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Published ahead of print on June 21, 2007, doi:10.1164/rccm.200610-1534OC
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American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 795-804, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200610-1534OC

Original Article

An Early PEEP/FIO2 Trial Identifies Different Degrees of Lung Injury in Patients with Acute Respiratory Distress Syndrome

Jesús Villar1, Lina Pérez-Méndez1,2, José López3, Javier Belda4, Jesús Blanco5, Iñaki Saralegui6, Fernando Suárez-Sipmann7, Julia López8, Santiago Lubillo1,9, Robert M. Kacmarek10 and on behalf of the HELP Network*

1 Multidisciplinary Organ Dysfunction Evaluation Research Network, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Canary Islands, Spain; 2 Division of Clinical and Genetic Epidemiology, Hospital Universitario N.S. de Candelaria, Tenerife, Spain; 3 Intensive Care Unit, Hospital General de Leon, Leon, Spain; 4 Department of Anesthesia, Hospital Clínico de Valencia, Valencia, Spain; 5 Intensive Care Unit, Hospital Universitario Rio Hortega, Valladolid, Spain; 6 Hospital Santiago Apóstol, Vitoria, Spain; 7 Intensive Care Unit, Fundación Jimenez Diaz, Madrid, Spain; 8 Intensive Care Unit, Hospital Universitario La Paz, Madrid, Spain; 9 Intensive Care Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain; and 10 Respiratory Care, Massachusetts General Hospital, Harvard University, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Robert M. Kacmarek, Ph.D., R.R.T., Director, Respiratory Care, Massachusetts General Hospital, 55 Fruit Street, Ellison 401, Boston, MA 02114. E-mail: rkacmarek{at}partners.org


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Current American-European Consensus Conference definitions for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are inadequate for inclusion into clinical trials due to the lack of standardization for measuring the oxygenation defect.

Objectives: We questioned whether an early assessment of oxygenation on specific ventilator settings would identify patients with established ARDS (persisting over 24 h).

Methods: At the time of meeting ARDS criteria (Day 0) and 24 hours later (Day 1), arterial blood gases were obtained on standard ventilator settings, VT 7 ml/kg predicted body weight plus the following positive end-expiratory pressure (PEEP) and FIO2 settings in sequence: (1) PEEP ≥ 5 cm H2O and FIO2 ≥ 0.5, (2) PEEP ≥ 5 cm H2O and FIO2 1.0, (3) PEEP ≥ 10 cm H2O and FIO2≥0.5, and (4) PEEP ≥ 10 cm H2O and FIO2 1.0.

Measurements and Main Results: One hundred seventy patients meeting ARDS criteria (PaO2/FIO2 128 ± 33 mm Hg) were enrolled. Overall hospital mortality was 34.1%. The standard ventilator settings that best identified patients with established ARDS and predicted differences in intensive care unit (ICU) mortality were PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 at Day 1 (P = 0.0001). Only 99 (58.2%) patients continued to meet ARDS criteria (PaO2/FIO2, 155.8 ± 29.8 mm Hg; ICU mortality, 45.5%), whereas 55 patients were reclassified as having ALI (PaO2/FIO2, 246.5 ± 25.6 mm Hg; ICU mortality, 20%) and 16 patients as having acute respiratory failure (PaO2/FIO2, 370 ± 54 mm Hg; ICU mortality, 6.3%) (P = 0.0001) on these settings.

Conclusions: Patients meeting current American-European Consensus Conference ARDS criteria may have highly variable levels of lung injury and outcomes. A systematic method of assessing severity of lung injury is required for enrollment of patients with ARDS into randomized controlled trials.

Clinical trial registered with www.clinicaltrials.gov (NCT 00435110).

Key Words: acute respiratory distress syndrome • acute lung injury • positive end-expiratory pressure • standard ventilator settings • definitions • inclusion criteria



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are currently defined without reference to the positive end-expiratory pressure (PEEP) and FIO2 applied. The impact of various PEEP and FIO2 levels on the classification of patients as having ARDS/ALI is unknown.

What This Study Adds to the Field
The definitions of ARDS and ALI require the use of standard ventilator settings to ensure that patients with consistent levels of lung injury are properly classified as having ARDS or ALI.

