- ข้อความ
- ประวัติศาสตร์
indicates benefit for the odds rati
indicates benefit for the odds ratio analyses and harm (decrease in ventilator free days) for the mean difference analysis. We also used Bayesian meta regression14 to determine the relation between the odds of mortality and time to treatment in ARDS, total dose of steroids, and year of study completion. The slope (β) with 95% credible intervals and the prob- ability that β was 0 or more are presented. Wepresented heterogeneity as the standard deviation between studies. For all analyses a standard deviation close to 0 indicates little heterogeneity, whereas for the odds ratio meta-analyses a standard deviation of more than 1 might be considered to reflect substantial heterogeneity. Similarly, for the mean difference analysis, a standard deviation greater than, for exam- ple, 10 might be considered to indicate substantial heterogeneity. Publication bias was not formally assessed, as the two subgroups each had fewer than 10 studies.15
We analysed the data with WinBUGS16 using three simultaneous runs of the program with disparate starting values. The first 100000 iterations were discarded and results were reported as posterior medians and intervals on the basis of a further 100 000 iterations. We used various diagnostics avail- able in the package Bayesian Output Analysis to assess convergence.17 In all cases we found no evidence against convergence. We used the same diffuse priors as described elsewhere14 for the odds ratio models and the metaregressions. A diffuse or non-informative prior should not greatly influence the results and reflects little or no prior belief about a particular problem. Mathematically diffuse priors aim to have about equal probability over all plausible values of the variable. For the mean difference model we placed a non-informative normal prior distribution with mean 0 and variance 105 on the overall mean difference. A normal distribution with mean 0 and variance of 13.5 and truncated below 0 was placed on the variable forstandard deviation between studies.18 Such a distribu- tion was derived from the notion that the median difference between any two studies was about four days and that a difference of more than 11 days would be extremely unlikely. To determine the influence on the overall results we also undertook a sensitivity analysis in which the priors were made even less informative.
RESULTS
Of the 7093 articles screened on ARDS or sepsis, 439 pertained to steroids in either condition. One investi- gator reviewed the abstracts of these articles and 62 articles were retrieved for further assessment by three investigators. Fifty five studies were excluded, includ- ing two controlled retrospective studies (fig 1),w6 w7 a randomised trial of steroids in severe community acquired pneumonia, 19 and five other prospective trials identified by an additional search (see bmj.com). w8-w12 This left nine studies, including two identified by an additional search. Four studies evaluated the preventive use of steroids in critically ill patientsw13- w16 and five assessed the role of steroids after the onset of ARDS.w1-w5 The definitions of ARDS in the studies done before the publication of the American-European consensus definition 13 were generally consistent with the consensus definition (table 2). The treatment and control arms had similar baseline characteristics (table 3). Table 4 presents a summary of the studycharacteristics and quality scores; the lag time from study completion to publication ranged from two to seven years. The reporting of mortality was variable. The steroid dose ranged from methylprednisolone 1 mg/kg/day to 120 mg/kg/day (or equivalent doses of hydrocortisone or dexamethasone) administered from four hours to 30 days (table 5).
The credible interval for the preventive use of steroids in critically ill patients included 1, indicating that a null effect could not be ruled out. The probability (odds ratio ≥1) was 86.6% suggesting some evidence of an association between steroid therapy and the subsequent development of ARDS: four studies, odds ratio 1.55 (95% credible interval 0.58 to 4.05); SD 0.58 for variability between studies (table 6 and fig 2). Similarly, the probability suggested a weakly increased risk of death associated with steroid therapy in patients who developed ARDS: probability (odds ratio ≥1) =72.8% (table 6 and fig 3), although again the credible interval included 1.
In the five therapeutic studies the probability that the odds ratio was one or more was small indicating that giving corticosteroids after the onset of ARDS was associated with a trend (table 6 and fig 4) to reduced mortality (overall odds ratio 0.62, 95% credible interval 0.23 to 1.26, probability (odds ratio ≥1)=6.8%), although the credible interval included 1 so that a null effect could not be ruled out. Some heterogeneity was evident between the studies (standard deviation 0.53). Steroid therapy was associated with substantially more ventilator free days (three studies) compared with controls (mean difference 4.05 days, 95% credible interval 0.22 to 8.71, probability (mean difference ≥0) =97.9%, SD 2.39). When the effect of moderators (time or dose of steroid therapy, year of study completion) on outcomes was explored in the five therapeutic studies, no evidence was found of an association between odds of mortality and time to treatment (fig 4) in (log) hours; β(time)=−0.08 (95% credible interval −1.00 to 0.62), probability (β≥0)=38.7%; total steroid dose; β(dose) =0.06 (95% credible interval −0.94 to 0.97), probability (β≥0)=57.8%; or year of study completion;β(completion year)=−0.01 (95% credible interval −0.17 to 0.14), probability (β≥0)=44.1%.
As anticipated, definitions for secondary infections varied considerably (table 7). Steroid therapy was not associated with an increase in the number of patients developing new infections. Within the four available therapeutic studies the trend was towards decreased odds of developing pneumonia (probability (odds ratio
We analysed the data with WinBUGS16 using three simultaneous runs of the program with disparate starting values. The first 100000 iterations were discarded and results were reported as posterior medians and intervals on the basis of a further 100 000 iterations. We used various diagnostics avail- able in the package Bayesian Output Analysis to assess convergence.17 In all cases we found no evidence against convergence. We used the same diffuse priors as described elsewhere14 for the odds ratio models and the metaregressions. A diffuse or non-informative prior should not greatly influence the results and reflects little or no prior belief about a particular problem. Mathematically diffuse priors aim to have about equal probability over all plausible values of the variable. For the mean difference model we placed a non-informative normal prior distribution with mean 0 and variance 105 on the overall mean difference. A normal distribution with mean 0 and variance of 13.5 and truncated below 0 was placed on the variable forstandard deviation between studies.18 Such a distribu- tion was derived from the notion that the median difference between any two studies was about four days and that a difference of more than 11 days would be extremely unlikely. To determine the influence on the overall results we also undertook a sensitivity analysis in which the priors were made even less informative.
RESULTS
Of the 7093 articles screened on ARDS or sepsis, 439 pertained to steroids in either condition. One investi- gator reviewed the abstracts of these articles and 62 articles were retrieved for further assessment by three investigators. Fifty five studies were excluded, includ- ing two controlled retrospective studies (fig 1),w6 w7 a randomised trial of steroids in severe community acquired pneumonia, 19 and five other prospective trials identified by an additional search (see bmj.com). w8-w12 This left nine studies, including two identified by an additional search. Four studies evaluated the preventive use of steroids in critically ill patientsw13- w16 and five assessed the role of steroids after the onset of ARDS.w1-w5 The definitions of ARDS in the studies done before the publication of the American-European consensus definition 13 were generally consistent with the consensus definition (table 2). The treatment and control arms had similar baseline characteristics (table 3). Table 4 presents a summary of the studycharacteristics and quality scores; the lag time from study completion to publication ranged from two to seven years. The reporting of mortality was variable. The steroid dose ranged from methylprednisolone 1 mg/kg/day to 120 mg/kg/day (or equivalent doses of hydrocortisone or dexamethasone) administered from four hours to 30 days (table 5).
