Heunks, Leo

Reep, Carmen A.T.

Wils, Evert Jan

English

EUR Research Repository

EUR Research Information PortalEffect of initiation of invasive ventilation in acute hypoxemic respiratory failure usingsequential trialsPublished in:Critical CarePublication status and date:Published: 03/06/2025DOI (link to publisher):10.1186/s13054-025-05464-xDocument VersionPublisher's PDF, also known as Version of recordDocument License/Available under:CC BYCitation for the published version (APA):Reep, C. A. T., Heunks, L., & Wils, E. J. (2025). Effect of initiation of invasive ventilation in acute hypoxemic respiratoryfailure using sequential trials: treatment efficacy instead of timing. Critical Care, 29(1), Article 221.https://doi.org/10.1186/s13054-025-05464-xLink to publication on the EUR Research Information PortalTerms and Conditions of UseExcept as permitted by the applicable copyright law, you may not reproduce or make this material available to any third partywithout the prior written permission from the copyright holder(s). Copyright law allows the following uses of this materialwithout prior permission:            • you may download, save and print a copy of this material for your personal use only;            • you may share the EUR portal link to this material.In case the material is published with an open access license (e.g. a Creative Commons (CC) license), other uses may beallowed. Please check the terms and conditions of the specific license.Take-down policyIf you believe that this material infringes your copyright and/or any other intellectual property rights, you may request itsremoval by contacting us at the following email address: openaccess.library@eur.nl. Please provide us with all the relevantinformation, including the reasons why you believe any of your rights have been infringed. In case of a legitimate complaint,we will make the material inaccessible and/or remove it from the website.Reep et al. Critical Care          (2025) 29:221  https://doi.org/10.1186/s13054-025-05464-xMATTERS ARISINGEffect of initiation of invasive ventilation in acute hypoxemic respiratory failure using sequential trials: treatment efficacy instead of timingCarmen A. T. Reep1*, Leo Heunks2 and Evert‑Jan Wils3 In Critical Care, Mellado-Artigas and colleagues [1] aimed to evaluate the effect of initiating invasive mechanical ventilation (IMV) immediately versus wait-ing in patients with hypoxemic respiratory failure on one-year mortality. They used the target trial emulation framework, which is an increasingly recognized approach for designing observational studies that aim to compare treatment strategies [2]. Specifically, the authors used a sequential trials approach [3, 4], in which eligibility for initiating IMV is reassessed hourly during the first 48 h following the onset of hypoxemia. At each hour, a new trial is emulated using all patients eligible at that time point, and all 48 trials are combined into a single analy-sis. This method efficiently leverages all available obser-vational data. However, it does not address whether immediate initiation of IMV reduces the hazard of dying compared to waiting, as implied by the title and research question. For example, a patient who remains eligible for IMV for 30 h before initiation cannot reasonably be considered as starting IMV “immediately.” The sequen-tial trials approach instead evaluates treatment efficacy, in this case that initiating IMV reduces the risk of death compared to not initiating it at all. The authors’ conclu-sion does align with this efficacy question. However, the intended question of optimal timing for IMV initiation remains unanswered and highly relevant in clinical prac-tice. While this can still be investigated within the target trial emulation framework, it would require a slightly dif-ferent analytical approach. We outline three such alterna-tives below.One option would be to stick to a clinical threshold at which IMV initiation is hypothesized to be beneficial, such as S/F < 200 (in line with the original paper). Then comparing two treatment strategies: early initiation (e.g., within 1 h of meeting these criteria) with delayed initia-tion (after 1  h). But now, instead of including patients each time they meet the criteria, only the first instance of meeting these criteria should be included. By moving away from the sequential trials approach, this method does directly address the question of whether immediate initiation of IMV reduces the risk of mortality.A second option is to define early versus delayed ini-tiation based on the severity of the patient’s illness. For instance, initiation during the ‘less severe stage of hypox-emia’ (e.g., S/F < 200) could be considered early, while initiation during ‘more severe stages’ (e.g., S/F < 100) could be considered delayed. Different treatment strat-egies could then be compared, each defined as ‘initiate IMV once the S/F ratio falls below a specific threshold,’ all Open Access© The Author(s) 2025. 