 
The American-European Consensus Conference (AECC) definitions (1) for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are as follows: (1) acute and sudden onset of severe respiratory distress; (2) bilateral infiltrates on frontal chest radiograph; (3) the absence of left atrial hypertension, a pulmonary capillary wedge pressure (PCWP) less than 18 mm Hg, or no clinical signs of left heart failure; and (4) severe hypoxemia (a PaO2/FIO2 ≤ 300 mm Hg for ALI or ≤200 mm Hg for ARDS, regardless of FIO2 or positive end-expiratory pressure [PEEP]). Patients with a PaO2/FIO2 more than 300 mm Hg are generally categorized as patients with acute respiratory failure (ARF). This current definition may not be adequate for inclusion of patients into clinical trials focusing on the management of ARDS. The PaO2/FIO2 in most patients can be easily manipulated by altering PEEP and FIO2 (2–5), potentially including in clinical trials patients with marked variability in lung injury and potentially different outcomes. There have been two reports (8, 9) on the effect of standard ventilator settings on PaO2/FIO2 and fulfillment of definitions of ARDS/ALI. Although both of these studies were able to separate patients with severe lung injury and high mortality from those with less severe injury and a lower mortality, both enrolled few patients and were secondary analysis of data obtained for other purposes.

We designed this study to determine whether standard ventilator settings applied on the day patients met ARDS AECC criteria (Day 0) or 24 hours later (Day 1) (1) would identify patients with different degrees of lung injury, established (persisting for 24 h) ARDS, ALI, or ARF, and (2) to determine if patients continuing to meet the AECC definition for ARDS at 24 hours would have outcomes different than those categorized as ALI and ARF at 24 hours. Our hypothesis was that the assessment of PaO2/FIO2 on standard ventilator settings 24 hours after patients originally met the AECC definition of ARDS would separate patients with established ARDS from those with less severe lung injury, patients with ALI or ARF. If this hypothesis is supported, it would suggest that patients with a better outcome could have been preferentially entered into one group of previously conducted clinical trials, resulting in a viable therapy being proved useless or a useless therapy proven viable.


   METHODS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Measurements
This protocol was approved by the ethics committee of the coordinating center and by the local institutional review boards in participating hospitals. A Spanish network of participating intensive care units (ICUs) (under the acronym HELP [Hospitales Españoles para el estudio de la Lesión Pulmonar]) (see APPENDIX) enrolled all patients. Patients admitted to participating ICUs were screened daily. All patients meeting AECC ARDS criteria were approached for enrollment regardless of their current status or past medical history. The only patients excluded were those for whom more than 24 hours had elapsed after initially meeting the AECC ARDS criteria before consent and results of initial standard ventilator settings could be obtained.

Patients admitted to participating ICUs were screened daily. Patients or their families provided informed consent before patients were enrolled. On the day of consent (Day 0) and 24 hours later (Day 1), arterial blood gases and hemodynamic and ventilator data were obtained on the following mandatory standard ventilator settings: volume assist/control mode, VT 7 ml/kg predicted body weight (PBW) (10), inspiratory : expiratory time ratio (I:E) < 1:1, ventilator rate to maintain PaCO2 of 35 to 50 mm Hg plus the following PEEP and FIO2 settings applied in the following order: (1) PEEP ≥ 5 cm H2O and FIO2 ≥ 0.5, (2) PEEP ≥ 5 cm H2O and FIO2 1.0, (3) PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5, and (4) PEEP ≥ 10 cm H2O and FIO2 1.0.

After each of these settings, patients were left undisturbed and blood gases were obtained 30 minutes later. Throughout the acute course of ventilatory care, it was recommended that patients be ventilated with a VT of 5 to 9 ml/kg PBW, a plateau pressure ≤ 30 cm H2O, at a ventilatory rate to maintain PaCO2 at 35 to 50 mm Hg and PEEP ≥ 10 cm H2O.

Rules for Setting PEEP and FIO2 during Standard Ventilator Setting Assessment
The rules for adjusting PEEP and FIO2 during the standard ventilator settings assessment are listed in Table 1. It is important to emphasize that these rules only applied during standard ventilator setting assessment. At other times, the settings of PEEP and FIO2 were up to the discretion of the managing clinician. Patients who met ARDS criteria on their clinician-selected PEEP and FIO2 settings were classified as having ARDS on all standard ventilator settings where evaluation could not be performed because PEEP or FIO2 was not adjusted based on the setting rules in Table 1 or because patients could not tolerate a decrease in PEEP or FIO2.