The credible interval for the preventive use of steroids in critically ill patients included 1, indicating that a null effect could not be ruled out. The probability (odds ratio ≥1) was 86.6% suggesting some evidence of an association between steroid therapy and the subsequent development of ARDS: four studies, odds ratio 1.55 (95% credible interval 0.58 to 4.05); SD 0.58 for variability between studies (table 6 and fig 2). Similarly, the probability suggested a weakly increased risk of death associated with steroid therapy in patients who developed ARDS: probability (odds ratio ≥1) =72.8% (table 6 and fig 3), although again the credible interval included 1.
In the five therapeutic studies the probability that the odds ratio was one or more was small indicating that giving corticosteroids after the onset of ARDS was associated with a trend (table 6 and fig 4) to reduced mortality (overall odds ratio 0.62, 95% credible interval 0.23 to 1.26, probability (odds ratio ≥1)=6.8%), although the credible interval included 1 so that a null effect could not be ruled out. Some heterogeneity was evident between the studies (standard deviation 0.53). Steroid therapy was associated with substantially more ventilator free days (three studies) compared with controls (mean difference 4.05 days, 95% credible interval 0.22 to 8.71, probability (mean difference ≥0) =97.9%, SD 2.39). When the effect of moderators (time or dose of steroid therapy, year of study completion) on outcomes was explored in the five therapeutic studies, no evidence was found of an association between odds of mortality and time to treatment (fig 4) in (log) hours; β(time)=−0.08 (95% credible interval −1.00 to 0.62), probability (β≥0)=38.7%; total steroid dose; β(dose) =0.06 (95% credible interval −0.94 to 0.97), probability (β≥0)=57.8%; or year of study completion;β(completion year)=−0.01 (95% credible interval −0.17 to 0.14), probability (β≥0)=44.1%.
As anticipated, definitions for secondary infections varied considerably (table 7). Steroid therapy was not associated with an increase in the number of patients developing new infections. Within the four available therapeutic studies the trend was towards decreased odds of developing pneumonia (probability (odds ratio
0/5000
indicates benefit for the odds ratio analyses and harm (decrease in ventilator free days) for the mean difference analysis. We also used Bayesian meta regression14 to determine the relation between the odds of mortality and time to treatment in ARDS, total dose of steroids, and year of study completion. The slope (β) with 95% credible intervals and the prob- ability that β was 0 or more are presented. Wepresented heterogeneity as the standard deviation between studies. For all analyses a standard deviation close to 0 indicates little heterogeneity, whereas for the odds ratio meta-analyses a standard deviation of more than 1 might be considered to reflect substantial heterogeneity. Similarly, for the mean difference analysis, a standard deviation greater than, for exam- ple, 10 might be considered to indicate substantial heterogeneity. Publication bias was not formally assessed, as the two subgroups each had fewer than 10 studies.15
We analysed the data with WinBUGS16 using three simultaneous runs of the program with disparate starting values. The first 100000 iterations were discarded and results were reported as posterior medians and intervals on the basis of a further 100 000 iterations. We used various diagnostics avail- able in the package Bayesian Output Analysis to assess convergence.17 In all cases we found no evidence against convergence. We used the same diffuse priors as described elsewhere14 for the odds ratio models and the metaregressions. A diffuse or non-informative prior should not greatly influence the results and reflects little or no prior belief about a particular problem. Mathematically diffuse priors aim to have about equal probability over all plausible values of the variable. For the mean difference model we placed a non-informative normal prior distribution with mean 0 and variance 105 on the overall mean difference. A normal distribution with mean 0 and variance of 13.5 and truncated below 0 was placed on the variable forstandard deviation between studies.18 Such a distribu- tion was derived from the notion that the median difference between any two studies was about four days and that a difference of more than 11 days would be extremely unlikely. To determine the influence on the overall results we also undertook a sensitivity analysis in which the priors were made even less informative.
RESULTS
Of the 7093 articles screened on ARDS or sepsis, 439 pertained to steroids in either condition. One investi- gator reviewed the abstracts of these articles and 62 articles were retrieved for further assessment by three investigators. Fifty five studies were excluded, includ- ing two controlled retrospective studies (fig 1),w6 w7 a randomised trial of steroids in severe community acquired pneumonia, 19 and five other prospective trials identified by an additional search (see bmj.com). w8-w12 This left nine studies, including two identified by an additional search. Four studies evaluated the preventive use of steroids in critically ill patientsw13- w16 and five assessed the role of steroids after the onset of ARDS.w1-w5 The definitions of ARDS in the studies done before the publication of the American-European consensus definition 13 were generally consistent with the consensus definition (table 2). The treatment and control arms had similar baseline characteristics (table 3). Table 4 presents a summary of the studycharacteristics and quality scores; the lag time from study completion to publication ranged from two to seven years. The reporting of mortality was variable. The steroid dose ranged from methylprednisolone 1 mg/kg/day to 120 mg/kg/day (or equivalent doses of hydrocortisone or dexamethasone) administered from four hours to 30 days (table 5).
The credible interval for the preventive use of steroids in critically ill patients included 1, indicating that a null effect could not be ruled out. The probability (odds ratio ≥1) was 86.6% suggesting some evidence of an association between steroid therapy and the subsequent development of ARDS: four studies, odds ratio 1.55 (95% credible interval 0.58 to 4.05); SD 0.58 for variability between studies (table 6 and fig 2). Similarly, the probability suggested a weakly increased risk of death associated with steroid therapy in patients who developed ARDS: probability (odds ratio ≥1) =72.8% (table 6 and fig 3), although again the credible interval included 1.
In the five therapeutic studies the probability that the odds ratio was one or more was small indicating that giving corticosteroids after the onset of ARDS was associated with a trend (table 6 and fig 4) to reduced mortality (overall odds ratio 0.62, 95% credible interval 0.23 to 1.26, probability (odds ratio ≥1)=6.8%), although the credible interval included 1 so that a null effect could not be ruled out. Some heterogeneity was evident between the studies (standard deviation 0.53). Steroid therapy was associated with substantially more ventilator free days (three studies) compared with controls (mean difference 4.05 days, 95% credible interval 0.22 to 8.71, probability (mean difference ≥0) =97.9%, SD 2.39). When the effect of moderators (time or dose of steroid therapy, year of study completion) on outcomes was explored in the five therapeutic studies, no evidence was found of an association between odds of mortality and time to treatment (fig 4) in (log) hours; β(time)=−0.08 (95% credible interval −1.00 to 0.62), probability (β≥0)=38.7%; total steroid dose; β(dose) =0.06 (95% credible interval −0.94 to 0.97), probability (β≥0)=57.8%; or year of study completion;β(completion year)=−0.01 (95% credible interval −0.17 to 0.14), probability (β≥0)=44.1%.
As anticipated, definitions for secondary infections varied considerably (table 7). Steroid therapy was not associated with an increase in the number of patients developing new infections. Within the four available therapeutic studies the trend was towards decreased odds of developing pneumonia (probability (odds ratio<1)=76.9%, table 6); although heterogeneity was substantial (SD 1.34, table 6). Metaregression showed a trend towards an increased number of patients devel- oping new infections as steroid dose increased; across seven studies (two preventive trials and five therapeutic trials), β=0.08 (95% credible interval −0.12 to 0.28), probability (β≥0)=81.2%.
