Randomized Study Comparing Ferric Carboxymaltose to Iron Sucrose to Treat Fe Deficiency in the Surgically Critically Ill

The inflammatory response associated with surgical critical illness rapidly induces a
functional iron deficiency, characterized by hypoferremia, decreased transferrin saturation
(TSAT), hyperferritinemia, and iron-deficient erythropoiesis (IDE). This functional iron
deficiency both contributes to intensive care unit (ICU) anemia and increases the packed red
blood cell (pRBCs) transfusion requirement.

The goals of iron supplementation of critically ill surgical patients are to reverse the
serum iron debt, eliminate IDE, improve anemia, and decrease pRBCs transfusions. Issues
surrounding iron supplementation of this patient population include formulation, dose, route
of administration, and mitigation of the complications of iron overload, including infection.

The investigators first randomized clinical trial (RCT) of iron supplementation of critically
ill surgical patients compared enteral ferrous sulfate 325 mg thrice daily to placebo
(NCT00450177). Although a significant reduction in pRBCs transfusion requirement for the iron
group was observed, low injury severity, intolerance of enteral medications, and a
predominance of traumatic brain injury limited generalizability. In a second multicenter RCT,
the investigators compared intravenous iron sucrose 100 mg thrice weekly to placebo among
critically ill trauma patients (NCT01180894). Iron supplementation at this dose increased the
TSAT only marginally (and not above the normal range) and increased the serum ferritin
concentration significantly; however, there was no effect on IDE, anemia, or pRBCs
transfusion requirement. In no instance did iron supplementation increase the risk of
infection, despite a relatively high incidence of marked hyperferritinemia (serum ferritin
concentration > 1,000 ng/mL) in the iron group.

The severity of both the serum and bone marrow iron debts observed in these trials led us to
investigate alternative dosing schemes that deliver larger quantities of bioavailable iron
safely. Ferric carboxymaltose (FCM) is a novel iron-containing complex that allows for the
administration of a large replenishment dose of iron (up to 750 mg) over a short infusion
period. Several pharmacodynamic properties of FCM render it appealing for use in the
treatment of functional iron deficiency associated with surgical critical illness, including
a short infusion time, a controlled, sustained delivery of iron to target tissues over a
relatively long period of time (up to one week), and minimal hypersensitivity reactions.
Increased efficacy and comparable safety have been reported for FCM as compared to iron
sucrose for treatment of outpatients with iron-deficiency anemia. There are currently no data
regarding the efficacy of FCM for the indication of functional iron deficiency associated
with surgical critical illness.

The aim of the current pilot trial is to compare two novel dosing schemes for treatment of
functional iron deficiency in surgical ICU patients, both of which involve delivery of a
larger total dose of iron as compared to both NCT00450177 and NCT01180894. The investigators
hypothesize that iron supplementation with FCM, as compared to both iron sucrose and placebo,
is more effective and equally safe for replacing the serum iron debt.

Inclusion Criteria:

- Anemia (hemoglobin < 12 g/dL).

- Functional iron deficiency:

1. Serum iron concentration < 40 ug/dL

2. TSAT < 25%

3. Serum ferritin concentration > 28 ng/mL

- < 72 hours from ICU admission.

- Expected ICU length of stay ≥ 7 days.

Exclusion Criteria:

- Age < 18 years.

- Active bleeding requiring pRBCs transfusion

- Iron overload (serum ferritin concentration ≥ 1,500 ng/mL). The serum ferritin
concentration is an acute phase reactant that is increased during critical illness
regardless of total body iron [3]. Substantial levels of hyperferritinemia (serum
ferrinin concentration > 1,000 ng/dL) were observed in both NCT00450177 and
NCT01180894 without increased risk of infection and despite both low TSAT and IDE. For
these reasons, we believe that relative hyperferritinemia (serum ferritin
concentration 500 - 1,500 ng/dL) is neither harmful nor indicative of bone marrow iron
availability.

- Infection, defined using US Centers for Disease Control and Prevention (CDC)
guidelines, with the exception of ventilator-associated pneumonia (VAP), which is
defined as clinical suspicion for pneumonia along with a lower respiratory tract
culture with ≥ 105 colony forming units per mL.

- Chronic inflammatory conditions (e.g., systemic lupus erythematosis, rheumatoid
arthritis, ankylosing spondilitis).

- Pre-existing hematologic disorders (e.g., thalassemia, sickle cell disease,
hemophilia, von Willibrand's disease, or myeloproliferative disease).

- Macrocytic anemia (admission mean corpuscular volume ≥ 100 fL).

- Current or recent (within 30 days) use of immunosuppressive agents.

- Use of any recombinant human erythropoietin formulation within the previous 30 days.

- Pregnancy or lactation.

- Legal arrest or incarceration.

- Prohibition of pRBCs transfusion.

- Stay of ≥ 48 hours duration in the ICU of a transferring hospital.

- History of intolerance or hypersensitivity to iron.

- Moribund state in which death was imminent.