acute respiratory distress syndrome ( ards ) is a sudden and catastrophic lung condition associated with low oxygen level in the blood . ards is a major cause of acute respiratory failure , and can be caused by a pulmonary insult or an indirect extra - pulmonary insult . in 1994 , the american and european consensus conference ( aecc ) established specific clinical criteria for ards and acute lung injury , including acute and sudden onset of severe respiratory distress , bilateral infiltrates on chest radiography , the absence of cardiogenic pulmonary edema , and severe hypoxemia . based on aecc definition , the incidence of ards was reported ranging from 5.0 to 33.8 per 100,000 people in several epidemiological studies . although the mortality of ards varies according to differences in study populations , co - morbidities , severity of lung injury , predisposing factors for ards , and the setting of mechanical ventilation ( mv ) ; the reported mortality of ards in adult remains > 40% and has not changed with time substantially . because severe hypoxemia is the hallmark of ards , various parameters of oxygenation or lung mechanics are assessed as appropriate indicators of disease severity or good predictors of deaths in several studies . however , aecc definition may not truly reflect the severity and outcome of this clinical entity due to pao2/fio2 may vary in response to ventilator settings , especially for the setting of positive end expiratory pressure ( peep ) . in 2012 , the berlin definition of ards proposed 3 categories of ards based on the degree of hypoxemia : mild ( 200  mm  hg < pao2/fio2  300  mm  hg ) , moderate ( 100  mm  hg < pao2/fio2  300  mm  hg ) , and severe ( pao2/fio2  100  mm  hg ) with a peep  5  cm h2o . despite the fact that the berlin criteria showed better predictive power of mortality in ards than the aecc definition , the absolute value of the area under the receiver - operating characteristic ( roc ) curve was only 0.577 . it suggests that some significant prognostic factors are still missing , and the initial hypoxemic level may not be the optimal predictor for prognosis . therefore , we are interested in knowing whether the stabilized pao2/fio2 ratio following a standard ventilator setting or any other factors are more precise predictors of the prognosis in patients with ards . this study aimed to determine whether pao2/fio2 ratio 24  h ( day 1 ) after standard ventilator setting would be a better outcome predictor than the pao2/fio2 ratio on the day patients met ards berlin criteria ( day 0 ) . this study was conducted at chi mei medical center , a 1288-bed tertiary medical center with total 96 intensive care unit ( icu ) beds for adults , including 57 medical and 39 surgical beds . the care in the icu is covered by intensivists , senior residents , nurses , respiratory therapists , dietitians , physical therapists , and clinical pharmacists . the icu team makes rounds at least once daily , and respiratory therapists are responsible for managing all mv , including weaning processes and spontaneous breathing trials . patients admitted to icus were screened daily to identify who met the berlin definition of ards and were collected prospectively between december 1 , 2012 and may 31 , 2015 . the following information of the included patients , including age ; gender ; co - morbidities ; cause of ards ; clinical features ; laboratory data ; comorbidities including congestive heart failure , chronic lung diseases , end - stage renal disease , liver cirrhosis , diabetes mellitus , acute or chronic encephalopathy , cancer , and immunocompromised condition ; daily intake / output ( i / o ) ; organs dysfunction ; acute physiology and chronic health evaluation ( apache ii ) score ; and lung injury score during the first 24  h in the icu before and after applying standard mv , were prospectively collected . in addition , arterial blood gas ( abg ) and ventilator setting on the day of enrolling ( day 0 ) as well as 24  h later ( day 1 ) were obtained following the mandatory standard ventilator setting  mode : volume assist / control ; tidal volume ( vt ) : 7  ml / kg of predicted body weight ( pbw ) ; ventilator rate : to maintain 35 to 50  mm  hg of paco2 , plus the peep and fio2 settings described in previous study according to ards clinical trials network . after the setting , patients were left undisturbed and blood gases were collected 30 min afterward . throughout the acute course of ventilatory care , patients were recommended to receive a vt of 5 to 9  ml / kg pbw at a plateau pressure < 30  cm