Sensitivity analysis was undertaken in which the prior for the variability between studies was made increasingly less informative. In all cases the point estimates remained stable, the credible interval became wider, and probabilitychanged slightly. This did not affect any of the interpretations given in the results except for that of ventilator free days, in which the credible interval included zero.DISCUSSIONThis systematic review failed to show a convincing treatment effect of steroids in acute respiratory distress syndrome (ARDS), although trends were found for treatment. Although preventive steroid therapy in critically ill patients may have been associated with detrimental effects on the incidence of ARDS and subsequent mortality, a trend was found to benefit when steroids were given after the onset of ARDS; in particular, a reduction in odds of mortality (probability of reduction 93.2%). The review, however, showed no discernible time or dose effect of steroids on mortality with the therapeutic use of steroids. Although steroids did not increase overall infection risk, a latent dose dependent effect of steroid therapy on infection rates seemed to exist.
The seemingly differential effect of preventive and therapeutic steroid therapy in ARDS, observed in the current meta-analysis, has been previously suggested,20 but the reasons for this are unclear. Key proinflamma- tory mediators such as tumour necrosis factor α and interleukin 1 have been implicated in the pathophy- siology of sepsis with organ dysfunction, the most common cause of ARDS.21 In clinical studies, inhibi- tion of these proinflammatory mediators has not improved outcome22; indeed, antagonism of tumour necrosis factor α23 or interleukin 124 increases mortality in some models of bacterial infection, suggesting a key role for their expression in survival from infection. Preventive steroids may not only impede normal homoeostatic response by inhibiting cytokine production,25 but also contribute to the pathogenesis of ARDS by stimulating the release of macrophage migration inhibiting factor, a proinflammatory cytokine.26 This latter effect remains speculative as release of macrophage migration inhibiting factor by glucocorticoids seems to have a biphasic dose dependency,26-28 and protective effects have also been described.29 In addition the high doses of methylpred- nisolone given to the preventive group may havecontributed to an increased risk of infection and poorer outcomes. Steroid therapy after the onset of ARDS may, however, have a different effect by modifying the persistent and protracted inflammation that exacer- bates lung injury.
The implications of time to starting therapeutic steroids after onset of ARDS are of some importance and have been highlighted in the recent National Heart, Lung, and Blood Institute ARDS clinical trials network report,w5 where an interaction between time and treatment 14 days after the onset of ARDS was found to be significant. Editorial responses4 30 have also embraced a time-difference of steroid effect; benefits occurring with steroid therapy if started within two weeks of ARDS onset and not subsequently. In theindividual trials included in the current meta-analysis, the start of steroid therapy ranged from within 72 hoursw4 to four weeksw5 after ARDS onset. Meta- regression with initiation time of treatment as a moderator (fig 5) failed to show any influence on mortality. Although such a differential steroid time effect may have biological plausibility, the inter- pretation of treatment response rates on the basis of data dependent time cut-off points, a
We analysed the data with WinBUGS16 using three simultaneous runs of the program with disparate starting values. The first 100000 iterations were discarded and results were reported as posterior medians and intervals on the basis of a further 100 000 iterations. We used various diagnostics avail- able in the package Bayesian Output Analysis to assess convergence.17 In all cases we found no evidence against convergence. We used the same diffuse priors as described elsewhere14 for the odds ratio models and the metaregressions. A diffuse or non-informative prior should not greatly influence the results and reflects little or no prior belief about a particular problem. Mathematically diffuse priors aim to have about equal probability over all plausible values of the variable. For the mean difference model we placed a non-informative normal prior distribution with mean 0 and variance 105 on the overall mean difference. A normal distribution with mean 0 and variance of 13.5 and truncated below 0 was placed on the variable forstandard deviation between studies.18 Such a distribu- tion was derived from the notion that the median difference between any two studies was about four days and that a difference of more than 11 days would be extremely unlikely. To determine the influence on the overall results we also undertook a sensitivity analysis in which the priors were made even less informative.
RESULTS
Of the 7093 articles screened on ARDS or sepsis, 439 pertained to steroids in either condition. One investi- gator reviewed the abstracts of these articles and 62 articles were retrieved for further assessment by three investigators. Fifty five studies were excluded, includ- ing two controlled retrospective studies (fig 1),w6 w7 a randomised trial of steroids in severe community acquired pneumonia, 19 and five other prospective trials identified by an additional search (see bmj.com). w8-w12 This left nine studies, including two identified by an additional search. Four studies evaluated the preventive use of steroids in critically ill patientsw13- w16 and five assessed the role of steroids after the onset of ARDS.w1-w5 The definitions of ARDS in the studies done before the publication of the American-European consensus definition 13 were generally consistent with the consensus definition (table 2). The treatment and control arms had similar baseline characteristics (table 3). Table 4 presents a summary of the studycharacteristics and quality scores; the lag time from study completion to publication ranged from two to seven years. The reporting of mortality was variable. The steroid dose ranged from methylprednisolone 1 mg/kg/day to 120 mg/kg/day (or equivalent doses of hydrocortisone or dexamethasone) administered from four hours to 30 days (table 5).
The credible interval for the preventive use of steroids in critically ill patients included 1, indicating that a null effect could not be ruled out. The probability (odds ratio ≥1) was 86.6% suggesting some evidence of an association between steroid therapy and the subsequent development of ARDS: four studies, odds ratio 1.55 (95% credible interval 0.58 to 4.05); SD 0.58 for variability between studies (table 6 and fig 2). Similarly, the probability suggested a weakly increased risk of death associated with steroid therapy in patients who developed ARDS: probability (odds ratio ≥1) =72.8% (table 6 and fig 3), although again the credible interval included 1.
In the five therapeutic studies the probability that the odds ratio was one or more was small indicating that giving corticosteroids after the onset of ARDS was associated with a trend (table 6 and fig 4) to reduced mortality (overall odds ratio 0.62, 95% credible interval 0.23 to 1.26, probability (odds ratio ≥1)=6.8%), although the credible interval included 1 so that a null effect could not be ruled out. Some heterogeneity was evident between the studies (standard deviation 0.53). Steroid therapy was associated with substantially more ventilator free days (three studies) compared with controls (mean difference 4.05 days, 95% credible interval 0.22 to 8.71, probability (mean difference ≥0) =97.9%, SD 2.39). When the effect of moderators (time or dose of steroid therapy, year of study completion) on outcomes was explored in the five therapeutic studies, no evidence was found of an association between odds of mortality and time to treatment (fig 4) in (log) hours; β(time)=−0.08 (95% credible interval −1.00 to 0.62), probability (β≥0)=38.7%; total steroid dose; β(dose) =0.06 (95% credible interval −0.94 to 0.97), probability (β≥0)=57.8%; or year of study completion;β(completion year)=−0.01 (95% credible interval −0.17 to 0.14), probability (β≥0)=44.1%.
As anticipated, definitions for secondary infections varied considerably (table 7). Steroid therapy was not associated with an increase in the number of patients developing new infections. Within the four available therapeutic studies the trend was towards decreased odds of developing pneumonia (probability (odds ratio<1)=76.9%, table 6); although heterogeneity was substantial (SD 1.34, table 6). Metaregression showed a trend towards an increased number of patients devel- oping new infections as steroid dose increased; across seven studies (two preventive trials and five therapeutic trials), β=0.08 (95% credible interval −0.12 to 0.28), probability (β≥0)=81.2%.
Sensitivity analysis was undertaken in which the prior for the variability between studies was made increasingly less informative. In all cases the point estimates remained stable, the credible interval became wider, and probabilitychanged slightly. This did not affect any of the interpretations given in the results except for that of ventilator free days, in which the credible interval included zero.DISCUSSIONThis systematic review failed to show a convincing treatment effect of steroids in acute respiratory distress syndrome (ARDS), although trends were found for treatment. Although preventive steroid therapy in critically ill patients may have been associated with detrimental effects on the incidence of ARDS and subsequent mortality, a trend was found to benefit when steroids were given after the onset of ARDS; in particular, a reduction in odds of mortality (probability of reduction 93.2%). The review, however, showed no discernible time or dose effect of steroids on mortality with the therapeutic use of steroids. Although steroids did not increase overall infection risk, a latent dose dependent effect of steroid therapy on infection rates seemed to exist.
