Online Letters to the Editor

measured values of pleural (esophageal) and transpulmonary pressure are not used in the calculation. For example, Grasso et al (6) calculated transpulmonary pressure at the end-inspiratory plateau from Ecw/Ers and plateau pressure values only. The elastance-based method is also evident in the calculated values of transpulmonary or pleural pressure at various lung volumes, which are nearly proportional to airway pressure (6, 7, 9). The correct Equation 2 is consistent with the conventional “direct” method of calculating transpulmonary pressure (3, 10), which requires measuring and using the actual values of transpulmonary (or esophageal) pressure, not just tidal changes in those pressures. Finally, we agree that the clinical utility of either method can only be determined through clinical trials. Dr. Loring received support for article research from the National Institutes of Health (NIH). Dr. Talmor received grant support from the National Heart, Lung, and Blood Institute and received support for article research from the NIH. Stephen H. Loring, MD, Daniel Talmor, MD, MPH, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

REFERENCES

1. Liu Y, Mu Y: Chest Wall Elastance in the Estimation of the Transpulmonary Pressure: How Should We Use It? Crit Care Med 2015; 43:e53–e54 2. Loring SH, O’Donnell CR, Behazin N, et al: Esophageal pressures in acute lung injury: Do they represent artifact or useful information about transpulmonary pressure, chest wall mechanics, and lung stress? J Appl Physiol (1985) 2010; 108:515–522 3. Gulati G, Novero A, Loring SH, et al: Pleural pressure and optimal positive end-expiratory pressure based on esophageal pressure versus chest wall elastance: Incompatible results. Crit Care Med 2013; 41:1951–1957 4. Gattinoni L, Carlesso E, Cadringher P, et al: Physical and biological triggers of ventilator-induced lung injury and its prevention. Eur Respir J Suppl 2003; 47:15s–25s 5. Gattinoni L, Chiumello D, Carlesso E, et al: Bench-to-bedside review: Chest wall elastance in acute lung injury/acute respiratory distress syndrome patients. Crit Care 2004; 8:350–355 6. Grasso S, Terragni P, Birocco A, et al: ECMO criteria for influenza A (H1N1)-associated ARDS: Role of transpulmonary pressure. Intensive Care Med 2012; 38:395–403 7. Staffieri F, Stripoli T, De Monte V, et al: Physiological effects of an open lung ventilatory strategy titrated on elastance-derived end-inspiratory transpulmonary pressure: Study in a pig model. Crit Care Med 2012; 40:2124–2131 8. Chiumello D, Carlesso E, Cadringher P, et al: Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. Am J Respir Crit Care Med 2008; 178:346–355 9. Chiumello D, Cressoni M, Carlesso E, et al: Bedside selection of positive end-expiratory pressure in mild, moderate, and severe acute respiratory distress syndrome. Crit Care Med 2014; 42:252–264 10. Talmor D, Sarge T, Malhotra A, et al: Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med 2008; 359:2095–2104 DOI: 10.1097/CCM.0000000000000804

Critical Care Medicine

Prone Positioning in Acute Respiratory Distress Syndrome To the Editor:

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egarding the effects of prone positioning on overall mortality, we believe that Lee et al (1) have misinterpreted the results of their own meta-analysis in a recent issue of Critical Care Medicine. In specific, we would like to report the following: 1. The authors report that no publication bias was seen on visual inspection of funnel plots. However, the funnel plot for main analysis, provided in supplement, clearly shows bias on visual inspection. In the absence of bias, the plot should approximately resemble a symmetrical (inverted) funnel. If there is bias, for example, because smaller studies without statistically significant effects remain unpublished, this will lead to an asymmetrical appearance of the funnel plot with a gap in a bottom corner of the plot. Supplement Figure 2 in (1) shows a wide gap in the right-bottom corner. 2. Risk ratio describes the multiplication of the risk that occurs with use of an experimental intervention (in this case, prone positioning). For example, a risk ratio of 2 for patients in the supine position group would imply that events in this group are twice than in those with prone positioning. We used the same data that the authors provided in Figure 2 in (1). Specifically, we used the “events” and total sample size (n) for patients in prone positioning and separately for those in supine position. Calculating the pooled risks ratio, we get a relative risk of 0.86 (95% CI, 0.75–1.0; p = 0.054). Clearly, the results get statistically insignificant when analyzed using this approach. 3. Constructing the funnel plot for the pooled relative risk estimate (above), we get a funnel plot that shows publication bias on visual inspection as well on statistical confirmation. From this funnel plot, we get an Eggers test of the intercept that has a p value of 0.03 (one-tailed), suggesting statistically significant publication bias. 4. The authors also report that no study unduly influenced the pooled estimate of the prone position. However, the analytic approach for this observation is not explained in their Methods section. We conducted a meta-analysis of the data (events/n) provided in Figure 2 in (1). Although, we arrived at the same pooled estimate of odds ratio, upon conducting a sensitivity analysis, we found that systematic exclusion of the studies by Gattinoni et al (2), Guerin et al (3), Chan et al (4), and Demory et al (5) leads to statistically significant results, whereas that for the remaining seven studies leads to statistically insignificant results. Clearly, some studies did exert influence on the overall pooled estimate. 5. In the meta-regression, authors stated that a negative trend for overall mortality was observed when the actual duration of prone positioning was longer and that the effect of the duration of prone positioning on mortality did not achieve statistical significance. However, a meta-regression using the unrestricted maximum likelihood method for the association of duration of prone positioning (per session) with www.ccmjournal.org

