The high mortality rate of sepsis and limited therapeutic options continue to drive the ongoing search for effective additions to standard therapy. A recent review article by Paweł Radkowski and colleagues summarizes the current evidence on the role of vitamins (C, B₁, B₉, B₁₂, and D) in supportive sepsis therapy.

Sepsis: Definition and Key Aspects

Sepsis is one of the greatest global challenges in modern intensive care medicine. The World Health Organization (WHO) defines sepsis as a life-threatening multiple organ failure (MOF) resulting from a dysregulated immune response to a suspected underlying infection. In 2017, according to the WHO, about 50 million people developed sepsis and about 11 million died of its consequences — approximately 20% of deaths worldwide.

Despite advances in modern intensive care such as fluid management, catecholamine therapy, antibiotic protocols, and close monitoring, the mortality rate remains high: According to data from the international Surviving Sepsis Campaign, the 28-day mortality rate is about 30% for sepsis and up to 50% for septic shock. Furthermore, high-income countries also report rising sepsis incidence in correlation with an aging population, widespread use of immunosuppressants, and a greater number of invasive procedures.

The clinical picture of sepsis is complex and presents with a broad spectrum of symptoms: fever, hypothermia, hypotension, rapid breathing, oliguria, altered neurologic status, and many others. For early sepsis detection, several scoring systems are available; Sequential Organ Failure Assessment (SOFA) is widely used. Pathophysiologically, sepsis manifests as a severe inflammatory reaction with immune dysregulation, endothelial damage, activation of the coagulation cascade, and progressive organ ischemia.

Role of Vitamins

Because of limited success of standard therapy and the complex metabolic processes involved, sepsis is currently the subject of intensive research. Attention is focused on adjunctive therapies that positively influence immune response, oxidative stress, and metabolic processes. In particular, interest has grown in the use of micronutrients and vitamins with pleiotropic properties.

The starting point was a 2017 study by Paul E. Marik and colleagues, which reported substantial clinical effects from the HAT — hydrocortisone, ascorbic acid, thiamine — protocol in sepsis therapy. Subsequent studies, however, reported neutral or even harmful effects. The current evidence base is very heterogeneous, which complicates the development of clinical concepts and evidence-based use of vitamins in sepsis therapy.

Vitamin C

Vitamin C is the best studied vitamin in the context of sepsis therapy because it

• possesses antioxidant properties,
• supports endogenous catecholamine synthesis, and
• has positive effects on the microcirculation.

Within the HAT protocol, vitamin C was the focus of scientific attention. The C-EASIE study (2025) investigated the effects of regular vitamin C administration on the SOFA score. The main study, however, found no significant effects. A planned substudy of high-risk patients (SOFA score ≥ 6) did show a significant reduction in organ dysfunction and the need for renal replacement therapy.

A retrospective analysis of the MIMIC-IV database by Yang He and Jinglan Liu found that vitamin C supplementation is linked to reduced mortality in patients with sepsis-associated acute kidney injury (SA-AKI). The effect was independent of clinical and demographic factors.

A substudy by J. Rynne and colleagues, conducted within the LOVIT trial (2025), examined the effect of vitamin C on inflammatory markers and 28-day mortality in patients with sepsis. No significant effect of vitamin C could be confirmed, and anti-inflammatory effects appeared to depend on concurrent glucocorticoid administration.

Other studies such as CITRIS-ALI and VICTAS were unable to confirm the positive effects of vitamin C in patients with sepsis, and some analyses warn of a potential increase in organ dysfunction and mortality risk.

Based on current evidence, routine administration of vitamin C to patients with sepsis is not recommended. However, personalized therapy shows potential, particularly in patients with SA-AKI.

B Vitamins

B vitamins — thiamine (B₁), folic acid (B₉), and cobalamin (B₁₂) — serve as cofactors in essential physiologic metabolic pathways. Thiamine supports the citric acid cycle, folic acid is involved in protein and nucleic acid metabolism, and cobalamin is involved in many processes in fatty acid, protein, and amino acid metabolism. Sepsis constitutes a metabolic emergency: Demands for nutrients and vitamins rise, and even subclinical deficiencies are suspected of worsening MOF.

