A Low ChloridE hyperTonic Solution for Brain Edema

This pilot study aimed to collect high-quality randomized and prospective information to help plan a future, larger multicenter trial. The study will compare the two hypertonic solutions currently used for subarachnoid hemorrhage (SAH) - related complications and to determine if the reduction of chloride load by using a sodium acetate and sodium chloride mixture can lead to a relative reduction of serum chloride, reduce kidney injury, and as efficacious as the classic hypertonic solution.

Hyperosmolar therapy is one of the mainstay treatments for SAH-related cerebral edema and vasospasm, in order to reduce delayed cerebral ischemia. Recent evidence from the literature correlates high chloride load when applying IV fluids with worse outcome in a variety of critically-ill patients. Hypertonic saline, with which most hyperosmolar treatment is done, contains a supra-physiologic chloride load. It is possible that by changing the hypertonic solution to a "chloride-lean" one, the study team would be able to reduce the side effects of hypertonic sodium-chloride without losing its efficacy in treating SAH-related complications.

• Sodium chloride /sodium acetate (16.4%) (Drug): Sodium Acetate is a sterile, nonpyrogenic solution of Sodium Acetate intended as an alternative to sodium chloride to provide sodium ion in parenteral (IV) fluid therapy. Sodium Chloride is sterile, nonpyrogenic hypertonic saline (concentrated sodium-chloride) solution for parenteral (IV) fluid therapy.
• Sodium chloride (23.4%) (Drug): Sodium Chloride is sterile, nonpyrogenic hypertonic saline (concentrated sodium-chloride) solution for parenteral (IV) fluid therapy.
• PlasmaLyte (Drug), also known as Placebo solution: PlasmaLyte is an isotonic IV solution that mimics human physiological plasma electrolyte concentrations, osmolality and pH.

Primary outcomes

• Difference between serum chloride level on randomization day and the peak afterwards [Baseline, up to once daily during a patient's stay in the ICU, and up to 90 days]: Serum chloride levels will be measured as part of standard of care. Difference between serum chloride level on randomization day and the peak afterwards will be calculated.

Secondary outcomes

• Number of patients with acute kidney injury (AKI) [Patients' stay in the ICU, and up to 90 days]: AKI diagnosis will be done on the basis of clinical parameters (serum creatinine ≥ 1.5 times baseline or ≥0.3 mg/dl and urine output (<0.5 ml/kg/h for 6 hours) according to Kidney Disease Improving Global Outcomes (KDIGO). Number of patients with acute kidney injury (AKI) will be recorded.
• All causes of in-hospital mortality. [Patients' stay in the ICU, and up to 90 days]: All causes of in-hospital mortality, including withdrawal of treatment or discharge to a hospice facility, will be recorded.
• All causes of 90 day mortality. [Up to 90 days]: All causes of mortality, 90 days post admission day, including withdrawal of treatment or discharge to a hospice facility, will be recorded.
• Change in intracerebral pressure (ICP) measured by ICP monitor following hypertonic treatment. [Continuous measurement as long as the patient has an indication for an ICP monitor, and up to 90 days]: Change in intracerebral pressure (ICP) following the administration of the hypertonic solution will be recorded.
• Change in serum sodium level following the administration of the hypertonic solution. [Baseline, and daily during a patient's stay in the ICU, and up to 90 days]: Serum sodium levels will be measured as part of standard of care. Difference between serum sodium level on randomization day and the peak afterwards will be calculated.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Spontaneous SAH with an identified aneurysmal source as identified on neuroimaging obtained at admission to Emory University Hospital or with imaging at an outside hospital
* Age ≥ 18 years

Exclusion Criteria:

* SAH related to non-aneurysmal vascular anomaly
* SAH thought due to trauma
* SAH occurring in relation to another medical procedure (cardiac catheterization, LVAD placement, etc.)
* SAH with a negative workup for cause ("angio-negative")
* Patients who arrive in a brain-death state or in a devastating clinical status that will be presumed to lead to brain death or early withdrawal of treatment
* Patient who suffer from end-stage renal disease at baseline and who are routinely treated with dialysis
* Known pregnancy

• Results publication: Sadan O, Singbartl K, Kraft J, Plancher JM, Greven ACM, Kandiah P, Pimentel C, Hall CL, Papangelou A, Asbury WH, Hanfelt JJ, Samuels O. Low-chloride- versus high-chloride-containing hypertonic solution for the treatment of subarachnoid hemorrhage-related complications: The ACETatE (A low ChloriE hyperTonic solution for brain Edema) randomized trial. J Intensive Care. 2020 May 4;8:32. doi: 10.1186/s40560-020-00449-0. eCollection 2020. PMID 32391156
• Results publication: Sadan O, Samuels O, Asbury WH, Hanfelt JJ, Singbartl K. Low-chloride versus high-chloride hypertonic solution for the treatment of subarachnoid hemorrhage-related complications (The ACETatE trial): study protocol for a pilot randomized controlled trial. Trials. 2018 Nov 14;19(1):628. doi: 10.1186/s13063-018-3007-7. PMID 30428930

• Owen Samuels, MD, Principal investigator, Emory University