November 26th, 2015: Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised placebo controlled trial

Presented by Dr Adrian Jubb

Traumatic brain injury (TBI) management is currently focused on manipulating physiology to provide optimal conditions (based on our current estimate of what they might be) for prevention of secondary brain injury whilst mitigating the accumulation of systemic complications of critical illness. Despite many attempts, and ever increasing knowledge of cellular function, there is a complete absence of targeted drug therapies proven to limit damage and promote recovery.

Erythropoietin (EPO) is a 34kDa peptide, primarily but not exclusively produced in the kidney in adults, which increases red cell numbers by prevention of erythrocyte apoptosis. A trial looking at EPO and transfusion in critical care suggested benefit of EPO in trauma patients. A direct link to anaemia was not established by the Corwin study and the receptor for EPO is expressed on many cell types, including in the brain. Moreover, multiple animal studies have suggested that there may be a direct neuroprotective effect, possibly through the anti-apoptotic effects, albeit at doses ten times that currently deemed safe for use in humans for example Meng et al 2011 and reviewed by Ponce et al. This led to the hypothesis that EPO may be beneficial in the management of TBI through non-eruthrogenic

In this context the first thing to be clear about <a href=" simvastatin”>EPO-TBI is what it isn’t: the trial (comment) we will discuss this week does not examine the effect of EPO on anaemia (this was discussed to some extent in a previous article and journal club). The question in this study asked whether EPO improves neurological status after TBI as measured by the extended Glasgow outcome scale (GOS-E), while the secondary outcomes looking examined thrombosis and mortality. Unfortunately the short answer is no, neurological outcome was no different. Analysis based on injury severity did replicate a mortality benefit seen in by in the Corwin study.

Improved mortality, as we have seen before, is not such a helpful measure of success following brain injury – we need more sophistication in our longer term outcome measures. In this context, can we be sure that EPO is of no benefit in TBI? Maybe, it could be argued that patients were relatively under-dosed and possibly treated too late to be absolutely sure. The rate of DVT highlights the risk of TBI patients for this complication and makes it hard to argue for a higher dose regimen. Another option is non-erythrogenic fragments of the peptide, these may provide a future theraputic route to examine – there has been some success in TBI models.

For discussion:

Should we put EPO permanently to one side?

How might we gain more granularity in phenotyping of disease to enhance the chance of a positive outcome from RCTs?

Do we know what we are trying to achieve?

How do we feel about extrapolation from rodent to man?

How could it this be further explored, is there anything to add to our assessments based on this study given the high risk of DVT evident in both arms?

Some other useful links

WICS – The Bottom Line summary

Results of EPO-TBI presented at ESICM by Dr. Craig French, one of the authors

Video introducing EPO mimetics as a therapeutic concept

Summary of approaches to neuroprotection in Critical Care

Article review on Intensive Care Network by Celia Bradford

Journal Club on Intensive Blog