Traumatic brain injury (TBI) is a public health concern with high morbidity and mortality rates. The estimated incidence of TBI is 69 million per year globally (1). Although many advances have been achieved to improve the prognosis of TBI, including temperature management, hypertonic saline, and multimodal monitoring (2, 3), research studies exploring the effectiveness of pharmacological interventions aimed at TBI, including nutritional supplementation, have never been interrupted (4, 5). Poor nutritional status is commonly observed in TBI patients and is associated with worse prognosis in these patients (6–8). The poor nutritional status of TBI patients may be attributable to multiple factors, including increased metabolic demand due to systemic inflammation, massive bleeding, and reduced absorption due to dysphagia and gastrointestinal dysfunction. Nutritional supplements including vitamins and trace elements are very important in improving the prognosis of critically ill patients, including those with TBI (9–11). Previous studies have investigated the influence of several nutrient supplements on the outcome of TBI animal models, including omega-3, zinc, vitamin D, vitamin E, and glutamine (12–16).

As an important member of B vitamins, thiamine participates in the formation of coenzymes for many important enzymes responsible for the carbohydrate metabolism, including pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase. The pyruvate dehydrogenase and α-ketoglutarate dehydrogenase catalyze the ATP production in the mitochondrion, while the transketolase promotes the pentose-phosphate cycle to produce ribose-5-phosphate and nicotinamide adenine dinucleotide phosphate, which play an important role in the biosynthesis of nucleotides, fatty acids, cholesterol, and steroid hormones (17, 18). Thiamine deficiency can disturb the carbohydrate metabolism with decreased energy production and the accumulation of lactate. Some studies have explored the effect of thiamine supplementation on the prognosis of several kinds of patients (19–22). While no clinical study has yet explored the effect of thiamine supplementation on the prognosis of TBI patients, we designed this study to verify the effect of thiamine supplementation on mortality in TBI patients and identify those who could benefit from the supplementation.

This study indicated that thiamine use might lead to an improved prognosis for most TBI patients, including lower 30-day mortality and shorter length of hospital stay. As a water-soluble vitamin essential for cellular metabolism, thiamine exists in several forms in the human body, including thiamine, thiamine monophosphate, and thiamine pyrophosphate (TPP) (25). TPP is closely associated with glycolysis promoting the transformation of glucose to pyruvate and the Krebs cycle, which is essential for ATP production. Therefore, thiamine deficiency could disturb the carbohydrate metabolism with decreased energy production and the accumulation of lactate.

Previous studies have indicated that thiamine deficiency is prevalent among critically ill patients, with an incidence rate of 20% in those admitted to the ICU and 21% in those admitted to the emergency department (26–28). Thiamine deficiency during hospitalizations may be attributable to factors such as increased consumption and inadequate intake of food. Systemic inflammatory response syndrome and oxidative stress commonly occur in conditions like severe sepsis, burns, and trauma, potentially due to the depletion of thiamine storage in the body (29–31). Impaired reabsorption and increased excretion from the kidney due to diuretic use is another important cause of thiamine deficiency (32, 33). Additionally, thiamine deficiency is often observed in alcoholic patients due to malnutrition, inadequate liver storage, and impaired gastrointestinal absorption (34–36). Finally, inadequate intake caused by chronic malnutrition, starvation, parenteral feeding, and chemotherapy could also promote the development of thiamine deficiency (37).

In TBI patients, thiamine deficiency may be caused by diverse factors, including a history of alcoholism, increased consumption due to inflammation and oxidative stress after injury, massive usage of furosemide, and inappropriate parenteral or enteral feeding. Thiamine deficiency could promote the development of lactic acidosis, which has been confirmed to be independently associated with a worse prognosis in TBI patients (38, 39). Furthermore, it can lead to decreased synthesis of TPP, which subsequently impairs the anabolic activity in the brain, including the carbohydrate metabolism, lipid metabolism, and amino acid metabolism. These metabolic activities are essential for the production of ATP, myelin, and neurotransmitters (34). One study involving general ICU patients found that supplementation of antioxidant micronutrients containing zinc, selenium, thiamine, and vitamin C did not reduce the risk of organ failure; however, it alleviated the inflammatory response in patients undergoing cardiac surgery or experiencing trauma (40). Another animal study found that α-ketoglutarate dehydrogenase was the major damaged site in the mitochondria after TBI and was associated with neuroinflammation in the rat model (41). However, thiamine could preserve the mitochondrial function after TBI by preventing the inactivation of α-ketoglutarate dehydrogenase. Therefore, adequate supplementation of thiamine to TBI patients may be essential to alleviate secondary brain injury and improve their prognosis.

Previous database studies have found that thiamine supplementation was associated with reduced mortality rates in various patient groups, including those diagnosed with acute kidney injury, sepsis, or ventilator-associated pneumonia (19–22). Another retrospective matched cohort study confirmed that thiamine supplementation within 24 h of admission was associated with improved lactate clearance and a reduction in 28-day mortality in septic shock patients (42). Because of its water-soluble nature, thiamine can be rapidly recovered in the body through intravenous or oral supplementation. The Recommended Daily Allowance (RDA) suggests the thiamine dose for adults as 1.1–1.2 mg/day, whereas the European Community directive for enteral nutrition recommends a minimum thiamine dose of 1.2 mg/day and a maximum dose of 10 mg/day (43, 44). While these recommendations are tailored for healthy adults, they may not be suitable for critically ill patients with widespread vitamin deficiency and increased vitamin requirements. In our study, the RCS showed an inflection point at the thiamine dose of 200 mg, which indicated that TBI patients receiving accumulative doses of thiamine >200 mg had relatively lower mortality than those without. The statistical significance, generalizability, and reliability of this finding were limited by the sample size and the lack of unadjusted analysis. Additionally, the optimal daily dose of thiamine was not fully explored because it may be influenced by multiple factors such as weight, hepatic and renal function, and baseline nutritional status. The most appropriate dose and the detailed regime of thiamine supplementation for TBI patients deserve further exploration.

This study has several limitations. First, this database study was performed using the dataset from a single medical center. The association between thiamine use and mortality in TBI patients should be further verified in other medical centers through randomized controlled trials. Second, although many clinical factors were matched using the PSM, some potential confounding factors were still not included, which may influence the reliability of the conclusion. Third, the daily dose, initiating time, and duration of thiamine supplementation were not recorded, so we could not explore the optimal regime of thiamine supplementation. Although we have analyzed the relationship between the total dose during hospitalizations and mortality in TBI patients, this relationship may be influenced by many confounding factors such as weight, hepatic and renal function, and baseline nutritional status. Fourth, we only recorded the mortality rate as the primary outcome due to the limited prognostic information in the database. Other outcomes of TBI patients, including functional status and cognitive status, may also be influenced by thiamine use. Finally, the baseline serum level of thiamine was not recorded in the database. Therefore, we could not identify the independent effect of thiamine deficiency or determine which patients would benefit most from thiamine supplementation.

Thiamine supplementation has been shown to improve survival outcomes in TBI patients, with the exception of those with mild TBI. The optimal daily dose and timing of thiamine supplementation for patients with TBI are worthy to be explored in future studies.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by the Review board of West China Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

RW: Conceptualization, Data curation, Formal analysis, Writing – original draft. YZ: Data curation, Formal analysis, Writing – original draft. MH: Supervision, Validation, Writing – review & editing. JX: Funding acquisition, Project administration, Supervision, Validation, Writing – review & editing.