RCT of Goal-directed Iron Supplementation of Anemic, Critically Ill Trauma Patients, With and Without Oxandrolone

The inflammatory response associated with traumatic critical illness rapidly induces a
functional iron deficiency, characterized by hypoferremia, decreased transferrin saturation
(TSAT), hyperferritinemia, and iron-deficient erythropoiesis (IDE). These derangements in
iron metabolism are primarily related to upregulation of the iron regulatory protein
hepcidin, which inhibits ferroportin-mediated release of iron from both duodenal enterocytes
and macrophages. The resultant functional iron deficiency both contributes to intensive care
unit (ICU) anemia and increases the packed red blood cell (pRBCs) transfusion requirement.

Treatment strategies for functional iron deficiency in critically ill patients may be divided
broadly into (1) iron supplementation and (2) mitigation of the effects of hepcidin. The
goals of treatment are to reverse the serum iron debt, eliminate IDE, improve anemia, and
ultimately decrease pRBCs transfusions. Given that approximately 90% of critically ill trauma
patients with an ICU length of stay (LOS) ≥ 7 days receive at least one pRBCs transfusion,
any strategy that has even a modest impact upon the transfusion requirement is likely to
improve overall health outcomes substantially.

Issues surrounding iron supplementation of critically ill patients include formulation, dose,
route of administration, hepcidin antagonism, and mitigation of the complications of iron
overload, particularly infection. Our first 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,
we compared intravenous iron sucrose 100 mg thrice weekly to placebo among critically ill
trauma patients (NCT01180894, NTI-ICU-008-01) [8]. Iron supplementation using this generic
dosing scheme did not impact the serum iron concentration, TSAT, IDE, anemia, or pRBCs
transfusion requirement. Rather, iron supplementation accumulated as ferritin as evidenced by
a significantly increased serum ferritin concentration in the iron as compared to the placebo
group at all time points. Iron supplementation did not increase the risk of infection in
either trial, despite a relatively high incidence of marked hyperferritinemia (serum ferritin
concentration > 1,000 ng/mL) in the iron group.

The results of these trials suggest that iron supplementation alone, and using a generic
dosing scheme, is ineffective. The current pilot trial aims to build upon the findings of the
prior two RCTs by incorporating both goal-directed iron supplementation and hepcidin
antagonism. The hypothesis is that the combination of goal directed iron supplementation and
hepcidin mitigation will safely eliminate both the serum and bone marrow iron debt of anemic,
critically ill trauma patients with functional iron deficiency.

Inclusion Criteria:

1. Informed consent from patient or patient representative.

2. Trauma patient

3. Anemia (hemoglobin < 12 g/dL).

4. Functional iron deficiency:

1. Serum iron concentration < 40 ug/dL

2. TSAT < 25%

3. Serum ferritin concentration > 28 ng/mL

5. < 72 hours from ICU admission.

6. Expected ICU length of stay ≥ 7 days.

Exclusion Criteria:

1. Age < 18 years.

2. Active bleeding requiring pRBCs transfusion.

3. 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. Substantial levels of hyperferritinemia (serum ferritin
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.

4. 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.

5. Chronic inflammatory conditions (e.g., systemic lupus erythematosis, rheumatoid
arthritis, ankylosing spondylitis).

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

7. Pre-existing hepatic dysfunction (cirrhosis, non-alcoholic steatohepatitis, hepatitis)

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

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

10. Known or suspected carcinoma of the breast or prostate.

11. Nephrosis, the nephrotic phase of nephritis.

12. Hypercalcemia (serum calcium concentration > 10.5 mg/dL).

13. Pregnancy or lactation.

14. Legal arrest or incarceration.

15. Prohibition of pRBCs transfusion.

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

17. History of intolerance or hypersensitivity to either iron or oxandrolone.

18. Moribund state in which death was imminent.