INNOVATIVE METHOD FOR INFECTIOUS COMPLICATIONS REDUCING AFTER ORTHOPEDIC INTERVENTIONS VIA PREVENTIVE HEMOCORRECTION. PROTOCOL FOR A RANDOMIZED CONTROLLED TRIAL

Introduction. Septic complications following orthopedic procedures remain a pressing challenge in modern surgical practice, contributing significantly to patient morbidity, prolonged hospital stays, increased healthcare costs, and, in severe cases, long-term disability. One of the modifiable but often overlooked risk factors is preoperative anemia, which is frequently underdiagnosed and undertreated. Existing evidence indicates that allogeneic blood transfusions, commonly used to correct anemia, are independently associated with a higher risk of postoperative infections. This underscores the urgent need to explore alternative, safer strategies for perioperative management, particularly those targeting the correction of anemia prior to surgery.

Aim. To evaluate the effectiveness of perioperative intravenous iron supplementation with ferric carboxymaltose in reducing the incidence of periprosthetic joint infections and improving clinical outcomes in patients undergoing elective orthopedic surgery.

Methods. The IRON study is a prospective, single-center, randomized, open-label, controlled clinical trial. A total of 170 adult patients scheduled for elective orthopedic interventions will be enrolled and randomized to receive perioperative intravenous ferric carboxymaltose at a dose of 15 mg/kg (up to a maximum of 1000 mg).

Primary endpoint. The incidence of periprosthetic joint infections within the postoperative follow-up period.

Secondary endpoints. 28-day all-cause survival, duration of stay in the intensive care unit and in the hospital, achievement of target hemoglobin levels (≥120 g/L in women, ≥130 g/L in men), number of vasopressor-free days, reduction in the frequency and volume of intraoperative and postoperative blood transfusions, and decreased utilization of the Cell Salvage System.

Expected Results: Although patient enrollment is ongoing, it is hypothesized that intravenous iron therapy will reduce the rate of infectious complications and the need for allogeneic transfusions, while improving postoperative recovery and hematologic parameters.

1. Seid M.H., Mangione A., Valaoras T.G., Anthony L.B., Barish C.F. Safety Profile of Iron Carboxymaltose, a New High Dose Intravenous Iron in Patients with Iron Deficiency Anemia. Blood. 2006; 108 (11): 3739. https:// doi.org/10.1182/blood.V108.11.3739.3739

2. Geisser P., Banké-Bochita J. Pharmacokinetics, safety and tolerability of intravenous ferric carboxymaltose: a dose-escalation study in volunteers with mild iron-deficiency anaemia. Arzneimittelforschung. 2010; 60(6a): 362-72. https://doi.org/10.1055/s-0031-1296301. PMID: 20648928.

3. Yang J., Zhang X., Liang W. A retrospective analysis of factors affecting surgical site infection in orthopaedic patients. Journal of International Medical Research. 2020; 48 (4). https://doi.org/10.1177/0300060520907776

4. Kim J.L., Park J.H., Han S.B., Cho I.Y., Jang K.M. Allogeneic Blood Transfusion Is a Significant Risk Factor for Surgical-Site Infection Following Total Hip and Knee Arthroplasty: A Meta-Analysis. J. Arthroplasty. 2017; 32 (1): 320-325. https://doi:10.1016/j.arth.2016.08.026

5. Everhart J.S., Sojka J.H., Mayerson J.L., Glassman A.H., Scharschmidt T.J. Perioperative Allogeneic Red Blood-Cell Transfusion Associated with Surgical Site Infection After Total Hip and Knee Arthroplasty. J. Bone Joint Surg Am. 2018; 100 (4): 288-294. https://doi:10.2106/ JBJS.17.00237

6. Fowler A.J., Ahmad T., Phull M.K., Allard S., Gillies M.A., Pearse R.M. Meta-analysis of the association between preoperative anaemia and mortality after surgery. Br. J. Surg. 2015; 102 (11): 1314-1324. https://doi.org/10.1002/bjs.9861

7. Friedman R., Homering M., Holberg G., Berkowitz S.D. Allogeneic blood transfusions and postoperative infections after total hip or knee arthroplasty. J. Bone Joint Surg. Am. 2014; 96 (4): 272-278. https://doi:10.2106/ JBJS.L.01268

8. Kiyatkin M.E., Mladinov D., Jarzebowski M.L., Warner M.A. Patient Blood Management, Anemia, and Transfusion Optimization Across Surgical Specialties. Anesthesiol. Clin. 2023; 41(1): 161-174. https://doi:10.1016/j. anclin.2022.10.003

9. Guo P., He Z., Wang Y., Gao F., Sun W., Guo W., Li Z., Cheng L. Efficacy and safety of oral tranexamic acid in total knee arthroplasty: A systematic review and metaanalysis. Medicine (Baltimore). 2018; 97 (18): e0587. https://doi:10.1097/MD.0000000000010587

10. Maniar R.N., Kumar G., Singhi T. Most effective regimen of tranexamic acid in knee arthroplasty: a prospective randomized controlled study in 240 patients. Clin. Orthop. Relat. Res. 2012; 470: 2605-2612. https://doi.org/10.1007/s11999-012-2310-y

