CORRESPONDENCE Prone Position–induced Improvement in Gas Exchange Does Not Predict Improved Survival in the Acute Respiratory Distress Syndrome
Gu´erin and colleagues (8) reported that prone ventilation for an average of 16 h/d improved oxygenation and reduced the mortality of patients with ARDS by 50%. We sought to determine if the improvements in gas exchange they observed predicted survival.
To the Editor:
Methods
Prone ventilation improves oxygenation in most, but not all, patients with the acute respiratory distress syndrome (ARDS) (1–4). Until recently, however, this improvement has not been associated with improved survival. The ARDS Management Arms (ARMA) study comparing low with standard tidal volume ventilation actually found that survival was better in subjects who had worse oxygenation (5). Two previous studies concluded that the changes in gas exchange that occurred with prone ventilation did not predict survival in ARDS (6, 7) but both only used prone ventilation 5–8 h/d, and neither found that prone ventilation improved overall survival. Recently,
This was a retrospective analysis of data collected prospectively by Gu´erin and colleagues (8). Inclusion criteria are described in the original article. Arterial blood gases (ABG) were analyzed prior to turning prone, 1 hour after turning, and after completing the first session of prone ventilation while the patients were still prone. Changes in ABGs were examined relative to 28-day mortality. The PaO2/FIO2 (P/F) ratio and PaCO2 were analyzed as means 6 SD, in quintiles of units or mm Hg, respectively, in quintiles of subjects, by classifying subjects as “responders” or “non-responders” per Gattinoni and colleagues (6) (i.e., an increase in P/F of >20 mm Hg or a decrease in PaCO2 of >1 mm Hg), and in subgroups based
Table 1: Gas Exchange 1 Hour after Initiating Prone Ventilation (Mean 6 SD) Variable
Survived (N = 194)
Died (N = 38)
P Value
7.34 6 0.10 0.01 6 07 49 6 14 20.5 6 9.4 119 6 65 38.9 6 63 74 6 16 23.9 6 11.4 12 6 3 21.6 6 3.0 166 6 83 60 6 79
7.27 6 0.12 0.01 6 0.05 52 6 12 22.7 6 9.1 118 6 59 38.8 6 59 78 6 17 26.5 6 11.6 12 6 2 21.3 6 3.2 152 6 62 55 6 60
0.004 0.764 0.149 0.182 0.950 0.987 0.205 0.220 0.654 0.602 0.321 0.618 0.78
pH, units D from pre–prone positioning PaCO2, mm Hg D from pre–prone positioning PaO2, mm Hg D from pre–prone positioning FIO2, % D from pre–prone positioning PEEP, cm H2O D from pre–prone positioning P/F, mm Hg D from pre–prone positioning P/F increase, mm Hg > 20, N (%) , 20, N (%) PaCO2 decrease, mm Hg > 1, N (%) , 1, N (%) Survival by quintile of P/F response after 1 h of prone ventilation, mm Hg, survivors/total patients (%) 286 to 21 0 to 85 86 to 171 172 to 257 258 to 343 Survival by quintile of change in PaCO2 after one hour of prone ventilation, mm Hg, survivors/total (%) 230 to 212 211 to 1 7 18 to 126 127 to 145 145 to 1 64 Survival by combined P/F and PaCO2 response, survivors/total (%) 1P/F response, no PaCO2 response 1P/F response, 1PaCO2 response No P/F response, no PaCO2 response No P/F response, 1PaCO2 response
123 (85) 71 (85)
25 (17) 13 (15)
99 (83) 95 (84)
20 (17) 18 (16)
0.86 0.410 39/43 99/121 37/47 13/15 6/6
(91) (82) (78) (87) (100) 0.210
13/20 160/189 16/18 4/4 1/1
(65) (85) (89) (100) (100) 0.670
15/16 18/23 80/97 81/97
(94) (78) (82) (87)
Author Contributions: Conception and design: R.K.A. and C.G.; analysis and interpretation: R.K.A., A.K., L.B., L.A., and C.G. Drafting the manuscript: R.K.A., A.K., and C.G.
