Parenteral iron for preoperative iron deficiency anemia: A safe choice?

A 70-year-old woman is referred by an orthopedic surgeon for preoperative evaluation for bilateral total hip arthroplasty scheduled in four weeks. Her medical history is positive for osteoarthritis, well-controlled hypertension, and remote in situ breast cancer post-lumpectomy and post-radiation with no active recurrence. Her mother had Alzheimer's dementia. She is a non-smoker and drinks alcohol occasionally (30 oz of red wine per week). She has taken 25 mg of hydrochlorothiazide daily for the past 10 years. For the past six months, she has taken 500 mg of naproxen twice daily and 650 mg of acetaminophen four times a day for hip pain.

The patient is able to climb one flight of stairs if pain is well controlled and denies chest pain, shortness of breath, palpitations, dizziness, pallor, diaphoresis, syncope or cyanosis.

Her physical examination is relevant for normal vital signs, minimal conjunctival pallor and decreased bilateral hip flexion and abduction. Otherwise it is unremarkable.

Laboratory results showed a hemoglobin level of 9.9 g/dL, a hematocrit of 30% red blood cells, and a platelet count of 400 k/uL. Her basic metabolic panel, urinalysis, liver function panel and coagulation profile were normal.

Upon further discussion, the patient reports no melena, hematochezia, rectorrhagia, hematemesis, abdominal pain, hematuria, nocturnal diaphoresis, and lymphadenopathy or weight loss. She has no diarrhea and denies gluten intolerance. She has kept a mostly vegetarian diet for the past year to lose weight due to osteoarthritis.

Given that the patient will undergo bilateral hip replacement, it is expected she will lose at least 2 to 3 g/dL of hemoglobin; she is at risk of allogeneic blood transfusion if levels drop below 7 g/dL. The patient was told about this risk and requested blood storage for “auto-transfusion.”

Following our institutional guidelines for preoperative anemia evaluation, further studies were obtained to determine the etiology of the anemia and whether it could be corrected prior to surgery (see Table 1).

The results were consistent with iron deficiency anemia and the patient was started on oral iron supplementation—dietary as well as pharmacological—of 325 mg of iron sulfate, three times daily. A stool sample was negative for occult blood.

Given the proximity of surgery, it was recommended to administer parenteral iron to replenish the patient's iron stores. A regimen of 200 mg of intravenous iron sucrose every other day for five doses was started (total dose, 1 g). Ten days after the last dose of IV iron, her hemoglobin was 12.5 g/dL and her hematocrit was 36%. She continued with the oral iron supplementation and underwent surgery uneventfully with no requirement of allogeneic blood transfusion.

After surgery, the patient was referred for further investigation of iron deficiency by her primary care physician; the evaluation showed only erosive gastritis with normal duodenal biopsy, negative celiac serology and a normal colonoscopy. Dietary teaching regarding iron-rich food was provided as well.

What is the significance of perioperative anemia?

Anemia is a strong risk factor for mortality, morbidity and poor outcomes in surgical patients. In the last decade, its management has shifted away from allogeneic blood transfusion. There is a wide variation in the reported prevalence of anemia in this population (from 5% to 76%), which depends on a variety of factors, such as the patient's comorbid conditions, the surgical procedure and its associated blood loss, and cutoff hemoglobin values. In addition, the prevalence of anemia increases with patient age and is higher in women than in men (1-3).

In the perioperative setting, preoperative hemoglobin values are correlated with the risk of death at 30 days after surgery; low hemoglobin levels have the most significant impact on patients with cardiovascular disease (4). In addition, even mild anemia is independently associated with increased comorbid events (cardiac events, pneumonia, urosepsis, venous thromboembolism, postoperative delirium, etc.) at 30 days post-surgery (5).

What is the role of a blood management program in the perioperative setting?

Blood transfusion to correct anemia is currently considered a marker of poor outcomes in medicine for multiple reasons. In the current state of a decreasing donor pool, arbitrary use of blood impedes effective resource allocation. It is associated with serious complications (e.g. transfusion-related acute lung injury, immune-modulation, transfusion-associated circulatory overload), and there is substantial cost associated with the blood banking process. In addition, recent studies have shown that a blood-restrictive approach is associated with improved outcomes in hip surgery patients (6).

Medical centers with high surgical volumes are expected to have a more careful and parsimonious approach to blood utilization and to reexamine their current perioperative transfusion practices. This has triggered an aggressive blood management program to minimize perioperative blood utilization. In addition, The Joint Commission recently endorsed measures for appropriate blood management (7).

