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. 2023 Feb 7;27:51. doi: 10.1186/s13054-023-04328-6

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© The Author(s) 2023

Open AccessThis 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.

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Fig. 1 — Sequential emulation of the target trial. The target trial (as defined in Additional file 1: Table S2) was emulated several times in a sequence of nested trials, to make coincide treatment assignment and start of follow-up, thus avoiding immortal-time bias. This figure describes the construction of the observations in each nested trial with their respective treatment assignment, measurement of confounders, and follow-up. A hypothetical cohort is presented for simplicity. Panel A: The figure depicts the construction of the first emulated trial. At day 0 (first day of ECMO support), no patient received levosimendan; thus, the target trial was not emulated as the comparison was not feasible between patient receiving and not receiving levosimendan. At day 1 (D1), five patients (P5 to P9) started levosimendan, and so could be compared to the four patients (P1 to P4) that did not receive levosimendan. Their treatment assignment is in line with the received strategy at the day of the target trial emulation (here day 1). In addition, baseline confounders for the first nested trial are measured on day 1 (red rectangle), that is, day 1 since beginning of ECMO. Follow-up is restarted at day 1 for the first emulated trial to make coincide eligibility, treatment assignment and time-zero. Panel B: The figure depicts the construction of the second emulated trial. At day 2 after beginning of ECMO support, three patients did not receive levosimendan (P1, P2, and P4) and one patient received levosimendan (P3). Patients that received levosimendan in the previous nested trial at day 1 are not eligible anymore, as defined in the target trial protocol (new-user design). As for day 1 nested trial, treatment assignment of cloned copies of eligible patients is based on the treatment received the day of the emulated trial (blue rectangle) and baseline confounders for the second nested trial are measured on day 2. Follow-up is again restarted on the day 2 of the nested trial. Each of these nested emulated trials data is then stacked in a unique dataset, built with cloned copies of participants with assigned treatment, reset follow-up and baseline confounders in each nested trial. A multivariable Cox model is then fitted on the stacked cohort of observations and adjusted for confounders measured at ICU admission and at baseline of each nested trial (lactatemia, ECMO output, VIS, and SOFA score)