Improving outcomes of critically-ill patients with acquired brain injury

  • 24 January 2024
  • Professor Alistair Nichol on behalf of the Irish Critical Care-Clinical Trials Network (ICC-CTN)
  • Academic, Economic, Educational, Health, Political


Acquired brain injury (ABI) is a leading cause of death and disability worldwide. In Ireland, 19,000 new brain injuries occur annually, and 120,000 people currently live with an ABI. Brain injury occurs in 80% of patients resuscitated from cardiac arrest, and following a severe traumatic brain injury, 25% of patients die and 50% cannot live independently.

The ICC-CTN ABI Programme consists of seven major global studies, several of which are ongoing, that provide definitive evidence to guide clinicians providing care. The research, which was informed by patient need, addresses long-standing questions around key aspects of ABI care, including CO₂ management, temperature, drug therapy, oxygen, sedation, and blood pressure management. This has informed clinical guidelines, thereby improving outcomes for hundreds of thousands of patients, and reducing the healthcare and societal costs of ABI.

Research description

More than 10 years ago, the Irish Critical Care-Clinical Trials Network (ICC-CTN) began a programme of research into acquired brain injury (ABI), led by Professor Nichol. The research was initiated when the father of a son who died following a traumatic brain injury gave the team a personal insight into the impact of ABI on his son’s and his family’s life, asking for better treatments.

The team started by investigating different treatments for ICU patients with the poorest outcomes: those who have suffered severe traumatic brain injuries or out-of-hospital cardiac arrest. Since then, they have delivered 4 global studies (several others are ongoing), to determine effective treatments safely and definitively, using the highest standards of trial design. Together, the trials involved almost 5,000 patients across 22 countries.

The first of these, launched in 2015, was the largest global trial of a drug called “erythropoietin alfa” in traumatic brain injury. This study found that the drug did not reduce severe neurological outcomes, but may reduce mortality following multiple traumatic injuries (a question that the team is now exploring in ongoing research).

Two further global studies – one in 2018 and one in 2021 – determined that lowering a patient’s body temperature through targeted hypothermia does not improve outcomes for ABI. This definitively ended a resource- and cost-intensive practice believed to be beneficial for more than 20 years.

Finally, a 2023 study co-led by the ICC-CTN, found that allowing slightly raised CO₂ levels in the blood does not improve neurological outcomes or mortality among patients who are resuscitated after out-of-hospital cardiac arrest. This research provides the latest certainty that current CO₂ management practices are safe and effective, and that slightly elevated carbon dioxide levels in the blood is not dangerous.

The results of these trials inform the ICC-CTN’s ongoing programme of research to improve patient outcomes. As well as further research into the use of erythropoietin alfa in critically-ill trauma patients, this includes studies into brain oxygen monitoring and intervention in severe TBI, and optimal oxygen, temperature, sedation and blood pressure management in out-of-hospital cardiac arrest. Around 900 biological samples collected by the team will provide key insights into patient care and future treatments.

Alongside this, the team has worked with Irish charity ABI Ireland to establish two Irish ABI Patient and Public Involvement in Research (PPI) groups, in addition to their critical care group (ICC-PPI). The involvement of patients and their families is crucial for the research. The team works closely with PPI groups for a range of activities, including developing patient leaflets, improving the consent process, determining research priorities, and biological sampling. 

Research team and collaborators

  • The Irish Critical Care-Clinical Trials Network: team of clinician-researchers, project managers, research coordinators and researchers coordinating ICC-CTN’s ABI programme throughout Ireland and internationally.
  • Team leaders: Professor Alistair Nichol, Dr Kate Ainscough, Dr Leanne Hays, Ms Kathy Brickell, Professor Patrick Murray, Ms Alex Sherry, Ms Sian Donnelly, Ms Aideen Sharry
  • ANZIC-RC and TTM trials group: ANZIC-RC (an international methods centre based in Melbourne, Australia) led many of these studies globally and has a long-standing successful collaboration with the ICC-CTN. The TTM trials group led the TTM2 trial with successful harmonisation with the TAME trial.
  • Irish researchers: TAME and its associated biobank have brough together Ireland’s largest hospital group (Ireland East) and largest university (UCD) with Irish investigators, sites and key laboratory supports across Irish Medical Universities.
  • Ms Ellen Conlon, Research Officer, Acquired Brain Injury Ireland


