Fludrocortisone in ICU patients with aneurysmal subarachnoid haemorrhage (FLASH trial)
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Background
Aneurysmal subarachnoid haemorrhage (aSAH) is a severe and life-threatening form of stroke that affects approximately 2,000 Australians each year, with a mortality rate of around 30%. Survivors often experience long-term disability and reduced quality of life, contributing to the loss of 25,000 disability-adjusted life years annually. Despite advances in stroke care, no new treatments have emerged in the past 15 years to improve outcomes for these patients. Our research group, recognising this gap, formed a collaboration in 2017 to address the urgent need for improved clinical interventions in aSAH. Through a multicentre, binational study, we revealed that the case fatality rate of 29.2% has remained stagnant over the last decade, with patients requiring ICU admission facing a higher mortality rate and prolonged hospital stays compared to other neurological conditions.
Further research into the long-term outcomes of aSAH patients identified significant functional impairment six months after their ICU admission, with a particular focus on the role of hyponatremia, which was associated with worse recovery. Fludrocortisone, a synthetic mineralocorticoid, has shown potential in managing hyponatremia and fluid loss in aSAH patients, though previous studies were underpowered to conclusively demonstrate clinical benefits. A systematic review in 2018 suggested fludrocortisone may reduce urine output, natriuresis, and hyponatremia, but larger, high-quality randomised trials are needed to determine its effectiveness in improving patient outcomes. The current lack of robust evidence underscores the need for further research into fludrocortisone's role in treating aSAH.
Aim
The proposed research will examine the potential use of a low-cost, off-label medication in the treatment of a devastating disease that predominantly effects a young, previously healthy, population. There is a strong biological rationale and early evidence for its effectiveness, and the intervention is simple, readily available, and well-tolerated. Our primary outcome is patient-focused, and our trial design is intended to provide a definitive answer to the questions of clinical efficacy and healthcare resource use. Our team is diverse, experienced, and ideally placed to promulgate the results. A finding that fludrocortisone improves neurological outcomes will significantly improve the health and wellbeing of aSAH patients, both in Australia and worldwide.
Research Methodology
A multi-centre, prospective, blinded, randomised clinical trial of enteral fludrocortisone compared with placebo in patients presenting with aneurysmal subarachnoid haemorrhage to neurosurgical ICUs in Australia and New Zealand. Patients admitted to hospital with acute subarachnoid haemorrhage within the last four days and currently being treated in an intensive care or high dependency unit will be eligible if they meet ALL the inclusion criteria and none of the exclusion criteria. Following the consent process, randomisation will be via a dedicated, secure, web-based, portal with a computer-generated block randomisation sequence with variable block sizes stratified by site and by severity of the bleed as measured by the World Federation of Neurosurgeons (WFNS) grade. Study participants will receive either enteral fludrocortisone in a dose of 100μg six hourly or matched placebo in a blinded fashion, either orally or by nasogastric tube. Study drug will be continued for fourteen days or until discharge from hospital, whichever is earlier. All other treatments will be at the discretion of the treating physician. The dose and dosing intervals for fludrocortisone are based upon pharmacokinetic and pharmacodynamic data.
The George Institute for Global Health (TGI) will act as the trial sponsor and coordinating centre for Australian and New Zealand sites. Through the Human Research Ethics Application (HREA) under the National Mutual acceptance (NMA) scheme, 12 sites across 4 states in Australia, NSW, QLD, VIC, and Tasmania have approval to conduct the trial. Additionally, approval for sites in New Zealand is currently underway.
Current Status
Ethics approval has been secured, covering all participating sites located across New South Wales (NSW), Queensland (QLD), Victoria (VIC), Tasmania (TAS). Approval for sites in New Zealand (NZ) pending.
