Every year, thousands of people in the UK are rushed to intensive care with severe traumatic brain injury, and doctors must choose between two cheap, widely available drugs—mannitol or hypertonic saline—to reduce dangerous pressure inside the skull, but no one knows which one works better or is more cost-effective. This matters because raised intracranial pressure after a head injury can cause permanent brain damage or death. Current guidelines recommend both drugs, but the choice is based on weak evidence and local habit, not rigorous data. The SOS trial will randomly assign patients to receive either mannitol or hypertonic saline, then track their neurological recovery, survival, and quality of life for up to a year. If the trial shows one drug clearly outperforms the other, NHS intensive care units could adopt a single, evidence-based standard of care. That would mean fewer patients left with severe disability, shorter hospital stays, and lower costs for the health service. Even a modest improvement in outcomes would change how thousands of brain injury patients are treated each year, with no need for expensive new equipment or training—just a better-informed choice between two existing medicines.
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RESEARCH QUESTION: Does hyperosmolar therapy (hypertonic saline or mannitol) in traumatic brain injury (TBI) improve neurological function clinically and cost-effectively at 6 months? DESIGN: Multi-centre, open label, randomized controlled clinical and cost effectiveness trial with an internal pilot. 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. TARGET POPULATION: Adult patients (aged 16 years or over) with severe TBI and raised intracranial pressure (ICP). 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. EXCLUSION CRITERIA: 1) un-survivable injuries, 2) pregnancy, 3) severe hypernatremia (serum sodium >155mmol/L). HEALTH TECHNOLOGY BEING ASSESSED: • 2ml/kg bolus of 20% Mannitol • 2ml/kg bolus of 3% HTS (or equivalent osmolar bolus of HTS if different concentration used locally). 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. 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. 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). The health economic evaluation will compare costs and assess within-trial and lifetime cost-effectiveness from an NHS and personal social services (PSS) perspective. FOLLOW UP: Up to 12 months post-randomization. SAMPLE SIZE: 319 per group (638 in total), allowing for 6% drop out or loss to follow-up prior to 6 month follow-up. 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. 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.
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