Opportunities, challenges and future perspectives for target trial emulation in critical care clinical research

Target trial emulation (TTE) is a powerful framework for addressing causal questions using observational data. By explicitly designing analyses to mimic a hypothetical randomized trial, TTE enables researchers to more precisely define their research questions, leading to more clinically meaningful conclusions. Its forward-looking design also helps limit common biases, such as immortal time bias and selection bias. Understanding TTE principles is essential not only for researchers working with observational data but also for clinicians who aim to critically interpret the growing number of TTE studies, as well as studies addressing causal questions without explicit use of the TTE framework. In this review, using the timing of switch from controlled to assisted ventilation as a key example, we outline the core assumptions underpinning valid causal inference in TTE: consistency, conditional exchangeability, and positivity. We discuss practical challenges in dynamic critical care settings, including defining a meaningful time zero, handling grace periods, and selecting and properly adjusting for confounders. We also discuss caveats, such as TTE's applicability to non-modifiable interventions, limited applicability for intention-to-treat effects, and the need for high-resolution longitudinal data. Finally, we provide a visual summary linking each trial component to key indicators of high-quality emulation.