Abstract
Background
In our previously published article, we investigated the preventive efficacy of sodium oxybate against post-operative delirium (POD) in elderly patients undergoing orthopedic surgery and found that intraoperative sodium oxybate demonstrates possible time-specific efficacy, significantly reducing POD incidence exclusively in older patients undergoing morning orthopedic surgery.
Main body
In a Matters Arising correspondence, the authors raised several questions and suggestions regarding the methodology and interpretation of our findings. These concerns encompassed the control of perioperative factors, the definition and assessment of POD, as well as considerations related to post-operative pain management which may influence the effect of sodium oxybate on delirium prevention. We have provided point-by-point responses to each of these concerns and discussed directions for future research that may help address the limitations identified.
Conclusions
In the Matters Arising, the authors put forward a number of constructive comments, to which we have responded accordingly. These insights provide valuable guidance for the design and conduct of future research in this area.
Keywords: Major orthopedic surgery, Older patients, Post-operative delirium, Sodium oxybate
Main text
Background
In our previously published article [1], we investigated the preventive efficacy of sodium oxybate against post-operative delirium (POD) in elderly patients undergoing orthopedic surgery, and found that intraoperative sodium oxybate demonstrates possible time-specific efficacy, significantly reducing POD incidence exclusively in older patients undergoing morning orthopedic surgery.
In a Matters Arising correspondence, the authors raised several questions and suggestions regarding the methodology and interpretation of our findings. We have carefully reviewed the Matters Arising correspondence and sincerely appreciate the authors’ insightful questions and constructive suggestions. We will address the concerns raised herein.
Control of perioperative risk factors
Regarding the lack of adjustment for preoperative risk factors, we contend that the rigorous randomization employed in our study reduces the potential for significant bias in the interpretation of results attributable to preoperative variables. Nevertheless, we acknowledge that adjustment for postoperative risk factors, such as pain and sleep disturbances, may yield a more precise interpretation of our findings. Preoperative pain, functional status, and sleep disturbances are indeed well-established risk factors for POD, and we will consider incorporating these variables in future studies to optimize our study design.
Outcome measures
With respect to outcome measures, while the primary objective of the present study was to investigate the effect of sodium oxybate on POD, the authors’ suggestions remain highly valuable. In future multicenter trials, we concur that a more comprehensive assessment framework should be adopted, encompassing post-operative recovery and complications.
The primary outcome of our study was defined as POD with onset from post-operative day 1. This decision was based on the consideration that delirium occurring in the post-anesthesia care unit (PACU) may be confounded by the residual effects of anesthetic agents. Consequently, we distinguished between POD and PACU delirium (PACU-D) as separate entities in our analysis. This approach is consistent with the well-established Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) study [2, 3], which similarly defined POD as CAM-positive events occurring from post-operative day 1 onward, while delirium occurring in the PACU on the day of surgery was designated as an exploratory secondary outcome. The present study specifically addresses POD symptoms manifesting from post-operative day 1, while findings regarding PACU-D will be presented in a separate report that has not yet been published. Furthermore, regarding the assessment of POD, our study employed twice-daily Confusion Assessment Method (CAM) evaluations in conjunction with medical chart review. It is important to note that our CAM assessments commenced on the day of surgery, not from post-operative day 1; however, the primary outcome was defined as CAM-positive events occurring during post-operative days 1–7. Therefore, we do not believe that an underestimation of POD incidence occurred in our study. In future research, we plan to report POD and PACU-D findings within the same manuscript to minimize potential study design bias.
Subgroup analysis and multiple-adjustment of confounding factors
Additionally, the analysis of the primary subgroups (morning and afternoon cohorts) was likely less affected by confounding factors, as we implemented rigorous stratified randomization to ensure strict randomization within each primary subgroup, with well-balanced baseline characteristics. The baseline data for these subgroups are presented in Table 1. With respect to the secondary subgroup analysis (POD versus non-POD groups), given its exploratory nature and the constraints imposed by small sample size, adjustment for confounding factors was not performed. Table 2 presents the distribution of baseline characteristics in the POD population. We acknowledge this limitation, which will be addressed in future large-scale multicenter studies.