  • TAME was supported by grants from the Health Research Board (HRB) Ireland, NHMRC Australia and NZ HRC. Public Engagement and knowledge dissemination was funded by an HRB Knowledge Translation Award and UCD PPI Ignite award.
  • EPO-TBI was supported by grants from the National Health and Medical Research Council of Australia and the Transport Accident Commission of Victoria.
  • The POLAR trial was supported by grants from the National Health and Medical Research Council of Australia; the Victorian Neurotrauma Initiative (VNI for the Transport Accident Commission, Victoria, Australia); the Teaching Hospital of Besançon, France; and Health Research Board of Ireland Clinical Trial Network Program.
  • TTM2 is supported by independent research grants from nonprofit or governmental agencies (the Swedish Research Council [Vetenskapsrådet], Swedish Heart–Lung Foundation, Stig and Ragna Gorthon Foundation, Knutsson Foundation, Laerdal Foundation, Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research, and Regional Research Support in Region Skåne) and by governmental funding of clinical research within the Swedish National Health Service. It collaborated with the ICC-CTN and the TAME trial.
  • EPO-TRAUMA is supported by Health Research Board Ireland, Medical Research Futures Fund and Health Research Council of New Zealand.
  • BONANZA is supported by project grants from the Health Research Board in Ireland, National Health & Medical Research Council and the Medical Research Future fund. The study also has an unrestricted commitment by Integra Neurosciences in consumables and monitors to enable the trial.
  • LOGICAL is supported by a NHMRC Clinical Trials and Cohort Studies Grant.

Research impact

Meeting a societal need

ABI is a leading cause of death and disability worldwide. In Ireland, 19,000 new brain injuries occur annually, and 120,000 people currently live with an ABI. Brain injury occurs in 80% of patients resuscitated from cardiac arrest. Following a severe TBI, 25% of patients die and 50% cannot live independently. Reducing death and disability, the economic costs, long-term societal effects and loss of workforce, were key drivers of this research programme.

The ICC-CTN ABI programme responded by determining best practice for fundamental aspects of ABI prevention and care (temperature, CO2 management and drug therapy), ending decades of clinical uncertainty. Current studies continue to optimise clinical care, while biological samples will direct future patient care, including new treatments targets and personalised medicine.

Improving clinical practice and health outcomes

This body of research has directly improved and informed treatments, reduced disability, and improved survival and quality of life for hundreds of patients and their families in Ireland and hundreds of thousands globally. Through PPI and knowledge translation, the team is also ensuring that the research is relevant, meeting the needs of and reaching patients and the public.

The four global studies outlined above have addressed decades of uncertainty for clinicians, providing definitive evidence for care of their most vulnerable patients. Crucially, the team’s findings were rapidly translated into clinical guidelines and practice in Ireland and around the world, including in the EU, the UK, Australia, Chile, the US, the Middle East, and Finland (see References below for examples). These studies benefit our public healthcare system by ensuring more efficient use of crucial resources (ICU beds, treatments, etc.). This will have follow-on impacts for cerebral injury support providers.

On top of that, these studies have improved knowledge of ABI and its management among healthcare practitioners: the team provides training sessions to doctors and nurses, and share their findings widely at hospitals, conference, publications and social media. And the work has created opportunities for doctors and early-career researchers to gain valuable experience in research.

Saving taxpayer money

By fostering better and more efficient treatment of ABI, this research has reduced both short- and longer-term healthcare costs. The team’s collaborator previously demonstrated a simple intervention in severe TBI reduced costs by €666 million per year in Australia.

Catalysing future research

These studies have expanded the ICC-CTN's local and global ABI network, establishing Ireland as a clinical trials hub, and giving local investigators, research teams and Irish patients opportunities to participate in global trials. The team has also established a global network of out-of-hospital cardiac arrest hospitals and investigators for future research to improve patient outcomes. The biological samples collected through this work will drive future innovation, enabling researchers to uncover biomarkers of poor outcomes and treatment response.

Project websites

Published trials

Selected guidelines influenced

POLAR influenced guidelines in the EU, the UK, Australia, Chile and the US

TTM2 influenced guidelines in the US, Europe, the UK, the Middle East

 EPO-TBI influenced guidelines in Finland, the US and the UK

Selected media

Selected project metrics

  • Cross-project: >4700 participants, 22 countries, >20,000 social media views, 1 global/European network established, 1 Critical Care PPI established, 2 ABI-PPI groups established
  • TAME (2023): 15 news articles, 14 citations
  • POLAR (2018): 7 news articles, 11 blogs, 149 citations, 7 book citations, 5 international guidelines
  • TTM2 (2021): 464 citations, 11 blogs, 10 international guidelines
  • EPO-TBI (2015): 193 citations, 11 book citations, 5 international guidelines

Selected awards

  • Resuscitation Science Symposium 2022, Ian G. Jacobs Award
  • Runner up, ACTA Clinical Trial of the Year, 2016

Selected academic outputs

  • Eastwood G, et al. Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest. N Engl J Med 2023; 389:45-57 DOI: 1056/NEJMoa2214552
  • Nichol A, et al. Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial. Lancet. 2015 Dec 19;386(10012):2499-506. DOI: 1016/S0140-6736(15)00386-4
  • Cooper DJ, Nichol AD, Bailey M, et al. Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial. JAMA. 2018;320(21):2211–2220. DOI: 1001/jama.2018.17075
  • Dankiewicz J, et al.. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021 Jun 17;384(24):2283-2294. DOI: 1056/NEJMoa2100591