We tested the hypothesis that transtentorial herniation (TTH) represents a state of cerebral ischemia that can be reversed by hypertonic saline. Because of the high mortality associated with TTH, new therapeutic strategies need to be developed for rapid and effective reversal of this process. We produced TTH (defined by acute dilatation of one or both pupils) by creating supratentorial intracerebral hemorrhage with autologous blood injection in seven mongrel dogs anesthetized using intravenous pentobarbital and fentanyl. We measured serial rCBF (regional cerebral blood flow) using radiolabeled microspheres in regions around and distant to the hematoma. Cerebral oxygen extraction and oxygen consumption (CMRO2) were measured by serial sampling of cerebral venous blood from the sagittal sinus. Mean arterial pressure (MAP) and intracranial pressure (ICP) were continuously monitored. TTH was successfully reversed over a mean period of 25.7 ± 4.9 minutes after intravenous administration of 23.4% sodium chloride (1.4 mL/kg) in all animals. All measurements were recorded 15, 30, 60, and 90 minutes after administration of 23.4% sodium chloride. Compared to prehematoma ICP (14.1 ± 1.7 mm Hg, mean ± SE), elevation in ICP was observed during TTH (36.2 ± 7.2 mm Hg) with no change in cerebral perfusion pressure (CPP) (80.4 ± 4.7 vs. 76.7 ± 10.1 mm Hg) because of concomitant elevation in mean arterial pressure. Compared to baseline values, there was a reduction in rCBF (mL/100 gm/min ± SE) in brainstem (12.1 ± 2.0 vs. 21.4 ± 1.4), gray matter (18.2 ± 2.1 vs. 31.4 ± 1.8), and white matter (8.6 ± 1.7 vs.18.7 ± 0.9) in the hemisphere contralateral to the hematoma; and gray matter (12.9 ± 2.9 vs. 27.9 ± 2.2) and white matter (8.3 ± 2.0 vs.19.9 ± 1.0) in the ipsilateral hemisphere distant from the hematoma. Administration of 23.4% sodium chloride resulted in reduced ICP at 15 minutes (12.7 ± 1.4) and 30 minutes (15.6 ± 3.1) after administration. RCBF values were restored in all regions studied after administration of 23.4% sodium chloride with an increase in CMRO2(1.8 ± 0.4 vs. 3.9 ± 0.7 mL O2/100 gm/min). Compared with baseline values, rCBF increased in the ipsilateral (31.7 ± 2.5 vs. 63.4 ± 11.7) and contralateral (28.7 ± 1.9 vs. 45.5 ± 5.7) thalamus at 15 minutes after administration of 23.4% sodium chloride. TTH represented a state of ischemia in brainstem and supratentorial gray and white matter in the presence of adequate CPP, suggesting mechanical compression of vessels at the level of tentorium. Hypertonic saline reversed TTH, and restored both rCBF and CMRO2, although hyperemia was observed immediately after reversal of TTH. Administration of hypertonic saline may preserve neurologic function during the interim period between TTH and surgical intervention.