BJA
Correspondence
Reply from the authors
Low intraoperative tidal volume ventilation with minimal PEEP is associated with increased mortality
Table 1 Unadjusted Hazard Ratio for 30-day mortality TV IBW group
Unadjusted Hazard Ratio
P-value
3– 6
5.109
,0.0001
6– 8
2.559
,0.0001
10 –12
0.849
0.4302
12 –20
1.260
0.5521
Table 2 30-day mortality by TV IBW group Tidal Volume IBW group
30-day mortality
3– 6
3.9%
6– 8
2%
8– 10 (reference)
0.8%
10 –12
0.7%
12 –20
1%
Table 3 Percentage of patients transfused per TV IBW group Tidal Volume IBW group
% receiving PRBCs
3– 6
13.5%
6– 8
9.4%
8– 10 (reference)
8.4%
10 –12
9.8%
12 –20
11.7%
P,0.0001 for comparison between groups.
522
Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on February 19, 2015
Editor—In response to the letters of Neto and of Xue and colleagues, we would first like to thank both authors for their thoughtful comments. We agree that retrospective studies can only show association, not causation, and that even though the propensity score matching analysis supported the results found in the Cox regression model,1 the magnitude of the biases in distributions between the tidal volume (TV) groups for certain covariates were considerable and unlikely to be fully offset by the propensity score. We stated this clearly in our discussion. In our final model however, many of the systematically distributed variables had no statistically significant effect on the observed outcome despite disproportionate representation. Among those that did, short length of intubation, low BMI, and female gender were all associated with lower TV IBW (ideal body weight) and increased mortality. Therefore, it is not surprising that after adjusting for these variables and others, the hazard ratios for low TV decreased as compared with the unadjusted hazard ratios shown in Table 1 below:
Neto asked what the 30-day mortality rates were per tidal volume (TV) per IBW group. The rates are shown in Table 2. Unfortunately due to the retrospective design of this study we are unable to comment as to the causes leading to mortality. In regards to the overall mortality reported in our paper, we believe that 1.2% is consistent with another large population based study (1.85%).2 Neto also asked whether it would be possible to perform an analysis using PEEP as the primary variable of interest rather than TV. The range of PEEP in our entire cohort was 2.2–5 cm H2O. Consequently, we were unable to investigate a low TV, high PEEP combination. Additionally, we were unable to find a strong correlation between PEEP and tidal volume (r ¼ 0.033) (Fig 2c of original article). Xue commented that we did not control for preoperative factors such as anaemia and for details of intraoperative management such as RBC transfusions, blood loss, and episodes of haemodynamic instability. Preoperative haemoglobin level was available for only 9177/29 343 patients (31.3%). Of these, only 124 patients (1.4%) had a haemoglobin level of less than or equal to 7 g/dl. Therefore we believe it is unlikely that preoperative anaemia was a significant contributor to post-operative mortality in this cohort. As for other preoperative risk factors, we believe that our use of the all patient refined-diagnosis related group (APR-DRG) Severity of Illness and Risk of Mortality scores provided sufficient risk adjustment to account for additional comorbid conditions. In regards to intraoperative factors, it is beyond the scope of this reply, and was well beyond the scope of our original analysis, to fully analyse the detailed anaesthetic course. We did however re-analyse our data set to examine the use of intraoperative blood transfusions. 2672/29 343 patients (9.1%) received at least one unit of packed red blood cells. The 30-day mortality among patients who were transfused was 5.3% vs 0.76% among patients who were not transfused. Among those patients who were transfused, the median number of units was 2 (1 –3) regardless of tidal volume group. Median TV per kg IBW was 8.6 ml kg21 IBW in patients who were transfused vs 8.62 ml kg21 IBW in patients who were not. The percentage of cases that were transfused per TV IBW group is shown in Table 3. It is interesting to note that both the low and high TV groups had a higher percentage of transfusions than the reference group, yet mortality in the high TV group was significantly less than both the reference 8–10 ml kg21 IBW group and the low TV groups. We re-ran the Cox regression analysis including an additional variable for transfusion (yes/no) and found that the hazard ratio for TV 6–8 ml kg21 IBW vs 8–10 ml kg21 IBW was essentially unchanged, 1.62 (1.26–2.1), P¼0.0002. Similarly, when we repeated the propensity score analysis with the inclusion of transfusion as a matching variable, the adjusted hazard ratio for TV 6–8 ml kg21 IBW vs 8–10 ml kg21 IBW was 1.68 (1.25–2.27), P,0.001, again essentially unchanged (in fact slightly higher) than in the original analysis. Thus we feel comfortable concluding that use of RBC transfusion was not a significant confounder in this cohort.
