Some experimental observations on the action of intravenous hypertonic urea in dogs, with particular reference to plasma volume and tissue urea changes.

Several publications in recent years by Javid and his colleagues have reported on the use of hypertonic urea solutions to reduce the brain bulk in intracranial operations and to lower intracranial and intraocular tension (Javid, 1958a and b, 1959). That urea is a primary diuretic substance has long been known, but that the effect of hypertonic urea is not due to this diuretic action has been shown on nephrectomized monkeys (Javid and Anderson, 1959b). It has also been shown that the plasma electrolyte levels do not change appreciably (Garvin, Jennings, and Gesler, 1959). Two explanations have been put forward to account for the shrinking action of urea on brain tissue. (1) A blood cerebrospinal fluid barrier is implicated by Javid and his colleagues: "The prolonged fall in cerebrospinal fluid pressure in nephrectomized monkeys is due to a prolonged osmotic pressure differential between blood and cerebrospinal fluid". (2) A blood-brain barrier, as originally postulated to exist by Weed and McKibben (1919), is implicated by Stubbs and Pennybacker (1960): "The reduction in brain bulk is obviously much greater than that of other soft tissues and we think that a barrier to the entry of urea into brain best explains our clinical observations". The withdrawal of water from brain and cerebrospinal fluid must produce an increase in volume in some other compartment of the interstitial space and most writers acknowledge that the plasma volume rises and a state of hypervolaemia is induced (Tench, Javid, and Gilboe, 1960). We have not, however, encountered an assessment of this increase in plasma volume, and a neurosurgical case indicated that there was a very large increase in plasma volume. Estimations of plasma volume by the dye dilution technique in an average-sized adult patient who was given hypertonic urea before a neurosurgical operation revealed an increase in plasma volume of the order of 2 litres. This was far greater than could be accounted for even had all the water been removed from brain and cerebrospinal fluid and prompted us to question the blood-brain barrier explanation. To elucidate the point a small series of experiments in dogs was performed with hypertonic urea infusions and the results are presented.