Letter to the Editor: Magnesium supplementation in sepsis: A promising metabolic resuscitation strategy

Abstract

Sepsis remains a major cause of mortality worldwide despite advances in modern critical care. Elevated serum lactate is a key marker of metabolic dysfunction and is strongly associated with adverse outcomes of sepsis. Magnesium plays a crucial role in mitochondrial function, energy production, and cellular metabolism, and its deficiency is frequently observed in critically ill patients with reduced lactate clearance. The recent randomized controlled trial by Anbarasan et al published in World Journal of Critical Care Medicine provided an important evidence that magnesium supplementation enhance lactate clearance, reduced vasopressor requirements, and shortened both intensive care unit and hospital length of stay of septic patients. Their results are quite promising, but have several limitations. The absence of baseline magnesium measurements makes it difficult to determine whether the observed benefits are resulted from correction of hypomagnesemia or from other pharmacological effects of magnesium. Furthermore, the single-center design with relatively small sample size, and the lack of statistically significant mortality benefit limit the generalizationn of the findings. Overall, magnesium supplementation appears to be a promising, safe, and cost-effective adjunctive therapy for sepsis, large multicenter randomized trials and mechanistic studies are required before recommendation for routine clinical use.

Key Words: Sepsis; Magnesium supplementation; Lactate clearance; Mitochondrial dysfunction; Metabolic dysfunction

Core Tip: Magnesium is a key co factor in ATP synthesis and mitochondrial electron transport and plays an important role in immune metabolic regulation. Hypomagnesemia impairs cellular energy metabolism and contributes to lactate accumulation, while hepatic dysfunction further compromises lactate clearance. Together, these mechanisms may exacerbate lactic acidosis and worsen outcomes in septic patients.

TO THE EDITOR

Sepsis remains a leading cause of mortality worldwide and is characterized by a dysregulated host response to infection resulting in life-threatening multi-organ dysfunction. Despite advances in intensive care management, mortality rates of sepsis remain high, reflecting persistent gaps in the understanding of its complex pathophysiology[1]. Elevated serum lactate level is widely recognized as a marker of impaired tissue oxygen utilization and mitochondrial dysfunction, and thus, serum lactate level is an important prognostic indicator and therapeutic target in sepsis management[2].

Magnesium functions as a critical cofactor in aerobic metabolism by activating pyruvate dehydrogenase, thereby reducing lactate production and enhancing lactate clearance; correction of hypomagnesemia has been shown to improve lactate reduction and lower serum lactate levels in critically ill septic patients[3].

In this context, in the recent issue of World Journal of Critical Care Medicine, Anbarasan et al[4] evaluated the effect of magnesium supplementation on lactate clearance in septic patients in a randomized clinical trial. The authors reported that magnesium administration significantly reduced lactate clearance time, decreased vasopressor requirements, and shortened intensive care unit (ICU) and hospital stay, although it did not result in a statistically significant reduction in mortality. These findings provide timely and clinically relevant evidence for the efficacy of magnesium supplementation and align with emerging evidence emphasizing the role of mitochondrial dysfunction and metabolic failure in the pathogenesis of sepsis[3].

Role of magnesium in lactate clearance during sepsis

Magnesium plays a central role in oxidative phosphorylation, ATP synthesis, and cellular metabolism. Hypomagnesemia is common in critically ill patients and has been associated with increased morbidity and mortality[5]. Thus, correction of magnesium deficiency is a biologically plausible therapeutic strategy.

Anbarasan et al[4] evaluated the clinical significance of lactate clearance as a prognostic marker in sepsis. They showed that accelerated lactate clearance was consistently associated with improvements in multiple physiological and clinical outcomes, including reduced vasopressor requirements and shorter ICU stay.

Furthermore, magnesium supplementation supports the growing concept of metabolic resuscitation, which focuses on restoring cellular energetics in addition to correcting macro- and microcirculatory abnormalities. Magnesium is essential for mitochondrial energy production. It acts as a cofactor in ATP synthesis and the electron transport chain. Magnesium deficiency may impair pyruvate metabolism, promoting lactate accumulation. In addition, hepatic dysfunction commonly observed in sepsis further reduces lactate clearance, thereby amplifying lactic acidosis and adverse outcomes. Hypomagnesemia is independently associated with elevated lactate levels and increased mortality in septic patients, particularly when liver injury is present[6].

