Songfeng Li1†
Shaojin Bu- 1Department of Anesthesiology, Fengdu People's Hospital, Chongqing, China
- 2Department of Emergency, Fengdu People's Hospital, Chongqing, China
- 3Department of Pediatrics, Fengdu People's Hospital, Chongqing, China
A Commentary on
ED50 and ED95 of hypobaric ropivacaine during unilateral spinal anesthesia in older patients undergoing hip replacement surgery
by Lin, C., Xian, W.-L., Xu, J., Zhao, T., Wu, Z.-Q., and Wang, F.-J. (2025). Front. Med. (Lausanne) 12:1571574. doi: 10.3389/fmed.2025.1571574
Introduction
Lin et al. (1) provided crucial clinical insights into dosage optimization for unilateral spinal anesthesia in older adults, a demographic vulnerable to anesthetic complications. Although the authors utilized Dixon's sequential design, a methodologically apt approach for estimating median effective doses, a thorough examination of the reported dose-response parameters reveals a significant pharmacological inconsistency that warrants discussion for the accurate interpretation of the findings.
A pharmacological impossibility: ED95 < ED50
In Table 2 and the Results section, the authors reported an ED50 of 11.13 mg (95% CI: 10.85–11.42 mg) and an ED95 of 10.30 mg (95% CI: 9.04–10.65 mg). This result contradicts the established pharmacological principles. By definition, within any monotonic dose-response framework (including Probit and Logit regression models), the dose needed to elicit a response in 95% of the population (ED95) must be greater than that for 50% (ED50) (2, 3). The reported inversion of these values is mathematically unexpected and may suggest an underlying issue in the model specification or interpretation.
Methodological considerations: evidence of a coding artifact
A detailed examination of these figures reveals the source of this inconsistency. Figure 3 presents a dose-response curve labeled “Incidence of Negative Reactions (%),” which descends from 100% to 0% with increasing doses. This indicates that the authors modeled the probability of a negative response (failure to achieve a blockade) instead of a positive response (successful blockade). Hence, the reported “ED95” mathematically represents the dose at which 95% of patients do not achieve surgical anesthesia, while “ED50” reflects the dose for 50% failure. This misinterpretation inevitably inverts the expected relationship between the two values.
Additionally, the sequential design (Figure 2) constrains data points within a narrow range (10.0–12.0 mg) with alternating outcomes, typical of the up-down method focused on estimating ED50. This limited sampling can exacerbate the instability of extreme quantile estimates, such as ED95, when combined with a mis-specified model outcome.
Clinical implications and the path to clarification
Accurate determination of ED95 is vital for patient safety in elderly individuals, who often exhibit reduced physiological reserve and altered pharmacodynamics. Published values may misguide the clinical dosing strategies. A reevaluation of the probit model specification is recommended, particularly with regard to the definition of the response variable. A re-analysis defining “success” as achieving surgical anesthesia should restore a monotonically increasing dose-response relationship and yield pharmacologically plausible values, where ED95 > ED50.
In the spirit of transparency and reproducibility, we included the complete statistical code used for our methodological verification as Supplementary material. This demonstrates the impact of response variable coding on the model output in the probit regression framework.
Discussion
This commentary elucidates a critical yet often overlooked methodological pitfall in dose-response analysis: the accurate definition of the binary outcome variable in regression models. The inversion of the ED95 and ED50 values reported by Lin et al. stems specifically from modeling the probability of block failure rather than success. It is crucial to emphasize that this critique pertains to a methodological artifact in data analysis, not to the fundamental concept of the study or the integrity of the collected data. The original observations retain value and, if reanalyzed with the correct outcome specifications, are likely to yield pharmacologically plausible and clinically useful parameters.
Our analysis reinforces a fundamental tenet of pharmacodynamic research: meticulous verification of outcome coding is a prerequisite for the biological plausibility. This case serves as a salient reminder for researchers to rigorously validate the model protocols when employing binary outcomes. Beyond this specific error, our commentary highlights broader methodological considerations for dose-finding studies, particularly in vulnerable populations. Studies aiming to estimate extreme quantiles (ED95) must explicitly acknowledge the inherent limitations of sequential designs, such as Dixon's up-and-down method, which is optimized for estimating the median (ED50) and often yields unstable estimates at the tails of the distribution.
To enhance methodological rigor in future research, we recommend: (1) adopting clear, pre-specified definitions for “success” and “failure” outcomes prior to model fitting; (2) supplementing sequential design data with larger, confirmatory cohorts, where feasible, to improve the stability of extreme quantile estimates; and (3) considering more efficient contemporary trial designs that can jointly model multiple endpoints and adaptively allocate patients based on accumulating data, thereby providing more robust dose-response characterization (4, 5).
In conclusion, a correctly specified model will not only resolve the presented pharmacological impossibility but also significantly enhance the clinical utility and reliability of the authors' study. This discussion underscores the importance of methodological transparency and adherence to pharmacometric principles, aiming to contribute to the advancement of rigorous and reproducible dose-response research in anesthesiology.
Author contributions
SB: Project administration, Supervision, Writing – review & editing, Methodology, Funding acquisition, Formal analysis, Software, Resources, Conceptualization. SL: Data curation, Writing – review & editing, Writing – original draft, Investigation. YT: Data curation, Writing – original draft, Investigation, Writing – review & editing. ST: Investigation, Writing – original draft, Writing – review & editing. TT: Writing – original draft, Investigation, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This study was supported by the Chongqing Municipal Public Health Bureau, Chongqing People's Municipal Government, China (2023MSXM033) and the Fengdu Municipal Public Health Bureau, Fengdu People's Municipal Government, China (2024FDKW002). The funders had no role in the study design, data collection and analysis, publication decisions, or manuscript preparation.
Acknowledgments
The authors acknowledge Paperpal (https://paperpal.com) for the grammar checking and language polishing.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declared that generative AI was not used in the creation of this manuscript.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2025.1724654/full#supplementary-material
References
1. Lin C, Xian WL, Xu J, Zhao T, Wu ZQ, Wang FJ. ED50 and ED95 of hypobaric ropivacaine during unilateral spinal anesthesia in older patients undergoing hip replacement surgery. Front Med (Lausanne). (2025) 12:1571574. doi: 10.3389/fmed.2025.1571574
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3. Cai YH, Dong LQ, Zhong JW, Lin Z, Chen C-D, Zhu L-B, et al. ED50 and ED95 of remimazolam for loss of consciousness in young children: a dose-finding study for induction of anaesthesia. Br J Anaesth. (2025) 134:1709–16. doi: 10.1016/j.bja.2025.02.004
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Keywords: dose-response relationship, geriatric anesthesia, methodology, probit analysis, ropivacaine, spinal anesthesia
Citation: Li S, Tian Y, Tian S, Tan T and Bu S (2026) Commentary: ED50 and ED95 of hypobaric ropivacaine during unilateral spinal anesthesia in older patients undergoing hip replacement surgery. Front. Med. 12:1724654. doi: 10.3389/fmed.2025.1724654
Received: 14 October 2025; Revised: 26 December 2025;
Accepted: 30 December 2025; Published: 20 January 2026.
Edited by:
Fei Fan, China Academy of Chinese Medical Sciences, ChinaReviewed by:
Dmytro Dmytriiev, National Pirogov Memorial Medical University, UkraineCopyright © 2026 Li, Tian, Tian, Tan and Bu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Shaojin Bu, YnV6aGFuZzY2NkAxMjYuY29t
†These authors have contributed equally to this work and share first authorship