Preoperative Iron Infusion Works Better than Blood Transfusion for Some Anemia Patients

The World Health Organization (WHO) recognizes iron deficiency anemia or IDA as the most common nutritional deficiency in the world. According to the agency, approximately  30% of the global population is affected by this condition.

Gastrointestinal bleeding and, in women, menstruation, decreases dietary iron. In addition, decreased iron absorption in combination with decreased dietary iron are considered major causes of IDA. Treatment generally aims at replenishing iron stores and returning hemoglobin levels to a normal level, which, in turn, will improve health-related Quality of Life (hrQoL), reduces morbidity and improves prognosis in chronic disease and enhance outcomes in pregnancy. [1]

Iron and hemoglobin
Iron is a mineral that the human body needs to make hemoglobin, a protein in red blood cells that carries oxygen to organs throughout the body. If there is insufficient iron in a patient’s blood, the person becomes anemic, meaning there are not enough healthy red blood cells to deliver enough oxygen. This is particularly concerning for patients undergoing surgery because there is almost always (some amount of) blood loss during any surgical procedure.

In surgical patients, low-level hemoglobin, which may, especially in patients diagnosed with cancer, be a result of their disease and/or treatment, has been shown to significantly impact treatment outcomes, including survival.[2]*

Acute and chronic bleeding, iron deficiency, as well as renal and oncological diseases may lead to preoperative anemia. Furthermore, if non-anemic hematinic deficiencies are also prevalent, they may hamper preoperative hemoglobin optimization and/or recovery from postoperative anemia.[3]

Modifiable risk
Considered a modifiable risk factor, anemia and hematinic deficiencies should be detected, and corrected before major surgical procedures. [3] Such an approach, generally referred to as patient blood management or PBM involves taking care of prospective surgical patients at risk for anemia, which includes detecting and treating anemia before surgery.

Preoperative oral iron may benefit prospective surgical patients with mild-to-moderate anemia, if there is sufficient time before the scheduled intervention (on average between 6 to 8 weeks) and the patients can adequately tolerate oral iron preparations.  In contrast, intravenous (IV) iron is preferentially used in cases of moderate-to-severe iron deficiency anemia and may be used in combination with erythropoiesis-stimulating agents a relatively short time before surgery for nonelective procedures.

Available data shows that anemia is more common after surgery than before surgery. This is, in part, due to surgery-associated blood loss, inflammation-induced blunted erythropoiesis, and/or preexisting anemia. However, multiple studies have shown that postoperative oral IV iron may be of little value and is rife with gastrointestinal adverse events.[3]

Risk of allogenic blood transfusion
Despite the reported benefits of intravenous (IV) iron therapy for correcting iron deficiency anemia before any major surgery and the evidence thereof, perioperative allogenic blood transfusions are still considered the only real and viable treatment option. Therefore, to compensate for severe and life-threatening blood loss during surgery, doctors generally opt to use allogenic blood transfusion. While allogenic blood transfusions may indeed work, they also carry serious risks, including the development of blood clots, hospital-acquired infections, allergic reactions, and pulmonary complications. Blood transfusion may further increase the likelihood of cardiac complications, longer hospital stays, and higher mortality among the patients, hence the growing number of physicians are opting to reserve the practice of allogenic blood transfusion to severe and critical cases (Hb level < 7 g/dl).

In addition, it can be difficult to find a donor match if a patient has certain antibodies or a condition such as sickle cell disease. As a result, healthcare professionals, including a growing number of physicians and (clinical) researchers have long sought strategies to minimize the use of allogenic blood transfusions. Alternative interventions to treat preoperative anemia such as the use of iron supplementation or replenishment (oral / IV) with or without erythro-stimulating agents (ESAs; like recombinant human erythropoietin / r-HuEPO, epoetin alfa), in the treatment of prospective surgical patients, could help decrease the use of allogenic blood transfusion and prove beneficial from both the clinical and economic standpoint. [4]**

Understanding iron replacement versus allogeneic blood transfusion
However, while preoperative anemia is associated with adverse perioperative outcomes, the benefits of treatment with iron replacement versus allogenic blood transfusion remain uncertain.

To better understand the benefits of preoperative iron-deficiency anemia treatment, Johns Hopkins Medicine researchers conducted a propensity-matched retrospective cohort *** analysis from 2003 to 2023 using data from TriNetX Research Network, a global network of health care organizations that pool de-identified patient information, which included 154,358 surgical patients over 18 years old diagnosis with iron-deficient anemia 3 months before surgery.

