Thiamine administration in septic shock: a post hoc analysis of two randomized trials

Thiamine has been proposed as a mitochondrial resuscitator that may attenuate organ injury and lessen mortality in septic shock [1, 2]. Kidney injury is frequently seen in patients with septic shock and has been associated with poor clinical outcomes, including longer length of intensive care unit (ICU) stay and higher mortality [3]. Kidney injury in septic shock has been traditionally ascribed to renal hypoperfusion from cytokine-mediated vasodilation, ultimately resulting in tubular necrosis and renal failure [4, 5]. However, studies have shown that kidney injury can occur even in the absence of prolonged hypoperfusion. The histopathologic pattern of kidney injury in sepsis often features apoptosis, hinting at alternative mechanisms beyond impaired oxygen delivery, such as mitochondrial dysfunction [6].

Thiamine is a cofactor for pyruvate dehydrogenase and critical for aerobic respiration [7, 8]. Thiamine is also a necessary component of the pentose phosphate pathway, which plays a role in reducing oxidative stress [9, 10]. Thiamine deficiency has been associated with organ dysfunction and has been studied in patients with septic shock [10‐13]. Prior studies from our group have explored thiamine as a renal protective agent in sepsis [1, 2]. Although these studies showed promising results with point estimates favoring thiamine supplementation, the relatively small sample sizes of the trials may have led to type 2 error. In addition, there have been several other studies [14‐16] that have evaluated thiamine supplementation in septic shock; they did not specifically investigate renal outcomes or focus on baseline thiamine levels.

In this study, we pooled patient-level data from our two prior randomized control trials (RCTs) of thiamine supplementation in septic shock [1, 2] to test the hypotheses that (1) thiamine supplementation improves the odds of being alive and renal replacement therapy (RRT) free at the time of discharge and (2) thiamine supplementation has greater benefit in those with thiamine deficiency.

In this post hoc analysis of two RCTs, thiamine administration resulted in a greater proportion of patients who were alive and RRT-free compared to placebo. Thiamine administration was also found to improve several secondary outcomes. Significant heterogeneity of treatment effect was seen, such that the effects of thiamine were greater in patients with thiamine deficiency.

Recently, three other RCTs have investigated the effect of thiamine administration in septic shock [14‐16]. In all three studies, thiamine administration resulted in no difference in mortality, although thiamine administration was associated with significant lactate reduction in the study by Petsakul et al. [15]. It is worth noting that the proportion of patients with thiamine deficiency in the studies by Petsakul et al. and Pereira et al. [16] was significantly lower than the 26% in of patients who were thiamine-deficient in the present cohort (Harun et al. did not report baseline thiamine levels). The lower rate of thiamine deficiency in RCTs not included in the present study may be due to different approaches to predictive enrichment, alternative measures of thiamine level, or a combination thereof. In addition, the three other RCTs described were not focused on kidney outcomes, included patients with end-stage kidney disease, and did not provide a comprehensive assessment of acute kidney injury as was the focus in the present trial. Differential rates of thiamine deficiency and different inclusion criteria may explain differences in results of the present study and existing RCTs.

A component network meta-analysis by Fujii et al., assessing the effect of vitamin C, thiamine, and glucocorticoids on long-term mortality in septic shock found possible harm with thiamine treatment [17]. This study analyzed trials with multiple treatments and assumed an additive effect in order to estimate the effects of individual treatments. However, this finding is inconsistent with thiamine-only trials in septic shock and does not include data from the TRPSS trial [2, 10, 14‐16]. Further, the network meta-analysis suffers from the same considerations outlined in the preceding paragraph—namely it does not focus on a thiamine-deficient population, does not exclude patients with pre-existing ESRD, and does not comprehensively describe kidney-specific outcomes.

This study has several limitations. First, the analysis was post hoc and excluded some patients with baseline ESRD from the TSS trial. Second, plasma thiamine levels were measured for the analyzed trials in this study. Given the heterogeneity of treatment effect seen by thiamine level, it is clear that this approach provides clinically relevant data regarding thiamine deficiency status. Other approaches to thiamine measurement have been previously described, most notably the measurement of thiamine diphosphate from whole blood, and should be further explored in future studies. In addition, rapid assessment of thiamine level is currently not feasible. An important future work includes investigating the feasibility of predicting thiamine deficiency using other clinically available data as a predictive enrichment strategy for future clinical trials of thiamine in septic shock.

In this post hoc analysis of two RCTs, intravenous thiamine administration was associated with a greater proportion of patients who were alive and RRT-free compared to placebo. The signal for benefit was stronger in the group of patients who had low thiamine levels.