494
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 4 | February 15 2014
CORRESPONDENCE on changes in the P/F ratio coupled with changes in the PaCO2 per Lemasson and colleagues (7) (i.e., an increase in P/F of >20% or ,20% and a decrease in PaCO2 of >1 or ,1 mm Hg). Analyses were performed using SAS Enterprise Guide 4.3 (SAS Institute, Inc., Cary, NC) or SPSS Statistics 17.0 (SPSS, Chicago, IL). Data were compared using paired or unpaired t tests and chi-squared analysis. P , 0.05 was considered significant. Gas exchange variables measured prior to turning prone that were significantly different between survivors and those who died were analyzed by receiver operating characteristic (ROC) curves. Results
Paired ABGs were available for 232 of 237 subjects (98%) who received prone ventilation for 1 hour, and for 228 of 237 subjects (96%) at the completion of the first prone session; 194 (82%) survived. Gas exchange prior to instituting prone ventilation was similar in those who survived and those who died with the exception that survivors had a higher pH (7.33 6 0.10 vs. 7.27 6 0.14, P = 0.003), a lower PaCO2 (49 6 13 vs. 55 6 17, P = 0.036), and a slightly higher FIO2 (0.78 6 15 vs. 0.84 6 16, P = 0.021). The area under the ROC curve for pH was 0.62; at a pH of 7.29 (the pH of maximum sensitivity and minimum 1 2 specificity), the sensitivity of pH for predicting survival was 0.67 and the specificity was 0.53. The area under the ROC curve for PaCO2 was 0.59; at a PaCO2 of 45 mm Hg (the maximum sensitivity and minimum 1 2 specificity), the sensitivity of PaCO2 for predicting survival was 0.44 and the specificity was 0.68. Accordingly, these differences in gas exchange seen prior to initiating prone ventilation were neither sensitive nor specific for predicting survival. After 1 hour of prone ventilation, subjects who survived had a higher pH, but no difference was observed with respect to any change in ABGs on turning prone between subjects who survived or died (Table 1). The P/F ratio decreased on turning prone in 43 subjects at 1 hour, and 39 (91%) of these survived. Of the 38 subjects who died, 4 (11%) had P/F ratios that decreased an average of 225 6 35 mm Hg, and of the 194 subjects who survived, 39 (20%) had P/F ratios that decreased an average of 214 6 14 mm Hg after turning prone (P = 0.25). No difference in survival was observed when examining the change in P/F or the change in PaCO2 by quintiles of change (P = 0.41 and P = 0.21, respectively), by quintiles of subjects (P = 0.55 and P = 0.94, respectively, data not shown), or when combining the change in P/F with the change in PaCO2 (P = 0.670) (Table 1). ABGs prior to, and at the completion of, the first session of prone ventilation were similar in those who survived and those who died with the exception that those who died had a lower pH (7.37 6 0.08 vs. 7.30 6 0.12, P , 0.0001). No differences between the changes in ABGs in survivors versus those who died were found by any method of analysis (data not shown). Discussion
This is the first study assessing the relationship between the effect of prone ventilation on gas exchange and survival in a population of patients with ARDS in which prone ventilation improved survival. Although gas exchange improved and mortality was reduced, we found no association between the improvement in gas exchange and survival. We suggest that prone ventilation improves survival in ARDS by reducing ventilator-induced lung injury (VILI) as first theorized in 1997 (9), three years prior to publication of the ARMA study that reached the same conclusion with respect to low tidal Correspondence
volume ventilation (8). VILI is thought to occur as a result of cyclical airspace opening and closing and/or from lung overdistension. Prone positioning reduces the gravitational pleural pressure gradient (10–13). This results in a more uniform distribution of end-expiratory lung volume and, accordingly, a more uniform distribution of tidal volume, which, in turn, reduces cyclical airspace opening and closing (14) and the surfactant depletion that occurs as a result of larger volume excursions (15) in dependent lung regions, and also reduces the overdistension that occurs in nondependent regions. We conclude that the increase in survival seen in patients with ARDS who receive prone ventilation does not depend on whether the change in position improves gas exchange and infer that it results from the ability of prone positioning to reduce VILI. Accordingly, we suggest that prone ventilation should not be considered as salvage therapy for patients with severe hypoxemia but that it should be routinely initiated early in ARDS, certainly when the P/F ratio is
Gu´erin and colleagues (8) reported that prone ventilation for an average of 16 h/d improved oxygenation and reduced the mortality of patients with ARDS by 50%. We sought to determine if the improvements in gas exchange they observed predicted survival.