The seemingly differential effect of preventive and therapeutic steroid therapy in ARDS, observed in the current meta-analysis, has been previously suggested,20 but the reasons for this are unclear. Key proinflamma- tory mediators such as tumour necrosis factor α and interleukin 1 have been implicated in the pathophy- siology of sepsis with organ dysfunction, the most common cause of ARDS.21 In clinical studies, inhibi- tion of these proinflammatory mediators has not improved outcome22; indeed, antagonism of tumour necrosis factor α23 or interleukin 124 increases mortality in some models of bacterial infection, suggesting a key role for their expression in survival from infection. Preventive steroids may not only impede normal homoeostatic response by inhibiting cytokine production,25 but also contribute to the pathogenesis of ARDS by stimulating the release of macrophage migration inhibiting factor, a proinflammatory cytokine.26 This latter effect remains speculative as release of macrophage migration inhibiting factor by glucocorticoids seems to have a biphasic dose dependency,26-28 and protective effects have also been described.29 In addition the high doses of methylpred- nisolone given to the preventive group may havecontributed to an increased risk of infection and poorer outcomes. Steroid therapy after the onset of ARDS may, however, have a different effect by modifying the persistent and protracted inflammation that exacer- bates lung injury.
The implications of time to starting therapeutic steroids after onset of ARDS are of some importance and have been highlighted in the recent National Heart, Lung, and Blood Institute ARDS clinical trials network report,w5 where an interaction between time and treatment 14 days after the onset of ARDS was found to be significant. Editorial responses4 30 have also embraced a time-difference of steroid effect; benefits occurring with steroid therapy if started within two weeks of ARDS onset and not subsequently. In theindividual trials included in the current meta-analysis, the start of steroid therapy ranged from within 72 hoursw4 to four weeksw5 after ARDS onset. Meta- regression with initiation time of treatment as a moderator (fig 5) failed to show any influence on mortality. Although such a differential steroid time effect may have biological plausibility, the inter- pretation of treatment response rates on the basis of data dependent time cut-off points, a
การแปล กรุณารอสักครู่..
indicates benefit for the odds ratio analyses and harm (decrease in ventilator free days) for the mean difference analysis. We also used Bayesian meta regression14 to determine the relation between the odds of mortality and time to treatment in ARDS, total dose of steroids, and year of study completion. The slope (β) with 95% credible intervals and the prob- ability that β was 0 or more are presented. Wepresented heterogeneity as the standard deviation between studies. For all analyses a standard deviation close to 0 indicates little heterogeneity, whereas for the odds ratio meta-analyses a standard deviation of more than 1 might be considered to reflect substantial heterogeneity. Similarly, for the mean difference analysis, a standard deviation greater than, for exam- ple, 10 might be considered to indicate substantial heterogeneity. Publication bias was not formally assessed, as the two subgroups each had fewer than 10 studies.15
We analysed the data with WinBUGS16 using three simultaneous runs of the program with disparate starting values. The first 100000 iterations were discarded and results were reported as posterior medians and intervals on the basis of a further 100 000 iterations. We used various diagnostics avail- able in the package Bayesian Output Analysis to assess convergence.17 In all cases we found no evidence against convergence. We used the same diffuse priors as described elsewhere14 for the odds ratio models and the metaregressions. A diffuse or non-informative prior should not greatly influence the results and reflects little or no prior belief about a particular problem. Mathematically diffuse priors aim to have about equal probability over all plausible values of the variable. For the mean difference model we placed a non-informative normal prior distribution with mean 0 and variance 105 on the overall mean difference. A normal distribution with mean 0 and variance of 13.5 and truncated below 0 was placed on the variable forstandard deviation between studies.18 Such a distribu- tion was derived from the notion that the median difference between any two studies was about four days and that a difference of more than 11 days would be extremely unlikely. To determine the influence on the overall results we also undertook a sensitivity analysis in which the priors were made even less informative.
RESULTS
Of the 7093 articles screened on ARDS or sepsis, 439 pertained to steroids in either condition. One investi- gator reviewed the abstracts of these articles and 62 articles were retrieved for further assessment by three investigators. Fifty five studies were excluded, includ- ing two controlled retrospective studies (fig 1),w6 w7 a randomised trial of steroids in severe community acquired pneumonia, 19 and five other prospective trials identified by an additional search (see bmj.com). w8-w12 This left nine studies, including two identified by an additional search. Four studies evaluated the preventive use of steroids in critically ill patientsw13- w16 and five assessed the role of steroids after the onset of ARDS.w1-w5 The definitions of ARDS in the studies done before the publication of the American-European consensus definition 13 were generally consistent with the consensus definition (table 2). The treatment and control arms had similar baseline characteristics (table 3). Table 4 presents a summary of the studycharacteristics and quality scores; the lag time from study completion to publication ranged from two to seven years. The reporting of mortality was variable. The steroid dose ranged from methylprednisolone 1 mg/kg/day to 120 mg/kg/day (or equivalent doses of hydrocortisone or dexamethasone) administered from four hours to 30 days (table 5).
The credible interval for the preventive use of steroids in critically ill patients included 1, indicating that a null effect could not be ruled out. The probability (odds ratio ≥1) was 86.6% suggesting some evidence of an association between steroid therapy and the subsequent development of ARDS: four studies, odds ratio 1.55 (95% credible interval 0.58 to 4.05); SD 0.58 for variability between studies (table 6 and fig 2). Similarly, the probability suggested a weakly increased risk of death associated with steroid therapy in patients who developed ARDS: probability (odds ratio ≥1) =72.8% (table 6 and fig 3), although again the credible interval included 1.
In the five therapeutic studies the probability that the odds ratio was one or more was small indicating that giving corticosteroids after the onset of ARDS was associated with a trend (table 6 and fig 4) to reduced mortality (overall odds ratio 0.62, 95% credible interval 0.23 to 1.26, probability (odds ratio ≥1)=6.8%), although the credible interval included 1 so that a null effect could not be ruled out. Some heterogeneity was evident between the studies (standard deviation 0.53). Steroid therapy was associated with substantially more ventilator free days (three studies) compared with controls (mean difference 4.05 days, 95% credible interval 0.22 to 8.71, probability (mean difference ≥0) =97.9%, SD 2.39). When the effect of moderators (time or dose of steroid therapy, year of study completion) on outcomes was explored in the five therapeutic studies, no evidence was found of an association between odds of mortality and time to treatment (fig 4) in (log) hours; β(time)=−0.08 (95% credible interval −1.00 to 0.62), probability (β≥0)=38.7%; total steroid dose; β(dose) =0.06 (95% credible interval −0.94 to 0.97), probability (β≥0)=57.8%; or year of study completion;β(completion year)=−0.01 (95% credible interval −0.17 to 0.14), probability (β≥0)=44.1%.
As anticipated, definitions for secondary infections varied considerably (table 7). Steroid therapy was not associated with an increase in the number of patients developing new infections. Within the four available therapeutic studies the trend was towards decreased odds of developing pneumonia (probability (odds ratio<1)=76.9%, table 6); although heterogeneity was substantial (SD 1.34, table 6). Metaregression showed a trend towards an increased number of patients devel- oping new infections as steroid dose increased; across seven studies (two preventive trials and five therapeutic trials), β=0.08 (95% credible interval −0.12 to 0.28), probability (β≥0)=81.2%.
