==== Front Crit Care Critical Care 1364-8535 1466-609X BioMed Central London 37386506 4547 10.1186/s13054-023-04547-x Correspondence Authors’ reply to the comment from Benavides-Zora et al. Kotani Yuki 123 Pruna Alessandro 1 Lee Todd C. 4 Roth Dominik 5 Landoni Giovanni landoni.giovanni@hsr.it 12 1 grid.18887.3e 0000000417581884 Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy 2 grid.15496.3f 0000 0001 0439 0892 School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy 3 grid.414927.d 0000 0004 0378 2140 Department of Intensive Care Medicine, Kameda Medical Center, 929 Higashi-cho, Kamogawa, Chiba 296-8602 Japan 4 grid.14709.3b 0000 0004 1936 8649 Division of Infectious Diseases, Department of Medicine, McGill University, Montreal, QC Canada 5 grid.22937.3d 0000 0000 9259 8492 Department of Emergency Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria 29 6 2023 29 6 2023 2023 27 2559 6 2023 22 6 2023 © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2023 ==== Body pmcWith the goal of including all available randomized controlled trials (RCTs) on propofol, we meta-analyzed 252 trials reporting mortality at 18 different time-points and pooled data at the longest follow-up available as previously validated [1]. Even if our analysis would violate the proportional hazards assumption, this would only lead to an underestimation of pooled effect size, further strengthening the robustness of our findings [2]. Sensitivity analyses on the five most frequently reported time-points arrived at a similar magnitude and direction as the primary analysis. Interestingly, further mRCT evidence (not included in our meta-analysis because of inclusion criteria) confirms a detrimental effect of propofol on survival persisting up to one year [3]. We adopted an intention-to-treat approach when extracting mortality data to prevent exaggeration of treatment effects that can occur in per-protocol analyses [4]. In the cardiovascular setting, including Likhvantsev et al. study using the evaluable patients’ data (not the correctly extracted intention-to-treat data), the impact remains statistically significant (RR, 1.36; 95% CI, 1.06–1.76; Additional file 1: Table S1). We acknowledge clinical heterogeneity across different subgroups. However, our subgroup analyses consistently showed results similar to our main analysis in magnitude and direction. The debate “fixed versus random-effects models” goes beyond the scope of this letter and was addressed in another reply. However, when repeating the analysis using random-effects model and trim-and-fill approach, results remained consistent with the main analysis (Additional file 1: Table 1). The composition of intensive care unit (ICU) and perioperative RCTs in our analysis was similar to Roth et al. in which 16% of included studies were set in medical ICUs [1]. Although our meta-analysis also included perioperative studies, more than 50% of the deaths occurred in ICU studies. The ICU subgroup also had > 10% relative mortality increase (15% vs. 13%) with Bayesian approach indicating 75.7% probability of harm. Since the outcome is death, it is maybe cavalier to dismiss such probability as “no difference,” especially given a pediatric RCT suggested harm leading to a FDA warning [5] and the manufacturer’s promise for a second RCT which was never conducted. With millions of patients exposed, and the potential for increased mortality, we would disagree with the suggestion this is “spin.” Considering the availability of other sedation strategies (e.g., alternative hypnotic agents, sedation rotation, dose minimization), we believe our findings warrant careful consideration. Our study aims to raise awareness about potential propofol-associated risks and support the kind of pragmatic mRCTs that clinicians need and patients deserve. Supplementary Information Additional file 1. Supplemental Table 1. Abbreviations CI Confidence interval FDA Food and Drug Administration ICU Intensive care unit mRCT Multicenter randomized controlled trials RCT Randomized controlled trial RR Risk ratio Acknowledgements Not applicable. Author contributions YK, AP, TCL, DR, and GL wrote and approved the final manuscript. Funding Not applicable. Availability of data and materials Further information on the original manuscript is available from the corresponding authors upon reasonable request. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. Roth D Heidinger B Havel C Herkner H Different mortality time points in critical care trials: current practice and influence on effect estimates in meta-analyses Crit Care Med 2016 44 e737 e741 10.1097/ccm.0000000000001631 26963325 2. Schemper M Cox analysis of survival data with non-proportional hazard functions J R Stat Soc Ser D (The Statistician) 1992 41 455 465 3. De Hert S Vlasselaers D Barbé R Ory J-P Dekegel D Donnadonni R A comparison of volatile and non volatile agents for cardioprotection during on-pump coronary surgery Anaesthesia 2009 64 953 960 10.1111/j.1365-2044.2009.06008.x 19686479 4. Mostazir M Taylor G Henley WE Watkins ER Taylor RS Per-Protocol analyses produced larger treatment effect sizes than intention to treat: a meta-epidemiological study J Clin Epidemiol 2021 138 12 21 10.1016/j.jclinepi.2021.06.010 34161805 5. Felmet K, Nguyen T, Clark RS, Orr D, Carcillo J. The FDA warning against prolonged sedation with propofol in children remains warranted. Pediatrics. 2003;112:1002–3; author reply 1002–3. 10.1542/peds.112.4.1002