Magnesium is indispensable for mitochondrial bioenergetics, as it forms the Mg-ATP complex that enables phosphate transfer and energy release. It functions as a cofactor for critical dehydrogenases in the tricarboxylic acid cycle and directly supports ATP synthase activity[7]. Magnesium also stabilizes mitochondrial membranes, preserving oxidative phosphorylation efficiency and preventing ion leakage[8].

Magnesium plays a critical role in the pathophysiology of sepsis by modulating both inflammatory and immune responses. As a natural calcium antagonist, magnesium deficiency promotes intracellular Ca²⁺ accumulation, which activates NF-κB and drives excessive production of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6, thereby amplifying the systemic inflammatory cascade. Low magnesium also enhances mast cell degranulation, histamine release, and phagocyte-derived reactive oxygen species, contributing to oxidative stress and tissue injury[9]. In adaptive immunity, magnesium supports T-cell receptor signalling and regulatory T-cell function, maintaining immune tolerance and preventing dysregulated responses. Deficiency impairs these processes, skewing the Th1/Th2 balance toward a Th2-dominant state, which can exacerbate immune dysfunction in sepsis[10]. Collectively, magnesium deficiency intensifies inflammation and immune dysregulation, worsening outcomes in septic patients.

Hypomagnesemia is associated with poor outcomes in critically ill patients[5], while hypermagnesemia has also been reported as a strong predictor of in-hospital mortality in critically ill populations. Therefore, indiscriminate magnesium supplementation may increase the risk of hypermagnesemia, particularly in patients with renal dysfunction, and should be applied with caution[11]. Lactate clearance primarily depends on hepatic and renal metabolism, with the liver accounting for approximately 60% of systemic lactate removal through gluconeogenesis and oxidation, while the kidneys contribute significantly, particularly during recovery[12].

As mentioned above, mortality remains the most important clinical outcome in sepsis research, and previous large multicentre trials have demonstrated that improvements in physiological parameters do not always translate into survival benefits[13]. In addition, patients undergoing renal replacement therapy may influence both lactate kinetics and magnesium balance and should be carefully considered in future studies.

Clinical implications

The findings of this study highlight the growing importance of metabolic optimization in sepsis management. Traditional sepsis therapy has focused primarily on restoring macro circulatory perfusion through fluid resuscitation and vasopressor support. However, increasing evidence indicates that mitochondrial dysfunction and impaired cellular energetics play a central role in the development of organ failure during sepsis[14].

Nevertheless, routine magnesium supplementation for all septic patients cannot yet be recommended. Further evidence is required before this strategy can be incorporated into standard sepsis management guidelines.

Future research

Future research should focus on several key issues. Large multicentre randomized controlled trials are required to confirm the therapeutic effects of magnesium supplementation, including improvement in survival. Measurement of baseline magnesium levels should be incorporated to identify patients suitable for magnesium supplementation therapy.

In addition, mechanistic studies are needed to explore the effects of magnesium on mitochondrial function, inflammation, and microcirculatory perfusion. Combination metabolic therapies involving magnesium, vitamin C, and thiamine should also be evaluated. Finally, future studies should assess long-term outcomes, including organ recovery and quality of life, to better define the role of metabolic resuscitation in sepsis care.

Conclusion

Magnesium supplementation represents a promising adjunctive strategy in the management of sepsis. The randomized trial by Anbarasan et al[4] demonstrated that magnesium may accelerate lactate clearance and improve several clinically relevant outcomes. However, the absence of a mortality benefit and methodological limitations preclude definitive conclusions. Large multicentre trials are required before routine clinical use can be recommended. Targeting metabolic dysfunction through magnesium supplementation may represent an important step toward metabolic resuscitation strategies aimed at correcting cellular dysfunction in sepsis.

ACKNOWLEDGEMENTS

The author would like to express sincere gratitude to Professor Yukifumi Nawa for his invaluable contribution to English editing. The author also extend my appreciation to all the reviewers for their insightful comments and constructive feedback during the review process.