Sensitivity analysis was undertaken in which the prior for the variability between studies was made increasingly less informative. In all cases the point estimates remained stable, the credible interval became wider, and probabilitychanged slightly. This did not affect any of the interpretations given in the results except for that of ventilator free days, in which the credible interval included zero.DISCUSSIONThis systematic review failed to show a convincing treatment effect of steroids in acute respiratory distress syndrome (ARDS), although trends were found for treatment. Although preventive steroid therapy in critically ill patients may have been associated with detrimental effects on the incidence of ARDS and subsequent mortality, a trend was found to benefit when steroids were given after the onset of ARDS; in particular, a reduction in odds of mortality (probability of reduction 93.2%). The review, however, showed no discernible time or dose effect of steroids on mortality with the therapeutic use of steroids. Although steroids did not increase overall infection risk, a latent dose dependent effect of steroid therapy on infection rates seemed to exist.
The seemingly differential effect of preventive and therapeutic steroid therapy in ARDS, observed in the current meta-analysis, has been previously suggested,20 but the reasons for this are unclear. Key proinflamma- tory mediators such as tumour necrosis factor α and interleukin 1 have been implicated in the pathophy- siology of sepsis with organ dysfunction, the most common cause of ARDS.21 In clinical studies, inhibi- tion of these proinflammatory mediators has not improved outcome22; indeed, antagonism of tumour necrosis factor α23 or interleukin 124 increases mortality in some models of bacterial infection, suggesting a key role for their expression in survival from infection. Preventive steroids may not only impede normal homoeostatic response by inhibiting cytokine production,25 but also contribute to the pathogenesis of ARDS by stimulating the release of macrophage migration inhibiting factor, a proinflammatory cytokine.26 This latter effect remains speculative as release of macrophage migration inhibiting factor by glucocorticoids seems to have a biphasic dose dependency,26-28 and protective effects have also been described.29 In addition the high doses of methylpred- nisolone given to the preventive group may havecontributed to an increased risk of infection and poorer outcomes. Steroid therapy after the onset of ARDS may, however, have a different effect by modifying the persistent and protracted inflammation that exacer- bates lung injury.
The implications of time to starting therapeutic steroids after onset of ARDS are of some importance and have been highlighted in the recent National Heart, Lung, and Blood Institute ARDS clinical trials network report,w5 where an interaction between time and treatment 14 days after the onset of ARDS was found to be significant. Editorial responses4 30 have also embraced a time-difference of steroid effect; benefits occurring with steroid therapy if started within two weeks of ARDS onset and not subsequently. In theindividual trials included in the current meta-analysis, the start of steroid therapy ranged from within 72 hoursw4 to four weeksw5 after ARDS onset. Meta- regression with initiation time of treatment as a moderator (fig 5) failed to show any influence on mortality. Although such a differential steroid time effect may have biological plausibility, the inter- pretation of treatment response rates on the basis of data dependent time cut-off points, a
We analysed the data with WinBUGS16 using three simultaneous runs of the program with disparate starting values. The first 100000 iterations were discarded and results were reported as posterior medians and intervals on the basis of a further 100 000 iterations. We used various diagnostics avail- able in the package Bayesian Output Analysis to assess convergence.17 In all cases we found no evidence against convergence. We used the same diffuse priors as described elsewhere14 for the odds ratio models and the metaregressions. A diffuse or non-informative prior should not greatly influence the results and reflects little or no prior belief about a particular problem. Mathematically diffuse priors aim to have about equal probability over all plausible values of the variable. For the mean difference model we placed a non-informative normal prior distribution with mean 0 and variance 105 on the overall mean difference. A normal distribution with mean 0 and variance of 13.5 and truncated below 0 was placed on the variable forstandard deviation between studies.18 Such a distribu- tion was derived from the notion that the median difference between any two studies was about four days and that a difference of more than 11 days would be extremely unlikely. To determine the influence on the overall results we also undertook a sensitivity analysis in which the priors were made even less informative.
RESULTS
Of the 7093 articles screened on ARDS or sepsis, 439 pertained to steroids in either condition. One investi- gator reviewed the abstracts of these articles and 62 articles were retrieved for further assessment by three investigators. Fifty five studies were excluded, includ- ing two controlled retrospective studies (fig 1),w6 w7 a randomised trial of steroids in severe community acquired pneumonia, 19 and five other prospective trials identified by an additional search (see bmj.com). w8-w12 This left nine studies, including two identified by an additional search. Four studies evaluated the preventive use of steroids in critically ill patientsw13- w16 and five assessed the role of steroids after the onset of ARDS.w1-w5 The definitions of ARDS in the studies done before the publication of the American-European consensus definition 13 were generally consistent with the consensus definition (table 2). The treatment and control arms had similar baseline characteristics (table 3). Table 4 presents a summary of the studycharacteristics and quality scores; the lag time from study completion to publication ranged from two to seven years. The reporting of mortality was variable. The steroid dose ranged from methylprednisolone 1 mg/kg/day to 120 mg/kg/day (or equivalent doses of hydrocortisone or dexamethasone) administered from four hours to 30 days (table 5).
The credible interval for the preventive use of steroids in critically ill patients included 1, indicating that a null effect could not be ruled out. The probability (odds ratio ≥1) was 86.6% suggesting some evidence of an association between steroid therapy and the subsequent development of ARDS: four studies, odds ratio 1.55 (95% credible interval 0.58 to 4.05); SD 0.58 for variability between studies (table 6 and fig 2). Similarly, the probability suggested a weakly increased risk of death associated with steroid therapy in patients who developed ARDS: probability (odds ratio ≥1) =72.8% (table 6 and fig 3), although again the credible interval included 1.
In the five therapeutic studies the probability that the odds ratio was one or more was small indicating that giving corticosteroids after the onset of ARDS was associated with a trend (table 6 and fig 4) to reduced mortality (overall odds ratio 0.62, 95% credible interval 0.23 to 1.26, probability (odds ratio ≥1)=6.8%), although the credible interval included 1 so that a null effect could not be ruled out. Some heterogeneity was evident between the studies (standard deviation 0.53). Steroid therapy was associated with substantially more ventilator free days (three studies) compared with controls (mean difference 4.05 days, 95% credible interval 0.22 to 8.71, probability (mean difference ≥0) =97.9%, SD 2.39). When the effect of moderators (time or dose of steroid therapy, year of study completion) on outcomes was explored in the five therapeutic studies, no evidence was found of an association between odds of mortality and time to treatment (fig 4) in (log) hours; β(time)=−0.08 (95% credible interval −1.00 to 0.62), probability (β≥0)=38.7%; total steroid dose; β(dose) =0.06 (95% credible interval −0.94 to 0.97), probability (β≥0)=57.8%; or year of study completion;β(completion year)=−0.01 (95% credible interval −0.17 to 0.14), probability (β≥0)=44.1%.
As anticipated, definitions for secondary infections varied considerably (table 7). Steroid therapy was not associated with an increase in the number of patients developing new infections. Within the four available therapeutic studies the trend was towards decreased odds of developing pneumonia (probability (odds ratio<1)=76.9%, table 6); although heterogeneity was substantial (SD 1.34, table 6). Metaregression showed a trend towards an increased number of patients devel- oping new infections as steroid dose increased; across seven studies (two preventive trials and five therapeutic trials), β=0.08 (95% credible interval −0.12 to 0.28), probability (β≥0)=81.2%.
