We read with interest the FluDReSS trial by Walsham et al., which investigated the dose–response relationship of enteric fludrocortisone in patients with septic shock [1]. Notably, while significant changes in plasma concentrations were observed, these changes were not correlated with dosage. Furthermore, no benefits in terms of sepsis resolution or mortality were reported. While we commend the authors for the completion of this important trial, we would like to address several concerns.

First, the authors acknowledged that the study was underpowered due to early termination. However, it is noteworthy that no formal sample size calculation was conducted prior to randomization. Moreover, the observed 28-day mortality rate in the study was substantially lower than rates reported in previous randomized trials (11–24% vs 36.3% in the APROCCHSS trial) [2]. It is important to consider that the benefits of glucocorticoid treatment in sepsis, as demonstrated in prior trials, are often highly dependent on patient selection criteria. Studies with favorable outcomes for fludrocortisone and hydrocortisone have typically included patients with higher sequential organ failure assessment scores and those requiring more prolonged and aggressive vasopressor support at baseline [3]. Therefore, robust conclusions regarding the efficacy of fludrocortisone in septic shock remain elusive based on the current evidence.

Second, the pharmacokinetic analysis of fludrocortisone in this study requires further exploration. Although baseline plasma fludrocortisone levels (t = 0 h) did not demonstrate statistical significance, there were notable potential differences that merit attention. More importantly, a subset of patients in both the 100 mcg and 200 mcg dosage groups experienced a decline in plasma fludrocortisone concentrations, raising questions about the appropriateness of the 3-h post-injection time point used for measurement. Sequential testing at multiple time points following injection could provide valuable insights into the pharmacokinetic profile of fludrocortisone. Additionally, it is concerning that plasma fludrocortisone levels were only measured in 74 out of 115 patients (approximately 65%), with no explanation provided for the missing data in over 30% of the cohort. Clarification on this issue is essential to understand the potential impact of this missing data. Furthermore, the pharmacokinetics of only the first dose were extensively explored in the main analysis. While some data were presented in the supplementary material, the cumulative effects and pharmacokinetics of a 5-day course of treatment remain unclear, which is critical for evaluating the full therapeutic potential of fludrocortisone in septic shock.

Finally, we believe that the potential effects of a combination of fludrocortisone and hydrocortisone on inflammation modulation warrant further investigation. Previously, it has been proposed that fludrocortisone may have important effects on the immune system in humans [4]. Animal studies primarily elucidated that mineralocorticoid receptors, which are expressed in monocytes and macrophages, could be involved in the regulation of T-cell migration, macrophage polarization and cytokine production [5]. Given that sepsis involves a complex neuro-humoral response that regulates inflammation, the combined impact of glucocorticoids and mineralocorticoids on immune function deserves closer scrutiny.

In conclusion, fludrocortisone's role in septic shock remains uncertain. Further trials are needed to assess its clinical benefits, optimal timing, patient populations, and dosing regimens.