**Background:** Perioperative anemia is highly prevalent in orthopaedic trauma, affecting up to 87% of patients after hip fracture fixation. It is associated with increased hospital length of stay, need for blood transfusion, surgical site infection, cardiovascular complications, and death. Current standard of care relies on restrictive packed red blood cell transfusion thresholds (hemoglobin <7 g/dL), leaving many patients untreated despite functional iron deficiency driven by trauma-induced systemic inflammation. Intravenous iron therapy (IVIT) offers a potential alternative, with prior meta-analyses showing a 31% reduction in transfusion requirements, 1.6-day shorter hospital stay, and 33% lower postoperative infection rate. However, no high-quality randomized trials have examined IVIT's effect on patient-reported quality of life in orthopaedic trauma. The authors' preliminary data show that less than 5% of post-fracture patients have normal serum iron, total iron binding capacity, transferrin saturation, and transferrin values, while ferritin remains normal in approximately two-thirds, suggesting functional iron deficiency due to hepcidin-mediated iron sequestration. Additionally, prior work by the team in iron-deficient premenopausal women demonstrated that IVIT decreases platelet count, increases platelet integrin activation and alpha-granule secretion, and enhances platelet adhesion to type-1 collagen, indicating iron's vital role in platelet function.
**Methods:** This single-center, double-blind, parallel-design pilot RCT will enroll 60 patients (30 per arm) at Oregon Health & Science University, a Level 1 trauma center with over 4000 trauma activations yearly. Enrollment is planned from June 2022 through May 2024. Eligible patients are adults aged 18–89 admitted with lower extremity or pelvis fracture requiring surgical stabilization, with hemoglobin 7.0–11.0 g/dL within 7 days postoperatively. Key exclusion criteria include iron intolerance, active hemorrhage requiring >2 units transfused, multiple planned procedures, pre-existing hematologic disorders, chronic kidney or liver disease, known infection/inflammatory condition/malignancy, pregnancy, iron overload (ferritin ≥1000 ng/mL, serum iron >160 µg/dL, or transferrin saturation ≥50%), Jehovah's Witness faith, vulnerable populations, inability to refrain from oral iron, recent immunosuppressive use, or prior IVIT/erythropoietin within 30 days. The intervention is a single 1000 mg dose of low-molecular weight iron dextran infused over 1 hour; placebo is 250 mL normal saline. Opaque bags and tube covers applied by an unblinded pharmacist ensure blinding. Randomization uses a computer-generated schema (randomization.com) performed by Research Pharmacy Services. Patients are followed for 3 months with assessments at 2 weeks, 4 weeks, 6 weeks, and 3 months. Feasibility outcomes include enrollment rate (target: 60 patients in 2 years), screening failure rate, follow-up completion proportion, missing data proportion, adverse event rate, and protocol adherence. The primary clinical outcome is PROMIS Fatigue score. Secondary outcomes include hemoglobin normalization (>12 g/dL women, >13.5 g/dL men), ferritin and iron panel normalization, PROMIS Physical Function and Depression scores, EQ-5D-5L for cost-utility analysis, and immune cell functional testing (flow cytometry, platelet aggregation assays, proteomics, Luminex/ELISA). Safety monitoring includes documentation of all adverse events in a secure REDCap database, with severe infusion reactions managed per a predefined algorithm (stop infusion, rapid response, oxygen, epinephrine, steroids, ACLS if needed). Hypersensitivity medications (diphenhydramine, famotidine, hydrocortisone, epinephrine, saline bolus) are ordered with the study drug.
**Key Results:** This is a protocol paper; no results are reported. The authors note that based on prior studies, a significant increase from baseline hemoglobin of 1.2 g/dL ± 1.4 was observed within a median follow-up of 3 weeks after LMW ID administration. The minimum number of subjects required to detect a clinically meaningful change in PROMIS score (defined as 5 points with SD of 10) is informed by the minimally important change for PROMIS measures of 3–6 points. Analysis will use t-tests for hemoglobin change, ANCOVA for PROMIS scores (with treatment as factor and baseline score as covariate), and multivariate analysis adjusting for age, sex, BMI, and transfusion status. Subgroup analyses will compare patients receiving ≤2 units perioperative transfusion versus none. Multiple imputation will handle missing data. Significance is set at 95%, and all analyses will be conducted by blinded statisticians using R.
**Clinical Implications:** Successful completion will determine feasibility for a definitive large-scale multicenter RCT. If IVIT proves effective in improving quality of life after traumatic lower extremity fracture, clinical relevance could extend to other fracture types and broader orthopaedic surgery applications. The study addresses a critical gap—no prior orthopaedic studies have examined IVIT's effect on patient-reported quality of life outcomes. The translational component investigating immune cell physiology, particularly platelet function, may reveal mechanisms by which iron repletion improves hemostasis and recovery. The single-dose LMW ID regimen (1000 mg over 1 hour) addresses prior trial limitations where only 16% of patients received full dosing due to multi-dose requirements. The FDA-recognized safety profile of IVIT (2.2 life-threatening adverse events per million doses, 0.4 deaths per million) compares favorably to blood transfusion (10 per million units and 4 per million units, respectively). Cost-effectiveness analysis using QALYs will provide economic data to support potential adoption. Limitations include the single-center design, pilot sample size precluding definitive clinical conclusions, and the exploratory nature of all clinical outcome analyses.