Intravenous iron administration during sepsis: Outcomes, safety, and hemoglobin response

Abstract Background Sepsis is a life-threatening syndrome characterized by a dysregulated immune response and ensuing organ dysfunction. Anemia is a common complication in sepsis, often arising from inflammation, blood loss, and impaired erythropoiesis. Intravenous (IV) iron is a cornerstone in managing anemia among critically ill patients; however, its safety and efficacy during sepsis remain uncertain. A primary concern is that free iron may fuel microbial growth and impair immune function, including neutrophil and T-cell activity, via molecular pathways such as NF-κB, c-Fos, c-Jun, AP-1, and HIF-1α. Methods Using the TriNetX database, we conducted a retrospective cohort study of 34,040 patients diagnosed with both sepsis and iron deficiency anemia to assess the impact of IV iron administration on mortality. A 1:1 propensity score matching was performed to account for potential confounders, including baseline hemoglobin, comorbidities, and demographic characteristics. Results IV iron administration within one week of sepsis diagnosis was associated with significantly reduced mortality at all assessed time points. - 14-day mortality: 4.4% in the IV iron group vs. 7.9% in controls (Risk Difference [RD] −3.5%, 95% CI: −4.9% to −2.2%; Relative Risk [RR] 0.55, 95% CI: 0.44–0.80; p < 0.0001) - 30-day mortality: 8.2% vs. 12% (RD −3.5%, 95% CI: −5.2% to −1.8%; RR 0.70, 95% CI: 0.59–0.83; Hazard Ratio [HR] 0.68, 95% CI: 0.57–0.82; p < 0.0001) - 60-day mortality: 11.0% vs. 16% (RD −4.1%, 95% CI: −6.0% to −2.2%; RR 0.74, 95% CI: 0.64–0.85; HR 0.71, 95% CI: 0.61–0.84; p < 0.0001) - 90-day mortality: 13% vs. 18% (RD −4.8%, 95% CI: −6.8% to −2.7%; RR 0.74, 95% CI: 0.64–0.84; HR 0.71, 95% CI: 0.61–0.82; p < 0.0001) No significant differences were observed in the duration of antibiotic therapy or ventilator use between the two groups. Across all time frames, IV iron was consistently associated with improved survival. Conclusion In this large cohort of patients with sepsis and iron deficiency anemia, early IV iron administration was linked to a significant reduction in mortality at 14, 30, 60, and 90 days. These findings challenge the longstanding concerns regarding IV iron use during active infection and suggest a potential role for iron supplementation in improving sepsis outcomes. Prospective studies are needed to elucidate the underlying mechanisms and to define optimal patient selection and timing for IV iron therapy in this high-risk population.