BJA
Correspondence
Finally, we disagree with Neto’s comment implying that PEEP should not be used with low TV, since that combination in conjunction with recurrent recruitment manoeuvres is precisely what has been promulgated as a protective ventilation strategy. In conclusion, we once again thank the authors for their observations and hope that our reply adequately addresses their concerns.
Declaration of interest None declared.
1 Levin MA, McCormick PJ, Lin HM, Hosseinian L, Fischer GW. Low intraoperative tidal volume ventilation with minimal PEEP is associated with increased mortality. Br J Anaesth 2014; 113: 97–108 2 Noordzij PG, Poldermans D, Schouten O, Bax JJ, Schreiner FA, Boersma E. Postoperative mortality in The Netherlands: a population-based analysis of surgery-specific risk in adults. Anesthesiology 2010; 112: 1105–15
doi:10.1093/bja/aev008
Limited benefit of prophylactic continuous positive airway pressure following lung resection surgery Editor—We read with great interest the results of Garutti and colleagues1 concerning gas exchange and other clinical parameters after prophylactic use of continuous positive airway pressure (CPAP) in patients undergoing lung resection surgery. The major finding of the study was that prophylactic CPAP during the first 6 h after surgery with a pressure of 5– 7 cm H2O improved PaO2/FIO2 ratios at 24 h. This effect was more evident in patients at increased risk of postoperative pulmonary complications. This study raises controversy regarding the use of CPAP in high-risk postoperative hypoxaemic patients. There are some key points, however, to be taken into account when considering the findings of this trial. In comparison with other postoperative non-invasive ventilation studies there are a number of important differences to be noted: a relatively low level of CPAP was used in the study group; the patients had very good PaO2/FIO2 ratios (40) at enrolment and had baseline characteristics suggesting good baseline respiratory function; and only a short period of CPAP (6 h) was used in comparison to previously published randomized controlled trials examining similar patient populations.2 – 8 As CPAP has been widely demonstrated to reverse atelectasis in surgical patients and bi-level positive airway pressure has been demonstrated to be effective in the treatment of respiratory failure in patients following lung resection,2 one must question what this study adds to the current evidence pool. A
Declaration of interest None declared. A. J. Glossop1* A. Esquinas 2 1 Sheffield, UK 2 Murcia, Spain * E-mail: [email protected] 1 Garutti I, Puente-Maestu L, Laso J, et al. Comparison of gas exchange after lung resection with a Boussignac CPAP or Venturi mask. Br J Anaesth 2014; 112: 929–35
523
Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on February 19, 2015
G. W. Fischer* M. A. Levin New York, USA *E-mail: [email protected]
period of 6 h appears to be significantly shorter than that used in previous studies, so why was this period selected for the duration of treatment? All of the studies detailed above used significantly longer periods of time for treatment with non-invasive ventilation. The patients included in the study by Garutti and colleagues1 all had very good PaO2/FIO2 ratios before treatment with CPAP. Squadrone and colleagues3 treated to a PaO2/FIO2 ratio of 40 with CPAP in abdominal surgery patients and then stopped once this threshold was reached, whereas patients in the trial by Garutti and colleagues1 had PaO2/FIO2 ratios of 40 at the time of inclusion. It is also noteworthy that the baseline demographics of both groups of patients report predicted forced expiratory volume in 1 s (FEV1) readings of above 90% and FEV1/forced vital capacity ratios above 70%. In addition, nearly two-thirds (65%) of patients included were graded either ASA I or II score, suggesting that underlying respiratory disease was not a prominent feature in the patients studied. These factors raise several questions. Was CPAP really needed at all? How much further could the patients be improved by treating with CPAP? Are the authors effectively over-treating patients without significant underlying respiratory compromise whose oxygenation is already optimized? Finally, the findings of the study demonstrate that oxygenation was improved but with no impact on measured clinical outcomes. As patients started at a good level of oxygenation, is this really a surprise? It also casts some doubt on the requirement for use of CPAP in this manner if clinical end-points are unaffected. Additionally, the authors report an inaccuracy in the PaO2/FIO2 ratio calculation at 7 h in the treatment (CPAP) group (to their credit, this is addressed in the Discussion), but it is a potential source of bias in the reporting of findings. Perhaps the message from this study should be that at PaO2/ FIO2 ratios of 40 or above, CPAP prophylaxis is not needed following lung resection surgery, because it will not affect clinical outcomes. Whilst we congratulate the authors on their work, we feel that further large prospective studies, in which clinical parameters and treatment protocols are aligned with those previously presented in the literature and patients with more severe underlying respiratory disease are included, are warranted in this area.
