Thiamin (B1) and Its Application in Patients with Critical Condition

4.1 Recommended daily intake of thiamin

Recommended daily thiamin intake in healthy adult men is 1.2 mg/day, while adult women are 1.1 mg/day. For children aged 1–8 years, recommended intake of vitamin B1 ranges from 0.5 to 0.6 mg/day and for ages 9–13 years, it starts from 0.9 mg/day (Table 1) [5]. Thiamin is water-soluble across the placenta. Its requirements increase during pregnancy. Pregnancy also increases the risk of thiamin deficiency when prolonged nausea and vomiting (including hyperemesis gravidarum). The dose of parenteral nutritional supplements is 6 mg/day. The parenteral form can be given by intramuscular (IM) or intravenous (IV) injection. Administration of thiamin intravenously can be given as much as 100 mg over 5 minutes [11].

4.2 Side effects of thiamin

Adverse reactions to thiamin administration have been reported as reactions at the injection site, but their frequency is unknown. Other side effects can be diaphoresis, pruritus, skin sclerosis (at the injection site after IM administration), urticaria, nausea, bleeding (in the digestive tract). For hypersensitivity side effects, reported anaphylaxis (after IV administration), angioedema, hypersensitivity reactions (following IV administration). Side effects of intravenous thiamin are rarely reported. A prospective study by Wrenn in 989 samples given thiamin 100 mg IV found adverse reactions in the form of minor reactions, which were transient local irritation in 1.1% and pruritus in 0.0093% of patients. Thiamin hydrochloride can be given intravenously without problems. An intradermal test dose before administration is not required unless the patient had a previous allergic reaction [12]. Local side effects for larger doses can be minimised by slow administration into a larger and more proximal vein. Thiamin should be administered before parenteral glucose solutions to prevent Thiamin deposition as a symptom of acute thiamin deficiency in malnourished patients [11].

Alcohol consumption can interfere with intestinal absorption of vitamin B1, and chronic alcoholism leads to Wernicke-Korsakoff syndrome (WKS) [2]. Intoxication may occur with ingestion of more than 3000 mg thiamin in the long term. Based on animal research, thiamin lethal dose/LD50 are 8224 mg/kg, while the LD50 in rats are 3710 mg/kg [13]. Sporadic anaphylactic reactions have been reported. Some researchers suggest that intravenous thiamin should be administered in a resuscitation facility. However, due to the life-threatening nature of WKS, EFNS (European Federation of Neurological Society) guidelines recommend starting treatment immediately, even in the absence of facilities for resuscitation [14].

4.3 Thiamin and brain metabolism

Thiamin has an essential role in brain metabolism. Nerve cells use glucose as the primary fuel in producing energy. Glucose reaches brain tissue by diffusion across the blood–brain barrier. Around 30% of glucose absorbed by the brain undergoes complete oxidation through the Krebs cycle [15]. Various mechanisms contribute to selective brain lesions observed in WKS and thiamin deficiency. Recent evidence of early microglial activation and increased production of free radicals suggests that oxidative stress processes play a vital role in brain cell death associated with thiamin deficiency. Recent studies in animal models of WKS demonstrated changes in thiamin-dependent enzymes in the brain and suggested that changes in these enzyme activities may result in neuronal death, characteristic of this syndrome [16].

Thiamin is needed as an enzyme cofactor essential for brain metabolism, and around 80% of total thiamin is in the neural tissues [10, 17]. In addition to its co-enzymatic function in metabolism, thiamin also has a structural role [18, 19]. Thiamin affects membrane structure and function, including axoplasmic, mitochondrial, and synaptosomal membranes, which act against agent-induced cytotoxicity and improve membrane location [20, 21]. Thiamin also intervenes in synaptic transmission and plays a role in cell differentiation, synapse formation, axonal growth, and myogenogenesis [2].

4.4 Thiamin as a novel treatment for sepsis

Thiamin deficiency is common in critically ill patients and correlated with increased mortality in some cases. In addition, its levels are depleted throughout the illness, and administration of thiamin during critical illness can improve organ dysfunction [22]. Predisposing factors to thiamin deficiency result from several associated problems associated with nutritional disorders and other accompanying diseases. Several conditions can reduce thiamin levels, such as impaired carbohydrate metabolism, increased metabolic requirements for parenteral or enteral nutrition, diuretics, and haemodiafiltration. Several studies have found the presence of thiamin deficiency in critically ill patients. Thiamin deficiency is associated with poor prognostic outcomes [23].

A cohort study in Australia with 129 patients found no association between plasma thiamin concentrations with systemic inflammation and mortality in critically ill patients. In addition, it also shows that level of thiamin intake in patients who had not received its supplementation before ICU admission did not differ between patients who died and those who survived, 264 compared 268 nanomol/L (normal value: 190–400 nanomol/L). Besides that, only a weak correlation was found between thiamin levels and disease severity index. A study had investigated the correlation of thiamin, APACHE II, SOFA score, maximum SOFA score, SOFA delta (DSOFA), and CRP. However, the correlation is not statistically significant [24].

Thiamin deficiency can also be observed in septic shock patients, occurring in 8.5–72% depending on the cutoff value used to determine thiamin deficiency [4, 22, 25, 26]. Lack of thiamin reduces pyruvate access to the Krebs cycle, increasing lactate production as it converts metabolism to anaerobic [23].

A prospective observational study examined the association between thiamin levels and lactic acidosis in 30 septic shock patients and found no correlation between these variables. However, after excluding patients with abnormal liver function, a significant negative correlation was found between thiamin concentrations and lactic acidosis (r = −0.53, P = 0.01). This finding implies a potential relationship between thiamin levels and lactic acidosis in septic shock patients with normal liver function. Thus, by reducing pyruvate dehydrogenase complex activity, thiamin deficiency contributes to an increase in lactic acid in septic patients [26].

Parenteral administration of thiamin 250 mg once daily for 3–5 consecutive days is recommended to treat thiamin deficiency. Slow intravenous administration of thiamin diluted in isotonic NaCl or 5% dextrose is also safe. However, there is no consensus on the optimal daily dose of thiamin, its formulation, and duration of treatment [14]. The half-life of unphosphorylated thiamin blood is 96 hours. Therefore, two or three daily doses can achieve better concentrations in the brain than a single daily dose. In patients who do not consume alcohol, a daily intravenous dose of 100 or 200 mg is sufficient to meet thiamin requirements. However, alcoholic patients with WKS may require doses as high as 500 mg three times daily [14].

A clinical trial of ascorbic acid and Thiamin effect in septic shock (ATESS) conducted in South Korea compare outcomes of a combination of ascorbic acid (IV 50 mg/kg, maximum dose per dose of 3 g) and thiamin (200 mg) every 12 hours for two days with placebo groups on 111 subjects. The results showed no significant differences in SOFA scores and organ function but found an increase in serum levels of vitamin C and thiamin [27].

This finding is in contrast to another clinical study in 94 patients who received a combination of 1500 mg of vitamin C IV q6, 200 mg of thiamin IV q12 for four days or until discharge from ICU, and 50 mg of hydrocortisone IV q6 (with the optional alternative of 50 mg bolus, followed by continuous infusion of 200 mg in 24 hours) for four days. Thiamine administration had significantly reduced the progression of organ dysfunction and mortality in patients with severe sepsis and septic shock. However, the research design had weaknesses include small study size, pre-and post-study design, single-centre, absence of blinding, and presence of three simultaneous interventions limiting the generalizability of the conclusion. Although it can help invent new hypotheses in future, this study is still not strong enough to produce a change in clinical practice [22].