Weed and McKibben [
1,
2] first reported brain tissue shrinkage and reduced cerebrospinal fluid pressure after intravenous injection of concentrated salt solutions. These findings challenged notions of fixed brain volume held by Kellie [
3] and contemporaries. With the advent of continuous intracranial pressure (ICP) measurement [
4], these experiments formed the foundation of hyperosmolar therapy for traumatic brain injury (TBI). Early approaches used varying concentrations of sodium chloride, glucose, glycerol, and urea [
5‐
12]. Mannitol was predominately used starting in the 1960s [
13], with hypertonic saline adopted in the 1980s [
5,
14]. …