Letter to the Editor

Volume 17, Number 12, December 2025, pages 740-742

Postoperative Delirium and Vitamin C: Rethinking Unfavorable Outcomes Through the Lens of Underdosing

We read with great interest in the pilot study examining the effects of perioperative ascorbic acid (2 g/day for 2 days) in preventing postoperative delirium (POD) among older cardiovascular surgery patients [1]. In that study, a 33% incidence of POD was observed, aligning with previous observational findings [2]. The authors concluded that ascorbic acid administration may not be effective in reducing the incidence of POD [1].

The pathophysiological mechanisms underlying POD are multifactorial and complex. Neuroinflammation has emerged as one of the most widely recognized contributors [3]. Surgical trauma initiates an inflammatory cascade characterized by significant elevations in circulating pro-inflammatory cytokines. Moreover, both surgery and anesthetic agents - whether volatile anesthetics or propofol - can disrupt the blood-brain barrier [4]. Disruption of the blood-brain barrier facilitates the entry of peripheral inflammatory mediators into the central nervous system, thereby amplifying neuroinflammation within the brain parenchyma. Age-related disruption of the blood-brain barrier increases susceptibility to delirium in elderly individuals, especially in the presence of systemic inflammation [5]. Consequently, older patients are particularly vulnerable to developing POD, notably following cardiac surgery.

Vitamin C (ascorbic acid) is well known for its antioxidant and anti-inflammatory properties, as well as for its potential to stabilize the blood-brain barrier [6]. Importantly, the potential therapeutic activity of vitamin C is dose- and time-dependent [7]. In animal studies, high-dose vitamin C (400 - 2,000 mg/kg/day) significantly improved cognitive or neurological outcomes through attenuation of neuroinflammation and preservation of the blood-brain barrier [8-10]. Based on the Nair-Jacob dose conversion principles, which account for interspecies differences in metabolic rate [11], the translated equivalents range from 4 to 20 g/day for a 60-kg adult - far exceeding the dose used in the pilot study, which employed the maximum permitted dose of ascorbic acid in Japan (2 g/day) [1]. Direct extrapolation to human dosing should be approached with caution due to species-specific differences in absorption and plasma saturation kinetics. Due to active transport via sodium-dependent vitamin C transporters, vitamin C concentrations in cerebrospinal fluid and neurons substantially exceed plasma levels, thereby enhancing neuroprotection against oxidative stress [12-14]. According to the study by Padayatty et al, the predicted peak plasma vitamin C concentrations after intravenous administration at a rate of 1 g/min were approximately 1,000 µmol/L for 1.25 g, 2,870 µmol/L for 5 g, 5,580 µmol/L for 10 g, and 13,350 µmol/L for 50 g. The pharmacokinetics of intravenous vitamin C are non-linear with a short plasma half-life (about 2 h) although 100% bioavailability of intravenous vitamin C is assumed [14]. Therapeutic targets in humans should be based on achievable concentrations in plasma and neurons. Furthermore, vitamin C concentrations decreased markedly in patients after cardiac surgery [15]. Maintaining therapeutic plasma concentrations may thus require repeated or continuous high-dose infusions, which are crucial in the context of neuroprotection [16]. Indeed, intravenous vitamin C at 3,000 mg/day is recommended for at least the first 3 days following severe stress from trauma or infection due to increased turnover and catabolism of ascorbic acid [17]. Based on the above, subtherapeutic dosing may partly explain the neutral findings of Iizuka et al [1]. Although their regimen (2 g/day) complied with the national dose ceiling [1], it likely failed to achieve truly neuroprotective thresholds. In addition, the limitations of the study design - specifically the small sample size and the absence of a control group - substantially restrict the ability to draw firm conclusions regarding the effectiveness of vitamin C. A more comprehensive and rigorous study design is required to better clarify its true therapeutic efficacy.

Based on animal studies [8-10] and clinical research [17], higher cumulative intravenous doses (3 - 20 g/day) may be associated with a reduced POD incidence among older surgical patients, although these findings remain hypothesis-generating and require validation in controlled trials. Therefore, we propose that unfavorable outcomes imply underdosing as a confounder and suboptimal pharmacokinetic coverage, not the inherent inefficacy of the compound. Future clinical studies should integrate validated dose-response data, appropriate pharmacokinetic modeling, and timing optimization to reassess vitamin C as a perioperative neuroprotectant.

Acknowledgments

None to declare.

Financial Disclosure

This research was funded by Chi Mei Medical Center, Tainan, Taiwan (grant number CMHCR112043).

Conflict of Interest

All authors declare that there was no conflict of interest.

Informed Consent

Not applicable.

