Title: “OSMOTIC Study” - Investigating the mechanisms of action of hyperosmolar therapy on neurological outcomes following acute severe traumatic brain injury
Funder: Medical Research Council

Abstract: STUDY AIMS:_x000D_ _x000D_ We are planning to look in detail at patients taking part in an existing research study. The existing study is testing two existing drug treatments for patients with severe head injury. We plan to take additional blood tests to measure brain damage and analyse CT scans of the brain. This will help us understand how and why these drugs work._x000D_ _x000D_ BACKGROUND:_x000D_ _x000D_ Over 1 million people attend hospital after a head injury every year in the UK. Some will have a severe injury causing swelling of their brain. If left untreated, the swelling causes the pressure inside their skulls to increase. This compresses their brains leading to further damage. There are three main treatments for brain swelling. Patients can be placed in a coma to rest the brain, given drugs to reduce the swelling, or have surgery to release pressure. Even with these treatments, over half of people with severe brain injuries die or have long-term brain damage. To improve outcomes for patients, doctors need to know how best to treat brain swelling. The two common drugs used are hypertonic saline (a strong salt solution) and mannitol (a sugary solution). Both drugs reduce swelling and decrease pressure on the brain. We are already running a study in the UK called the "SOS” (Salt or Sugar) trial. The “SOS” trial has been designed to see which of these drugs is more effective. However, we do not fully understand how these drugs work and if they have other beneficial effects. The “OSMOTIC” study will look in detail at patients recruited to the “SOS” trial. We will investigate the benefits of hypertonic saline and mannitol._x000D_ _x000D_ DESIGN AND METHODS:_x000D_ _x000D_ The “OSMOTIC“ study will provide detailed information about how the drugs mannitol and hypertonic saline work. We will be taking blood samples from patients recruited to the “SOS” trial. These will tell us which drug is better at reducing brain damage and swelling. We will also find out how these effects improve patients’ outcomes. Finally, we will use computer image analysis of the CT scans of the brain that these patients receive. This will tell us the types of head injury that best respond to these treatments._x000D_ _x000D_ PATIENT AND PUBLIC INVOLVEMENT:_x000D_ _x000D_ We are working with Headway. This is a charity that supports people with severe brain injuries. They ensured that patient and carer perspectives are a key part of this study. Patients and carers helped us design the project. They also helped us decide how the project should be run and analysed. Patients and carers will help us share the research with others. Two members of the charity have joined the research team._x000D_ _x000D_ DISSEMINATION:_x000D_ _x000D_ Our patient and public partners will ensure the findings of the research are clear. We will share the results widely. We will make sure we share the results with patients and the public. We will also share results with doctors, nurses, and other healthcare workers. We will do this through talks, social media, reports, and scientific publications.

Lay abstract: RESEARCH QUESTION: _x000D_ _x000D_ Is any difference in neurological outcomes seen between the osmotherapy agents mannitol and hypertonic saline (HTS), used in the management of raised intracranial pressure (ICP) after severe traumatic brain injury (TBI), due to differential effects of each drug on neuronal injury, inflammation, and oedema-suppression?_x000D_ _x000D_ BACKGROUND:_x000D_ _x000D_ TBI is a major cause of death and severe disability throughout the world. Long term outcomes from TBI remain poor with high mortality and significant risk of poor neurological outcomes in survivors. The NIHR HTA funded “Salt or Sugar” (SOS) trial (HTA reference 17/120/01) is a UK-wide pragmatic phase 3, multi-centre randomised controlled trial which will determine the clinical and cost effectiveness of hyperosmolar therapy regimes involving mannitol and hypertonic saline in adult patients with TBI and raised ICP. However, the combination of equipotent osmotherapy in both intervention arms and a dynamic system where other ICU treatments will be manipulated to control ICP means that it is highly likely that on average both arms will show near-equivalent ICP control. Therefore, any potential overall benefit in long-term neurological outcome seen with either mannitol or HTS in the SOS trial will likely not be directly attributable to an overall improvement in ICP control. What is needed is a greater mechanistic understanding of the effects of osmotherapy on the pathophysiological effects of TBI to help inform the results of the SOS trial and future research plans._x000D_ _x000D_ DESIGN: _x000D_ _x000D_ The OSMOTIC study is designed as a prospective, multi-centre, mechanistic, cohort observational study embedded within the SOS trial._x000D_ _x000D_ SETTING: _x000D_ _x000D_ 28 UK NHS intensive care units (ICUs) who manage adults with severe brain injury and are recruiting patients to the SOS trial._x000D_ _x000D_ TARGET POPULATION: _x000D_ _x000D_ 360 adult patients (aged >16 years) with severe TBI and raised intracranial pressure (ICP) recruited to intervention with mannitol or HTS as part of the SOS trial_x000D_ _x000D_ METHODS:_x000D_ _x000D_ Blood samples from patients recruited into the OSMOTIC study will be taken at enrolment and at 12 and 48 hours after enrolment. Serum biomarkers of neuronal injury (S100ß/NSE/NF-L) and inflammatory pathways (IL-1, IL-6, TNF-alpha) will be assayed at each time point and differences between timepoints compared between the mannitol and HTS groups to look for differential effects. CT brain images acquired as part of routine clinical care will also be analysed to assess novel approaches to objectively quantifying changes in brain volume and investigate differential effects of mannitol/HTS. Follow up data (Glasgow Outcome Scale - extended) acquired at 6 months post-randomisation to the SOS trial will be used to assess neurological outcomes._x000D_ _x000D_ PROJECT TIMELINE: _x000D_ _x000D_ The SOS trial is planned to run for 54 months (with a 6 month internal pilot). The OSMOTIC trial will commence recruitment following the completion of this pilot. Estimating recruitment at 1 patient per month per centre, we anticipate completion of patient recruitment and data collection in 17 months, with a total study length of 33 months. _x000D_ _x000D_ EXPERTISE:_x000D_ _x000D_ The trial will be co-ordinated by Warwick Clinical Trials Unit. The study team comprises expert methodologists/clinical trialists and national leaders in neurointensive care and neuroinflammation and is supported by regional members of the UK charity Headway which supports patients/carers with TBI.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INJURIES AND ACCIDENTS