Table 1.
Baseline demographic, clinical, and psychometric characteristics—morning and afternoon subgroup
|
SO (N = 82) |
Con (N = 81) |
P value | |
|---|---|---|---|
| Morning subgroup | |||
| Age, median (IQR), year | 69 (65–71) | 70 (66–73) | 0.061 |
| BMI, median (IQR) | 24.8 (22.2–26.3) | 24.4 (22.2–26.9) | 0.670 |
| Gender, male, No. (%) | 33 (40.2%) | 38 (46.9%) | 0.391 |
| MMSE, median (IQR) | 26 (24–28) | 26 (25–28) | 0.652 |
| HADS-A, median (IQR) | 4 (2–6) | 4 (2–7) | 0.784 |
| HADS-D, median (IQR) | 3 (1–7) | 3 (1–6) | 0.504 |
| AIS, median (IQR) | 4 (0–8) | 5 (1–9) | 0.293 |
| Surgery type | 0.944 | ||
| Spine surgery, No. (%) | 0.838 | ||
| Open spine surgery | 37 (45.1%) | 35 (43.2%) | |
| Minimally invasive endoscopic surgery | 17 (20.7%) | 19 (23.5%) | |
| Joint replacement, No. (%) | 0.755 | ||
| Hip replacement | 10 (12.2%) | 8 (9.9%) | |
| Knee replacement | 11 (13.4%) | 13 (16.0%) | |
| Others, No. (%) | 7 (8.5%) | 6 (7.4%) | 1.000 |
| Co-morbidities | |||
| CVS disease, No. (%) | 43 (52.4%) | 37 (45.7%) | 0.388 |
| Respiratory system disease, No. (%) | 3 (3.7%) | 1 (1.2%) | 0.620 |
| CNS disease, No. (%) | 5 (6.1%) | 5 (6.2%) | 1.000 |
| Diabetes, No. (%) | 9 (11.0%) | 13 (16.0%) | 0.343 |
| Surgery duration, median (IQR), minute | 109 (90–133) | 125 (101–144) | 0.146 |
| PCIA use, No. (%) | 54 (65.9%) | 52 (64.2%) | 0.825 |
| Afternoon subgroup | |||
| Age, median (IQR), year | 67 (65–70) | 67 (65–70) | 0.869 |
| BMI, median (IQR) | 24.7 (22.9–27.0) | 24.7 (22.4–27.2) | 0.572 |
| Gender, male, No. (%) | 34 (41.0%) | 31 (37.8%) | 0.678 |
| MMSE, median (IQR) | 25 (24–27) | 26 (25–28) | 0.066 |
| HADS-A, median (IQR) | 5 (0–7) | 5 (2–8) | 0.362 |
| HADS-D, median (IQR) | 4 (1–7) | 3 (0–6) | 0.258 |
| AIS, median (IQR) | 4 (1–8) | 3 (1–8) | 0.883 |
| Surgery type | 0.701 | ||
| Spine surgery, No. (%) | 0.409 | ||
| Open spine surgery | 33 (39.8%) | 38 (46.3%) | |
| Minimally invasive endoscopic surgery | 20 (24.1%) | 15 (18.3%) | |
| Joint replacement, No. (%) | 0.767 | ||
| Hip replacement | 13 (15.7%) | 10 (12.2%) | |
| Knee replacement | 12 (14.5%) | 11 (13.4%) | |
| Others, No. (%) | 5 (6.0%) | 8 (9.8%) | 0.374 |
| Co-morbidities | |||
| CVS disease, No. (%) | 44 (53.0%) | 43 (52.4%) | 0.941 |
| Respiratory system disease, No. (%) | 4 (4.8%) | 4 (4.9%) | 1.000 |
| CNS disease, No. (%) | 6 (7.2%) | 9 (11.0%) | 0.403 |
| Diabetes, No. (%) | 12 (14.5%) | 12 (14.6%) | 0.974 |
| Surgery duration, median (IQR), minute | 111 (90–145) | 101 (86–132) | 0.554 |
| PCIA use, No. (%) | 50 (60.2%) | 48 (58.5%) | 0.824 |
BMI body mass index, MMSE Mini-Mental State Examination, HADS-A Hospital Anxiety and Depression Scale—Anxiety subscale, HADS-D Hospital Anxiety and Depression Scale—Depression subscale, AIS Athens Insomnia Scale, NRS numerical rating scale, CVD cardiovascular disease, CNS central nervous system
*P < 0.05
Table 2.
