Global brain water increases after experimental focal cerebral ischemia: Effect of hypertonic saline

Thomas J.K. Toung, Patricia D. Hurn, Richard J. Traystman, Anish Bhardwaj

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Objective: Isolated experiments suggest that global cerebral edema is a sequela of large hemispheric ischemic lesions, presumably as an extension of the initial ischemic insult into areas of vital, noninjured tissue. Diuretics and osmotic agents are controversial and poorly defined therapeutic modalities after large infarction. By using a rat model of middle cerebral artery occlusion (MCAO), we tested the hypothesis that significant edema occurs in the contralateral uninjured hemisphere and that this postischemic complication can be manipulated by hypertonic saline therapy. Design: Prospective laboratory animal study. Setting: Research laboratory in a teaching hospital. Subjects: Halothane-anesthetized, male Wistar rats. Interventions: Under controlled conditions of normoxia, normocarbia, and normothermia, rats were subjected to 2 hrs of MCAO. Measurements and Main Results: Adequacy of MCAO and reperfusion was assessed by laser Doppler flowmetry. All animals except naive rats received continuous infusion of 0.9% saline at 0.5 mL/hr throughout the experiment. Brains were harvested, and tissue water content was estimated by comparing the wet-to-dry weight ratios of ipsilateral and contralateral cerebral hemispheres at 12 hrs, 24 hrs, or 2, 3, or 7 days postischemia. Naive and sham-operated rats served as control cohorts. In a second series of randomized experiments, wet-to-dry weight ratios were determined in rats treated with continuous intravenous infusion of 7.5% hypertonic saline (0.5 mL/hr; acetate/chloride, 50:50) and were compared with well-studied antiedema therapy: 20% mannitol (2.5 g/kg bolus every 6 hrs) or furosemide (2.5 mg/kg bolus every 6 hrs). Treatments were started at 24 hrs of reperfusion, and brain water was assessed at 2 days of reperfusion. In a third series of experiments, wet-to-dry ratios were determined in brains harvested at 2 days of reperfusion from rats that were subjected to 2 hrs of MCAO and did not receive any intravenous fluids. All values are mean ± SEM. There were no differences between sham-operated and naive control cohorts. At 24 hrs of reperfusion, water content was higher in both ipsilateral ischemic (82.80 ± 0.86%) and contralateral hemispheres (80.53 ± 0.29%), compared with naive animals (ipsilateral, 79.62 ± 0.12%; contralateral, 79.53 ± 0.13%). Maximal cerebral edema was measured at 2 days in both hemispheres (ipsilateral, 83.94 ± 0.47%; contralateral, 80.63 ± 0.13%). Edema was present for up to 3 days in contralateral tissue (80.27 ± 0.26%) and persisted to 7 days in the injured hemisphere (81.07 ± 0.34%). Maximal edema (as assessed at 2 days postocclusion) was robustly attenuated with hypertonic saline therapy (ipsilateral, 81.59 ± 0.52%; contralateral, 78.44 ± 0.22%). The efficacy of hypertonic saline was equivalent to furosemide (ipsilateral, 82.09 ± 0.50%; contralateral, 79.13 ± 0.17%) but less robust than mannitol (ipsilateral, 79.89 ± 0.36%; contralateral, 78.73 ± 0.17%). Conclusions: These data demonstrate that cerebral edema persists in both injured and contralateral hemispheres for days after MCAO. The global, maximal increase in brain water is responsive to continuous 7.5% hypertonic saline treatment begun at 24 hrs postischemia and to standard diuretic/osmotic agents. These results may have implications for diuretic and osmotic therapy in clinical ischemic stroke.

Original languageEnglish (US)
Pages (from-to)644-649
Number of pages6
JournalCritical care medicine
Issue number3
StatePublished - 2002
Externally publishedYes


  • Edema
  • Focal cerebral ischemia
  • Furosemide
  • Hypertonic saline
  • Mannitol
  • Reperfusion

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine


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