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the overall mortality gives us a point estimate for the regression slope of –0.04 (95% CI, –0.08 to –0.009; p = 0.013) (statistically significant). 6. Finally, inclusion of two studies (4, 5) does not meet their prespecified inclusion criteria. The study by Chan et al (4) is an observational study not a randomized clinical trial (RCT). The study by Demory et al (5) is strictly speaking an “active-comparator study” (in which the comparator group received active intervention—high-frequency oscillatory ventilation) not an RCT. Based on these findings, we disagree with the authors’ assertion that current evidence supports the use of prone positioning to improve survival in acute hypoxemic respiratory failure. The authors have disclosed that they do not have any potential conflicts of interest. Imran H. Iftikhar, MD, FACP, FCCP, Meredith A. Donley, MD, William B. Owens, MD, FCCP, Division of Pulmonary, Critical Care and Sleep Medicine, University of South Carolina, School of Medicine, Columbia, SC

REFERENCES

1. Lee JM, Bae W, Lee YJ, et al: The Efficacy and Safety of Prone Positional Ventilation in Acute Respiratory Distress Syndrome: Updated Study-Level Meta-Analysis of 11 Randomized Controlled Trials. Crit Care Med 2014; 42:1252–1262 2. Gattinoni L, Tognoni G, Pesenti A, et al; Prone-Supine Study Group: Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001; 345:568–573 3. Guerin C, Gaillard S, Lemasson S, et al: Effects of systematic prone positioning in hypoxemic acute respiratory failure: A randomized controlled trial. JAMA 2004; 292:2379–2387 4. Chan MC, Hsu JY, Liu HH, et al: Effects of prone position on inflammatory markers in patients with ARDS due to community-acquired pneumonia. J Formos Med Assoc 2007; 106:708–716 5. Demory D, Michelet P, Arnal JM, et al: High-frequency oscillatory ventilation following prone positioning prevents a further impairment in oxygenation. Crit Care Med 2007; 35:106–111 DOI: 10.1097/CCM.0000000000000761

The authors reply:

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e thank Iftikhar et al (1) for their thoughtful comments and concerns regarding our recent metaanalysis (2). Iftikhar et al (1) noted the asymmetric appearance of the funnel plots on visual inspection, suggested using the risk ratio (RR) instead of the odds ratio (OR) for analysis, and highlighted problems with the quality of some of the included studies. Overall, the choice to use RR or OR in a meta-analysis allows authors’ differences in the interpretation of results, and this choice can be controversial. In general, effects tend to be statistically overestimated when using OR compared with RR. However, for this meta-analysis, but not for each cohort or case-control study, we needed to use summary statistics of the included studies when there were variations in control group event rates. In a comparison of the summary statics of a sample of 551 systematic reviews and meta-analyses, no differences

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were observed between RR and OR in empirical investigations (3). The selection of summary statistics based solely on the identification of a best-fit model by comparing tests of heterogeneity is always problematic, primarily due to a small number of trials. Nevertheless, it is possible that the effects seen in our analysis would have been statistically different using RR instead of OR. Still, our primary outcome was robust in the randomeffect model. Additionally, two meta-analyses (4, 5) about prone positioning in this special issue showed similar results to ours using RR and not OR. Eight of nine (4) and nine of 11 (5) trials in each meta-analysis are also included in our analysis (2). We also disagree with the assertion by Iftikhar et al (1) regarding the study by Chan et al (6). It is true that the term “observational” was used to describe the original study, but it was methodologically conducted as randomized trial, with the exception of allocation concealment. Furthermore, all metaanalyses that have investigated this issue included the study by Chan et al (6) as a randomized controlled trial, including a recent meta-analysis (5) that Chan coauthored. Regarding two trials including high-frequency oscillatory ventilation, we already discussed similar critique in the previous response to our publication (7). Finally, we considered evaluating the significance of the meta-regression analysis using another method, but the times and sessions differed among the three meta-analyses included our study. Specifically, the PROSEVA trial (8) required a prone position for at least 16 consecutive hours, which was the maximum duration of prone positioning among the three meta-analyses. The quality of original data is an important consideration in the criticism of meta-analyses. Publication bias and the attributes of the original study are principal determinants of a meta-analysis’s validity. As we mentioned in our Methods section, we assessed publication bias using The Cochrane Collaboration’s tool and the Jadad score, and we determined that biased evidence was not included. We do not fully agree with the critique by Iftikhar et al (1), which noted that the publication bias was based on mixed interpretations, including the selection of RR or OR and the quality of the included trials. Nevertheless, results indicating bias might be due to the fact that the included trials were conducted with high-quality data and methodology. As full-time intensivists, we use a prone position for some patients with acute respiratory distress syndrome who are near death. This positioning requires no additional costs, special devices, or invasive procedures. Furthermore, prone positioning is a rescue therapy for life-threatening hypoxemia, and it reduces the potential for ventilator-induced lung injury (9). Iftikhar et al (1) can disagree with our assertions from a methodological point of view, but we hope that they do not ignore the needs of “real-world” patients in an effort to simplify treatment strategies (10). The authors have disclosed that they do not have any potential conflicts of interest. Young-Jae Cho, MD, MPH, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South February 2015 • Volume 43 • Number 2

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