h2o with a ventilatory rate to maintain paco2 at 35 to 50  mm  hg and peep  5  cm h2o . cardiovascular failure was defined as systolic blood pressure ( sbp ) of 90 mm  hg or a mean arterial pressure ( map ) 65 mm  hg for at least 1 h despite adequate fluid resuscitation ; or the need for vasoactive agents ( dopamine 5  mg / kg per min ) to maintain sbp  90 mm  hg or map  65 mm hg . metabolic failure was defined as ph  7.30 or base deficit  5.0  meq / l and a plasma lactate level > 3 hematologic failure was considered as a platelet count < 80,000 per mm or 50% decrease in platelet count from the highest value recorded over the past 3 days . kidney failure was considered as oliguria with an average urine output < 0.5  ml / kg per h for 4  h despite adequate fluid resuscitation or creatinine 2  mg / dl . hepatic failure was defined as markedly increased serum bilirubin level 4  mg / dl . in addition , the differences of baseline characteristics and clinical variables between the survival and nonsurvival groups were evaluated using student test ( for continuous variables ) and pearson chi - squared test ( for categorical variables ) . logistic regression analysis was performed to estimate the association between the predictors of mortality and death at day 28 . the variables with significant difference at p value < 0.05 were selected as predictors in the multiple logistic regression analysis . the cochran  armitage trend test was used to determine proportions of mortality trend according to the severity of ards . sas 9.4 for windows ( sas institute , cary , nc ) was used for all analyses . the roc curves were plotted using stata ( version 12 ; stata corp . , college station , tx ) . this study was conducted at chi mei medical center , a 1288-bed tertiary medical center with total 96 intensive care unit ( icu ) beds for adults , including 57 medical and 39 surgical beds . the care in the icu is covered by intensivists , senior residents , nurses , respiratory therapists , dietitians , physical therapists , and clinical pharmacists . the icu team makes rounds at least once daily , and respiratory therapists are responsible for managing all mv , including weaning processes and spontaneous breathing trials . patients admitted to icus were screened daily to identify who met the berlin definition of ards and were collected prospectively between december 1 , 2012 and may 31 , 2015 . the following information of the included patients , including age ; gender ; co - morbidities ; cause of ards ; clinical features ; laboratory data ; comorbidities including congestive heart failure , chronic lung diseases , end - stage renal disease , liver cirrhosis , diabetes mellitus , acute or chronic encephalopathy , cancer , and immunocompromised condition ; daily intake / output ( i / o ) ; organs dysfunction ; acute physiology and chronic health evaluation ( apache ii ) score ; and lung injury score during the first 24  h in the icu before and after applying standard mv , were prospectively collected . in addition , arterial blood gas ( abg ) and ventilator setting on the day of enrolling ( day 0 ) as well as 24  h later ( day 1 ) were obtained following the mandatory standard ventilator setting  mode : volume assist / control ; tidal volume ( vt ) : 7  ml / kg of predicted body weight ( pbw ) ; ventilator rate : to maintain 35 to 50  mm  hg of paco2 , plus the peep and fio2 settings described in previous study according to ards clinical trials network . after the setting , patients were left undisturbed and blood gases were collected 30 min afterward . throughout the acute course of ventilatory care , patients were recommended to receive a vt of 5 to 9  ml / kg pbw at a plateau pressure < 30  cm h2o with a ventilatory rate to maintain paco2 at 35 to 50  mm  hg and peep  5  cm h2o . cardiovascular failure was defined as systolic blood pressure ( sbp ) of 90 mm  hg or a mean arterial pressure ( map ) 65 mm  hg for at least 1 h despite adequate fluid resuscitation ; or the need for vasoactive agents ( dopamine 5  mg / kg per min ) to maintain sbp  90 mm  hg or map  65 mm hg . metabolic failure was defined as ph  7.30 or base deficit  5.0  meq / l and a plasma lactate level > 3  mmol / l . hematologic failure was considered as a platelet count < 80,000 per mm or 50% decrease in platelet count from the highest value recorded over the past 3 days . kidney failure was considered as oliguria with an average urine output < 0.5  ml / kg per h for 4  h despite adequate fluid resuscitation or creatinine 2  mg / dl . hepatic failure was defined as markedly