Reply to: Timing‐specific neutrality in a Rigorous ICU anabolic trial

We thank the authors for their balanced appraisal of our randomized controlled trial evaluating combined intravenous amino acid boluses and cycle ergometry initiated on ICU days 3–4 for a median of six days. We appreciate their careful summary of the methodological rigor of the study and their accurate interpretation of the primary findings. We agree with their central observation that, under the specific conditions tested, the intervention did not attenuate first-week loss of muscle (ultrasound) or myofiber (biopsy) cross-sectional area, and that the increase in the myofiber protein-to-DNA ratio in the intervention group, despite no structural preservation, may point towards a temporal lag between anabolic signaling and measurable changes in muscle architecture. We further concur that both phenotype and phase play a role in determining responsiveness to anabolic interventions.1-4 The intervention was delivered in a predominantly young trauma cohort with presumed low nutritional risk and without significant acute kidney injury, over a relatively short duration during what may be considered the late acute phase of critical illness. However, it is important to acknowledge that patients do not progress through metabolic phases uniformly, and validated metabolic markers to define these transitions are currently lacking.1-5 Reliance on chronological ICU day thresholds may therefore not accurately reflect an individual patient's metabolic readiness for anabolic interventions.5 These considerations suggest that initiating anabolic strategies later in the course of illness, potentially after Day 5, and maintaining exposure for longer may be necessary to achieve structural effects, particularly in light of the observed lag between molecular signaling and measurable changes in muscle mass, although the identification of metabolic markers to guide timing would be preferable to fixed day-based cutoffs.1-5 Research is ongoing to identify such markers, with recent studies proposing trajectories in insulin resistance as a possible physiological indicator of metabolic transition.5 As acknowledged in the manuscript, the biphasic ultrasound trajectory and exploratory secondary outcomes should be interpreted as hypothesis-generating. We agree that fluid shifts and edema remain important considerations when assessing ultrasound-derived muscle measures in early critical illness. Although these factors were addressed through sensitivity analyses adjusting for fluid status, the methods used to monitor edema were not entirely objective; therefore, a residual influence of fluid shifts cannot be fully excluded. However, the inclusion of biopsy-derived myofiber cross-sectional area, which is less susceptible to interstitial fluid shifts, and the concordant loss observed across the two primary time points between ultrasound and biopsy measures, support the interpretation that the findings were not driven by edema. Mechanistic analyses of anabolic and catabolic signaling pathways were prespecified secondary outcomes and have been presented in abstract form,6 with the full manuscript currently in preparation. While beyond the scope of the present report, these data may provide additional insight into the observed divergence between early molecular responses and short-term structural endpoints and help guide future phase-targeted intervention studies. We thank the authors for their engagement with our work and for contributing to the ongoing discussion on optimizing the timing and design of anabolic interventions in critical illness. Your sincerely, Dr Lizl Veldsman On behalf of all co-authors The authors declare no conflicts of interest.