Effect of Duration of Osmotherapy on Blood–Brain Barrier Disruption and Regional Cerebral Edema after Experimental Stroke

Abstract

Osmotherapy is the cornerstone of medical management for cerebral edema associated with large ischemic strokes. We determined the effect of duration of graded increases in serum osmolality with mannitol and hypertonic saline (HS) on blood-brain barrier (BBB) disruption and regional cerebral edema in a well-characterized rat model of large ischemic stroke. Halothane-anesthetized adult male Wistar rats were subjected to transient (2-h) middle cerebral artery occlusion (MCAO) by the intraluminal occlusion technique. Beginning at 6 h after MCAO, rats were treated with either no intravenous fluids or a continuous intravenous infusion (0.3 mL/h) of 0.9% saline, 20% mannitol, 3% HS, or 7.5% HS for 24, 48, 72, and 96 h. In the first series of experiments, BBB permeability was quantified by the Evans blue (EB) extravasation method. In the second series of experiments, water content was assessed by comparing wet-to-dry weight ratios in six predetermined brain regions. Blood-brain barrier disruption was maximal in rats treated with 0.9% saline for 48 h, but did not correlate with increases in serum osmolality or treatment duration with osmotic agents. Treatment with 7.5% HS attenuated water content in the periinfarct regions and all subregions of the contralateral nonischemic hemisphere to a greater extent than mannitol did with no adverse effect on survival rates. These data show that (1) BBB integrity is not affected by the duration and degree of serum osmolality with osmotic agents, and (2) attenuation of increases in brain water content with HS to target levels > 350 mOsm/L may have therapeutic implications in the treatment of cerebral edema associated with ischemic stroke.

Temporary loss of perivascular aquaporin-4 in neocortex after transient middle cerebral artery occlusion in mice

“…This finding could be exploited diagnostically in attempts to assess the relative volumes of the central part and border zone of the ischemic lesion, given the availability of a ligand that binds selectively to the perivascular pool of AQP4. Our findings are in agreement with a recent study (15) which shows that osmotherapy with 7.5% hyperosmotic saline at 24 hr after MCAO in rats leads to a significant decrease in the brain water content in the cortical border zone (where the perivascular AQP4 expression is retained) but not in the central part of the lesion (where the perivascular AQP4 expression is strongly reduced).…”

Effect of osmotherapy with hypertonic saline on regional cerebral edema following experimental stroke: a study utilizing magnetic resonance imaging

“…In well-characterized animal models of ischemic stroke, institution and maintenance of a hyperosmolar state with continuous intravenous (IV) HS infusion ameliorates cerebral edema and improves survival [9][10][11].…”

“…There is abundance of literature that supports the conventional theory of action of osmotic agents. Their potent anti-edema action is attributed to be primarily on undamaged brain regions with an intact blood-brain barrier (BBB), theoretically causing egress of water from the interstitial and extracellular space into the intravascular compartment, resulting in improved intracranial elastance [3][4][5][6][7][8][9][10][11]. In addition, osmotic agents have been shown to exert beneficial non-osmotic cerebral effects, such as augmentation of regional cerebral blood flow (CBF) resulting in enhanced tissue oxygen delivery, free radical scavenging, and modulation of cerebrospinal fluid formation and reabsorption [3][4][5][6][7][10][11][12].…”

Can Soy Diet be Protective in Severe and Diffuse Traumatic Brain Injury?

“…Data from a study have indicated the maximum of BBB permeability at 48 h after brain injury [35]. In the present study, BBB permeability (vasogenic edema) was evaluated at 48 h post-trauma.…”