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  		TABLE 1. RULES FOR SETTING POSITIVE END-EXPIRATORY PRESSURE AND FIO2 DURING ASSESSMENT ON STANDARD SETTINGS

 
Data Gathering and Analysis
Patients were stabilized for 30 minutes on the selected settings before arterial blood gases were obtained. Mechanical ventilation parameters and hemodynamic data (see Tables 2 and 3) were collected on Days 0, 1, 3, 6, and 12, and every 6 days, including the last day of mechanical ventilation. On each day, the lowest and the highest values of each parameter were recorded. APACHE II (Acute Physiology and Chronic Health Evaluation II), SAPS (Simplified Acute Physiology Score), and lung injury scores were recorded on Days 0 and 1. Organ failure was documented daily. Any organ failure occurring during the 6-hour period before death was considered part of the terminal event and not counted. Standard definitions for sepsis and organ failure were used (11, 12).


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  		TABLE 2. PATIENT DEMOGRAPHICS, PHYSIOLOGIC AND CLINICAL PARAMETERS AT STUDY ENTRY (DAY 0)

 

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  		TABLE 3. PATIENT DEMOGRAPHICS, PHYSIOLOGIC AND CLINICAL PARAMETERS AT STUDY ENTRY (DAY 0) OF PATIENT CATEGORIES BY RESPONSE ON DAY 1 TO ≥ 10 CM H2O POSITIVE END-EXPIRATORY PRESSURE AND FIO2 ≥ 0.5

 

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  		TABLE 4. RESULTS OF THE MULTIVARIATE ANALYSIS

 
The primary goal of this study was to determine the number of patients categorized as having established ARDS, ALI, or ARF using the four standard ventilatory settings at Day 0 and Day 1, and to determine which standard ventilator setting and day identified groups of patients with different outcomes, specifically: ICU and hospital mortality, ventilator-free days (to Day 28), development of extrapulmonary organ failures, and incidence of barotrauma. Data are expressed as percentages, as means ± SD, or as medians and interquartile ranges. Differences between percentage distributions among groups for different settings were analyzed by {chi}2 or Fisher's exact tests. For continuous variables, the data were evaluated by analysis of variance and the Kruskal-Wallis test. To assess the consistency of the standard ventilator setting best classifying patients, the general linear model (GLIM) for repeated measures was used to test PaO2/FIO2 progression over time within and among groups. A multiple logistic regression analysis was performed to adjust the odds ratio of the ventilatory settings that best identified patients with established ARDS. A two-sided P value less than 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
From May 2004 to October 2005, 170 patients meeting the AECC definition for ARDS were enrolled (baseline PaO2/FIO2, 128 ± 33 mm Hg) (Table 2). Patients' median age was 54 (35–66) years, 68.2% were males, and their APACHE score was 19.9 ± 8.3. In 54.7% of patients, ARDS was of pulmonary origin. Sepsis was the primary cause of ARDS in 49 patients (28.8%) and pneumonia in 46 patients (27%). The overall ICU mortality was 33.5% and hospital mortality was 34.1%.