Sensitivity analysis was undertaken in which the prior for the variability between studies was made increasingly less informative. In all cases the point estimates remained stable, the credible interval became wider, and probabilitychanged slightly. This did not affect any of the interpretations given in the results except for that of ventilator free days, in which the credible interval included zero.DISCUSSIONThis systematic review failed to show a convincing treatment effect of steroids in acute respiratory distress syndrome (ARDS), although trends were found for treatment. Although preventive steroid therapy in critically ill patients may have been associated with detrimental effects on the incidence of ARDS and subsequent mortality, a trend was found to benefit when steroids were given after the onset of ARDS; in particular, a reduction in odds of mortality (probability of reduction 93.2%). The review, however, showed no discernible time or dose effect of steroids on mortality with the therapeutic use of steroids. Although steroids did not increase overall infection risk, a latent dose dependent effect of steroid therapy on infection rates seemed to exist.
The seemingly differential effect of preventive and therapeutic steroid therapy in ARDS, observed in the current meta-analysis, has been previously suggested,20 but the reasons for this are unclear. Key proinflamma- tory mediators such as tumour necrosis factor α and interleukin 1 have been implicated in the pathophy- siology of sepsis with organ dysfunction, the most common cause of ARDS.21 In clinical studies, inhibi- tion of these proinflammatory mediators has not improved outcome22; indeed, antagonism of tumour necrosis factor α23 or interleukin 124 increases mortality in some models of bacterial infection, suggesting a key role for their expression in survival from infection. Preventive steroids may not only impede normal homoeostatic response by inhibiting cytokine production,25 but also contribute to the pathogenesis of ARDS by stimulating the release of macrophage migration inhibiting factor, a proinflammatory cytokine.26 This latter effect remains speculative as release of macrophage migration inhibiting factor by glucocorticoids seems to have a biphasic dose dependency,26-28 and protective effects have also been described.29 In addition the high doses of methylpred- nisolone given to the preventive group may havecontributed to an increased risk of infection and poorer outcomes. Steroid therapy after the onset of ARDS may, however, have a different effect by modifying the persistent and protracted inflammation that exacer- bates lung injury.
The implications of time to starting therapeutic steroids after onset of ARDS are of some importance and have been highlighted in the recent National Heart, Lung, and Blood Institute ARDS clinical trials network report,w5 where an interaction between time and treatment 14 days after the onset of ARDS was found to be significant. Editorial responses4 30 have also embraced a time-difference of steroid effect; benefits occurring with steroid therapy if started within two weeks of ARDS onset and not subsequently. In theindividual trials included in the current meta-analysis, the start of steroid therapy ranged from within 72 hoursw4 to four weeksw5 after ARDS onset. Meta- regression with initiation time of treatment as a moderator (fig 5) failed to show any influence on mortality. Although such a differential steroid time effect may have biological plausibility, the inter- pretation of treatment response rates on the basis of data dependent time cut-off points, a
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Indicates benefit for the odds ratio analyses and harm (decrease in ventilator free days) for the mean difference, analysis We also used Bayesian meta regression14 to determine the relation between the odds of mortality and time to treatment in ARDS total dose, of steroids and year, of study completionThe slope (β) with 95% credible intervals and the prob - ability that β was 0 or more are presented. Wepresented heterogeneity As the standard deviation between studies. For all analyses a standard deviation close to 0 indicates, little heterogeneity Whereas for the odds ratio meta-analyses a standard deviation of more than 1 might be considered to reflect substantial Similarly heterogeneity,For the mean, difference analysis a standard deviation, greater than for exam - ple 10 might, be considered to indicate Substantial heterogeneity. Publication bias was not formally assessed as the, two subgroups each had fewer than 10 studies.15
We Analysed the data with WinBUGS16 using three simultaneous runs of the program with disparate starting valuesThe first 100000 iterations were discarded and results were reported as posterior medians and intervals on the basis of A further 100 000 iterations. We used various diagnostics avail - able in the package Bayesian Output Analysis to assess Convergence.17 In all cases we found no evidence against convergenceWe used the same diffuse priors as described elsewhere14 for the odds ratio models and the metaregressions. A diffuse Or non-informative prior should not greatly influence the results and reflects little or no prior belief about a particular Problem. Mathematically diffuse priors aim to have about equal probability over all plausible values of the variableFor the mean difference model we placed a non-informative normal prior distribution with mean 0 and variance 105 on the Overall mean difference. A normal distribution with mean 0 and variance of 13.5 and truncated below 0 was placed on the Variable forstandard deviation between studies18 Such a distribu - tion was derived from the notion that the median difference between any two studies was about four Days and that a difference of more than 11 days would be extremely unlikely. To determine the influence on the overall results We also undertook a sensitivity analysis in which the priors were made even less informative.
Of RESULTS the 7093 articles Screened on ARDS, or sepsis439 pertained to steroids in either condition. One investi - Gator reviewed the abstracts of these articles and 62 articles Were retrieved for further assessment by three investigators. Fifty five studies, were excluded includ - ing two controlled Retrospective studies (Fig 1), W6 W7 a randomised trial of steroids in severe community, acquired pneumonia19 and five other prospective trials identified by an additional search (see bmj.com). W8-w12 This left, nine studies Including two identified by an additional search. Four studies evaluated the preventive use of steroids in critically ill Patientsw13 - w16 and five assessed the role of steroids after the onset of ARDSW1-w5 The definitions of ARDS in the studies done before the publication of the American-European consensus definition 13 were Generally consistent with the consensus definition (Table 2). The treatment and control arms had similar baseline characteristics (Table 3). Table 4 presents a summary of the studycharacteristics and quality scoresThe lag time from study completion to publication ranged from two to seven years. The reporting of mortality was, variable The steroid dose ranged from methylprednisolone 1 mg / kg / day to 120 mg / kg / day (or equivalent doses of hydrocortisone or dexamethasone) Administered from four hours to 30 days (Table 5).
The credible interval for the preventive use of steroids in critically ill patients included 1 indicating that, a null Effect could not be ruled out. The probability (odds ratio > = 1) was 86.6% suggesting some evidence of an association between Steroid therapy and the subsequent development of ARDS: four studies odds ratio, 1.55 (95% credible interval 0.58 to 4.05);? SD 058 for variability between studies (Table 6 and fig 2). Similarly the probability, suggested a weakly increased risk of Death associated with steroid therapy in patients who developed ARDS: probability (odds ratio > = 1) = 72.8% (Table 6 and fig 3), although again the credible interval included 1.
In the five therapeutic studies the probability that the odds ratio was one or more was small indicating that giving corticosteroids After the onset of ARDS was associated with a trend (Table 6 and fig 4) to reduced mortality (overall odds ratio 0.62 95% credible, Interval 0.23, to 1.26 probability (odds ratio > = 1) = 6.8%)Although the credible interval included 1 so that a null effect could not be ruled out. Some heterogeneity was evident Between the studies (standard deviation 0.53). Steroid therapy was associated with substantially more ventilator free days (three studies) compared with controls (mean difference 4.05 days 95% credible, interval 0.22, to 8.71 probability (mean Difference > = 0) = 97.9% SD, 2.39)When the effect of moderators (time or dose of, steroid therapy year of study completion) on outcomes was explored in The five, therapeutic studies no evidence was found of an association between odds of mortality and time to treatment (Fig 4) in (log) hours; β (time) = − 0.08 (95% credible interval − 1.00 to 0.62), probability (β > = 0) = 38.7%; total steroid dose; β (dose) = 006 (95% credible interval − 0.94 to 0.97), probability (β > = 0) = 57.8%; or year of study completion; β (completion year) = − 0.01 (95% credible interval − 0.17 to 0.14), probability (β > = 0) = 44.1%.