11. Iwai T., Tsuji S., Tomita T. Repeat-dose intravenous tranexamic acid further decreases blood loss in total knee arthroplasty. Int. Orthop. 2013; 37: 441-445. https://doi. org/10.1007/s00264-013-1787-7

12. Ren X., Ling L., Qi L., Liu Z., Zhang W., Yang Z., Wang W., Tu C., Li Z. Patients' risk factors for periprosthetic joint infection in primary total hip arthroplasty: a metaanalysis of 40 studies. BMC Musculoskelet. Disord. 2021; 22 (1): 776. https://doi:10.1186/s12891-021-04647-1

13. Kunutsor S.K., Whitehouse M.R., Blom A.W., Beswick A.D. Patient-Related Risk Factors for Periprosthetic Joint Infection after Total Joint Arthroplasty: A Systematic Review and Meta-Analysis. PLoS One. 2016; 11 (3): e0150866. https://doi:10.1371/journal.pone.0150866

14. Rodriguez-Merchan E.C., Delgado-Martinez A.D. Risk Factors for Periprosthetic Joint Infection after Primary Total Knee Arthroplasty. J. Clin. Med. 2022; 11: 6128. https://doi.org/10.3390/jcm11206128

15. Jans O., Jorgensen C., Kehlet H., Johansson P. I. Lundbeck Foundation Centre for fast-track hip and knee replacement collaborative group. Role of preoperative anaemia for risk of transfusion and postoperative morbidity in fast-track hip and knee arthroplasty. Transfusion. 2014; 54 (3): 717-726.

16. Muñoz M., Gómez-Ramírez S., Kozek-Langeneker S. «Fit to fly»: overcoming barriers to preoperative haemoglobin optimization in surgical patients. Br. J. Anaesth. 2015; 115 (1): 15-24.

17. Konkayeva M., Kadralinova A., Zhanarystan N., Akhatov N., Konkayev A. Case Report: High-Dose Ferric Carboxymaltose as an Antianaemic Agent to Avoid Haemotransfusions after Total Hip Replacement. Medicina (Kaunas). 2024; 60 (8): 1274. https://doi.org/10.3390/medicina60081274

18. Li X., Xie H., Liu S. Analysis of the incidence and risk factors of blood transfusion in total knee revision: a retrospective nationwide inpatient sample database study. BMC Musculoskelet. Disord. 2024; 25: 225. https://doi.org/10.1186/s12891-024-07331-2

19. Lucenti L., Testa G., Caldaci A., Sammartino F., Cicio C., Ilardo M., Sapienza M., Pavone V. Preoperative Risk Factors for Periprosthetic Joint Infection: A Narrative Review of the Literature. Healthcare. 2024; 12: 666. https:// doi.org/10.3390/healthcare12060666

20. Bekarissov O., Batpen A., Ospanov K., Jaxybekova G., Bermagambetova G. The role of the National Scientific Center of Traumatology and Orthopedics named after academician Batpenov N.D. in the formation and development of traumatology orthopedic service of the Republic of Kazakhstan. Traumatology and Orthopаedics of Kazakhstan. 2021; 58: 4-15. https://doi.org/10.52889/16849280-2021-58-4-15

21. Antonelli B., Chen A.F. Reducing the risk of infection after total joint arthroplasty: preoperative optimization. Arthroplasty. 2019; 1: 4. https://doi.org/10.1186/s42836019-0003-7

22. Yuste Gutierrez A.M., Alonso-Moreno M., Perez Blanco J.L., Berlana D., Peña Fernandez M.A., Perez Maroto M.T., Torralba M. Use and Effectiveness of Carboximaltose Iron in Preoperative Anemia Treatment: A Multicenter and Retrospective Study. J. Blood Med. 2024; 15: 477-486. https://doi.org/10.2147/JBM.S460422

23. Yang H.Y., Park K.S., Shin H.H., Choi J.H., Seon J.K. Preoperative Intravenous Ferric Carboxymaltose Improves Recovery from Anemia in Patients Undergoing Revision Joint Arthroplasty: A Randomized Controlled Trial. Preprints. 2023: 2023121984. https://doi.org/10.20944/preprints202312.1984.v1

24. Kim S.K., Seo W.Y., Kim H.J., Yoo J.J. Postoperative Intravenous Ferric Carboxymaltose Reduces Transfusion Amounts after Orthopedic Hip Surgery. Clin. Orthop. Surg. 2018; 10 (1): 20-25. https://doi.org/10.4055/cios.2018.10.1.20

25. Benjumea-Carrasco A., Guembe M., Díaz-Navarro M., Muñoz P., Vaquero-Martin J., Chana-Rodriguez F. The role of tranexamic acid for infection prevention after fracture fixation. Injury. 2024; 55 (6): 111846. https://doi.org/10.1016/j.injury.2024.111846

26. Zacharowski K., Zoller H., Steinbicker A.U. Patient blood management and patient safety. Curr. Opin. Anaesthesiol. 2022; 35 (6): 733-737. https://doi.org/10.1097/ACO.0000000000001196

27. Jones J.J., Mundy L.M., Blackman N., Shwarz Ferric Carboxymaltose for Anemic Perioperative Populations: ASystematic Literature Review of Randomized Controlled Trials. J. Blood. Med. 2021; 12: 337-359. https:// doi.org/10.2147/JBM.S295041. PMID: 34079413; PMCID: PMC8165212.