A double-blind randomised controlled trial reported in the Lancet has called into question the routine use of erythropoietin (EPO) treatment of patients with traumatic brain injury. The international research study carried out in more than 600 patients across seven countries was led by Professor Alistair Nichol, UCD Professor of Critical Care Medicine at St Vincent’s University Hospital and Co-chair of the Study Management Committee based in Melbourne Australia. The group has concluded that erythropoietin does not improve functional outcome at six months as would be shown by a reduction in the number of patients with an Extended Glasgow Outcome Scale (GOS-E) measure of 4 or lower. While there are some indications that EPO treatment might reduce mortality in patients with traumatic brain injury, rigorous future investigations are required in this patient population before its routine use could be recommended.
Professor Nichol noted,
This study would appear to rule out calls for the routine use of EPO in patients with traumatic brain injury (TBI). EPO gained notoriety as a performance-enhancing drug amongst distance runners and cyclists due to the way in increases the amount of oxygen that the blood can carry. However, EPO has many different affects in the body, such as encouraging new brain cell growth, which is independent of effects on blood. And early research results suggested that it might improve patient outcomes after trauma. While our study, a double-blind, placebo-controlled clinical trial, found no improvement as measured by the amount of patients who could live independently after TBI, it did show a trend towards lower mortality with EPO.
As patients with traumatic brain injury have a high incidence of proximal deep venous thrombosis, careful clinical and diagnostic monitoring is necessary. This latest study objectively described the incidence of proximal deep venous thrombosis in patients with moderate or severe traumatic brain injury. The results of an adjusted 6-month mortality analysis suggest a potential reduction in mortality in patients with traumatic brain injury who receive erythropoietin treatment. However, further investigation is required to examine this clinical outcome before investigators could encourage routine use of erythropoietin in traumatically injured patients.
Evidence before this Study
At the time when the Eryrthropoietin in Traumatic Brain Injury (EPO-TBI) protocol was developed, two large randomised controlled trials studying the effect of erythropoietin in critically ill patients as a transfusion-sparing agent had reported significantly lower mortality with erythropoietin compared with placebo in subgroups of critically ill trauma patients.
Those findings had led to calls for the routine use of erythropoietin in trauma patients. Preclinical data suggested that neurocytoprotective effects attributable to erythropoietin had the potential to ameliorate secondary brain injury. The EPO-TBI Investigators postulated that the recorded reduction in mortality could be attributable to these effects and therefore undertook a multicentre randomised controlled trial. Iinvestigators used a factorial study design to assess the effect of erythropoietin and transfusion thresholds on neurological recovery in patients with traumatic brain injury. Their findings showed no improvement in neurological function of survivors at 6 months. Fewer deaths at 6 months were recorded in patients who received were recorded in patients who received erythropoietin. However, this difference was not statistically significant. The study enrolled 200 patients and was therefore probably underpowered to detect clinically important differences in patient-centred outcomes and did not actively screen for deep venous thrombosis.
Added Value of this Study
The study reported by Nichol et al provides high-level evidence that, after traumatic brain injury, erythropoietin does not improve functional outcome at 6 months as would be shown by a reduction in the number of patients with a GOS-E of 4 or lower. It also, for the first time, objectively describes the incidence of proximal deep venous thrombosis in patients with moderate or severe traumatic brain injury. The results of the adjusted 6-month mortality analysis suggest a potential reduction in mortality in patients with traumatic brain injury who receive erythropoietin treatment, especially when considered in conjunction with those of the other published randomised controlled trials in this patient group, but this effect remains uncertain. The findings also add to the body of evidence suggesting that erythropoietin might improve survival in patients with brain trauma. Further investigation of EPO in this patient group is required.
Commenting on the study, Graham Love the Chief Executive of the Health Research Board said,
I would like to congratulate Professor Nichol and his team on their contribution to this significant finding and it’s publication in the Lancet. Sometimes ruling a treatment out, will make as big an impact on patient care and health service delivery, as confirming a new discovery.
In either case, what is crucial to the delivery of improved patient care is the capability to conduct clinical trials to the highest international standards.
Professor Nichol recently won a substantial award from the HRB to dramatically increase the capacity of the HRB Irish Critical-Care Clinical Trials Group. I would hope that this is just the start of a very long and very productive cycle of results that will constantly improve and enhance the delivery of quality care to patients in Ireland and internationally,
HRB Irish Critical Care Clinical Trials Group
The HRB Irish Critical-Care Clinical Trials Group (ICC-CTG) led by Professor Alistair Nichol, UCD Professor of Critical Care Medicine at St Vincent’s University Hospital. Thousands of critically ill patients pass through Irish intensive care units (ICU) each year. Sadly the nature of their conditions can often result in death, or mean they survive with a long term disability. The HRB Irish Critical-Care Clinical Trials Group aims to bring together doctors, nurses and researchers to test new treatments that can improve outcomes for these patients. Prof Nichol and his Colleagues in the Irish Critical Care Trials Group and Beaumont hospital (Dr Rory Dwyer, Dr James O’Rourke and Dr Criona Walsh) were able to enroll patients in Ireland into this study. Furthermore, Prof Nichol’s collaborations with the Australian and New Zealand Intensive Care Research Centre in Melbourne has facilitated the conduct of these world-class international studies in Ireland.
Our network will offer ICU patients the highest quality care, give them access to the latest innovations in intensive care and ensure future patients benefit from the lessons learned in national and international research. The group includes the academic leadership in our specialty and encompasses more than 75% of all the ICU capacity in Ireland,
says Professor Alistair Nichol, Chair of the network who is UCD Professor of Critical Care Medicine at St Vincent’s University Hospital and Monash University Melbourne.
Initial work to be addressed by the ICC-CTG:
- PHARLAP- will establish whether the way we ‘set’ the breathing machine helps reduce further lung damage in patients with a severe lung disease (Acute Respiratory Distress Syndrome or ‘ARDS’). A small research study by some of the group members showed that reducing the size of each breath in conjunction with an occasional sustained deep breath through the ventilator appeared to reduce further damage to the lungs. But the study size was too small to make definitive conclusions. So a larger study, which this HRB network now makes possible, will assess whether patients with ARDS are better off on this PHARLAP breathing strategy.
- TRANSFUSE- Does giving ‘fresher’ blood versus ‘older blood’ in transfusions make a difference to patients who are admitted to ICU. This study will result in a worldwide practice change if it finds freshest available blood use is best for ICU patients, but if there is no difference this will provide great confidence to blood banks that current practice is optimal.
- The network will also carry out test studies to determine which of the common treatments used to help reduce bleeding from the stomach when people are very unwell is best.
- The network will also provide extra training for junior doctors and nurses in Ireland, so they can be future world leaders in research within the Irish health system.