Thiamine

Thiamine is essential for both healthy individuals and patients with sepsis. As a cofactor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, it supports mitochondrial function and adenosine triphosphate production. Thiamine deficiency can be regularly detected in patients with severe sepsis or septic shock. It is suspected that thiamine deficiency in sepsis exacerbates mitochondrial dysfunction, lactic acidosis, and oxidative stress. A review by Nara Aline Costa and colleagues reported that 30%-35% of critically ill patients with sepsis had thiamine deficiency, which was associated with increased mortality.

Jacob Vine and colleagues investigated thiamine monotherapy in patients with sepsis and septic shock in a post hoc analysis: The probability of survival without dependence on renal replacement therapy was significantly increased — particularly in the subgroup of patients who had an initial thiamine deficiency. A study by Suttasinee Petsakul and colleagues as well as a meta-analysis of five randomized controlled trials (RCTs) confirmed improvements in metabolic parameters under thiamine monotherapy but could not demonstrate a significant effect on clinical endpoints.

Further studies examined the HAT combination therapy: A systematic review of 16 RCTs showed a larger effect of the combination therapy vs thiamine monotherapy on SOFA scores and lactate levels. However, no effect on mortality could be demonstrated. The RCTs VITAMINS, ACTS, and VICTAS reported comparable results for combination therapy and standard glucocorticoid therapy.

Based on current evidence, thiamine administration appears well tolerated and without adverse effects. Patients with severe sepsis and those at a risk for thiamine deficiency — for example, patients with gastrointestinal disease, alcoholism, or recent abdominal surgery — should be identified and supplemented.

Folic Acid and Cobalamin

Folic acid and cobalamin are important cofactors for folic acid metabolism. Folic acid is required for DNA methylation and detoxification of homocysteine. In sepsis, these processes are relevant to maintaining endothelial function and reducing oxidative stress.

Studies on these two vitamins have so far yielded inconclusive results. Some studies consider plasma levels to be of limited value: Rapid redistribution and changes in binding and storage proteins during the acute phase could significantly influence measurements.

Yénifer Gamarra-Morales and colleagues demonstrated that elevated folic acid levels correlated significantly with increased 28-day mortality in sepsis. This was less likely due to excessive intake and more likely due to impaired cellular uptake and metabolism. This unmetabolized folic acid appears to promote oxidative stress and endothelial dysfunction. Elevated folic acid levels also correlate with clinical parameters such as fibrinogen level, oxygen requirements, and duration of mechanical ventilation.

Other studies reported that low folic acid levels also have negative clinical effects. For cobalamin, both elevated and reduced levels have been associated with a poorer prognosis.

Both B vitamins should not be substituted indiscriminately but rather tailored to baseline levels and the clinical context, consistent with a personalized therapy approach. The European Society for Clinical Nutrition and Metabolism recommends monitoring B vitamins in the intensive care setting. Oral supplementation should be preferred when possible.

Vitamin D

Vitamin D supports bone mineralization and, via the vitamin D receptor, influences gene expression in immune cells such as monocytes, macrophages, and lymphocytes. Through these mechanisms, it indirectly modulates the production and secretion of inflammatory cytokines and antimicrobial peptides.

A study by Tarek Mohamed Ashoor and colleagues in mechanically ventilated patients with sepsis showed several results:

• High doses of vitamin D achieved significant improvements in clinical parameters, including SOFA score, procalcitonin levels, and length of stay.
• No toxic effects were detected, even when the therapeutic threshold of 30 ng/mL was exceeded.

A retrospective study of the MIMIC-IV database found that patients with sepsis who received vitamin D had significantly shorter hospital stays and lower 28-day mortality. However, the overall evidence is very heterogeneous: Study protocols differ dramatically in some cases, and many participants remained below the therapeutic threshold.

Conclusion

Sepsis is a severe and complex disease and remains one of the greatest challenges in modern intensive care medicine. Because therapeutic options are limited, there is increasing interest in adjunctive therapies to support metabolism and the immune system. To date, the evidence on the mechanisms and potential effects of vitamins on patients with sepsis is inconclusive and warrants cautious conclusions:

• Vitamin C: Large-scale studies have not found positive effects on mortality.
• Vitamin B₁: Deficiencies correlate with more severe courses and should be corrected.
• Vitamin D: It shows potential when therapeutic target levels are achieved and when used in selected patient groups.

Based on current evidence, routine vitamin supplementation in sepsis therapy is not advised. However, supportive therapy shows potential with a targeted, patient-centered approach: Future multicenter studies should develop evidence-based clinical concepts for appropriate patient selection and dosing protocols.

This story was translated from Univadis Germany, part of the Medscape Professional Network.