Title: Sugar or Salt (SOS) trial: Hyperosmolar therapy in traumatic brain injury
Funder: Department of Health and Social Care

Abstract: AIM: To work out which is the safest and most effective drug to treat the swelling of the brain that occurs after severe trauma to the head._x000D_ _x000D_ BACKGROUND: Over one million people a year suffer injuries to their heads which are sufficient enough to require them to go to hospital. The most severe injuries often result in significant brain swelling. If left untreated, this swelling causes the pressure inside the head to increase, compressing the brain and causing further brain damage. The main treatments used for severe brain swelling involve placing the patient into an artificial coma (to rest the brain), giving drugs (to reduce brain swelling) or brain surgery (to release the pressure). Even with current treatments delivered in intensive care, over half of people with severe brain injury die or are left with severe brain damage._x000D_ _x000D_ To improve outcomes for patients, doctors need to know the best treatments for severe brain swelling after head injuries. The two main drugs that are currently used to treat brain swelling are hypertonic saline (a strong salt solution) and mannitol (a sugary solution). Both of these drugs work by reducing brain swelling which helps to reduce pressure on the brain. Currently, it is not known which drug is the most effective treatment. Both drugs have un-desirable side effects (hypertonic saline causes an imbalance of salts in the blood and Mannitol can cause kidney failure). To deliver the best treatment we need to know which is most the safest and most effective. _x000D_ _x000D_ DESIGN AND METHODS: This study is designed to work out whether the salty or sugary solution is the most effective treatment for brain swelling. 638 patients who have sustained a severe injury to the brain and require treatment in intensive care will be invited to take part. Half the patients will receive the salty solution and half will receive the sugary solution. Which of the two treatments they receive will be decided by chance using a computer programme. _x000D_ _x000D_ The study will compare how effective the different drugs are at reducing the pressure on the brain. It will also assess which was better at helping the patient to recover and what the side effects of treatment were. The study team will keep in contact with patients for 12 months after the study to check on how well they have recovered over time. Researchers will also calculate how much each treatment costs and compare this to how beneficial they were._x000D_ _x000D_ PATIENT AND PUBLIC: We are working closely with Headway, a national charity which supports people who have suffered severe brain injuries. They have helped us ensure that the patient and carers perspectives remain central to how the research is designed, conducted, analysed and shared with others. Two (1 patient, 1 carer) members of the charity have agreed to work closely with us as part of the research team._x000D_ _x000D_ DISSEMINATION: Our patient and public partners will help us ensure that the findings of the research are summarised clearly. We will share the findings of the research widely. Our plan includes sharing the results with patients, the public, doctors and nurses. We will do this through talks, social media, written reports and scientific publications. We will work closely with our colleagues in professional organisations to ensure that the findings of this study are included in NHS clinical guidelines.

Lay abstract: RESEARCH QUESTION: Does hyperosmolar therapy (hypertonic saline or mannitol) in traumatic brain injury (TBI) improve neurological function clinically and cost-effectively at 6 months?_x000D_ _x000D_ DESIGN: Multi-centre, open label, randomized controlled clinical and cost effectiveness trial with an internal pilot. _x000D_ _x000D_ SETTING: 25-28 intensive care units (ICUs) within NHS hospitals with patient case mix typical of UK critical care, who manage adults with severe brain injury, selected from an established network who have a proven track record of successful participation in clinical trials._x000D_ _x000D_ TARGET POPULATION: Adult patients (aged 16 years or over) with severe TBI and raised intracranial pressure (ICP)._x000D_ _x000D_ INCLUSION CRITERIA: 1) Age 16 or over, 2) traumatic brain injury, 3) Intracranial pressure > 20 mm Hg for more than 5 minutes despite stage 1 procedures, 4) < 10 days from the initial head injury, 5) abnormal CT scan consistent with traumatic brain injury. _x000D_ _x000D_ EXCLUSION CRITERIA: 1) un-survivable injuries, 2) pregnancy, 3) severe hypernatremia (serum sodium >155mmol/L). _x000D_ _x000D_ HEALTH TECHNOLOGY BEING ASSESSED: _x000D_ • 2ml/kg bolus of 20% Mannitol_x000D_ • 2ml/kg bolus of 3% HTS (or equivalent osmolar bolus of HTS if different concentration used locally)._x000D_ _x000D_ Patients will be randomized via a web-based system to one of the intervention groups in a 1:1 ratio (hypertonic saline: Mannitol) by use of a minimization procedure to balance assignments by age, Glasgow Coma Scale (GCS) motor score, pupillary response and site._x000D_ _x000D_ MEASUREMENT OF COSTS AND OUTCOMES: Outcomes will be assessed at hospital discharge, 3, 6 and 12 months. The primary clinical outcome for the study will be GOS-E measured at 6 months after randomization._x000D_ _x000D_ The secondary outcomes will comprise measurement of efficacy (ICP control); resource use (organ support requirements defined by the Critical Care Minimum Dataset, duration of critical care and hospital stay); patient outcomes (mOHS at hospital discharge, GOS-E at 12 months), mortality (hospital discharge, 3m, 6m, 12m), quality of life EQ-5D-5L (hospital discharge, 3m, 6m and 12m), progression to stage 3 therapies, which stage 3 therapies were required (barbiturate therapy, decompressive craniectomy, extra-ventricular CSF drainage), Serious adverse events, hypernatraemia, acute kidney injury (initiation of renal replacement therapy)._x000D_ _x000D_ The health economic evaluation will compare costs and assess within-trial and lifetime cost-effectiveness from an NHS and personal social services (PSS) perspective._x000D_ _x000D_ FOLLOW UP: Up to 12 months post-randomization._x000D_ _x000D_ SAMPLE SIZE: 319 per group (638 in total), allowing for 6% drop out or loss to follow-up prior to 6 month follow-up. _x000D_ _x000D_ PROJECT TIMELINE: After a 6 month set-up period, an internal pilot will run for 6 months. Assuming pre-defined milestones are achieved, the internal pilot will run seamlessly into the main trial. We will accrue our target sample size in a further 30 months (total recruitment 36 months) and follow up for 6 months. Analysis and reporting will require a further 6 months. Therefore the total project duration is 54 months._x000D_ _x000D_ EXPERTISE: The trial will be co-ordinated by Warwick Clinical Trials Unit. Our team comprises patient and public members, expert methodologists, clinical trialists and national leaders in neuro-medical and neuro-surgical intensive care. This proposal is supported by the Intensive Care Foundation, British Neurotrauma Group (Society of British Neurological Surgeons) and National Critical Care Speciality Group, CRN.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INJURIES AND ACCIDENTS