increased serum bilirubin level 4  mg / dl . categorical variables were presented as frequency counts with percentages . in addition , the differences of baseline characteristics and clinical variables between the survival and nonsurvival groups were evaluated using student test ( for continuous variables ) and pearson chi - squared test ( for categorical variables ) . logistic regression analysis was performed to estimate the association between the predictors of mortality and death at day 28 . the variables with significant difference at p value < 0.05 were selected as predictors in the multiple logistic regression analysis . the cochran  armitage trend test was used to determine proportions of mortality trend according to the severity of ards . sas 9.4 for windows ( sas institute , cary , nc ) was used for all analyses . the roc curves were plotted using stata ( version 12 ; stata corp . , college station , tx ) . during the 30-month period , a total of 238 cases met the berlin criteria for ards were enrolled , and their demographic characteristics were summarized in table 1 . the mean age of the patients was 62.7    16.5 years and male comprised most of the patients ( 72.3% ) . most of the patients were transferred from emergency department ( 53.8% ) , followed by general ward ( 37.0% ) . pneumonia was the most common etiology of ards ( n  =  168 , 70.6% ) , followed by nonpulmonary sepsis , transfusion - related acute lung injury , and lung contusion . organ failure in cardiovascular system was the most common systemic failure , followed by hematological , renal , and metabolic failure . the average number of organ failure and comorbidity were 1.8    1.2 and 1.0    0.9 , respectively . the apache ii scores were 21.4    8.7 , and the glasgow coma scale scores were 8.9    4.2 . the average lung injury score was 2.6    0.5 , and the baseline pao2/fio2 was 147.5    64.3  mm  hg . based on berlin definition , most of the patients were classified as moderate ards ( n  =  125 , 52.5% ) on day 0 . the average length of icu and hospital stays were 18.0    11.3 and 32.6    30.9 , respectively . demographics of the patients the responses to standard ventilator setting at days 0 and 1 were shown in table 2 . twelve ( 5% ) of the 238 cases who originally were classified as ards did not continually meet berlin definition . in addition , a total of 134 ( 56% ) patients had the changes regarding the severity of ards from day 0 to day 1 . according to the criteria for severity determination in berlin definition , 79 patients had better oxygenation on day 1 while 55 patients had worse oxygenation on day 1 . among 50 patients with initial mild ards , more than half of them had the pao2/fio2 ratios changed to within 100 and 200  mm  hg when only 11 ( 22% ) patients remained the ratio within 200 and 300  mm  hg . for 125 patients with initial moderate ards , most of their pao2/fio2 ratios remained within 100 and 200  mm  hg . in 63 patients with initial severe ards , about half of their pao2/fio2 ratios were improved to the level between 100 and 200  mm  hg . case number according to berlin definition and the ratio of partial pressure arterial oxygen and fraction of inspired oxygen ratio on day 1 a total of 117 patients died during this study and the rate of 28-day mortality was 49.1% . we further compared the clinical variables between patients with survival and mortality outcomes ( table 3 ) . significant differences between mortality and survival groups were found as follows : age , disease severity , sepsis relevance , number of organ failure , fluid balance , length of icu stay , and pao2/fio2 ratio on day 1 . on the contrary , the following variables , including gender , body mass index , lung injury score , cause of ards , vt / pbw , baseline data of abg , number of comorbidity , oxygenation , and pao2/fio2 ratio on day 0 , were not significantly different . comparisons between patients with survival and mortality table 4 shows the crude and adjusted odds ratio ( or ) of the predictor for 28-day mortality . this multivariate analysis identified age , pao2/fio2 on day 1 , number of organ failures , and positive fluid balance within 5 days as significant risk factors of death . predictors of 28-d mortality outcome figures 1 and 2 show the mortality according to the pao2/fio2 ratio and ards severity using berlin definition on days 0 and 1 . in figure 1 , we found that the mortality rate was increased along with the pao2/fio2 ratio on day 1 ( p  <  0.0001 ) rather than on day 0 ( p  =  0.290 ) . moreover , the same trend of increased