Aggravation of vasogenic cerebral edema by multiple-dose mannitol

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✓ The authors investigated the pharmacokinetics of mannitol administered for treatment of vasogenic cerebral edema. A cortical cold injury was produced in 23 cats maintained under general anesthesia for 5 or 21 hours. Control animals received no mannitol, while treatment groups received either a single dose or five doses administered at 4-hour intervals of 0.33 gm/kg radiolabeled mannitol. Liquid scintillation counting was carried out to determine the concentrations of mannitol in the cerebral tissue, cerebrospinal fluid, plasma, and urine. Cerebral water content and linear progression of edema were also measured.

Rapid plasma clearance prevented accumulation of mannitol after multiple intravenous injections, as 84% ± 2% (mean ± standard error of the mean) of the infused mannitol was excreted through the urine. However, there was progressive accumulation of mannitol within the cerebral tissue, especially in the edematous white matter where it reached a level of 0.33 ± 0.03 mg/gm after five doses, exceeding the trough plasma concentrations by a ratio of 2.69:1. Water content measurement showed that a single dose of mannitol failed to reduce cerebral water content or edema progression at 4 hours postinjection, while multiple doses produced a 3% increase in water content in edematous regions (p > 0.0003). The results of this study demonstrated a reversal of the osmotic concentration gradient between edematous brain and plasma following multiple mannitol injections, associated with exacerbation of vasogenic cerebral edema.

Article Information

Address reprint requests to: Anthony M. Kaufmann, M.D., Section of Neurosurgery, University of Manitoba, 61 Emily Street, Winnipeg, Manitoba R3E IY9, Canada.

© AANS, except where prohibited by US copyright law.

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Figures

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    Clearance curves of mannitol from plasma after multiple doses, infused at 4-hour intervals, showing no accumulation after repeated administration.

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    Diagram representation of a parasagittal section of the lesioned hemisphere in a cat brain (right) and a bar graph of the corresponding concentrations of radiolabeled mannitol (left). The cortical cold injury is the black region of the diagram. Mannitol concentrations were determined in nonedematous frontal white matter (A) and in three areas of edematous white matter: the advancing edge of edema (B), the central area of edema (C), and directly beneath the cold lesion (D).

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    Bar graphs showing that regional cerebral water content after single-dose mannitol treatment (left) produced no significant changes in normal and edematous brain at 4 hours postinjection. Repeated doses of mannitol (right), however, raised the water content of edematous white matter by 3% without affecting nonedematous regions. The asterisk indicates the statistically significant increase (p = 0.003).

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    Graph showing the measured mannitol concentration in plasma after repeated injections of mannitol. The horizontal interrupted line represents the estimated concentration of mannitol in the cerebral extracellular space after five injections at 4-hour intervals. There was reversal of the mannitol concentration between plasma and cerebral extracellular space, which favored an influx of water into the tissue.

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