To the Editor:
Methods
Prone ventilation improves oxygenation in most, but not all, patients with the acute respiratory distress syndrome (ARDS) (1–4). Until recently, however, this improvement has not been associated with improved survival. The ARDS Management Arms (ARMA) study comparing low with standard tidal volume ventilation actually found that survival was better in subjects who had worse oxygenation (5). Two previous studies concluded that the changes in gas exchange that occurred with prone ventilation did not predict survival in ARDS (6, 7) but both only used prone ventilation 5–8 h/d, and neither found that prone ventilation improved overall survival. Recently,
This was a retrospective analysis of data collected prospectively by Gu´erin and colleagues (8). Inclusion criteria are described in the original article. Arterial blood gases (ABG) were analyzed prior to turning prone, 1 hour after turning, and after completing the first session of prone ventilation while the patients were still prone. Changes in ABGs were examined relative to 28-day mortality. The PaO2/FIO2 (P/F) ratio and PaCO2 were analyzed as means 6 SD, in quintiles of units or mm Hg, respectively, in quintiles of subjects, by classifying subjects as “responders” or “non-responders” per Gattinoni and colleagues (6) (i.e., an increase in P/F of >20 mm Hg or a decrease in PaCO2 of >1 mm Hg), and in subgroups based
Table 1: Gas Exchange 1 Hour after Initiating Prone Ventilation (Mean 6 SD) Variable
Survived (N = 194)
Died (N = 38)
P Value
7.34 6 0.10 0.01 6 07 49 6 14 20.5 6 9.4 119 6 65 38.9 6 63 74 6 16 23.9 6 11.4 12 6 3 21.6 6 3.0 166 6 83 60 6 79
7.27 6 0.12 0.01 6 0.05 52 6 12 22.7 6 9.1 118 6 59 38.8 6 59 78 6 17 26.5 6 11.6 12 6 2 21.3 6 3.2 152 6 62 55 6 60
0.004 0.764 0.149 0.182 0.950 0.987 0.205 0.220 0.654 0.602 0.321 0.618 0.78
pH, units D from pre–prone positioning PaCO2, mm Hg D from pre–prone positioning PaO2, mm Hg D from pre–prone positioning FIO2, % D from pre–prone positioning PEEP, cm H2O D from pre–prone positioning P/F, mm Hg D from pre–prone positioning P/F increase, mm Hg > 20, N (%) , 20, N (%) PaCO2 decrease, mm Hg > 1, N (%) , 1, N (%) Survival by quintile of P/F response after 1 h of prone ventilation, mm Hg, survivors/total patients (%) 286 to 21 0 to 85 86 to 171 172 to 257 258 to 343 Survival by quintile of change in PaCO2 after one hour of prone ventilation, mm Hg, survivors/total (%) 230 to 212 211 to 1 7 18 to 126 127 to 145 145 to 1 64 Survival by combined P/F and PaCO2 response, survivors/total (%) 1P/F response, no PaCO2 response 1P/F response, 1PaCO2 response No P/F response, no PaCO2 response No P/F response, 1PaCO2 response
123 (85) 71 (85)
25 (17) 13 (15)
99 (83) 95 (84)
20 (17) 18 (16)
0.86 0.410 39/43 99/121 37/47 13/15 6/6
(91) (82) (78) (87) (100) 0.210
13/20 160/189 16/18 4/4 1/1
(65) (85) (89) (100) (100) 0.670
15/16 18/23 80/97 81/97
(94) (78) (82) (87)
Author Contributions: Conception and design: R.K.A. and C.G.; analysis and interpretation: R.K.A., A.K., L.B., L.A., and C.G. Drafting the manuscript: R.K.A., A.K., and C.G.