The responses to the four standard ventilator settings at Day 0 and Day 1 are illustrated in Figure 1. Regardless of standard ventilator setting or time of assessment, we found that some patients who originally were classified as having ARDS did not continue to meet the AECC definition. These patients were identified by standard ventilatory settings as having ALI (PaO2/FIO2, 201 to 300 mm Hg) or ARF (PaO2/FIO2 > 300 mm Hg). The only standard ventilator setting that categorized patients into established ARDS, ALI, and ARF with a significant difference (P < 0.0001) in ICU mortality was PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 on Day 1. Under these standard ventilator settings, 99 patients (58.2%) continued to meet the AECC definition for ARDS (PaO2/FIO2, 155.8 ± 29.8 mm Hg; ICU mortality, 45.5%), whereas 55 patients were classified as having ALI (PaO2/FIO2, 246.5 ± 25.6 mm Hg; ICU mortality, 20%) and 16 patients met ARF criteria with a PaO2/FIO2 of 370 ± 54 mm Hg and an ICU mortality of 6.3% (Figure 1). On Day 0, 58 patients, and on Day 1, 44 patients could not have their PEEP level or FIO2 decreased to 5 cm H2O and 0.5; on Day 0, 34 patients, and on Day 1, 25 patients could not have their PEEP level or FIO2 decreased to 10 cm H2O and 0.5; on Day 0, 47 patients, and on Day 1, 39 patients could not have their PEEP level or FIO2 decreased to 5 cm H2O and 1.0; on Day 0, 17 patients, and on Day 1, 15 patients could not have their PEEP level decreased to 10 cm H2O with an FIO2 of 1.0. Because all of these patients met ARDS criteria on their clinician-selected PEEP and FIO2 settings, they were classified as having ARDS on all standard settings where evaluation could not be performed because PEEP or FIO2 could not be adjusted based on setting rules in Table 1 or because of patient intolerance to a decrease in PEEP or FIO2.


Figure 1
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  		Figure 1. Classification of patients into established acute respiratory distress syndrome (ARDS), acute lung injury (ALI), or acute respiratory failure (ARF) together with mortality for each group based on response to the four standard ventilator settings. (A) Results from Day 0; (B) results from Day 1. P values refer to the differences in mortality rates.

 
The GLIM for repeated measures showed that the PaO2/FIO2 during the first week of ventilation clearly separated the three groups of patients defined by standard ventilator settings (PEEP ≥ 10 cm H2O, FIO2 ≥ 0.5) on Day 1 (GLIM, P < 0.0001; Figure 2). Although the AECC definition for ARDS showed 97% sensitivity, it had a very high rate (76.1%) of false positives when compared with those patients who met ARDS criteria on FIO2 ≥ 0.5 and PEEP ≥ 10 cm H2O on Day 1.


Figure 2
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  		Figure 2. Mean PaO2/FIO2 ratios in all patients classified by their response to a positive end-expiratory pressure ≥ 10 cm H2O and FIO2 ≥ 0.5 on Day 1 during the first week in the intensive care unit (ICU). ALI = acute lung injury; ARDS = acute respiratory distress syndrome; ARF = acute respiratory failure; GLIM = general linear model.

 
Table 3 shows the demographic, physiologic, and initial clinical parameters at Day 0 of all patients categorized by response to PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 on Day 1 into established ARDS, ALI, and ARF. We found significant differences for SAPS, PEEP, lung injury score, FIO2, PaO2/FIO2, respiratory rate, PaCO2, pH, and number of organ system failures among the three categories of lung injury. Multivariate analysis identified lung injury score, PaO2, and SAPS score at Day 0 as significant predictors of classification as established ARDS, ALI, and ARF by PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 on Day 1. The adjusted odds ratios for covariables are shown in Table 4.

Mean and median values of ventilatory and hemodynamic parameters for all patients by category determined by PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 on Day 1 during the first 12 days after study entry are shown in Tables 5 and 6. Over the 6 days from study entry, patients identified as having established ARDS (PaO2/FIO2 ≤ 200 mm Hg on standard ventilator settings of PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 on Day 1) required a higher plateau pressure, PEEP, FIO2, and respiratory rate, with a lower VT than those with ALI or ARF. The PaO2/FIO2, PaO2, pH, and systolic blood pressure trended lower, and PaCO2 and heart rate trended higher in the ARDS group compared with the ALI and ARF groups (Tables 5 and 6). Data in Tables 5 and 6 were obtained on clinician-selected settings of the ventilator, and not as a result of a response to any standard ventilator setting.