As anticipated definitions for, secondary infections varied Considerably (Table 7). Steroid therapy was not associated with an increase in the number of patients developing new infectionsWithin the four available therapeutic studies the trend was towards decreased odds of developing pneumonia (probability (odds ratio < 1) = 76.9% table, 6); although heterogeneity was substantial (SD, 1.34 table 6). Metaregression showed a trend Towards an increased number of patients devel - oping new infections as steroid dose increasedAcross seven studies (two preventive trials and five therapeutic trials), β = 0.08 (95% credible interval − 0.12 to 0.28), Probability (β > = 0) = 81.2%.
Sensitivity analysis was undertaken in which the prior for the variability between studies was Made increasingly less informative. In all cases the point estimates remained stable the credible, interval, became wider And probabilitychanged slightlyThis did not affect any of the interpretations given in the results except for that of ventilator free days in which, The credible interval included zero.DISCUSSIONThis systematic review failed to show a convincing treatment effect of steroids In acute respiratory distress syndrome (ARDS), although trends were found for treatmentAlthough preventive steroid therapy in critically ill patients may have been associated with detrimental effects on the Incidence of ARDS and subsequent mortality a trend, was found to benefit when steroids were given after the onset of ARDS;? In particular a reduction, in odds of mortality (probability of reduction 93.2%). The review however,Showed no discernible time or dose effect of steroids on mortality with the therapeutic use of steroids. Although steroids Did not increase overall infection risk a latent, dose dependent effect of steroid therapy on infection rates seemed to Exist.
The seemingly differential effect of preventive and therapeutic steroid therapy in ARDS observed in, the current Meta-analysisHas been previously suggested 20 but, the reasons for this are unclear. Key proinflamma - tory mediators such as tumour Necrosis factor α and interleukin 1 have been implicated in the pathophy - siology of sepsis with, organ dysfunction the Most common cause of ARDS.21 In, clinical studies inhibi - tion of these proinflammatory mediators has not improved outcome22;? IndeedAntagonism of tumour necrosis factor α 23 or interleukin 124 increases mortality in some models of, bacterial infection Suggesting a key role for their expression in survival from infection. Preventive steroids may not only impede normal homoeostatic Response by inhibiting, cytokine production25 but also contribute to the pathogenesis of ARDS by stimulating the release of macrophage migration, inhibiting factor A proinflammatory cytokine.26 This latter effect remains speculative as release of macrophage migration inhibiting factor By glucocorticoids seems to have a biphasic dose dependency 26-28 and, protective effects have also been described29 In addition the high doses of methylpred - nisolone given to the preventive group may havecontributed to an increased Risk of infection and poorer outcomes. Steroid therapy after the onset of, ARDS may however have a, different effect by Modifying the persistent and protracted inflammation that exacer - Bates lung injury.
The implications of time to starting therapeutic steroids after onset of ARDS are of some importance and have been highlighted In the recent, National Heart Lung and Blood, Institute ARDS clinical trials, network report W5 where an interaction between Time and treatment 14 days after the onset of ARDS was found to be significantEditorial responses4 30 have also embraced a time-difference of steroid effect; benefits occurring with steroid therapy If started within two weeks of ARDS onset and not subsequently. In theindividual trials included in the, current meta-analysis The start of steroid therapy ranged from within 72 hoursw4 to four weeksw5 after ARDS onsetMeta - regression with initiation time of treatment as a moderator (Fig 5) failed to show any influence on mortality. Although Such a differential steroid time effect may have, biological plausibility the inter - pretation of treatment response rates On the basis of data dependent time, cut-off points a
We Analysed the data with WinBUGS16 using three simultaneous runs of the program with disparate starting valuesThe first 100000 iterations were discarded and results were reported as posterior medians and intervals on the basis of A further 100 000 iterations. We used various diagnostics avail - able in the package Bayesian Output Analysis to assess Convergence.17 In all cases we found no evidence against convergenceWe used the same diffuse priors as described elsewhere14 for the odds ratio models and the metaregressions. A diffuse Or non-informative prior should not greatly influence the results and reflects little or no prior belief about a particular Problem. Mathematically diffuse priors aim to have about equal probability over all plausible values of the variableFor the mean difference model we placed a non-informative normal prior distribution with mean 0 and variance 105 on the Overall mean difference. A normal distribution with mean 0 and variance of 13.5 and truncated below 0 was placed on the Variable forstandard deviation between studies18 Such a distribu - tion was derived from the notion that the median difference between any two studies was about four Days and that a difference of more than 11 days would be extremely unlikely. To determine the influence on the overall results We also undertook a sensitivity analysis in which the priors were made even less informative.
Of RESULTS the 7093 articles Screened on ARDS, or sepsis439 pertained to steroids in either condition. One investi - Gator reviewed the abstracts of these articles and 62 articles Were retrieved for further assessment by three investigators. Fifty five studies, were excluded includ - ing two controlled Retrospective studies (Fig 1), W6 W7 a randomised trial of steroids in severe community, acquired pneumonia19 and five other prospective trials identified by an additional search (see bmj.com). W8-w12 This left, nine studies Including two identified by an additional search. Four studies evaluated the preventive use of steroids in critically ill Patientsw13 - w16 and five assessed the role of steroids after the onset of ARDSW1-w5 The definitions of ARDS in the studies done before the publication of the American-European consensus definition 13 were Generally consistent with the consensus definition (Table 2). The treatment and control arms had similar baseline characteristics (Table 3). Table 4 presents a summary of the studycharacteristics and quality scoresThe lag time from study completion to publication ranged from two to seven years. The reporting of mortality was, variable The steroid dose ranged from methylprednisolone 1 mg / kg / day to 120 mg / kg / day (or equivalent doses of hydrocortisone or dexamethasone) Administered from four hours to 30 days (Table 5).
The credible interval for the preventive use of steroids in critically ill patients included 1 indicating that, a null Effect could not be ruled out. The probability (odds ratio > = 1) was 86.6% suggesting some evidence of an association between Steroid therapy and the subsequent development of ARDS: four studies odds ratio, 1.55 (95% credible interval 0.58 to 4.05);? SD 058 for variability between studies (Table 6 and fig 2). Similarly the probability, suggested a weakly increased risk of Death associated with steroid therapy in patients who developed ARDS: probability (odds ratio > = 1) = 72.8% (Table 6 and fig 3), although again the credible interval included 1.
In the five therapeutic studies the probability that the odds ratio was one or more was small indicating that giving corticosteroids After the onset of ARDS was associated with a trend (Table 6 and fig 4) to reduced mortality (overall odds ratio 0.62 95% credible, Interval 0.23, to 1.26 probability (odds ratio > = 1) = 6.8%)Although the credible interval included 1 so that a null effect could not be ruled out. Some heterogeneity was evident Between the studies (standard deviation 0.53). Steroid therapy was associated with substantially more ventilator free days (three studies) compared with controls (mean difference 4.05 days 95% credible, interval 0.22, to 8.71 probability (mean Difference > = 0) = 97.9% SD, 2.39)When the effect of moderators (time or dose of, steroid therapy year of study completion) on outcomes was explored in The five, therapeutic studies no evidence was found of an association between odds of mortality and time to treatment (Fig 4) in (log) hours; β (time) = − 0.08 (95% credible interval − 1.00 to 0.62), probability (β > = 0) = 38.7%; total steroid dose; β (dose) = 006 (95% credible interval − 0.94 to 0.97), probability (β > = 0) = 57.8%; or year of study completion; β (completion year) = − 0.01 (95% credible interval − 0.17 to 0.14), probability (β > = 0) = 44.1%.
