Iron-deficiency anaemia in the Emergency Room: a new opportunity for the use of intravenous iron

Anaemia is a common condition, affecting nearly three billion people. Many patients present to emergency rooms in need of evaluation for both acute and chronic anaemia, and allogeneic red cell transfusion remains a possible treatment. The use of intravenous iron in emergency departments as part of a fast-track anaemia management programme, elucidated by Quintana-Diaz et al.¹ in this issue of Blood Transfusion, has not yet been considered as a treatment option.

Problems with transfusions include infections, transfusion reactions, immune suppression, lung injury, alloimmunisation, significant expense, and the use of a limited and stressed blood supply. Properly prescribed and administered, intravenous iron is less expensive, more convenient, and safe, with an estimated incidence of serious adverse events of <1:200,000². Much of the limitation of the use of intravenous iron as an alternative to transfusion is due to the historical perception of danger, especially anaphylactic shock and death. Early formulations of parenteral iron were associated with a variety of toxic reactions, probably due to the release of labile free iron by iron-binding carbohydrate carriers which bound the elemental iron less tightly. However, newer formulations with complex carbohydrate shells consisting of a core of an iron-oxyhydroxy gel surrounded by a shell of carbohydrate that stabilises the gel, slows the release of iron and maintains the particles in colloidal suspension³, are much safer. These newer formulations of intravenous iron share this structure but differ from each other only by the size of the core and the identity of the surrounding carbohydrate⁴. This concept is supported by a recent study measuring labile free iron after standard bolus injections of intravenous iron in which levels of free iron were significantly lower with the newer formulations than with the older ones⁵.

Nonetheless there are always small amounts of labile free iron. In sensitive individuals the free iron can cause flushing, myalgias, swelling of the extremities and sometimes nausea. Generations of physicians who were trained that intravenous iron is dangerous, often misinterpret this minor, self-limited infusion reaction, which resolves in minutes without therapy, as a serious adverse event. Too often, it is then treated over-aggressively with antihistamines and pressors, transforming the minor infusion reaction into a haemodynamically significant serious adverse event. For example, diphenhydramine is often used as premedication, and can cause side effects such as somnolence, tachycardia, diaphoresis and hypotension, which, mistakenly attributed to the intravenous iron, leads to clinical confusion. It is only recently that admonitions to avoid diphenhydramine premedication have been published^6,7. However, in patients with a history of multiple drug allergies or asthma, in whom there is a higher incidence of infusion reactions, premedication with corticosteroids may be of benefit⁸.

The authors of the article in this issue of Blood Transfusion have previously reported on the use of intravenous iron for transfusion avoidance in common clinical settings. These include the peri-operative setting⁹, after knee replacement¹⁰, after total hip replacement¹¹, and after colorectal surgery¹². These are all examples of rational blood conservation and Patient Blood Management.

In their current study, they establish the benefit of the formation of a fast-track anaemia centre within emergency departments, employing a collaborative approach with emphasis on early intervention with intravenous iron (ferric carboxymaltose in this case)¹. Patients with moderate-to-severe anemia (<11 g/dL), usually due to chronic gastrointestinal bleeding or heavy uterine bleeding, were rapidly and thoroughly evaluated, with the prudent exclusion of active bleeding and haemodynamic instability. During the programme’s operational hours, the evaluation of iron deficiency included measurements of serum iron, total iron binding capacity, percent saturation of transferrin, and serum ferritin, with results reported on the same day. Patients not requiring immediate transfusion or hospitalisation were referred to the institution’s fast-track anaemia clinic.

The results were impressive. The use of intravenous iron was associated with a mean increment of haemoglobin concentration of 3.9 g/dL at 4 weeks in 149 out of 183 patients, translating into a response rate of 81%. By addressing the cause and using intravenous iron as replacement therapy, a far more physiological management of iron deficiency was achieved. The results, with a high level of statistical significance, demonstrate a sustained benefit of ongoing erythropoiesis, along with avoidance of allogeneic red cells and cost reduction while increasing convenience for patients and staff.

This study could be criticised for not having a control group. However, it would be unethical to not treat clinically significant anaemia. The marked improvement in haematological parameters, combined with what is already known about the benefits of iron infusion, argues against a placebo effect.

Muñoz et al. have shown that diagnosing and treating clinically significant anaemia in an acute and sub-acute setting is possible, beneficial, and safe. This opens the door to an untapped opportunity to improve patients’ care and reduce health care costs. Initially pilot programmes should be started at hospitals with large volumes of patients. Resource allocations would include appropriate space, a dedicated haematologist, capable and responsive laboratories, training time, pharmacies and key support personnel. The programme must be structured to facilitate, and not impede, emergency department flow. To do this, haematologists and emergency medicine physicians will need to work together in ways they typically have not done before. Although emergency physicians have a broad range of knowledge and skills, the administration of intravenous iron represents an innovative approach to the management of a large subset of patients. It would allow emergency physicians to manage anaemic patients more efficiently and reserve the use of red cell transfusions for those who urgently require them.

Furthermore, there is pressure on healthcare systems to reduce costs. While the actual substrate, packed red cells, is inexpensive or free, when administration and facility fees are factored in, two units of red cells cost several thousand Euros. By contrast the equivalent cost of a dose of intravenous iron is only several hundred euros.

Given the large number of complete blood counts ordered in emergency departments and the high prevalence of anaemia, another potential benefit of a fast-track programme is the earlier identification and treatment of mild-to-moderate anaemia which may be due to more serious underlying conditions. We urge our colleagues in both these fields to initiate a process, involving institutional support, to explore how a fast-track anaemia programme can be created in their respective facilities.