Authors’ reply to the comment from Uchida et al.
Critical Care volume 27, Article number: 327 (2023)
We thank Uchida and Hayashi for their comments on our study . As pointed out by Uchida et al. , we acknowledge the potential survivor treatment selection bias resulting from the use of data from a retrospective observational study (the JSEPTIC-DIC study) to identify the best criteria for polymyxin B hemadsorption (PMX-HA). However, because the derived criteria were validated in the analysis using data from the EUPHRATES trial, in which treatment allocation is randomized, we believe that the impact of selection bias was well minimized.
To address the potential immortal time bias , we analyzed only those cases that were alive for at least 54 h after randomization (i.e., the maximum time from randomization to the end of the standard regimen of two PMX-HA regimens) [4, 5]. As shown in Additional file 1: Fig. S1, the hazard ratios up to 28 days using the Cox proportional hazard model, adjusted for baseline APACHE II and SOFA scores, are 0.79 (95% CI 0.53–1.19, p = 0.26) and 0.64 (95% CI 0.41–0.99, p = 0.04) in all and targeted population, respectively. Therefore, we believe that these results from the analysis considering immortal time remained consistent with the original findings. However, it should be noted that the results of this additional analysis may underestimate the effect of PMX-HA by assuming that early deaths in the control group that were excluded from the analysis considering immortal time, could have been saved if they had been assigned to the PMX-HA group.
Although the two potential biases indicated by Uchida et al. could pose limitations to our study, they do not significantly undermine the target subpopulation of PMX-HA when considering the results of our additional analysis. However, the validity of our findings needs to be verified in future prospective studies.
Availability of data and materials
The data from the JSEPTIC-DIC study are publicly available (Sci Data. 2018;5:180243). The data from the EUPHRATES trial will not be shared beyond the requests from investigators of its trial.
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Uchida M, Hayashi K. Suspected bias in selection criteria of target subpopulation and its validation. Crit Care. 2023;27(1):284.
Yadav K, Lewis RJ. Immortal time bias in observational studies. JAMA. 2021;325(7):686–7.
Klein DJ, Foster D, Schorr CA, Kazempour K, Walker PM, Dellinger RP. The EUPHRATES trial (evaluating the use of polymyxin B hemoperfusion in a randomized controlled trial of adults treated for endotoxemia and septic shock): study protocol for a randomized controlled trial. Trials. 2014;15:218.
Dellinger RP, Bagshaw SM, Antonelli M, et al. Effect of targeted polymyxin B hemoperfusion on 28-day mortality in patients with septic shock and elevated endotoxin level: the EUPHRATES randomized clinical trial. JAMA. 2018;320(14):1455–63.
Ethics approval and consent to participate
The study protocol entitled "Targeted therapy using Polymyxin B hemadsorption in patients with sepsis" was approved by the Institutional Review Board of the University of Tokyo Hospital (No. 2022332NI) on February 27, 2023. This study was a secondary data analysis of de-identified data, and therefore, the requirement for informed consent was waived.
Consent for publication
The authors declare that they have no competing interests.
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Osawa, I., Doi, K. Authors’ reply to the comment from Uchida et al.. Crit Care 27, 327 (2023). https://doi.org/10.1186/s13054-023-04606-3