494
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 4 | February 15 2014
CORRESPONDENCE on changes in the P/F ratio coupled with changes in the PaCO2 per Lemasson and colleagues (7) (i.e., an increase in P/F of >20% or ,20% and a decrease in PaCO2 of >1 or ,1 mm Hg). Analyses were performed using SAS Enterprise Guide 4.3 (SAS Institute, Inc., Cary, NC) or SPSS Statistics 17.0 (SPSS, Chicago, IL). Data were compared using paired or unpaired t tests and chi-squared analysis. P , 0.05 was considered significant. Gas exchange variables measured prior to turning prone that were significantly different between survivors and those who died were analyzed by receiver operating characteristic (ROC) curves. Results
Paired ABGs were available for 232 of 237 subjects (98%) who received prone ventilation for 1 hour, and for 228 of 237 subjects (96%) at the completion of the first prone session; 194 (82%) survived. Gas exchange prior to instituting prone ventilation was similar in those who survived and those who died with the exception that survivors had a higher pH (7.33 6 0.10 vs. 7.27 6 0.14, P = 0.003), a lower PaCO2 (49 6 13 vs. 55 6 17, P = 0.036), and a slightly higher FIO2 (0.78 6 15 vs. 0.84 6 16, P = 0.021). The area under the ROC curve for pH was 0.62; at a pH of 7.29 (the pH of maximum sensitivity and minimum 1 2 specificity), the sensitivity of pH for predicting survival was 0.67 and the specificity was 0.53. The area under the ROC curve for PaCO2 was 0.59; at a PaCO2 of 45 mm Hg (the maximum sensitivity and minimum 1 2 specificity), the sensitivity of PaCO2 for predicting survival was 0.44 and the specificity was 0.68. Accordingly, these differences in gas exchange seen prior to initiating prone ventilation were neither sensitive nor specific for predicting survival. After 1 hour of prone ventilation, subjects who survived had a higher pH, but no difference was observed with respect to any change in ABGs on turning prone between subjects who survived or died (Table 1). The P/F ratio decreased on turning prone in 43 subjects at 1 hour, and 39 (91%) of these survived. Of the 38 subjects who died, 4 (11%) had P/F ratios that decreased an average of 225 6 35 mm Hg, and of the 194 subjects who survived, 39 (20%) had P/F ratios that decreased an average of 214 6 14 mm Hg after turning prone (P = 0.25). No difference in survival was observed when examining the change in P/F or the change in PaCO2 by quintiles of change (P = 0.41 and P = 0.21, respectively), by quintiles of subjects (P = 0.55 and P = 0.94, respectively, data not shown), or when combining the change in P/F with the change in PaCO2 (P = 0.670) (Table 1). ABGs prior to, and at the completion of, the first session of prone ventilation were similar in those who survived and those who died with the exception that those who died had a lower pH (7.37 6 0.08 vs. 7.30 6 0.12, P , 0.0001). No differences between the changes in ABGs in survivors versus those who died were found by any method of analysis (data not shown). Discussion
This is the first study assessing the relationship between the effect of prone ventilation on gas exchange and survival in a population of patients with ARDS in which prone ventilation improved survival. Although gas exchange improved and mortality was reduced, we found no association between the improvement in gas exchange and survival. We suggest that prone ventilation improves survival in ARDS by reducing ventilator-induced lung injury (VILI) as first theorized in 1997 (9), three years prior to publication of the ARMA study that reached the same conclusion with respect to low tidal Correspondence
volume ventilation (8). VILI is thought to occur as a result of cyclical airspace opening and closing and/or from lung overdistension. Prone positioning reduces the gravitational pleural pressure gradient (10–13). This results in a more uniform distribution of end-expiratory lung volume and, accordingly, a more uniform distribution of tidal volume, which, in turn, reduces cyclical airspace opening and closing (14) and the surfactant depletion that occurs as a result of larger volume excursions (15) in dependent lung regions, and also reduces the overdistension that occurs in nondependent regions. We conclude that the increase in survival seen in patients with ARDS who receive prone ventilation does not depend on whether the change in position improves gas exchange and infer that it results from the ability of prone positioning to reduce VILI. Accordingly, we suggest that prone ventilation should not be considered as salvage therapy for patients with severe hypoxemia but that it should be routinely initiated early in ARDS, certainly when the P/F ratio is