Baseline demographic, clinical, and psychometric characteristics—POD subgroup
|
SO (N = 17) |
Con (N = 22) |
P value | |
|---|---|---|---|
| Age, median (IQR), year | 68 (66–71) | 71 (67–75) | 0.200 |
| BMI, median (IQR) | 23.9 (22.5–25.9) | 24.3 (20.0–28.6) | 0.812 |
| Gender, male, No. (%) | 7 (41.2%) | 10 (45.5%) | 0.789 |
| MMSE, median (IQR) | 24 (23–26) | 26 (23–27) | 0.146 |
| HADS-A, median (IQR) | 6 (2–12) | 5 (4–8) | 0.726 |
| HADS-D, median (IQR) | 6 (2–10) | 5 (3–7) | 0.305 |
| AIS, median (IQR) | 5 (1–8) | 9 (4–16) | 0.052 |
| Surgery type | 0.264 | ||
| Spine surgery, No. (%) | 0.080 | ||
| Open spine surgery | 7 (41.2%) | 4 (18.2%) | |
| Minimally invasive endoscopic surgery | 2 (11.8%) | 8 (36.4%) | |
| Joint replacement, No. (%) | 0.608 | ||
| Hip replacement | 2 (11.8%) | 5 (22.7%) | |
| Knee replacement | 2 (11.8%) | 2 (9.1%) | |
| Others, No. (%) | 4 (23.5%) | 3 (13.6%) | 0.677 |
| Co-morbidities | |||
| CVS disease, No. (%) | 3 (17.6%) | 9 (40.9%) | 0.119 |
| Respiratory system disease, No. (%) | 4 (23.5%) | 0 (0.0%) | 0.029* |
| CNS disease, No. (%) | 2 (11.8%) | 3 (13.6%) | 1.000 |
| Diabetes, No. (%) | 6 (35.3%) | 4 (18.2%) | 0.282 |
| Surgery duration, median (IQR), minute | 99 (86–120) | 119 (102–148) | 0.236 |
| PCIA use, No. (%) | 12 (70.6%) | 15 (68.2%) | 0.872 |
BMI body mass index, MMSE Mini-Mental State Examination, HADS-A Hospital Anxiety and Depression Scale—Anxiety subscale, HADS-D Hospital Anxiety and Depression Scale—Depression subscale, AIS Athens Insomnia Scale, NRS numerical rating scale, CVD cardiovascular disease, CNS central nervous system
*P < 0.05
Concerns about pain management strategies
Post-operative analgesia was managed using patient-controlled intravenous analgesia (PCIA), administered using sufentanil 2 μg kg−1 in 100 mL of 0.9% saline (background infusion 2 mL h−1, bolus 0.5 mL, lockout time 15 min). Loxoprofen sodium (60 mg) was used as rescue analgesia for pain scores ≥ 4. The PCIA utilization rate in our study was approximately 60%, as PCIA was recommended by physicians but ultimately determined by patient choice, rather than being mandatorily applied to all patients, thus not achieving a 100% PCIA rate. This analgesic approach provided adequate pain control, consistent with established PCIA strategies in major orthopedic surgery patients [4–9], which employ sufentanil 1–2 μg kg−1 with or without adjuvant medications. Regarding the implementation of standardized post-operative pain management and a rehabilitation strategy, the authors have provided constructive recommendations. We intend to incorporate and implement these measures in future large-scale multicenter studies to enhance the generalizability of our findings.
Conclusions
We sincerely appreciate the authors’ valuable and pertinent suggestions. In future studies, we will address the limitations of the present investigation by comprehensively accounting for factors influencing POD and incorporating comprehensive post-operative outcome measures. We anticipate that these efforts will provide more robust scientific evidence regarding the application of sodium oxybate in the prevention of POD in elderly surgical patients.
