Richard L. Applegate, Gang Chen, Hua Feng and John H. Zhang (eds.)Brain Edema XVIActa Neurochirurgica Supplement12110.1007/978-3-319-18497-5_1

The Evolution of the Clinical Use of Osmotic Therapy in the Treatment of Cerebral Edema

Michael N. Diringer¹

(1)

Neurocritical Care Division, Department of Neurology, Washington University, Campus Box 8111, 660 S Euclid Ave, St Louis, MO 63110, USA

Michael N. Diringer

Email: diringerm@wustl.edu

Keywords

Cerebral edemaHypertonic salineIntracranial hypertensionMannitol

Introduction

For decades, one of the primary medical interventions to treat cerebral edema has been the administration of hyperosmolar solutions. The agents used, how they are administered, and the therapeutic targets have evolved considerably over the last century. A review of the process highlights lessons learned, provides insight into current practice, and raises important questions.

Weed and McKibbens [1] were the first to report the ability of hyperosmolar solutions to shrink nervous tissue in 1919. They noted that infusion of a 30 % saline solution produced a marked decrease in brain volume, whereas free water administration resulted in brain swelling. In that same year, Hayden [2] reported a similar effect with 25 % glucose solutions. This was followed by Fay’s [3] description of “the treatment of cerebral trauma, by methods of dehydration.” Fay initially administered oral hypertonic saline solutions, but because of poor patient tolerance, he switched to intravenous boluses of 15–35 % sodium and magnesium chloride solutions.

Over the next half century, various compounds were investigated, including 50 % glucose, 50 % sucrose, 25 % sodium chloride, 25 % urea, 50 % magnesium sulfate, glycerol, concentrated albumin, and concentrated plasma. Their use was tempered by the caveat that “most of these dehydrating agents have only a temporary effect, which may be followed by a ‘rebound phenomenon’ during which the intracranial pressure may exceed that which existed before they were administered” [4]. Because of these concerns, osmotic agents were rarely used to treat cerebral edema after the mid-1930s.

After the introduction of intracranial pressure monitoring (ICP) monitoring to the management of head injury in the1960s, there was a resurgence of interest in the use of osmotic agents. At the same time, mannitol was added to the list of potential osmotic agents [5, 6]. Although initially administered as continuous infusion, the practice of using of intermittent bolus administration evolved rapidly. Mannitol quickly became one of the primary osmotic agents used to treat cerebral edema, primarily because it did not cross the cell membrane, like urea, and was not metabolized, like other sugar solutions. Over time, other concerns about mannitol were noted, including its marked diuretic effect leading to hypovolemia, its association with renal failure, and the identification of “mannitol-resistant” patients.

Hypertonic saline has gained favor because it does not appear to be burdened with these side effects. It has challenged mannitol’s position as the preferred osmotic agent [7]. Debates in the literature lay out arguments for and against its use [8, 9]. Additionally, its use has transitioned from administration as a bolus to use as a continuous infusion. This has shifted management to slowly increasing osmolality to a stable high value rather than intermittently and sharply raising osmolality followed by a return to normal levels.

Currently, osmotic therapy is routinely used to treat cerebral edema in a wide range of conditions. Numerous retrospective and prospective series confirm that, in most conditions, a bolus of mannitol or hypertonic saline will lower intracranial pressure, usually to a similar degree. What remains unstudied and poorly understood is the impact of repeated dosing, appropriate fluid management during osmotic therapy, and how to guide therapy. In addition, controversy persists regarding whether osmotic agents act only on normal brain, whether they lose efficacy over time, and whether they leak into the brain. No appropriately designed and powered studies have assessed the impact of osmotic therapy on outcome.

Physiology of Osmotic Agents

Osmotic Effects

Intravenous administration of a hypertonic solution that is impervious to the cell membrane creates osmotic disequilibrium between the intracellular and extracellular compartments. Water moves rapidly into the extracellular compartment to restore equilibrium. This net shift of water out of the intracellular space results in cell shrinkage.

In the brain, the distribution of osmotic agents is further governed by the blood-brain barrier (BBB), which limits entry of most osmotic agents into the extravascular extracellular space of the central nervous system. The osmotic reflection coefficient indicates the degree to which a solute crosses the BBB; 0 indicating free passage and 1 complete exclusion. Mannitol and sodium are highly excluded by the BBB; the osmotic reflection coefficient for mannitol is 0.9 and that for sodium approaches 1. Yet, in disease states, the integrity of the BBB is often impaired, increasing permeability to solutes as well as increasing hydraulic conductivity.

Hydraulic conductivity (the ease with which water can pass through a membrane) of brain capillaries must also be considered [10, 11]. A family of aquaporin receptors has been identified that appears to play a key role in hydraulic conductivity across the BBB [12]. Changes in permeability of the channels determine the magnitude of the response to osmotic stimuli [13]. Movement of water across the BBB is driven by Starling forces; hydrostatic pressure and osmotic pressure act in opposite directions across the capillary wall, with hydrostatic forces driving fluid out and osmotic pressures pulling it back. The net flux is determined by membrane permeability to solutes (osmotic agents) and solvent (water). The net result of all these factors is described by the tonicity or osmotic effectiveness of a solution, which depends on both the osmotic gradient created and the osmotic reflection coefficient of the membrane for that solute.

Brain Adaptation to the Hyperosmolar State

The beneficial effects of osmotic agents are thought to be the result of their ability to shrink the brain; a single dose of mannitol acutely reduces brain volume by 6–8 % in patients with large stroke and cerebral edema [14]. As this fluid comes from the intracellular compartment, cells shrink, initiating a series of responses targeted at restoring cell size to normal. This process acts in several ways to increase the absolute number of intracellular osmotically active particles to counteract the dehydrating influence of hyperosmolar plasma. Over a few hours, the intracellular content of electrolytes rises, followed by a slower accumulation of organic [15] and idiogenic osmoles [16], which draw water back into the cell. The net effect is restoration of cell size with maintenance of the hyperosmolar state.

This response limits the impact on brain volume that can be achieved when the brain is exposed to a sustained hyperosmolar state. The beneficial reduction in brain volume is lost over time as intracellular osmoles rise. Over 24–48 h, a state is reached where both intracellular and extracellular compartments are hyperosmolar, but cell size has returned to baseline and the reduction in brain volume has been lost. This creates a high risk of rebound edema if osmolality is lowered too quickly. Overly rapid correction that outpaces the dissipation of the accumulated osmoles can have disastrous consequences [17].

Non-osmotic Effects

Administration of any hypertonic solution produces a shift of water into the extracellular (and, thus, intravascular) compartments, increasing blood volume. This leads to hemodilution, increased cardiac output, and increased blood pressure. If the osmotic agent is mannitol, a marked diuresis soon follows, which can lead to hypovolemia and hypotension. Because hypertonic saline is not a diuretic it produces sustained volume expansion, giving it a distinct advantage over mannitol in the setting of hypovolemia.

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