Abstract
Background
Thiamine and ascorbic acid have been proposed to mitigate the devastating consequences of sepsis and septic shock. To date, randomized controlled trials have failed to demonstrate a benefit of these therapies and heterogeneity of treatment effect is suspected. In this study, we aimed at assessing the heterogeneity of treatment effect of thiamine (B1) and the combination of B1 plus ascorbic acid (AA + B1) in critically ill patients with sepsis.
Methods
We conducted a bi-centric retrospective cohort study. All adult patients admitted to the ICU with sepsis or septic shock between January 2012 and August 2022 were included. Patient clusters were identified using latent variable analysis based on demographics and physiological variables obtained within 24 h of admission. Within each cluster and using inverse probability weighted Cox models, we compared in-hospital mortality between patients who received standard treatment (control), standard treatment plus B1 (B1 group), and standard treatment plus a combination of thiamine and ascorbic acid (AA + B1 group).
Results
A total of 3465 septic patients were included, 2183, 1054 and 228 in the standard, B1 and AA + B1 groups respectively. Five clusters of patients were identified in an unsupervised manner. The “Cluster Severe” included the most severely ill patients, the “Cluster Resp” patients presented with predominantly respiratory failure, the “Cluster Old” included elderly patients with multiple comorbidities, the “Cluster Fit” patients were young, healthy with low severity indices and “Cluster Liver” included patients with predominant liver failure. B1 treatment was associated with different outcomes across the five clusters. It was associated with a lower in-hospital mortality in the “Cluster Severe” and “Cluster Resp”. On the other hand, the combination of thiamine and ascorbic acid was not associated with reduced mortality in any cluster but an increased mortality in”Cluster Old”.
Conclusions
These results reinforce the lack of efficacy of the combination of AA + B1 reported in recent trials and even raise concerns about potential harm in older patients with comorbidities. On the contrary, we reported improved ICU survival associated with B1 supplementation in the most severe patients and those with predominant respiratory failure, supporting the need for further trials in this specific population.
Key Points:
- Sepsis and Adjunctive Therapies: Thiamine and ascorbic acid are evaluated as adjunctive therapies in septic patients due to their potential benefits in cellular and metabolic function.
- Study Design: A retrospective analysis of ICU patients with sepsis or septic shock was conducted across two hospitals from 2012–2022.
- Patient Clusters: Five distinct patient clusters were identified—Severe, Respiratory Failure, Elderly with Comorbidities, Young and Healthy, and Predominant Liver Failure—using latent variable analysis.
- Thiamine Benefits: Thiamine supplementation improved survival in patients with severe sepsis or respiratory failure.
- Combination Therapy Concerns: The combination of AA + B1 showed no survival benefits and increased mortality in elderly patients with multiple comorbidities.
- Cluster-Specific Outcomes: Treatment effects varied significantly by patient cluster, emphasizing the need for individualized therapeutic approaches.
- Propensity Score Adjustments: Propensity score weighting and further adjustments were used to account for potential confounders.
- Potential Toxicity of Ascorbic Acid: Findings suggest possible antagonistic or harmful effects of AA in specific populations, particularly older individuals.
- Call for Targeted Trials: The study highlights the necessity of targeted clinical trials to validate the observed benefits of thiamine in specific septic populations.
- Limitations and Hypothesis Generation: The retrospective design and lack of standardized dosing highlight the need for prospective studies to confirm these findings.
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