However, no clear recommendations currently exist for the management of isolated preoperative iron deficiency (i.e., patients without anemia but with iron deficiency). The prevalence of isolated iron deficiency in the surgical population (40%) is higher than that of anemia [8]. Evidence suggests that in nonanemic patients undergoing cardiac surgery, iron deficiency is associated with increased perioperative transfusion requirements and postoperative mortality [9].

A randomized controlled trial conducted by Spahn et al. [10] compared a combination treatment consisting of intravenous iron, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid with a placebo in patients with preoperative anemia or isolated iron deficiency undergoing elective cardiac surgery. They concluded that administering combination treatment the day before surgery significantly reduced the number of RBC and total blood product transfusions during the first seven days postoperatively. However, the study was underpowered to determine the efficacy of the intervention in the isolated iron deficiency subgroup. Additionally, no subgroup analysis was performed for the 37% of enrolled patients who underwent off-pump coronary artery bypass grafting (OPCAB) [10], a procedure characterized by lower transfusion requirements than on-pump surgery due to blood salvage procedures, lower levels of systemic heparinization, and protection from cardiopulmonary bypass-induced hemodilution and coagulopathy [6]. Therefore, evidence on the clinical significance of isolated preoperative iron deficiency in patients undergoing OPCAB is currently lacking.

In this issue of the Korean Journal of Anesthesiology, Shin et al. [11] present an important investigation addressing this knowledge gap. In this single-center study, the authors retrospectively analyzed a homogeneous cohort of 433 nonanemic patients undergoing OPCAB and explored the clinical significance of preoperative isolated iron deficiency [11]. The primary outcome was a composite of acute kidney injury, permanent stroke, deep sternal wound infection, hemostatic reoperation, prolonged mechanical ventilation, delirium, myocardial infarction, and 30-day mortality. The study found that approximately half of the cohort (52.9%) met the criteria for iron deficiency. In the multivariable logistic regression analysis, isolated iron deficiency was not associated with the composite outcome (odds ratio: 0.97, 95% CI [0.60–1.58], P = 0.921). The authors concluded that routinely correcting isolated iron deficiency should be performed with caution.

As definitive conclusions could not be made due to the retrospective design of this study and its limited sample size, the authors conducted two sensitivity analyses to confirm their findings [11]. First, an interaction term between iron deficiency and heart failure was added to the multivariable model. This interaction is particularly important because heart failure is common among patients undergoing OPCAB (18.6% in this cohort) and iron supplementation has been shown to improve outcomes in this population [12,13]. Second, considering the variability in the definition of iron deficiency, the authors repeated the multivariable analysis using an alternative definition (i.e., Grote-defined iron deficiency). Both sensitivity analyses yielded results that were consistent with the primary findings.

Shin et al. [11] should be commended for performing a post-hoc mediation analysis, particularly because the patients with iron deficiency were more likely to receive perioperative RBC transfusions (25.8% vs. 10.8%; P < 0.001). The analysis showed that iron deficiency had no direct effect on postoperative outcomes, whereas the indirect effect mediated by perioperative transfusions was statistically significant. This finding suggests a clinically important hypothesis that isolated iron deficiency primarily influences postoperative outcomes through transfusion-related pathways rather than through direct biological effects, further emphasizing that superficial associations may be misleading when interpreting complex clinical data. Indeed, transfusion practices are influenced by the attending clinician’s discretion, institutional protocols, preoperative iron profile of each patient, and perioperative hemodynamic instability. Consequently, questions regarding the impact of isolated iron deficiency on adverse outcomes after OPCAB remain, and larger prospective randomized trials are needed to provide more definitive guidance.