A Prospective, Blinded, Randomised Clinical Trial of Fludrocortisone Compared With Placebo in Critically Ill Patients Presenting With Aneurysmal Subarachnoid Haemorrhage

Aneurysmal subarachnoid haemorrhage (aSAH)is a devastating form of stroke, that predominately affects a younger age group. There are approximately 2000 cases per year in Australia, with the majority occurring in patients between 45 and 64 years of age and with a significant female preponderance. The burden of mortality of this condition is high; a review of 11,327 cases from 2000 to 2015 by our group revealed a mortality rate of 29% in patients who survived to hospital admission, with no annual improvement in that rate from 2003 onwards. Moreover, a substantial proportion of survivors from aSAH are left with residual neurological deficits. Persistent neurocognitive changes including deficits in memory, executive functioning and language, fatigue, depression and post-traumatic stress have been reported in survivors, resulting in lower than normal health related quality of life (HRQoL).

Cognitive impairment persists even in patients with supposedly good neurological recovery, with up to 40% of patients unable to return to their previous occupation. Data from our group support these findings, suggesting that approximately 50% of patients report at least a moderate disability six months after hospital discharge.

The healthcare costs associated with aSAH are substantial. In Australia and New Zealand, most patients with aSAH are admitted to an Intensive Care Unit (ICU), and have a median length of stay of 9 and 20 days in ICU and hospital, respectively. The median hospital cost for managing a patient with high grade aSAH is A$41,824 (interquartile range A$9,933-A$97,332); without considering the need for rehabilitation, ongoing care, and loss of earnings. Data from a single centre estimated total hospital costs over a ten year period for this cohort at $8.3 million; only 52 patients out of 139 survived hospitalisation. In contrast, a 14 day course of fludrocortisone costs just over A$12 compared with A$4800 for an occupied ICU bed day. A low cost intervention which reduced ICU stay and improved outcomes would therefore be anticipated to have a substantial economic benefit.

There are a number of complications associated with aSAH, of which hyponatraemia (defined as a serum sodium concentration <135mmol/L) is one of the most common with a reported prevalence of between 35% to 77%.7,8 The primary cause appears to be a salt wasting syndrome caused by secretion of natriuretic peptides and associated with large urine outputs and hypovolaemia. Hyponatraemia in the setting of aSAH is of particular concern, as it may exacerbate cerebral oedema and is also associated with an increased risk of cerebrovascular vasospasm and cerebral infarction, as well as a longer duration of ICU admission. Our group has recently completed a prospective analysis of 356 patients with aSAH from Australia and New Zealand and demonstrated that patients in whom the sodium concentration decreases over the ICU stay have a higher likelihood of a worse neurological outcome at 6-months compared to those patients in whom the sodium concentration remains steady.

Management of hyponatraemia in aSAH is complicated by the need to maintain a neutral fluid balance, as a reduced circulating blood volume is associated with an increased risk of cerebral vasospasm and delayed neurological deficit. Standard treatment comprises IV volume resuscitation and use of hypertonic saline solutions. These interventions require frequent blood tests, strict attention to fluid balance and central venous access, which can only be provided in ICU or high dependency units.