The history of urea as a hyperosmolar agent to decrease brain swelling

Abstract

In 1919, it was observed that intravascular osmolar shifts could collapse the thecal sac and diminish the ability to withdraw CSF from the lumbar cistern. This led to the notion that hyperosmolar compounds could ameliorate brain swelling. Since then, various therapeutic interventions have been used for the reduction of intracranial pressure and brain volume. Urea was first used as an osmotic agent for the reduction of brain volume in 1950. It was associated with greater efficacy and consistency than alternatives such as hyperosmolar glucose. Its use became the standard of clinical practice by 1957, in both the intensive care unit and operating room, to reduce intracranial pressure and brain bulk and was the first hyperosmolar compound to have widespread use. However, the prime of urea was rather short lived. Reports of side effects and complications associated with urea emerged. These included coagulopathy, hemoglobinuria, electrocardiography changes, tissue necrosis with extravasation, and a significant potential for rebound intracranial hypertension. Mannitol was introduced in 1961 as a comparable and potentially superior alternative to urea. However, mannitol was initially purported to be less effective at rapidly reducing intracranial pressure. The debate over the two compounds continued for a decade until mannitol eventually replaced urea by the late 1960s and early 1970s as the hyperosmolar agent of choice due to the ease of preparation, chemical stability, and decreased side effect profile. Although urea is not currently the standard of care today, its rise and eventual replacement by mannitol played a seminal role in both our understanding of cerebral edema and the establishment of strategies for its management.

Urea for hyponatremia?

“…If kidney function is normal, all of the administered urea is excreted within approximately 12 h. 2,4,7 Assuming urine osmolarity to be 500 mosmol/l, excretion of 500 mosmol of urea will promote excretion of 1 liter of electrolyte-free water, enough to increase the serum sodium concentration by approximately 5 mequiv./l in our 50-kg woman (Figure 1b). Thus, as the urea gradient across the blood-brain barrier diminishes, it is replaced by an increase in serum sodium concentration that prevents plasma water from reentering the brain.…”

“…1 Despite initial skepticism, urea became the standard of care for increased intracranial and intraocular pressure in the 1960s. 2 Used successfully in thousands of patients, it was typically given intravenously in a commercially available preparation called Urovert: urea was mixed with invert sugar (glucose and fructose), to avoid intravascular hemolysis. After a decade of popularity, urea was eventually replaced by mannitol as the hyperosmolar agent of choice, because mannitol was easier to prepare, was more stable, was less likely to cause hemolysis, and caused less tissue injury after extravasation.…”

The Medical Management of Cerebral Edema: Past, Present, and Future Therapies

“…The use of hyperosmolar solutions of urea rapidly fell out of favor given the many negative side effects attributed to their infusion. Gastrointestinal disturbances, electrocardiographic complications, coagulopathy, and, perhaps most importantly, rebound cerebral edema, due to the relatively low reflection coefficient of urea (0.59) [46], were only some of the reason's urea fell out of favor [47]. This however allowed for the use of mannitol solutions to take hold in the medical management of cerebral edema.…”

“…Clinical experience has been reported in by Javid et al in the 1950s [45,48]. The majority of the physiologic evidence is obtained from animal models [47,49]. Mannitol First described in the early 1960s [50], mannitol remains part of the routine medical management of cerebral edema.…”

Conservatism strikes back: later is better than earlier dialysis for acute kidney injury

“…Whereas delaying RRT may lead to worsening azotemia and other metabolic deteriorations, higher serum urea level per se should never be an indication. Indeed, urea can be safely injected as an osmotic agent, e.g., in association with mannitol for management of cerebral edema (13). Fluid overload can be managed conservatively or in extreme circumstances that a patient needed to be intubated by positive airway pressure ventilation.…”