Erythropoietin

Reviewed and revised 12 September 2014

OVERVIEW

• Erythropoietin (EPO) is an endogenous hormone that stimulates erythrocytosis
• it’s role in critical illness is unclear and is limited by the complications of hematopoietic activation (e.g. VTE)

PHYSIOLOGY

• EPO is an endogenous hormone primarily produced by the kidney in response to hypoxia and other stimuli
• local production of EPO within the brain in response to hypoxia or ischemia also occurs, and protects neurons against injury via an anti-apoptotic effect
• erythropoietic effects of EPO are mediated by the classical EPOR, while the tissue-protective effects of EPO may be mediated by a heterocomplex between EPOR and the βcR

ERYTHROPOIETIN AGONISTS / ERYTHROPOIETIN STIMULATING AGENTS

• ESAs currently in use include Darbepoetin alfa, Epoetin alfa, Epoetin beta, Methoxy pegepoetin beta
• usually given IV or SC
• dose and dosing interval varies with the indication

INDICATIONS IN NON-CRITICAL ILLNESS

ESAs are indicated for the following conditions:

• Anaemia of chronic renal failure
• Chemotherapy-induced anaemia in non-myeloid malignancy
• Increasing yield of autologous blood collection
• Prevention of anaemia of prematurity where birth weight is 750–1500 g and gestational age <34 weeks

ROLE OF EPO IN CRITICAL ILLNESS

• Anaemia of critical illness is characterised by blunted EPO production and altered iron metabolism
• EPO use has been shown to reduce transfusion requirements (Corwin et al, 2002 in JAMA), but there in no proven benefit in terms of clinical outcome
• A potential benefit may exist in patients who are in ICU for > 1 wk, but data are lacking
• in a pilot study there was a reduced incidence of AKI after coronary artery bypass graft surgery (Song et al, 2009)
• The ANZICS study of EPO in TBI is currently underway… (there was a trend to mortality benefit in trauma patients in Corwin et al,2007 in NEJM)
•  local generation of EPO in the brain may limit the extent of ischemic injury (potential future role for EPO derivatives with non-hematopoietic effects)

DISADVANTAGES

These include:

• lack of evidence of benefit in critical illness
• ideal dose is unknown (different receptor effects and adverse effects may be dose-dependent
• potential for adverse effects

Known adverse effects of ESAs include:

• red cell aplasia
• EPO resistance
• thromboembolic complications (e.g. use before elective surgery contraindicated within 1 month of MI or stroke;thrombosis of vascular access in patients on dialysis, VTE (MI, TIA, stroke are rare))
• hypertension
• local pain if given SC
• headache, flu-like symptoms, bone pain, myalgia, fever, rash, hypotension, peripheral oedema, nausea, vomiting, diarrhoea, dyspnoea
• potential risk of stimulating growth of some malignancies

EVIDENCE

There is no high level evidence of patient-orientated outcome benefit for EPO in critical illness

Corwin, H. L., et al (2002) “Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial (EPO Critical Care Trials)” JAMA, 288:2827-2835

• MC DB RCT
• n = 1302
• weekly recombinant EPO (40,000IU) vs placebo
• 20% reduction in RBC transfusion in the treatment group

Corwin, H. L, et al (2007) “Efficacy and Safety of Epoetin Alfa in Critically Ill Patients” NEJM, 357:10 pages 965-76

• MC DB RCT
• n = 1460
• medical, surgical and trauma patients
• EPO vs placebo for 3 weeks
• primary outcome: RBC transfusion
• secondary outcomes: mortality, Hb
• Findings:
  -> no change in RBC transfusion
  -> higher Hb
  -> trend towards mortality advantage (more pronounced in trauma patients)
  -> significant increase in thrombotic events
  -> provided basis for EPO-TBI study

Robertson et al, 2014

• Administration of EPO to patients with TBI who are unable to follow commands did not improve mortality or neurological status compared to placebo.
• The study was under-powered, may have had poor external validity due to the large number of exclusions and outcomes were susceptible to reporting bias

AN APPROACH

• ESAs are indicated for certain non-critical illness conditions
• There is no role for use of these agents in the critically ill outside of these indications except in the context of a clinical trial

References and Links

Journal articles

• Patel NS, Nandra KK, Thiemermann C. Bench-to-bedside review: Erythropoietin and its derivatives as therapies in critical care. Crit Care. 2012 Jul 26;16(4):229. PMC3580677.

FOAM and web resources

• INTENSIVE — Robertson et al, 2014: EPO, transfusion and TBI (2014)