mortality as well as pao2/fio2 ratio on day 1 in patients with initial mild ards and in patients with moderate ards on day 0 were shown figure 2 . when we compared the receiver operating curve to predict mortality according to the pao2/fio2 on days 0 and 1 , we found that the area under curve ( auc ) for pao2/fio2 on day 1 was 0.657 ( 95% ci : 0.5890.726 , p  <  0.001 ) and 0.557 on day 0 ( 95% furthermore , auc for pao2/fio2 on day 1 was significant higher than for pao2/fio2 on day 0 ( p  =  0.0158 ) . the 28-d mortality according to the ratio of partial pressure arterial oxygen and fraction of inspired oxygen and the severity of acute respiratory distress syndrome using berlin definition on day 0 ( a ) and day 1 ( b ) . the 28-d mortality according to the severity of acute respiratory distress syndrome ( mild , a ; moderate , b ; and severe , c ) using berlin definition on day 0 . comparisons between the receiver operating curve for predictive validity of mortality according to the ratio of partial pressure arterial oxygen and fraction of inspired oxygen on days 0 and 1 . this study investigating 238 cases of ards based on berlin definition have several significant findings . first of all , the initial severity of ards on day 0 according to berlin definition was not significantly associated with the outcome . it may indicate that current berlin criteria for ards can not identify a uniform group of patients with a similar severity of lung injury and mortality . by contrast , pao2/fio2 ratio on day 1 following standard ventilator setting was found to be significantly associated with the outcome and thus could separate patients into subgroups with different clinical outcomes . it suggests that the 24 h standard ventilator setting application can effectively classify patients into different subgroups with significantly different mortality rates . in the original study of berlin definition for ards , the mortality proportionally increased with the severity of ards ( mild ards : 27% , 95% ci : 2430 ; moderate : ards : 32% , 95% ci : 2934 ; severe ards : 45% , 95% ci : 4248 , p  <  0.001 ) . et al 's prospective observation study , the 28-day mortality rate was 30.9% , 27.9% , and 49.3% in mild , moderate , and severe ards , respectively . however , they could not find that ards severity was significantly associated with the mortality in the cox proportional hazard regression analysis ( p  =  0.84 ) . in our study , mortality rates between mild , moderate , and severe ards patients ( 48.0% vs 45.6% vs 57.1% , p  =  0.457 ) at the onset of ards were not significantly different , and the mortality rates were not found significantly associated with the initial ards stage using further multivariate analysis ( p  =  0.136 ) . these findings indicated that pao2/fio2 at the onset of ards might not be an accurate predictor of mortality . on the contrary , villar et al showed that a standard ventilatory setting could effectively distinguish the 3 pao2/fio2 risk categories 24 h after the onset of ards ( p  =  0.0001 ) . by using this ventilatory setting , the mortality of patients were classified as mild ( 17% ) , moderate ( 40.9% ) , and severe ards ( 58.1% ) ( p  =  0.00001 ) , separately . costa and amato proposed that the use of stabilized pao2/fio2 ratio ( after the first 24  h ) might improve the distinguishability of the patients . in their results , the oxygenation level taken 24  h afterward in patients with moderate ards had significant higher unadjusted and adjusted ors for mortality ( 1.65 and 1.49 ) than in patients with mild ards . in our study , oxygenation measurements 24  h after the onset of ards among mild , moderate , and severe ards could be significantly identified ( 34.8% vs 50.0% vs 68.0% , p  =  0.001 ) , and further multivariate analysis also confirmed that pao2/fio2 ratio after 24  h was significantly associated with mortality ( p  <  0.001 ) . all the findings indicated that the pao2/fio2 ratio after stabilization might be a more appropriate predictor of death than the initial pao2/fio2 ratio at the onset of ards . we also found that the increases of pao2/fio2 from day 0 to day 1 were significantly higher among survivors than mortality subgroups ( 0.3  mm  hg vs 29.8  mm  hg , p  =  0.005 ) . this finding was consistent with previous study that the increase in pao2/fio2 was associated with mortality reduction ( adjusted or : 0.80 [ 95% ci : 0.720.89 ] per 25-mm  hg increase in pao2/fio2 ) . moreover , the association was more prominent in patients with severe disease ( baseline pao2/fio2  150  mm  hg ) . another