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  		TABLE 5. DAYS 1 AND 2 DATA FROM THE 170 PATIENTS MEETING THE AECC DEFINITION FOR ACUTE RESPIRATORY DISTRESS SYNDROME SEPARATED INTO THREE GROUPS ON DAY 1 BY POSITIVE END-EXPIRATORY PRESSURE ≥ 10 cm H2O AND FIO2 ≥ 0.5

 

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  		TABLE 6. DAYS 3, 6, AND 12 DATA FROM THE 170 PATIENTS MEETING THE AECC DEFINITION FOR ACUTE RESPIRATORY DISTRESS SYNDROME SEPARATED INTO THREE GROUPS ON DAY 1 BY POSITIVE END-EXPIRATORY PRESSURE ≥ 10 cm H2O AND FIO2 ≥ 0.5

 
In general, patients with established ARDS were ventilated for a longer period of time, had fewer ventilator-free days, a greater number of days with FIO2 > 0.5, and a greater number of days on PEEP > 10 cm H2O (P < 0.01 for all comparisons) than patients with either ALI or ARF (Table 7). In addition, the maximum PEEP and FIO2 and the number of organ failures were greater in the established ARDS group (P < 0.01 for all comparisons). Hospital mortality was also significantly different among the three groups (P = 0.001) (Table 7).


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  		TABLE 7. MECHANICAL VENTILATION AND CLINICAL DATA DURING INTENSIVE CARE UNIT STAY

 
Finally, we separated patients into those with pulmonary (93 patients, 54.7%) and nonpulmonary (77 patients, 45.3%) causes of ARDS and repeated the complete analysis. As with the total group, the only ventilatory settings that were able to categorize patients into established ARDS, ALI, and ARF with significant differences in mortality were PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 on Day 1. For patients with pulmonary ARDS, PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 on Day 1 separated patients into established ARDS (n = 55; mortality, 38.2%), ALI (n = 29; mortality, 17.2%), and ARF (n = 9; mortality, 11.0%) (P = 0.023). For patients with nonpulmonary ARDS, PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 on Day 1 separated patients into established ARDS (n = 44; mortality, 54.5%), ALI (n = 26; mortality, 23.1%), and ARF (n = 7; mortality, 0.0%) (P = 0.003). In addition, the mortality for pulmonary and nonpulmonary ARDS did not differ among patients with established ARDS, ALI, or ARF (P = 0.188). The evolution of PaO2 over time (GLIM analysis, P < 0.001 for both the pulmonary and nonpulmonary ARDS groups) was also equivalent to that of the total group (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The findings of this study have three major implications: (1) the current AECC definition overestimates the incidence of ARDS, (2) the AECC definition for ARDS underestimates ARDS mortality, and (3) the misclassification bias with the current AECC definition can result in the overestimation or underestimation of the beneficial effect of any therapeutic intervention. Response to standard ventilator settings 24 hours after meeting ARDS criteria separates patients into three groups with different degrees of lung injury and varying clinical outcome.

Impact on AECC Definition
The current AECC definition of ARDS is incapable of identifying a uniform group of patients with a similar level of lung injury and mortality. This definition, although it may have application in epidemiologic studies, must be questioned in its use in randomized controlled trials. As detailed in our results, changes in PEEP or FIO2 can grossly alter a patient's classification from ARDS to ALI or ARF even when assessed immediately after meeting the AECC ARDS definition (PaO2/FIO2 ≤ 200 mm Hg). Our findings are consistent with data comparing autopsy results with classification of ARDS by the use of various clinical definitions of ARDS (13, 14). Both Esteban and colleagues (13) and Ferguson and coworkers (14) found that the specificity and sensitivity of the AECC definition (1) as well as the lung injury score (15) and the definition for ARDS based on the Delphi technique (16) were only moderate when compared with autopsy finding of diffuse alveolar damage. The lack of a standard PEEP or FIO2 setting in the AECC definitions may also explain the marked difference in the epidemiologic estimates of the incidence of ARDS. Recently, Rubenfeld and colleagues (17) estimated the incidence of ARDS at 58.7 cases per 100,000 person-years. This is much higher than the 3.5 to 8.3 cases per 100,000 person-years provided by Villar and Slutsky (18) and others (19–22) who completed their estimates without using the AECC definition to classify patients.