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/.Critical CareThis comment refers to the article available online at https:// doi. org/ 10. 1186/ s13054‑ 024‑ 04926‑y.*Correspondence:Carmen A. T. Reepc.reep@erasmusmc.nl1 Department of Intensive Care, Erasmus Medical Center, Rotterdam, The Netherlands2 Department of Intensive Care, Radboud University Medical Center, Nijmegen, The Netherlands3 Department of Intensive Care, Franciscus Gasthuis & Vlietland, Rotterdam, The NetherlandsPage 2 of 2Reep et al. Critical Care          (2025) 29:221 using the same eligibility criteria as the start of follow-up. These strategies, in which treatment decisions depend on evolving patient characteristics, are known as dynamic treatment regimes [5]. This approach also allows for the inclusion of more than two treatment strategies, which is particularly useful when the optimal threshold for initiat-ing IMV is uncertain. For example, Yarnell and colleagues [6] applied such an approach using S/F ratio thresholds of 88, 98, and 110.In line with defining early versus delayed initiation based on severity of illness, a third option would be to keep the sequential trials approach but stratify patients by severity of illness at baseline, for example using differ-ent S/F ratio ranges. This would help determine whether initiating IMV is beneficial across all stages of hypox-emia, or whether the benefit is less evident in patients with milder hypoxemia (e.g., for those with an S/F ratio between 150 and 200), which could support a more delayed initiation strategy.In conclusion, Mellado and colleagues address a clini-cally relevant question using an innovative methodologi-cal framework. However, the analytical approach they apply does not align with the question they aim to answer. We propose three alternative analytical approaches that more directly address the issue of timing of IMV initia-tion. Of note, these approaches may also be applicable to other timing-dependent treatment questions in critical care.AbbreviationsIMV  Invasive mechanical ventilationS/F  SpO2/FiO2AcknowledgementsNot applicableAuthor contributionsCR created the first draft of the manuscript. EJ was a contributor in writing the manuscript. All authors read and approved the final manuscript.FundingZonMw, but without specific role in the conceptualization, design, data collec‑tion, analysis, decision to publish, or preparation of the manuscript.Availability of data and materialsNo datasets were generated or analysed during the current study.DeclarationsEthics approval and consent to participateNot applicable.Consent for publicationNot applicable.Competing interestsThe authors declare no competing interests.Received: 10 May 2025   Accepted: 17 May 2025References 1. Mellado‑Artigas R, Borrat X, Ferreyro BL, Yarnell C, Hao S, Wanis KN, et al. Effect of immediate initiation of invasive ventilation on mortality in acute hypoxemic respiratory failure: a target trial emulation. Crit Care. 2024;28(1):157. 2. Hernán MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not available. Am J Epidemiol. 2016;183(8):758–64. https:// doi. org/ 10. 1093/ aje/ kwv254. 3. Keogh RH, Gran JM, Seaman SR, Davies G, Vansteelandt S. Causal infer‑ence in survival analysis using longitudinal observational data: sequential trials and marginal structural models. Stat Med. 2023;42(13):2191–225. https:// doi. org/ 10. 1002/ sim. 9718. 4. Caniglia EC, Rojas‑Saunero LP, Hilal S, Licher S, Logan R, Stricker B, et al. Emulating a target trial of statin use and risk of dementia using cohort data. Neurology. 2020;95(10):E1322–32. 5. Morzywołek P, Steen J, Van Biesen W, Decruyenaere J, Vansteelandt S. On estimation and cross‑validation of dynamic treatment regimes with competing risks. Stat Med. 2022;41(26):5258–75. 6. Yarnell CJ, Angriman F, Ferreyro BL, Liu K, De Grooth HJ, Burry L, et al. Oxygenation thresholds for invasive ventilation in hypoxemic respiratory failure: a target trial emulation in two cohorts. Crit Care. 2023;27(1):67.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in pub‑lished maps and institutional affiliations.

Effect of initiation of invasive ventilation in acute hypoxemic respiratory failure using sequential trials:treatment efficacy instead of timing

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Effect of initiation of invasive ventilation in acute hypoxemic respiratory failure using sequential trials:treatment efficacy instead of timing

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