Correspondence
Reply from the authors
Low intraoperative tidal volume ventilation with minimal PEEP is associated with increased mortality
Table 1 Unadjusted Hazard Ratio for 30-day mortality TV IBW group
Unadjusted Hazard Ratio
P-value
3– 6
5.109
,0.0001
6– 8
2.559
,0.0001
10 –12
0.849
0.4302
12 –20
1.260
0.5521
Table 2 30-day mortality by TV IBW group Tidal Volume IBW group
30-day mortality
3– 6
3.9%
6– 8
2%
8– 10 (reference)
0.8%
10 –12
0.7%
12 –20
1%
Table 3 Percentage of patients transfused per TV IBW group Tidal Volume IBW group
% receiving PRBCs
3– 6
13.5%
6– 8
9.4%
8– 10 (reference)
8.4%
10 –12
9.8%
12 –20
11.7%
P,0.0001 for comparison between groups.
522
Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on February 19, 2015
Editor—In response to the letters of Neto and of Xue and colleagues, we would first like to thank both authors for their thoughtful comments. We agree that retrospective studies can only show association, not causation, and that even though the propensity score matching analysis supported the results found in the Cox regression model,1 the magnitude of the biases in distributions between the tidal volume (TV) groups for certain covariates were considerable and unlikely to be fully offset by the propensity score. We stated this clearly in our discussion. In our final model however, many of the systematically distributed variables had no statistically significant effect on the observed outcome despite disproportionate representation. Among those that did, short length of intubation, low BMI, and female gender were all associated with lower TV IBW (ideal body weight) and increased mortality. Therefore, it is not surprising that after adjusting for these variables and others, the hazard ratios for low TV decreased as compared with the unadjusted hazard ratios shown in Table 1 below:
Neto asked what the 30-day mortality rates were per tidal volume (TV) per IBW group. The rates are shown in Table 2. Unfortunately due to the retrospective design of this study we are unable to comment as to the causes leading to mortality. In regards to the overall mortality reported in our paper, we believe that 1.2% is consistent with another large population based study (1.85%).2 Neto also asked whether it would be possible to perform an analysis using PEEP as the primary variable of interest rather than TV. The range of PEEP in our entire cohort was 2.2–5 cm H2O. Consequently, we were unable to investigate a low TV, high PEEP combination. Additionally, we were unable to find a strong correlation between PEEP and tidal volume (r ¼ 0.033) (Fig 2c of original article). Xue commented that we did not control for preoperative factors such as anaemia and for details of intraoperative management such as RBC transfusions, blood loss, and episodes of haemodynamic instability. Preoperative haemoglobin level was available for only 9177/29 343 patients (31.3%). Of these, only 124 patients (1.4%) had a haemoglobin level of less than or equal to 7 g/dl. Therefore we believe it is unlikely that preoperative anaemia was a significant contributor to post-operative mortality in this cohort. As for other preoperative risk factors, we believe that our use of the all patient refined-diagnosis related group (APR-DRG) Severity of Illness and Risk of Mortality scores provided sufficient risk adjustment to account for additional comorbid conditions. In regards to intraoperative factors, it is beyond the scope of this reply, and was well beyond the scope of our original analysis, to fully analyse the detailed anaesthetic course. We did however re-analyse our data set to examine the use of intraoperative blood transfusions. 2672/29 343 patients (9.1%) received at least one unit of packed red blood cells. The 30-day mortality among patients who were transfused was 5.3% vs 0.76% among patients who were not transfused. Among those patients who were transfused, the median number of units was 2 (1 –3) regardless of tidal volume group. Median TV per kg IBW was 8.6 ml kg21 IBW in patients who were transfused vs 8.62 ml kg21 IBW in patients who were not. The percentage of cases that were transfused per TV IBW group is shown in Table 3. It is interesting to note that both the low and high TV groups had a higher percentage of transfusions than the reference group, yet mortality in the high TV group was significantly less than both the reference 8–10 ml kg21 IBW group and the low TV groups. We re-ran the Cox regression analysis including an additional variable for transfusion (yes/no) and found that the hazard ratio for TV 6–8 ml kg21 IBW vs 8–10 ml kg21 IBW was essentially unchanged, 1.62 (1.26–2.1), P¼0.0002. Similarly, when we repeated the propensity score analysis with the inclusion of transfusion as a matching variable, the adjusted hazard ratio for TV 6–8 ml kg21 IBW vs 8–10 ml kg21 IBW was 1.68 (1.25–2.27), P,0.001, again essentially unchanged (in fact slightly higher) than in the original analysis. Thus we feel comfortable concluding that use of RBC transfusion was not a significant confounder in this cohort.