study investigating the outcome of 216 ards patients treated with inhaled epoprostenol had the similar finding that hospital mortality was significantly associated with an incremental change in pao2/fio2 during the first 24  h of treatment ( adjusted or : 0.99 , 95% ci : 0.9880.994 , p  =  0.002 ) . therefore , these findings suggest that the change of pao2/fio2 may be another good predictor of outcome in patients with ards . in addition to pao2/fio2 ratio on day 1 , we also identified some independent risk factors of death , including age , number of organ failure , and positive fluid balance in this study . several previous studies published similar findings . in gong et al , age was a significant predictor of mortality with adjusted or of 1.96 ( 95% ci : 1.502.53 ) . in pacheco et al , the addition of cumulative fluid balance of > 4 l was an independent predictor ( adjusted or : 2.36 , 95% ci : 1.663.37 , p  =  0.02 ) . in zhang and chen , positive fluid balance in the first 8 days was significantly associated with increased risk of death after stepwise regression analysis ( or : 1.00057 ; 95% ci : 1.000341.00080 ) . in li et al , the logistic analysis showed that the number of organ dysfunction was related with prognosis in elderly patients with ards ( or : 2.328 , 95% ci : 1.1934.520 , p  =  0.029 ) . even for the young patients with ards , the numbers of organ dysfunctions in nonsurvivors were significantly higher than those of the survivors . however , in contrast to most of the above studies using aecc criteria for ards diagnosis , our study used berlin definition . therefore , a further large - scale study using berlin definition of ards is still needed to validate our findings . . it may be possible that at earlier time we are better capable of separating patients into different severity of ards . second , we only followed the lung - protective strategy , but we did not provide a specific protocol for adjusting the setting of mechanical ventilator throughout the all icu course . third , some managements for ards such as prone position , high frequency oscillatory ventilation , or lung recruitment maneuver were not recorded . fourth , this study was conducted in a single medical center , and the patient number was limited . a large and multicenter study should be warranted to clarify this issue . in conclusion , pao2/fio2 ratio on day 0 is not a good predictor of outcomes in patients with ards . in contrast , a stabilized ( 24-h delayed ) pao2/fio2 ratio after applying mechanical ventilator can accurately predict the outcomes in patients with ards . in addition , age , number of organ failure , and the status of fluid balance are found to be independently associated with mortality .
abstractthe initial hypoxemic level of acute respiratory distress syndrome ( ards ) defined according to berlin definition might not be the optimal predictor for prognosis . 
 we aimed to determine the predictive validity of the stabilized ratio of partial pressure arterial oxygen and fraction of inspired oxygen ( pao2/fio2 ratio ) following standard ventilator setting in the prognosis of patients with ards.this prospective observational study was conducted in a single tertiary medical center in taiwan and compared the stabilized pao2/fio2 ratio ( day 1 ) following standard ventilator settings and the pao2/fio2 ratio on the day patients met ards berlin criteria ( day 0 ) . 
 patients admitted to intensive care units and in accordance with the berlin criteria for ards were collected between december 1 , 2012 and may 31 , 2015 . 
 main outcome was 28-day mortality . 
 arterial blood gas and ventilator setting on days 0 and 1 were obtained.a total of 238 patients met the berlin criteria for ards were enrolled , and they were classified as mild ( n  =  50 ) , moderate ( n  =  125 ) , and severe ( n  =  63 ) ards , respectively . twelve ( 5% ) patients who originally were classified as ards did not continually meet the berlin definition , and a total of 134 ( 56% ) patients had the changes regarding the severity of ards from day 0 to day 1 . 
 the 28-day mortality rate was 49.1% , and multivariate analysis identified age , pao2/fio2 on day 1 , number of organ failures , and positive fluid balance within 5 days as significant risk factors of death . 
 moreover , the area under receiver - operating curve for mortality prediction using pao2/fio2 on day 1 was significant higher than that on day 0 ( p  =  0.016).pao2/fio2 ratio on day 1 after applying mechanical ventilator is a better predictor of outcomes in patients with ards than those on day 0 .