After matching the participating patients for the type of planned surgery as well as existing comorbidities, Johns Hopkins Medicine researchers compared a cohort of patients with preoperative IDA who were treated with preoperative intravenous (IV) iron but without allogenic blood transfusion (n = 77,179), with a cohort receiving preoperative allogenic blood transfusion but without IV iron (n = 77,179). As part of the study design, the primary outcome of the study was 30-day postoperative mortality with the secondary outcomes being 30-day morbidity, postoperative hemoglobin level, and 30-day postoperative allogenic blood transfusion.

Interpreting the results
Based on the results from this rigorous medical records study, Johns Hopkins Medicine researchers conclude that some patients with preoperative anemia have better outcomes if they get iron infusions before surgery rather than standard allogenic blood transfusions.

The findings, published July 22, 2024 edition of Anesthesia & Analgesia, contribute to mounting evidence that such iron infusions, which boost the production of a person’s own red blood cells, are better than relying on someone else’s blood.[5]

“Anemia is incredibly common, especially in surgical patients, and until recently the default treatment has been allogenic blood transfusion before the procedure,” noted Steven Frank, M.D., professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine.

“However, our retrospective study showed a benefit of iron infusions over preoperative blood transfusions in decreasing morbidity and mortality, increasing hemoglobin, and decreasing the need for (allogenic) blood transfusions,” Frank added.

The data were sorted into groups of patients who were treated with iron preoperatively but not with a blood transfusion, and patients who received a preoperative allogenic blood transfusion but no iron infusion. These infusions happened several weeks before a scheduled surgical procedure. Researchers then compared postoperative complication rates including respiratory problems, kidney issues, blood clots, infections and death rates.

Study results
Compared with allogenic blood transfusion, the use of preoperative IV iron was associated with an overall lower risk of postoperative mortality (n = 2550/77,179 [3.3%] vs n = 4042/77,179 [5.2%]; relative risk [RR], 0.63, 95% confidence interval [CI], 0.60–0.66), and a lower risk of postoperative composite morbidity (n = 14,174/77,179 [18.4%] vs n = 18,632/77,179 [24.1%]; RR, 0.76, 95% CI, 0.75–0.78) (both P = .001 after Bonferroni adjustment).

Furthermore, the study results demonstrated that compared with allogenic blood transfusion, IV iron was also associated with a higher hemoglobin in the 30-day postoperative period (10.1 ± 1.8 g/dL vs 9.4 ± 1.7 g/dL, P = .001 after Bonferroni adjustment) and a reduced incidence of postoperative allogenic blood transfusion (n = 3773/77,179 [4.9%] vs n = 12,629/77,179 [16.4%]; RR, 0.30, 95% CI, 0.29–0.31).

Summarizing these outcomes, Johns Hopkins Medicine researchers noted a 37% reduction in mortality and a 24% reduction in morbidity in patients who were treated with iron IV compared with those treated with allogenic blood transfusion. This finding means that patients receiving iron infusions may recover more quickly and fully from their surgical procedures without any added complications that may arise from a blood transfusion.

“The Joint Commission and the American Medical Association (AMA) named blood transfusion as the No. 1 overused procedure in 2012. For perspective, also on the list was antibiotic use to treat the common cold,” says Frank.

“Research shows reducing blood transfusions can improve patient outcomes, and providing patients with preoperative iron infusions is an easy way to do so,” Frank concluded.

The Johns Hopkins Medicine researchers hope that the outcomes of this the new study will encourage more widespread use of preoperative iron infusions in surgical patients. They also hope to examine if oral iron supplements garner the same outcomes as infusions.

Patient Blood Management
Treating preoperative anemia is one of several methods used in a comprehensive patient blood management program. Such a program, like the one at Johns Hopkins, can save blood and money while resulting in the same or better patient outcomes. In another recent publication, the researchers reported a substantial return on investment for their blood management program. They found that for every dollar spent to support the program, 7.5 dollars were saved or generated in a return.

Simple solutions
Simple things, like keeping patients warm and maintaining a lower blood pressure during surgery, or giving medications such as tranexamic acid, can reduce bleeding.

“In addition to treating preoperative anemia,” Frank says, “keeping the blood in the patient during surgery is one of the primary goals in any patient blood management program.”

Such programs, by reducing unnecessary transfusions, promote high-value practice by improving outcomes while reducing costs.