Acknowledgements
None.
Abbreviations
- POD
Postoperative delirium
- SO
Sodium oxybate
- CAM
Confusion Assessment Method
- MMSE
Mini-Mental State Examination
- HADS-A
Hospital Anxiety and Depression Scale-Anxiety
- HADS-D
Hospital Anxiety and Depression Scale-Depression
- AIS
Athens Insomnia Scale
- PCIA
Patient-controlled intravenous analgesia
- NRS
Numerical rating scale
- PACU
Post-anesthesia care unit
- IQR
Interquartile range
- BMI
Body mass index
Authors’ contributions
Manuscript drafting: MC, HX. Critical revision of manuscript: MC, HX, PZ. MC and HX contributed equally to this work as co-first authors. PZ was responsible for the final manuscript approval. All authors reviewed and approved the final manuscript version and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
This work was supported by the Outstanding Scientific Fund of Shengjing Hospital No.202208 to Ping Zhao.
Data availability
Yes. Data types: Deidentified participant data. Additional Information: On request. How to access data: On request: zhaoping_sj@163.com. When available: With publication. Who can access the data: researchers whose proposed use of the data has been approved.
Declarations
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Medical Ethics Committees of Shengjing Hospital (No. 2023PS1183K).
Written informed consent was obtained from all participants before enrollment.
Consent for publication
Not applicable. This study reports aggregate data only. No individual participant data, images, videos, or other materials requiring consent for publication are included.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Meiying Cui and Hang Xue contributed equally to this work.
References
- 1.Cui M, Xue H, Wang F, et al. Prophylactic effect of intraoperative sodium oxybate on postoperative delirium in older patients undergoing major orthopedic surgery: a randomized clinical trial. BMC Med. 2025;24(1):64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Deschamps A, Ben Abdallah A, Jacobsohn E, et al. Electroencephalography-Guided Anesthesia and Delirium in Older Adults After Cardiac Surgery: The ENGAGES-Canada Randomized Clinical Trial. JAMA. 2024;332(2):112–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Wildes TS, Mickle AM, Ben Abdallah A, et al. Effect of Electroencephalography-Guided Anesthetic Administration on Postoperative Delirium Among Older Adults Undergoing Major Surgery: The ENGAGES Randomized Clinical Trial. JAMA. 2019;321(5):473–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Tao M, Zhang S, Han Y, et al. Efficacy of transcranial direct current stimulation on postoperative delirium in elderly patients undergoing lower limb major arthroplasty: A randomized controlled trial. Brain Stimul. 2023;16(1):88–96. [DOI] [PubMed] [Google Scholar]
- 5.Nawan A, Wu Z, Jiang B, Wang G, Zhang W, Feng Y. Effect of combination of multiple anti-inflammatory drugs strategy on postoperative delirium among older patients undergoing hip fracture surgery: a pilot randomized controlled trial. BMC Med. 2025;23(1):108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Song JL, Zhang JT, Wang XJ, et al. Effect of ephedrine versus phenylephrine on postoperative delirium in elderly patients undergoing total hip or knee arthroplasty: a randomized controlled trial. Drug Des Devel Ther. 2025;19:10991–1005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Chen Z, Liu YY, Hu Q, et al. Effect of ciprofol on postoperative delirium in elderly patients undergoing hip surgery: a randomized controlled trial. Drug Des Devel Ther. 2025;19:6207–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Li X, Wu J, Lan H, et al. Effect of Intraoperative Intravenous Lidocaine on Postoperative Delirium in Elderly Patients with Hip Fracture: A Prospective Randomized Controlled Trial. Drug Des Devel Ther. 2023;17:3749–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Duan J, Ju X, Wang X, Liu N, Xu S, Wang S. Effects of remimazolam and propofol on emergence agitation in elderly patients undergoing hip replacement: a clinical, randomized, controlled study. Drug Des Devel Ther. 2023;17:2669–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Yes. Data types: Deidentified participant data. Additional Information: On request. How to access data: On request: zhaoping_sj@163.com. When available: With publication. Who can access the data: researchers whose proposed use of the data has been approved.