Blood management is a patient-centered standard of care whereby strategies and techniques are used to reduce, eliminate or optimize blood transfusions to improve patient outcomes. It ensures safe, efficient use of the many resources involved in the complex process of blood component therapy. Its objectives are the translation of evidence into clinical practice to minimize blood utilization, ensure consistency among different physicians' practice behavior and implement preoperative treatment focused on the etiology of anemia as a “best practice” for elective surgical patients. Perioperative blood management is poised at the confluence of patient safety, resource utilization and system integration, with consequent improvement in the overall quality of care (8-10).

How do we approach perioperative iron deficiency anemia?

In this case, we know that the patient's anemia is related to iron deficiency because she has low iron levels, low transferrin saturation and low ferritin; in addition her folate and vitamin B12 stores are normal. Iron deficiency can be measured by assessment of iron storage as well as erythropoiesis (11-13).

Iron storage is assessed by:

  • iron levels,
  • total iron-binding capacity,
  • transferrin saturation and
  • ferritin.

Erythropoiesis is assessed by:

  • hemoglobin/hematocrit,
  • average red blood cell size/hemoglobin amount per red blood cell,
  • red blood cell distribution and
  • reticulocyte count.

The indication to treat preoperative anemia depends on the severity of the anemia, as well as the expected surgical blood loss. For instance, if a patient has currently a hemoglobin level of 9 g/dL and is expected to lose more than 500 to 1000 mL of blood, there is an increased likelihood of dropping the hemoglobin to critical values (<7 g/dL) where transfusion is indicated. In this group of patients, the hemoglobin should be optimized, raising it by 2 to 3 g/dL preoperatively, to compensate for the expected postoperative drop and attempt to prevent the critical transfusion threshold.

Based on multiple studies in the surgical population and patients with chronic renal failure, the current recommended cutoff limits to provide parenteral iron supplementation are transferrin saturation less than 20% and ferritin less than 100 ng/mL; however, in patients with chronic renal disease, the cutoff limits to continue parenteral iron supplementation is a transferrin saturation less than 50% and ferritin less than 800 ng/mL (14).

How do we determine coexistence of anemia of chronic disease and iron deficiency?

Until recently, we had no practical studies to determine the coexistence of anemia of chronic disease and iron deficiency anemia. The assay of soluble transferrin receptor (sTfR) is now an extremely valuable tool in this situation, where sTfR levels will be raised in the presence of iron deficiency and where ferritin and transferrin levels are altered by the presence of inflammation (15, 16).

At the Cleveland Clinic, the STfR reference range is 1.9 to 4.4 mg/L; its reference intervals have not been established for pregnant females, patients under 18 years of age, and recent or frequent blood donors.

Is oral iron bioavailability sufficient to optimize patients?

Although oral iron replacement is a valid therapeutic choice, it is very inefficient given its erratic GI absorption. For example, in patients with chronic medical diseases such as uremia, multiple factors impair the enteral bioavailability of iron, such as bacterial overgrowth, chronic GI bleeding, platelet dysfunction, use of antiplatelets, frequent phlebotomy, proteinuria and increased iron utilization (use of erythropoietin-stimulating agents). In addition, other factors may impair iron absorption, such as celiac disease, whose prevalence is increasing given a higher index of detection (17, 18).

Is intravenous iron a safe medication? What evidence supports its use?

Multiple studies have been done in surgical patients, including cardiac, gynecologic, orthopedic and colorectal surgery. Most are observational studies, and there are few randomized controlled trials. On average, an administration of an IV iron dose of 1000 mg raises the hemoglobin by approximately 2.0 g/dL and even resolves the anemia in up to 58% of cases. The transfusion rate is decreased by 66% and the infection rate by 55% (19-23).

Oral versus parenteral iron administration has been compared in gynecologic patients, and patients who received IV iron sucrose had an increase in hemoglobin up to 3.0 g/dL after four weeks, compared with 0.8 g/dL in patients taking oral iron. In addition, in the IV iron group, the target hemoglobin was achieved in 76% of the patients, compared with only 11.5% of the patients taking oral iron (24, 25).

The Network for Advancement of Transfusion Alternatives (NATA), a European organization focused on blood management, proposes using preoperative IV iron in patients with ferritin less than 100 ng/mL, transferrin saturation less than 20%, or expected blood loss above 1500 mL. The cutoff limit to avoid further IV iron administration is when ferritin levels are above 300 ng/ml and transferrin saturation is above 50%, or when there is acute infection (26).

Are intravenous iron preparations safe?

The administration of iron requires its incorporation into a carbohydrate shield that can stabilize it and favor its absorption and incorporation into the reticuloendothelial system. Initial IV iron preparations, which were made using high-molecular-weight dextran, were associated with presumed anaphylactic reactions; this delayed widespread use until recently (27).

The development of newer non-dextran IV iron preparations in the past 20 years has increased use of parenteral iron. The current most common preparations are ferric gluconate and iron sucrose. Patients who had reactions with ferric gluconate have not had elevation in tryptase levels, which rules out an anaphylactic reaction (28).