Our data also bring into question the results of published trials of various therapeutic interventions on patients with ARDS/ALI (23–29). All of these trials were negative, few used the AECC definition for ARDS, and none required standard ventilator settings to qualify patients for enrollment. Because many patients without established ARDS may have been enrolled, it is conceivable that a disproportionate number of patients meeting ALI or ARF criteria ended up in the control arm, negating the beneficial effect of the treatment because of the lower mortality of these patients. This is contrary to the recently published data from Villar and colleagues (30) and Kacmarek and coworkers (31); both studies only selected patients after they qualified as having persistent disease on standard ventilator settings. As discussed by Marini (32), this resulted in the evaluation of a very homogenous group of patients in whom the benefit or lack of benefit of a therapy could be appropriately evaluated. In light of our data, the negative results of the recent ARDS Network's (ARDSnet) ALVEOLI trial (23), the recently published trials on prone positioning (24, 25), trials of inhaled nitric oxide in ARDS (26), as well as the early trials of lung-protective ventilation (27–29) may need to be reevaluated. Even with the original ARDSnet trial (33), a disproportionate number of mildly injured patients may have been present in the control arm of the trial, at least partially accounting for the low mortality of patients ventilated with a VT of 12 ml/kg PBW. It is important to remember that the ARDSnet trial enrolled patients with a PaO2/FIO2 ≤ 300 mm Hg without any FIO2 or PEEP criteria (23, 33).

Impact of FIO2 and PEEP
It is difficult to explain why patients initially meeting AECC ARDS criteria would fail to meet these criteria on standard ventilator settings 24 hours later, although it is well established that changes in PEEP and FIO2 alter the PaO2/FIO2 in lung-injured patients (2–7). At an FIO2 of 1.0, the effects of ventilation/perfusion mismatch are eliminated and true shunt is measured (4, 5). Ventilation with 100% oxygen can induce absorption atelectasis and increase true shunt unless adequate PEEP is applied (6, 7). Two specific issues partially explain our results. First, many of the patients studied had marked ventilation/perfusion mismatch. This is clear when the effect of the FIO2 increase to 1.0 at either PEEP level or time of assessment is analyzed (Figure 1). The usual concern raised when the FIO2 is increased to 1.0 in patients with ARDS is the development of additional shunt decreasing PaO2/FIO2. This was not systematically observed in the population studied. Regardless of timing, increasing the FIO2 to 1.0 resulted in improvement in PaO2/FIO2 in 18% (Day 0) and 26% (Day 1) of patients at 5 cm H2O PEEP. The second reason is the recruitment of lung that occurred when PEEP was increased to 10 cm H2O. The initial increase in peak airway pressure as PEEP was increased, recruited lung, and increased PaO2/FIO2. This is clear in Figure 1 because PEEP is increased at either FIO2 from 5 to 10 cm H2O. In fact, the combined effect of an increase in FIO2 and PEEP at Day 0 resulted in 33% and, at Day 1, 56% of patients converting to ALI or ARF. It is also important to realize that, on Day 0, none of our standard ventilator settings were capable of separating patients into groups with different mortalities. This may necessitate a lengthy process (24 h) for enrollment and subsequent randomization of patients in controlled trials.

The impact of PEEP that we observed is contrary to the recently published data of Gattinoni and colleagues (34). They noted that patients with recruitable lungs had a higher mortality than those with nonrecruitable lungs. Our data would indicate the opposite, at least in early ARDS. In patients in whom the setting of PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 markedly increased PaO2/FIO2, mortality was markedly decreased compared with those with established ARDS. A major reason for this finding may have been the timing of the evaluation. We evaluated patients during the first 24 hours after they met the AECC definition. Gattinoni and coworkers (34) evaluated patients after 5 ± 6 days of mechanical ventilation. As has been clearly shown by Grasso and colleagues (35), patients with ARDS ventilated for 7 days or longer are unlikely to be recruitable, whereas those ventilated for 1 to 2 days demonstrated marked recruitment. In addition, also contrary to the data from Gattinoni and coworkers (34), we found that patients with pulmonary versus nonpulmonary causes of ARDS responded to PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 in a similar manner and exactly the same as the total group.

The data in this study differ from those of previously published studies on standard ventilator settings (8, 9). There are a number of reasons for these differences. The previous studies were retrospective and enrolled a small number of patients (56 patients [8] and 41 patients [9]). In one of the studies, patients did not meet the current AECC ARDS definition and the PaO2/FIO2 cutoff for ARDS was 150 mm Hg, not 200 mm Hg (8). Finally, we cannot be sure that the timing of evaluations or the FIO2 and PEEP criteria identified in the current study are the best to categorize patients because only limited settings were evaluated.

