Adjunctive Thiamine Therapy in Children with Sepsis: A Randomized Clinical Trial Evaluating Organ Dysfunction and Clinical Outcomes

Technical Summary: Adjunctive Thiamine Therapy in Children with Sepsis

Problem Statement
Sepsis remains a leading cause of morbidity, mortality, and intensive care admission in children. Despite advances in antimicrobial therapy, outcomes remain suboptimal due to the condition's nature as a dysregulated host response causing life-threatening organ dysfunction. At the cellular level, sepsis is characterized by metabolic disturbances, including mitochondrial impairment, oxidative stress, and a shift toward anaerobic metabolism (evidenced by elevated lactate). Thiamine (vitamin B1), an essential cofactor for aerobic metabolism and antioxidant defense, is often depleted in critically ill patients due to increased metabolic demand and inadequate intake. While adult studies have explored thiamine supplementation for sepsis, evidence in pediatric populations is limited, and findings in adults have been inconsistent. Direct extrapolation of adult data to children is inappropriate due to physiological and disease progression differences. Consequently, there is a critical need for well-designed randomized clinical trials (RCTs) to evaluate thiamine's role in pediatric sepsis.

Methodology
This study was a phase III, randomized, controlled, open-label clinical trial conducted at a tertiary pediatric center in Iran (Bahonar Children's Educational, Therapeutic and Research Center).

• Participants: 168 children aged 3 months to 18 years with a clinical diagnosis of sepsis (based on SIRS criteria with suspected/confirmed infection).
• Exclusion Criteria: Patients with conditions affecting thiamine metabolism or sepsis outcomes independently (e.g., ongoing chemotherapy, congenital immunodeficiency, metabolic diseases affecting lactate, chronic cardiac/renal failure, or malnutrition syndromes) were excluded.
• Intervention: Participants were randomly assigned (1:1 ratio) to either the intervention group (thiamine 100 mg daily for 7 days, administered orally or via nasogastric tube) or the control group (standard care alone). Standard care included antimicrobial therapy, fluid resuscitation, and supportive care per institutional protocols.
• Outcomes:
  • Primary: Change in Sequential Organ Failure Assessment (SOFA) score from baseline to Day 7.
  • Secondary: In-hospital mortality, mechanical ventilation requirement, vasopressor use, ICU length of stay (LOS), and total hospital LOS.
• Analysis: Statistical analysis included independent t-tests or Mann–Whitney U tests for continuous variables and chi-square/Fisher's exact tests for categorical variables. Multivariable logistic regression adjusted for age, sex, baseline SOFA, and lactate. Subgroup analyses were performed based on baseline SOFA severity.

Key Results
A total of 168 patients (84 per group) were analyzed. Baseline characteristics, including age, sex, infection type, and baseline SOFA scores, were comparable between groups.

• Organ Dysfunction (SOFA Score): The Day 7 SOFA score was lower in the thiamine group (3.18 ± 2.15) compared to controls (3.57 ± 2.32), and the reduction in SOFA score was greater in the thiamine group (2.01 ± 1.31 vs. 1.56 ± 1.23). However, these differences were not statistically significant (P > 0.05).
• Mortality: Mortality was numerically lower in the thiamine group (3.6%) compared to controls (7.1%), with an odds ratio (OR) of 0.481 (95% CI: 0.116–1.993; P = 0.304). This difference was not statistically significant.
• Resource Utilization:
  • Mechanical Ventilation: Less frequent in the thiamine group (46.4% vs. 52.4%; P = 0.440), but not significant.
  • Vasopressor Use: Higher in the thiamine group (47.6% vs. 35.7%), though not significant (P = 0.118).
  • ICU Length of Stay: Patients in the thiamine group had a significantly shorter ICU stay (3.00 ± 2.28 days) compared to controls (4.64 ± 2.66 days), with a mean difference of −1.64 days (95% CI: −2.40 to −0.89; P < 0.001).
  • Hospital Length of Stay: Also significantly shorter in the thiamine group (7.92 vs. 9.09 days; P = 0.013).
• Subgroup Analysis: The benefit of thiamine on ICU LOS was most evident in patients with moderate (P = 0.012) and severe (P = 0.002) baseline SOFA scores. A significant treatment-by-SOFA interaction was observed (P = 0.004), suggesting that the relationship between initial organ dysfunction and ICU resource utilization differed by treatment allocation. In the thiamine group, greater SOFA reduction was significantly associated with shorter ICU stays, whereas this correlation was absent in the control group.
• Safety: No thiamine-related adverse events were documented.

Significance and Claims
The authors conclude that adjunctive thiamine therapy in children with sepsis is associated with a significantly shorter ICU and hospital length of stay. While trends toward reduced mortality, reduced need for mechanical ventilation, and improved organ dysfunction (SOFA score reduction) were observed, these did not reach statistical significance.

The paper posits that the study was likely underpowered to detect definitive differences in low-frequency outcomes like mortality, given the small number of events. However, the consistent direction of improvement across nearly all outcomes suggests a potential biological effect. The authors highlight that the reduction in ICU LOS is a clinically meaningful benefit, potentially indicating accelerated clinical stabilization.

Crucially, the study claims that the therapeutic benefit of thiamine appears more evident in children with moderate to severe baseline organ dysfunction. The authors assert that while routine use cannot yet be recommended for all pediatric sepsis patients based on this evidence, thiamine represents a low-cost, safe adjunctive therapy worth further evaluation. They call for larger, multicenter randomized trials to confirm these findings, particularly to identify specific subgroups (e.g., those with thiamine deficiency or severe organ dysfunction) that may derive the most benefit. The study emphasizes that its findings should be viewed as hypothesis-generating rather than definitive proof of efficacy.