senese o Siena (B. Biagioli); S. Martino of Genova (F. Bobbio Pallavicini); Azienda Ospedaliera S. Gerardo dei Tintori of Monza (A. Pesenti); Osp Regionale of Saronno (C. Capra); Ospedale Maggiore, University A. Avogadro of Novara (F. Della Corte); Osp. Molinette of Torino (P.P. Donadio); A.O. Umberto I Ancona, Rianimazione Clinica (A. Donati); Azienda Ospedaliera Universitaria Policlinico of Palermo (A. Giarratano); San Giovanni Di Dio of Florence (T. Giorgio); H San Raffaele IRCCS of Milano (D. Giudici); Ospedale Di Busto Arsizio (S. Greco); Civile Di Massa (A. Guadagnucci); San Paolo of Milano (G. Lapichino); S.Giovanni Bosco Torino (S. Livigni); Osp. San Giovanni of Sesto (G. Moise); S Camillo of Roma (G. Nardi); Vittorio Emanuele of Catania (E. Panascia); Hospital of Piacenza (M. Pizzamiglio); Universita di Torino-Ospedale S. Giovanni Battista (V. M. Ranieri); Policlinico Le Scotte of Siena (R. Rosi); Ospedale Maggiore Policlinico IRCCS of Milano (A. Sicignano); A. Uboldo of Cernusco Sul Naviglio (M. Solca); P.O. Civile Carrara of Massa (G. Vignali); San Giovanni of Roma (I. Volpe Rinonapoli); Netherlands: Boven IJ Ziekenhuis of Amsterdam (M. Barnas); UMC St Radboud of Nijmegen (E.E. De Bel); Academic Medical Center of Amsterdam (A-C. De Pont); VUMC of Amsterdam (J. Groeneveld); Groningen University Hospital (M. Nijsten); Waterlandziekenhuis of Purmerend (L. Sie); OLVG of Amsterdam (D.F. Zandstra); Norway: Sentralsjukehuset i Rogaland of Stavanger (S. Harboe); Sykehuset Østfold of Fredrikstad (S. Lindén); Aker University Hospital of Oslo (R.Z. Lovstad); Ulleval University Hospitalof Oslo (H. Moen); Akershus University Hospital of Nordbyhagen (N. Smith-Erichsen); Poland: Pediatric University Hospital of Lodz (A. Piotrowski); Central Clinic Hospital SLAM of Katowice (E. Karpel); Portugal: Garcia de Orta of Almada (E. Almeida); Hospital de St. António dos Capuchos of Lisboa (R. Moreno); Hospital de Santa Maria of Lisboa (A. Pais-De-Lacerda); Hospital S.Joao of Porto (J. A. Paiva); Fernado Fonseca of Masama (I. Serra); São Teotonio Viseu (A. Pimentel); Romania: Inst of Cardiovascular Diseases of Bucharest (D. Filipescu); Serbia and Montenegro: Military Medical Academy of Belgrade (K. Jovanovic); Slovakia: SUSCH of Bratislava (P. Malik); Slovenia: General Hospital of Novo Mesto (K. Lucka); General Hospital of Celje (G. Voga); Spain: Hospital Universitario Rio Hortega of Valladolid (C. Aldecoa Alvarez-Santullano); Sabadell Hospital (A. Artigas); Hospital Clinic of Barcelona (E. Zavala, A. Escorsell, J. Nicolas); Virgen del Camino of Pamplona (J. J. Izura Cea); Virgen de la Salud of Toledo (L. Marina); 12 de Octubre of Madrid (J. Montejo); Gregorio Maranon of Madrid (E. Palencia); General Universitario de Elche (F. Santos); Puerta del Mar of Cadiz (R. Sierra-Camerino); Fundación Jiménez Díaz of Madrid (F. Sipmann); Hospital Clinic of Barcelona (E. Zavala); Sweden: Central Hospital of Kristianstad (K. Brodersen); Stockholm Soder Hospital (J. Haggqvist); Sunderby Hospital of Luleå (D. Hermansson); Huddinge University Hospital of Stockholm (H. Hjelmqvist); Switzerland: Kantonsspital Luzern (K. Heer); Hirslanden Klinik Beau-Site of Bern (G. Loderer); University Hospital of Zurich (M. Maggiorini); Hôpital de la ville of La Chaux-de-Fonds (H. Zender); United Kingdom: Western General Hospital of Edinburgh (P. Andrews); Peterborough Hospitals NHS Trust of Peterborough (B. Appadu); University Hospital Lewisham, London (C. Barrera Groba); Bristol Royal Infirmary (J. Bewley); Queen Elizabeth Hospital Kings Lynn (K. Burchett); Milton Keynes General (P. Chambers); Homerton University Hospital of London (J. Coakley); Charing Cross Hospital of London (D. Doberenz); North Staffordshire Hospital of Stoke On Trent (N. Eastwood); Antrim Area Hospital (A. Ferguson); Royal Berkshire Hospital of Reading (J. Fielden); The James Cook University Hospital of Middlesbrough (J. Gedney); Addenbookes of Cambridge (K. Gunning); Rotherham DGH (D. Harling); St.Helier of Carshalton (S. Jankowski); Southport & Formby (D. Jayson); Freeman of Newcastle On Tyne (A. Kilner); University Hospital of North Tees at Stockton on Tees (V. Krishna-Kumar); St.Thomas Hospital of London (K. Lei); Royal Infirmary of Edinburgh (S. Mackenzie); Derriford of Plymouth (P. Macnaughton); Royal Liverpool University Hospital (G. Marx); Stirling Royal Infirmary (C. McCulloch); University Hospital of Wales, Cardiff (P. Morgan); St George’s Hospital of London (A. Rhodes); Gloucestershire Royal Hospital (C. Roberts); St. Peters of Chertsey (M. Russell); James Paget Hospital of Great Yarmouth (D. Tupper-Carey, M. Wright); Kettering General Hospital (L. Twohey); Burnley DGH (J. Watts); Northampton General Hospital (R. Webster); Dumfries Royal Infirmary (D. Williams)


   Footnotes
 
Abbreviations: ALI = acute lung injury; ARDSnet = ARDS Network; ED = emergency department; FIO2 = fraction of inspired oxygen; IQR = interquartile range; OR = operating room; PEEP = positive end-expiratory pressure; SAPS = simplified acute physiology score; SOAP = Sepsis Occurrence in Acutely Ill Patients; SOFA = sequential organ failure assessment

This study was endorsed by the European Society of Intensive Care Medicine and supported by an unrestricted grant from Abbott, Baxter, Eli Lilly, GlaxoSmithKline, and NovoNordisk.

Received for publication August 3, 2004. Accepted for publication April 25, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 

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