To the Editor,
We read with great interest the study by Cobo-Zubia et al. evaluating plasma ferric reducing antioxidant power (FRAP) as a prognostic biomarker in postoperative critically ill patients [1]. In this multicentre observational cohort of 464 patients, the authors demonstrated that elevated FRAP levels were associated with shock severity, endothelial dysfunction, and increased 90-day mortality. Moreover, FRAP exhibited discriminative performance comparable to APACHE II and remained independently associated with mortality after multivariable adjustment [1]. These findings highlight the potential clinical utility of a rapid and inexpensive biomarker reflecting redox-related alterations in critical illness.
However, we believe that the biological interpretation of elevated FRAP warrants further consideration. Throughout the manuscript, increased FRAP levels are discussed predominantly as evidence of a compensatory antioxidant response to overwhelming oxidative stress. While this explanation is biologically plausible, an alternative interpretation deserves greater emphasis: elevated FRAP may primarily reflect the accumulation of reducing metabolites secondary to organ dysfunction rather than enhanced antioxidant reserve.
The FRAP assay quantifies total plasma reducing capacity and is strongly influenced by circulating concentrations of uric acid, bilirubin, albumin, ascorbate, and other endogenous compounds [2]. Several of these determinants are themselves affected by the pathophysiological processes accompanying severe critical illness. In the present study, patients with shock exhibited significantly higher creatinine and bilirubin concentrations, a greater prevalence of chronic kidney disease, and substantially higher illness severity scores [1]. Furthermore, the authors reported independent associations between FRAP and bilirubin and acknowledged that “the contribution of metabolite accumulation and organ dysfunction cannot be excluded” Taken together, these observations raise the possibility that elevated FRAP may not necessarily represent a beneficial antioxidant adaptation, but instead serve as an integrative marker of metabolic derangement and impaired clearance mechanisms.
This distinction has important clinical implications. If higher FRAP reflects preserved antioxidant capacity, strategies aimed at augmenting endogenous antioxidant responses might be therapeutically relevant. Conversely, if FRAP elevation primarily mirrors the accumulation of reducing metabolites in the context of organ dysfunction, FRAP should be interpreted principally as a prognostic indicator rather than a therapeutic target. The inability of the FRAP assay to discriminate between these competing mechanisms therefore limits direct pathophysiological inference from total antioxidant capacity measurements alone.
Future investigations may benefit from combining FRAP with more specific markers of oxidative injury and antioxidant defence. Simultaneous assessment of lipid peroxidation products, protein oxidation markers, DNA oxidation biomarkers, and enzymatic antioxidant systems could help clarify whether elevated FRAP reflects effective redox compensation or progressive oxidative damage despite increased plasma reducing capacity [3–7]. In addition, serial measurements throughout the course of critical illness may provide insights into the temporal relationship between redox alterations, organ dysfunction, and patient outcomes. Such approaches would enhance our understanding of the biological significance of FRAP beyond its prognostic performance.
Nevertheless, the work by Cobo-Zubia et al. represents an important contribution to the growing interest in redox biology within intensive care medicine. Their findings support the concept that readily accessible biomarkers may complement conventional severity scores and improve risk stratification. Further studies are now required to determine precisely what elevated FRAP signifies in critically ill patients and whether this biomarker reflects adaptive antioxidant responses, the burden of organ dysfunction, or a combination of both.
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All listed authors have contributed significantly, directly, and intellectually to the work, and have approved it for publication.
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Sichu Liu, Email: zhaojingyuanlab@outlook.com.
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References
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Data Availability Statement
No datasets were generated or analysed during the current study.