The most commonly used preparations can be seen in Table 2.

The most common adverse reactions associated with newer parenteral preparations are related to transient capillary leak syndrome (nausea, hypotension, tachycardia, chest pain, dyspnea and edema). However, these reactions are dose dependent and will rarely occur with the currently dispensed parenteral iron dosage (ferric gluconate, 125 mg/d; iron sucrose, 200 mg/d).

From 2001 to 2003, the FDA has documented 30 million doses of IV iron. Eleven people who received a dose have died, and there have been 1,141 total adverse effects (most commonly anaphylactoid-type reactions, which are generally dose dependent). The rate of adverse effect is as follows (14, 31):

  • iron sucrose, 0.6 per million doses
  • ferric gluconate, 0.9 per million doses
  • low-molecular-weight dextran, 3.3 per million doses
  • high-molecular-weight dextran, 11.3 per million doses

What is the economic impact of using intravenous iron compared with blood transfusions?

In general, when we calculate the deficit of iron in an average patient with hemoglobin of around 10 to 11 g/dL, the iron deficit is approximately 1 to 1.5 g. This is the rationale to supplement a whole gram of iron preoperatively, which generally elevates the hemoglobin by around 2 g/dL.

Based on this dose, the cost of IV iron versus blood (with 1 g of iron) is as follows:

  • iron dextran, approximately $377/g
  • iron gluconate, approximately $688/g
  • iron sucrose, approximately $688/g
  • blood transfusion, approximately $761 ± 294 per unit (approximately 250 mg of iron per unit) × 4 = $3,044/g

In addition, the cost of packed red blood cells should include all the blood bank management, skilled nursing care and ancillary services (32).

What is the protocol for preoperative blood management and parenteral iron utilization?

At the Cleveland Clinic, patients with any of the following criteria are considered ideal for referral to the program:

  • suspected or known anemia (hemoglobin <12 g/dL)
  • high expected blood loss based on the nature of the surgery
  • requirement of multiple units of blood transfusions in recent surgeries
  • preference for no blood transfusion (e.g., for religious beliefs)

Early referral is encouraged to allow sufficient time to schedule treatments and follow up. This should be, on average, three to four weeks. An order for referral to blood management is available through computerized physician order entry (CPOE) in the electronic health record. The ideal workup should include any substrate that may be replaced, such as:

  • iron and total iron-binding capacity,
  • ferritin,
  • reticulocyte count (to be able to compare after replacement),
  • serum folic acid (in patients >60 years of age) and
  • vitamin B12 (in patients >60 years of age)

Subsequently, these anemia-specific laboratory tests are reviewed and a specific intervention is pursued, which generally includes:

  1. 1. replacement of iron, vitamin B12 or folate;
  2. 2. use of erythropoiesis-stimulating agents, mostly in patients with normal iron stores who decline transfusion due to religious beliefs or are scheduled for hip or knee replacement; and
  3. 3. provision of education regarding sources of iron and the importance of adequate nutrition.

Scheduling administration of parenteral iron or erythropoiesis-stimulating agents is patient-centered and highlights the importance of system integration across an expansive health care system. Based on patients' geographic preference, he or she receives parenteral iron in a blood management center, which can be a dedicated blood management clinic, a dialysis unit, or a hematology office. Patients complete their treatment and seamlessly transition back for follow-up tests (10).

The process for intravenous iron replacement, the most common procedure we pursue, is as follows:

  1. 1. The patients are referred to the blood management program by the surgeon and iron deficiency is identified by performing the laboratory work-up mentioned earlier.
  2. 2. The physician reviewing the labwork and confirming iron deficiency anemia places an order in the CPOE. Generally, for outpatients, the formula used in our system is iron sucrose, 200-mg IV push every other day for a total of five doses (to administer a total of 1 gram).
  3. 3. Generally repeat hemoglobin is obtained one week to 10 days after the last dose of iron. Usually this procedure yields an average increase of 2 g/dL of hemoglobin.
  4. 4. The primary care physician is notified for further workup of iron deficiency anemia once the surgery is completed.

Is auto-transfusion an entirely safe procedure?

The shelf life of the transfused blood directly affects clinical outcomes. Although currently the FDA allows blood to be stored for a maximum of 42 days, a study of cardiac surgery patients who were transfused intraoperatively found that those who received blood stored for more than 14 days had significantly higher rates of sepsis, prolonged intubation, renal failure, in-hospital mortality, and one-year mortality compared with those who received blood stored for 14 days or less (33).

Differences in outcomes depending on blood age are generally attributed to the so-called “storage defect”: Older blood loses components such as 2,3-DPG and adenosine diphosphate, the red blood cells lose deformability, and buildup of cytokines and free hemoglobin also occurs (2).