Author Contributions

CYK, SWL, ICT and JYC drafted the manuscript. JYC contributed to study planning and supervised the work. All authors discussed the results and provided critical comments on the manuscript.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

1. Iizuka Y, Fukano K, Oki S, Sawada I, Miyazawa K, Ono S, Yoshinaga K, et al. Effect of ascorbic acid on the incidence of postoperative delirium among elderly patients undergoing cardiovascular surgery: A Pilot Study. J Clin Med Res. 2025;17(3):145-152.
   doi pubmed
2. Iizuka Y, Yoshinaga K, Takahashi K, Oki S, Chiba Y, Sanui M, Kimura N, et al. Association between plasma ascorbic acid levels and postoperative delirium in older patients undergoing cardiovascular surgery: a prospective observational study. J Cardiovasc Dev Dis. 2023;10(7).
   doi pubmed
3. Alam A, Hana Z, Jin Z, Suen KC, Ma D. Surgery, neuroinflammation and cognitive impairment. EBioMedicine. 2018;37:547-556.
   doi pubmed
4. Hu X, Liu L, Da X, Zhu S, Wang J, Shan M, Liu Y, et al. Anesthesia/surgery leads to blood-brain barrier disruption via the transcellular and paracellular pathways, and postoperative delirium-like behavior: A comparative study in mice of different ages. Exp Neurol. 2025;383:115044.
   doi pubmed
5. Zeevi N, Pachter J, McCullough LD, Wolfson L, Kuchel GA. The blood-brain barrier: geriatric relevance of a critical brain-body interface. J Am Geriatr Soc. 2010;58(9):1749-1757.
   doi pubmed
6. Feng J, Zheng Y, Guo M, Ares I, Martinez M, Lopez-Torres B, Martinez-Larranaga MR, et al. Oxidative stress, the blood-brain barrier and neurodegenerative diseases: The critical beneficial role of dietary antioxidants. Acta Pharm Sin B. 2023;13(10):3988-4024.
   doi pubmed
7. Muhlhofer A, Mrosek S, Schlegel B, Trommer W, Rozario F, Bohles H, Schremmer D, et al. High-dose intravenous vitamin C is not associated with an increase of pro-oxidative biomarkers. Eur J Clin Nutr. 2004;58(8):1151-1158.
   doi pubmed
8. Zhang N, Zhao W, Hu ZJ, Ge SM, Huo Y, Liu LX, Gao BL. Protective effects and mechanisms of high-dose vitamin C on sepsis-associated cognitive impairment in rats. Sci Rep. 2021;11(1):14511.
   doi pubmed
9. Chang CY, Chen JY, Chen SH, Cheng TJ, Lin MT, Hu ML. Therapeutic treatment with ascorbate rescues mice from heat stroke-induced death by attenuating systemic inflammatory response and hypothalamic neuronal damage. Free Radic Biol Med. 2016;93:84-93.
   doi pubmed
10. Chang CY, Chen JY, Wu MH, Hu ML. Therapeutic treatment with vitamin C reduces focal cerebral ischemia-induced brain infarction in rats by attenuating disruptions of blood brain barrier and cerebral neuronal apoptosis. Free Radic Biol Med. 2020;155:29-36.
    doi pubmed
11. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7(2):27-31.
    doi pubmed
12. Nielsen TK, Hojgaard M, Andersen JT, Poulsen HE, Lykkesfeldt J, Mikines KJ. Elimination of ascorbic acid after high-dose infusion in prostate cancer patients: a pharmacokinetic evaluation. Basic Clin Pharmacol Toxicol. 2015;116(4):343-348.
    doi pubmed
13. Xu Y, Zheng H, Slabu I, Liehn EA, Rusu M. Vitamin C in cardiovascular disease: from molecular mechanisms to clinical evidence and therapeutic applications. Antioxidants (Basel). 2025;14(5).
    doi pubmed
14. Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, Wesley RA, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140(7):533-537.
    doi pubmed
15. Lassnigg A, Punz A, Barker R, Keznickl P, Manhart N, Roth E, Hiesmayr M. Influence of intravenous vitamin E supplementation in cardiac surgery on oxidative stress: a double-blinded, randomized, controlled study. Br J Anaesth. 2003;90(2):148-154.
    doi pubmed
16. Hill A, Wendt S, Benstoem C, Neubauer C, Meybohm P, Langlois P, Adhikari NK, et al. Vitamin C to improve organ dysfunction in cardiac surgery patients-review and pragmatic approach. Nutrients. 2018;10(8).
    doi pubmed
17. Spoelstra-de Man AME, Elbers PWG, Oudemans-van Straaten HM. Making sense of early high-dose intravenous vitamin C in ischemia/reperfusion injury. Crit Care. 2018;22(1):70.
    doi pubmed

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Journal of Clinical Medicine Research is published by Elmer Press Inc.