Hyperosmolar therapy and the brain: a hundred years of hard-earned lessons.

777 April 2013 I N 1898, Starling1 described the forces governing fluid movement across various membranes. In 1919, Weed and McKibben showed that hypertonic fluids reduced intracranial pressure (ICP) and brain bulk,2,3 a finding immediately adopted clinically. Different compounds were tried (saline, glucose, sucrose, magnesium sulfate, urea, glycerol, and others), with mannitol (introduced in the 1960s) and hypertonic saline as the mainstays of therapy today. And yet, despite 114 yr of study and 93 yr of use, clinicians often seem uncertain about which agent to select, about how to use them, and, most importantly, about how they work. The article in the current issue of Anesthesiology by Wang et al.4 is an example of the ongoing effort to resolve this uncertainty. The authors compared and contrasted the effects of mannitol and hypertonic saline, with and without added furosemide, on brain water content in normal rats. The authors gave carefully prepared, equivolume, equimolar doses of the two fluids* to normal rats and examined the time course of serum osmolality and brain water content. As expected, both solutions reduced water content. The initial decrease was slightly greater with mannitol than hypertonic saline probably because the resultant serum osmolality was slightly greater. Over the course of 5 h, average water content with mannitol was also lower than with hypertonic saline, again because osmolality tended to be higher. Furosemide had no effect on its own, but adding it to hypertonic saline resulted in a small increase in serum osmolality and a further reduction in brain water content. Those are the basic findings. But, what, in fundamental terms, does this study—and others—tell us about hyperosmolar therapy? The answers are perhaps more straightforward than often recognized. Without minimizing the work of Wang et al., almost everything about hyperosmolar therapy can be understood by a careful study of Starling, along with basic college-level physical chemistry and physiology. The following is intended as a brief (and somewhat simplified) primer on the subject. First, the osmolality of a solution is dependent only on the number of dissolved particles in a mass of water; a solution of 280 mOsm/kg contains 280 mmoles of independent particles per kilogram of water.† The nature of those particles does not matter; a mannitol molecule and a sodium ion are osmotically identical. Second, for osmotic forces to act, one must establish a concentration gradient across a semipermeable membrane (semipermeable defined as “water moves, solute doesn’t”). If no gradient can be established, for example, if the blood–brain barrier is disrupted, or if the “particle” can move across the membrane (e.g., glucose), then water will not move (or not move as much).‡ Third, osmotic forces are powerful; increasing serum osmolality by 20 mOsm/kg (easily achieved with 1 g/kg of mannitol) is equivalent to a 380 mmHg change in driving force! Small changes in the osmotic gradient can move a LOT of water rapidly. Hyperosmolar Therapy and the Brain