As anticipated definitions for, secondary infections varied Considerably (Table 7). Steroid therapy was not associated with an increase in the number of patients developing new infectionsWithin the four available therapeutic studies the trend was towards decreased odds of developing pneumonia (probability (odds ratio < 1) = 76.9% table, 6); although heterogeneity was substantial (SD, 1.34 table 6). Metaregression showed a trend Towards an increased number of patients devel - oping new infections as steroid dose increasedAcross seven studies (two preventive trials and five therapeutic trials), β = 0.08 (95% credible interval − 0.12 to 0.28), Probability (β > = 0) = 81.2%.
Sensitivity analysis was undertaken in which the prior for the variability between studies was Made increasingly less informative. In all cases the point estimates remained stable the credible, interval, became wider And probabilitychanged slightlyThis did not affect any of the interpretations given in the results except for that of ventilator free days in which, The credible interval included zero.DISCUSSIONThis systematic review failed to show a convincing treatment effect of steroids In acute respiratory distress syndrome (ARDS), although trends were found for treatmentAlthough preventive steroid therapy in critically ill patients may have been associated with detrimental effects on the Incidence of ARDS and subsequent mortality a trend, was found to benefit when steroids were given after the onset of ARDS;? In particular a reduction, in odds of mortality (probability of reduction 93.2%). The review however,Showed no discernible time or dose effect of steroids on mortality with the therapeutic use of steroids. Although steroids Did not increase overall infection risk a latent, dose dependent effect of steroid therapy on infection rates seemed to Exist.
The seemingly differential effect of preventive and therapeutic steroid therapy in ARDS observed in, the current Meta-analysisHas been previously suggested 20 but, the reasons for this are unclear. Key proinflamma - tory mediators such as tumour Necrosis factor α and interleukin 1 have been implicated in the pathophy - siology of sepsis with, organ dysfunction the Most common cause of ARDS.21 In, clinical studies inhibi - tion of these proinflammatory mediators has not improved outcome22;? IndeedAntagonism of tumour necrosis factor α 23 or interleukin 124 increases mortality in some models of, bacterial infection Suggesting a key role for their expression in survival from infection. Preventive steroids may not only impede normal homoeostatic Response by inhibiting, cytokine production25 but also contribute to the pathogenesis of ARDS by stimulating the release of macrophage migration, inhibiting factor A proinflammatory cytokine.26 This latter effect remains speculative as release of macrophage migration inhibiting factor By glucocorticoids seems to have a biphasic dose dependency 26-28 and, protective effects have also been described29 In addition the high doses of methylpred - nisolone given to the preventive group may havecontributed to an increased Risk of infection and poorer outcomes. Steroid therapy after the onset of, ARDS may however have a, different effect by Modifying the persistent and protracted inflammation that exacer - Bates lung injury.
The implications of time to starting therapeutic steroids after onset of ARDS are of some importance and have been highlighted In the recent, National Heart Lung and Blood, Institute ARDS clinical trials, network report W5 where an interaction between Time and treatment 14 days after the onset of ARDS was found to be significantEditorial responses4 30 have also embraced a time-difference of steroid effect; benefits occurring with steroid therapy If started within two weeks of ARDS onset and not subsequently. In theindividual trials included in the, current meta-analysis The start of steroid therapy ranged from within 72 hoursw4 to four weeksw5 after ARDS onsetMeta - regression with initiation time of treatment as a moderator (Fig 5) failed to show any influence on mortality. Although Such a differential steroid time effect may have, biological plausibility the inter - pretation of treatment response rates On the basis of data dependent time, cut-off points a
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ภาษาอื่น ๆ
การสนับสนุนเครื่องมือแปลภาษา: กรีก, กันนาดา, กาลิเชียน, คลิงออน, คอร์สิกา, คาซัค, คาตาลัน, คินยารวันดา, คีร์กิซ, คุชราต, จอร์เจีย, จีน, จีนดั้งเดิม, ชวา, ชิเชวา, ซามัว, ซีบัวโน, ซุนดา, ซูลู, ญี่ปุ่น, ดัตช์, ตรวจหาภาษา, ตุรกี, ทมิฬ, ทาจิก, ทาทาร์, นอร์เวย์, บอสเนีย, บัลแกเรีย, บาสก์, ปัญจาป, ฝรั่งเศส, พาชตู, ฟริเชียน, ฟินแลนด์, ฟิลิปปินส์, ภาษาอินโดนีเซี, มองโกเลีย, มัลทีส, มาซีโดเนีย, มาราฐี, มาลากาซี, มาลายาลัม, มาเลย์, ม้ง, ยิดดิช, ยูเครน, รัสเซีย, ละติน, ลักเซมเบิร์ก, ลัตเวีย, ลาว, ลิทัวเนีย, สวาฮิลี, สวีเดน, สิงหล, สินธี, สเปน, สโลวัก, สโลวีเนีย, อังกฤษ, อัมฮาริก, อาร์เซอร์ไบจัน, อาร์เมเนีย, อาหรับ, อิกโบ, อิตาลี, อุยกูร์, อุสเบกิสถาน, อูรดู, ฮังการี, ฮัวซา, ฮาวาย, ฮินดี, ฮีบรู, เกลิกสกอต, เกาหลี, เขมร, เคิร์ด, เช็ก, เซอร์เบียน, เซโซโท, เดนมาร์ก, เตลูกู, เติร์กเมน, เนปาล, เบงกอล, เบลารุส, เปอร์เซีย, เมารี, เมียนมา (พม่า), เยอรมัน, เวลส์, เวียดนาม, เอสเปอแรนโต, เอสโทเนีย, เฮติครีโอล, แอฟริกา, แอลเบเนีย, โคซา, โครเอเชีย, โชนา, โซมาลี, โปรตุเกส, โปแลนด์, โยรูบา, โรมาเนีย, โอเดีย (โอริยา), ไทย, ไอซ์แลนด์, ไอร์แลนด์, การแปลภาษา.
- ชีวิตคู่
- Off duty
- บริษัท อาชา ทัวร์ จำกัด
- สัส
- หากคุณไม่ได้รักษาสถานะภาพการเป็นนักศึกษา
- exactly
- Waiting for my mother to Cook
- platform
- Resume
- He go to my บ้าน on Sunday in the evenin
- การแยกแบคทเรียโปรไบโอติกส์จากไกไขที่ได
- หน้าผาก
- Want a rich swedish husband so get your
- ฉันต้องการปิดการใช้ Tll .คุณติดต่อฉันผ่า
- on the grill.
- I will looking forward you to submit the
- ใบเสนอราคาฉากกั้นห้อง
- เราส่งสินค้าให้คุณไม่ได้
- ประหยัดค่าใช้จ่ายกว่าการไปเที่ยวคนเดียว
- แอม
- ราคายังเเพงอยู่นะ ฉันจะให้ลูกค้าดูก่อน ถ
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- Poto release?
- ในประเทศไทยมีความต้องการโลหิตเพื่อช่วยชี
