MAnnitol for Cerebral oEdema after IntraCerebral Haemorrhage (MACE-ICH): a feasibility trial

Background Cerebral oedema complicates intracerebral haemorrhage (ICH) and in large strokes is associated with increased risk of death or disability through brain herniation and secondary brain injury. Although decompressive hemicraniectomy could be life-saving, there is limited evidence for surgical treatment in ICH. Mannitol, an osmotic diuretic, is readily available and easy to administer intravenously. It is licensed to treat cerebral oedema and used in traumatic brain injury and hepatic encephalopathy. Mannitol is known to reduce blood viscosity, facilitating flow and oxygen delivery to the brain. Little is known about its effects in ICH so well- designed clinical trials are needed. Aim To perform a prospective, randomised, open-label, blinded-endpoint, feasibility trial of intravenous mannitol in ICH patients with oedema or at risk to inform a definitive trial Objectives Is it feasible to: recruit, randomise and treat patients with ICH oedema or at risk < 72 hours of onset? deliver the protocol and is it acceptable to participants? collect preliminary safety data of mannitol? obtain clinical and radiological data during and after treatment? follow-up participants and collect proposed outcomes? identify barriers and facilitators to participant recruitment and retention? obtain feedback on trial methodology? Methods Setting Ten UK hospitals providing acute stroke services Participants Inclusion criteria Adults (>18 years) ICH confirmed by CT scan < 72 hours of onset Cerebral oedema with or without mass effect at baseline or subsequent scan or at risk (GCS <14 and NIHSS >8) neurosurgery not imminent signed consent Intervention Patients will be randomised 1:1:1 to one of three groups: 1 g/kg 10% single dose mannitol infusion at 10 ml/min 1 g/kg 10% mannitol at 10 ml/min followed by a second dose 1 g/kg repeated at 24 hours standard care alone Feasibility outcomes: Number of patients: Screened and those eligible Eligible recruited and reasons for not recruiting Proportion of eligible patients who received allocated treatment and reasons for non-allocation Recruitment rate Treatment adherence Retention rate Number of patients with outcome data and reasons for non-availability Incidence and type of adverse events, protocol violations, trial withdrawal The following variables are expected to inform a definitive trial: Laboratory: U&E s; e-GFR; serum osmolarity to correlate response to mannitol Day 2-7: GCS, NIHSS; death Day 5-7: follow-up CT brain to assess changes in oedema volume, oedema extension distance, haematoma volume, midline shift Day 28 mortality Day 180 (blinded follow-up): death or dependency; disability; mood; cognition; quality of life; length of stay; discharge destination Number of patients: needing high dependency or intensive care unit; undergoing neurosurgery Recurrent stroke Safety: death; thrombophlebitis; acute kidney injury; hyper/hyponatremia; pulmonary oedema; hypotension The long-term neurological sequelae associated with Covid-19 will be collected and factored into analysis. Comparisons will be made between each group assigned to mannitol plus standard care versus standard care alone. Trial duration: 2 years The results will be disseminated via: peer-reviewed journals scientific meetings our PPI network and social media The progression criteria to a definitive trial will use a red-amber-green strategy based on recruitment and retention together with feedback from performance reviews.