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Note: *** Blood loss during surgical procedures is independently associated with an increased risk of poorer clinical outcome. Hence, the use of hemostatic agents, and the use of minimally invasive surgical procedures can be instrumental in minimizing bleeding. To avoid adverse events when planning potentially high-blood-loss surgery (generally an expected blood loss of >500 mL), preoperative anemia is defined as hemoglobin <13 g/dL for both male and female patients. [6][7]

** Management of severe anemia in prospective surgical patients who, for religious reasons, may reject allogenic blood transfusion, a multifaceted approach with intravenous iron infusions, recombinant human erythropoietin, vitamin B₁₂, folate, and vitamin C, may be beneficial. [8]

*** In this study, propensity-score matching was performed for age, ethnicity, race, sex, overweight and obesity, type 2 diabetes (T2DM), hyperlipidemia, essential hypertension, heart failure, chronic ischemic heart disease, neoplasms, hypothyroidism, chronic kidney disease, nicotine dependence, surgery type, and lab values from the day of surgery including ferritin, transferrin, and, to account for the severity of anemia,  a hemoglobin level split into low (<7 g/dL), medium (7–<12 g/dL), and high (≥12 g/dL).

Reference
[1] Kumar A, Sharma E, Marley A, Samaan MA, Brookes MJ. Iron deficiency anaemia: pathophysiology, assessment, practical management. BMJ Open Gastroenterol. 2022 Jan;9(1):e000759. doi: 10.1136/bmjgast-2021-000759. PMID: 34996762; PMCID: PMC8744124.
[2] Littlewood TJ. The impact of hemoglobin levels on treatment outcomes in patients with cancer. Semin Oncol. 2001 Apr;28(2 Suppl 8):49-53. doi: 10.1016/s0093-7754(01)90213-1. PMID: 11395853.
[3] Gómez-Ramírez S, Bisbe E, Shander A, Spahn DR, Muñoz M. Management of Perioperative Iron Deficiency Anemia. Acta Haematol. 2019;142(1):21-29. doi: 10.1159/000496965. Epub 2019 Apr 10. PMID: 30970362.
[4] Ionescu A, Sharma A, Kundnani NR, Mihăilescu A, David VL, Bedreag O, Săndesc D, Dinu AR, Săndesc MA, Albulescu N, Drăgoi RG. Intravenous iron infusion as an alternative to minimize blood transfusion in peri-operative patients. Sci Rep. 2020 Oct 27;10(1):18403. doi: 10.1038/s41598-020-75535-2. PMID: 33110237; PMCID: PMC7591902.
[5] Choi UE, Nicholson RC, Thomas AJ, Crowe EP, Ulatowski JA, Resar LMS, Hensley NB, Frank SM. A Propensity-Matched Cohort Study of Intravenous Iron versus Red Cell Transfusions for Preoperative Iron-Deficiency Anemia. Anesth Analg. 2024 Jul 22. doi: 10.1213/ANE.0000000000006974. Epub ahead of print. PMID: 39037926. https://journals.lww.com/anesthesia-analgesia/abstract/9900/a_propensity_matched_cohort_study_of_intravenous.871.aspx
[6] Mueller MM, Van Remoortel H, Meybohm P, Aranko K, Aubron C, Burger R, Carson JL, Cichutek K, De Buck E, Devine D, Fergusson D, Folléa G, French C, Frey KP, Gammon R, Levy JH, Murphy MF, Ozier Y, Pavenski K, So-Osman C, Tiberghien P, Volmink J, Waters JH, Wood EM, Seifried E; ICC PBM Frankfurt 2018 Group. Patient Blood Management: Recommendations From the 2018 Frankfurt Consensus Conference. JAMA. 2019 Mar 12;321(10):983-997. doi: 10.1001/jama.2019.0554. PMID: 30860564.
[7] Busetto L, Dicker D, Azran C, Batterham RL, Farpour-Lambert N, Fried M, Hjelmesæth J, Kinzl J, Leitner DR, Makaronidis JM, Schindler K, Toplak H, Yumuk V. Practical Recommendations of the Obesity Management Task Force of the European Association for the Study of Obesity for the Post-Bariatric Surgery Medical Management. Obes Facts. 2017;10(6):597-632. doi: 10.1159/000481825. Epub 2017 Dec 6. PMID: 29207379; PMCID: PMC5836195.
[8] Ruan N, Shi C, Al-Momani Z, Jaber F, Ghaly R, Wooldridge D. Management of Severe Anemia in a Jehovah’s Witness Patient With Lung Abscess Secondary to Malpositioned Laparoscopic Adjustable Gastric Band: A Case Report. J Investig Med High Impact Case Rep. 2024 Jan-Dec;12:23247096241231649. doi: 10.1177/23247096241231649. PMID: 38353220; PMCID: PMC10868478.

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DOI: 10.14229/onco.2024.07.30.001