{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T07:04:11Z","timestamp":1784531051977,"version":"3.55.0"},"reference-count":115,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>High-dose intravenous vitamin C (HDIVC) has been investigated as a potential adjunctive therapy in critical illness, including sepsis, acute respiratory distress syndrome (ARDS), and COVID-19. Despite a strong mechanistic rationale, clinical trials have yielded inconsistent results. From a clinical pharmacology perspective, this variability may reflect, at least in part, differences in pharmacokinetic exposure, timing of administration, and patient selection rather than a lack of biological activity. Intravenous administration enables plasma concentrations in the millimolar range (\u22481\u20135 mM), far exceeding those achievable with oral dosing (&lt;100 \u00b5M), thereby reaching thresholds required for pharmacodynamic effects on oxidative stress, immune signaling, and endothelial function. This exposure-dependent transition distinguishes vitamin C as a pharmacological agent rather than a nutritional supplement in critically ill populations. Therapeutic response may be influenced by timing relative to disease progression, with earlier administration representing a biologically plausible strategy that warrants prospective evaluation rather than a clinically established therapeutic window. Interindividual variability in transporter function, redox status, and genetic background may further contribute to heterogeneous responses. Biomarkers such as interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, and markers of endothelial injury provide a framework for patient stratification and monitoring of pharmacodynamic effects. Integrated with pharmacokinetic principles, these markers support a shift toward biomarker-guided, precision-based therapeutic strategies. This review synthesizes current clinical and mechanistic evidence through an exposure\u2013response conceptual framework, framing HDIVC as a context-dependent pharmacological intervention and advancing a shift toward biomarker-guided, precision-based therapeutic strategies in critical illness.<\/jats:p>","DOI":"10.3390\/medsci14030400","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T06:09:09Z","timestamp":1784527749000},"page":"400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High-Dose Intravenous Vitamin C in Critical Illness: A Translational Exposure\u2013Response Framework for Biomarker-Guided Precision Therapy"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7958-068X","authenticated-orcid":false,"given":"Dejana","family":"Baji\u0107","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ljiljana","family":"Andrijevi\u0107","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nemanja","family":"Todorovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8354-3868","authenticated-orcid":false,"given":"Mladena","family":"Lali\u0107-Popovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"},{"name":"Centre for Medical and Pharmaceutical Investigations and Quality Control (CEMPhIC), Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bojan","family":"Zari\u0107","sequence":"additional","affiliation":[{"name":"Institute for Pulmonary Diseases of Vojvodina, 21204 Sremska Kamenica, Serbia"},{"name":"Department of Internal Medicine, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1265-228X","authenticated-orcid":false,"given":"Stefan","family":"Dimi\u0107","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Stoj\u010devi\u0107 Maleti\u0107","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"},{"name":"Department of Infectious Diseases, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4323-1776","authenticated-orcid":false,"given":"Dajana","family":"Lendak","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"},{"name":"Clinic for Infectious Diseases, University Clinical Center of Vojvodina, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4555-8801","authenticated-orcid":false,"given":"Boris","family":"Milija\u0161evi\u0107","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5286-3858","authenticated-orcid":false,"given":"Nata\u0161a","family":"Milo\u0161evi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Beltr\u00e1n-Garc\u00eda, J., Osca-Verdegal, R., Pallard\u00f3, F.V., Ferreres, J., Rodr\u00edguez, M., Mulet, S., Sanchis-Gomar, F., Carbonell, N., and Garc\u00eda-Gim\u00e9nez, J. 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