Fludrocortisone to treat patients with aneurysmal subarachnoid haemorrhage Protocol for an international phase 3 randomised placebocontrolled multicentre trial summary

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Hey there, critical care pharmacists! Welcome to another episode where we dive into critical literature impacting our practice. Today, I'm looking at a fascinating protocol for an international phase three randomized placebo-controlled multicenter trial, titled "Fludrocortisone to treat patients with aneurysmal subarachnoid haemorrhage." This protocol was published in *Critical Care Resuscitation*, authored by Cohen, Delaney, Udy, and their colleagues.

So, let's get into the study overview, which is, you know, a blueprint for what's to come. This is an international, phase three, randomized, placebo-controlled, multicenter trial protocol. The population they're targeting is patients with aneurysmal subarachnoid hemorrhage, or a. S. A. H. The core intervention here is fludrocortisone, a synthetic mineralocorticoid, which will be compared against placebo. The primary goal is to treat hyponatremia, a very common complication in these patients. And for outcomes, they're looking at the effect on hyponatremia incidence, of course, but also critical clinical outcomes like delayed cerebral ischemia and the composite outcome of death or disability.

Now, the rationale for this trial comes from some important observations. We know that hyponatremia is really common after a. S. A. H. and it's definitely linked to worse patient outcomes. The hypothesis is that fludrocortisone might help by reducing natriuresis and preventing volume depletion, particularly by mitigating something called cerebral salt wasting syndrome. There have been previous, smaller studies that showed fludrocortisone could reduce negative sodium balance, and some even suggested a possible lower risk of death or disability. However, the overall current evidence, honestly, lacks definitive proof for improved clinical outcomes with its use. That's exactly why this large phase three trial is so crucial: it aims to finally clarify fludrocortisone's role in the treatment of a. S. A. H.-associated hyponatremia and, more importantly, its effect on clinical outcomes.

To put this in context, let's briefly touch on some related research. Back in nineteen eighty-nine, Maeda and colleagues published a randomized controlled trial that actually showed fludrocortisone reduced negative sodium balance post-a. S. A. H. That's P. M. I. D. two-six-seven-two-four-two-six. More recently, Huang and co-authors in twenty twenty-three, in a retrospective analysis, found fludrocortisone linked to a lower ninety-day death or disability risk. Their P. M. I. D. is three-seven-eight-zero-eight-eight-six-nine. But it's not all clear-cut. A systematic review by Qureshi and others in twenty seventeen found no significant benefits of mineralocorticoids on clinical outcomes. That's P. M. I. D. two-eight-nine-eight-seven-eight-four-eight. And a meta-analysis by Kaneko and colleagues in twenty sixteen reported that while corticosteroids did reduce natriuresis, they didn't significantly improve neurological outcomes or symptomatic vasospasm. You can find that at P. M. I. D. two-seven-one-seven-three-six-six-nine. So, the current gaps really highlight the need for rigorous, large trials to confirm if fludrocortisone truly improves morbidity and mortality after a. S. A. H.

From a clinical implication standpoint for us as pharmacists, this means we should continue to monitor sodium and volume status very closely in our a. S. A. H. patients. If fludrocortisone is eventually proven effective by this trial, it could potentially be incorporated into our treatment protocols to prevent or correct hyponatremia and, hopefully, reduce complications. Of course, as critical care pharmacists, our awareness of potential mineralocorticoid side effects and appropriate dosing schedules will be absolutely critical. And, well, if it works, early intervention targeting cerebral salt wasting could significantly improve patient outcomes and potentially even decrease I. C. U. length of stay.

Now, thinking about the study's strengths and limitations, it's important to remember this is a protocol. Its strengths definitely include its multicenter, international, phase three randomized controlled trial design, making it the largest trial planned to evaluate mineralocorticoid therapy in a. S. A. H. Plus, it focuses on both biochemical and clinically important endpoints. However, the main limitation, obviously, is that it's still at the protocol stage; there are no outcome data yet. Also, there's potential variability in the standard of care across different centers, which is always a consideration in large international trials. And the mechanistic complexity of hyponatremia itself might limit the generalizability of the findings somewhat.

So, in conclusion, current evidence certainly highlights fludrocortisone's potential to mitigate hyponatremia after aneurysmal subarachnoid hemorrhage. But the definitive clinical outcome data, which is what we truly need to guide our practice, will have to await the results of this crucial phase three trial. That's it for today's literature update. I'm looking forward to the results of this one, and I'll catch you on the next episode with more critical care pharmacy insights.