BJA
Correspondence
Finally, we disagree with Neto’s comment implying that PEEP should not be used with low TV, since that combination in conjunction with recurrent recruitment manoeuvres is precisely what has been promulgated as a protective ventilation strategy. In conclusion, we once again thank the authors for their observations and hope that our reply adequately addresses their concerns.
Declaration of interest None declared.
1 Levin MA, McCormick PJ, Lin HM, Hosseinian L, Fischer GW. Low intraoperative tidal volume ventilation with minimal PEEP is associated with increased mortality. Br J Anaesth 2014; 113: 97–108 2 Noordzij PG, Poldermans D, Schouten O, Bax JJ, Schreiner FA, Boersma E. Postoperative mortality in The Netherlands: a population-based analysis of surgery-specific risk in adults. Anesthesiology 2010; 112: 1105–15
doi:10.1093/bja/aev008
Limited benefit of prophylactic continuous positive airway pressure following lung resection surgery Editor—We read with great interest the results of Garutti and colleagues1 concerning gas exchange and other clinical parameters after prophylactic use of continuous positive airway pressure (CPAP) in patients undergoing lung resection surgery. The major finding of the study was that prophylactic CPAP during the first 6 h after surgery with a pressure of 5– 7 cm H2O improved PaO2/FIO2 ratios at 24 h. This effect was more evident in patients at increased risk of postoperative pulmonary complications. This study raises controversy regarding the use of CPAP in high-risk postoperative hypoxaemic patients. There are some key points, however, to be taken into account when considering the findings of this trial. In comparison with other postoperative non-invasive ventilation studies there are a number of important differences to be noted: a relatively low level of CPAP was used in the study group; the patients had very good PaO2/FIO2 ratios (40) at enrolment and had baseline characteristics suggesting good baseline respiratory function; and only a short period of CPAP (6 h) was used in comparison to previously published randomized controlled trials examining similar patient populations.2 – 8 As CPAP has been widely demonstrated to reverse atelectasis in surgical patients and bi-level positive airway pressure has been demonstrated to be effective in the treatment of respiratory failure in patients following lung resection,2 one must question what this study adds to the current evidence pool. A
Declaration of interest None declared. A. J. Glossop1* A. Esquinas 2 1 Sheffield, UK 2 Murcia, Spain * E-mail: [email protected] 1 Garutti I, Puente-Maestu L, Laso J, et al. Comparison of gas exchange after lung resection with a Boussignac CPAP or Venturi mask. Br J Anaesth 2014; 112: 929–35
523
Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on February 19, 2015
G. W. Fischer* M. A. Levin New York, USA *E-mail: [email protected]
period of 6 h appears to be significantly shorter than that used in previous studies, so why was this period selected for the duration of treatment? All of the studies detailed above used significantly longer periods of time for treatment with non-invasive ventilation. The patients included in the study by Garutti and colleagues1 all had very good PaO2/FIO2 ratios before treatment with CPAP. Squadrone and colleagues3 treated to a PaO2/FIO2 ratio of 40 with CPAP in abdominal surgery patients and then stopped once this threshold was reached, whereas patients in the trial by Garutti and colleagues1 had PaO2/FIO2 ratios of 40 at the time of inclusion. It is also noteworthy that the baseline demographics of both groups of patients report predicted forced expiratory volume in 1 s (FEV1) readings of above 90% and FEV1/forced vital capacity ratios above 70%. In addition, nearly two-thirds (65%) of patients included were graded either ASA I or II score, suggesting that underlying respiratory disease was not a prominent feature in the patients studied. These factors raise several questions. Was CPAP really needed at all? How much further could the patients be improved by treating with CPAP? Are the authors effectively over-treating patients without significant underlying respiratory compromise whose oxygenation is already optimized? Finally, the findings of the study demonstrate that oxygenation was improved but with no impact on measured clinical outcomes. As patients started at a good level of oxygenation, is this really a surprise? It also casts some doubt on the requirement for use of CPAP in this manner if clinical end-points are unaffected. Additionally, the authors report an inaccuracy in the PaO2/FIO2 ratio calculation at 7 h in the treatment (CPAP) group (to their credit, this is addressed in the Discussion), but it is a potential source of bias in the reporting of findings. Perhaps the message from this study should be that at PaO2/ FIO2 ratios of 40 or above, CPAP prophylaxis is not needed following lung resection surgery, because it will not affect clinical outcomes. Whilst we congratulate the authors on their work, we feel that further large prospective studies, in which clinical parameters and treatment protocols are aligned with those previously presented in the literature and patients with more severe underlying respiratory disease are included, are warranted in this area.