The PaO2/FIO2 values on Day 1 at PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 for the three groups of patients (ARDS, 155.8 ± 29.8 mm Hg; ALI, 246.5 ± 25.6 mm Hg; and ARF, 370 ± 54 mm Hg) are different from those listed in Table 4. The reason for this difference is the actual maintenance levels of PEEP and FIO2 used throughout the course of ventilatory assistance. In many of the patients with ALI and ARF, PEEP was set at less than 10 cm H2O and FIO2 at less than 0.5 during their course of ventilatory assistance.

Limitations
The primary limitation of this study is that we only assessed patient response at 0 and 24 hours and only assessed four combinations of PEEP and FIO2. It may be possible that, at other times, FIO2 or PEEP levels are better capable of sorting patients into ARDS, ALI, and ARF. Second, we did not provide a specific protocol for mechanical ventilation throughout the ICU stay. However, patients were ventilated with a lung-protective strategy throughout their hospitalization.

Conclusions
The AECC definition for ARDS is not capable of identifying a group of patients with established ARDS. For clinical purposes, a precise definition may not be critical, but for research purposes, it is important to use a definition that identifies groups of patients with similar injury and outcome. The use of the AECC definition for ARDS to enroll patients into clinical trials may result in the inclusion of patients with highly variable lung injury and mortalities. A systematic method of assessing lung injury is required for enrollment into randomized controlled trials. Standard ventilator settings (PEEP ≥ 10 cm H2O and FIO2 ≥ 0.5 with a VT of 7 ml/kg PBW) applied 24 hours after classification as ARDS separates patients into three groups with markedly different mortalities: patients with established ARDS, ALI, or ARF. More research needs to be performed to identify the best method of categorizing the severity of injury in patients with ALI.


   FOOTNOTES
 
Supported, in part, by the Asociación Científica Pulmón y Ventilación Mecánica.

* A complete list of the members of the HELP (Hospitales Españoles para el estudio de la Lesión Pulmonar) Network may be found before the REFERENCES. Back

Originally Published in Press as DOI: 10.1164/rccm.200610-1534OC on June 21, 2007

Conflict of Interest Statement: J.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.P.-M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. I.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.S.-.S. received $60,000 in 2005–2006 as a consultancy fee and research funds from Maguet Critical Care, and $2,500 in 2005–2006 as lecture fees from Maguet Critical Care. J.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.M.K. was paid by Maguet, Inc., in September 2006 ($1,000), by Viasys, Inc., in October 2006 ($1,000), and by Respironics in November 2006 ($1,500) for lectures given, and has received research grants from Respironics ($60,000 and $25,000), Maguet ($60,000), and Hamilton Medical ($15,000).

Participating centers and investigators of the HELP (Hospitales Españoles para el estudio de la Lesión Pulmonar) Network: José López, M.D., Hospital General de León, León; Javier Belda, M.D., Gerardo Aguilar M.D., Ph.D., Francisco Martí, M.D., Ph.D., Armando Maruenda, M.D., Ph.D., Hospital Clínico de Valencia, Valencia; Jesús Blanco, M.D., Hospital Universitario Rio Hortega, Valladolid; Iñaki Saralegui, M.D., Hospital Santiago Apóstol, Vitoria; Fernando Suárez-Sipman, M.D., Hospital Jiménez Díaz, Madrid; Julia López, M.D., Hospital Universitario La Paz, Madrid; Santiago Lubillo, M.D., Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife; Dario Toral, M.D., Hospital Universitario 12 de Octubre, Madrid; Miguel Angel Romera, M.D., Hospital Universitario Puerta de Hierro, Madrid; Antonio Santos-Bouza, M.D., Ph.D., Hospitales Universitarios de Santiago, Santiago de Compostela; Eli Zavala, M.D., Ph.D., Hospital Clinic, Barcelona; Frutos del Nogal, M.D., Ph.D., Hospital Severo Ochoa, Madrid; Luis Ramos, M.D., Hospital General de La Palma, La Palma, Canary Islands; Gumersindo González-Díaz, M.D., Antonia López-Martínez, M.D., Hospital Morales Meseguer, Murcia; Santiago Macías, M.D., Noelia Albala, M.D., Hospital General de Segovia, Segovia.

Received in original form October 24, 2006; accepted in final form June 21, 2007


   REFERENCES
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
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