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Isovolemic hemodilution in experimental focal cerebral ischemia

Part 1: Effects on hemodynamics, hemorheology, and intracranial pressure

Yong-Kwang Tu, Roberto C. Heros, Guillermo Candia, Akio Hyodo, Karen Lagree, Ronald Callahan, Nicholas T. Zervas, and Dimitris Karacostas

✓ A total of 76 splenectomized dogs were entered in a study of the value and effects of isovolemic hemodilution. Of these, seven were not included in the analysis because of technical errors. Of the remaining 69 dogs, 35 were treated with hemodilution; 28 were subjected to a 6-hour period of temporary occlusion of the distal internal carotid artery and the proximal middle cerebral artery, and seven underwent a sham operation only, with arterial manipulation but no occlusion. The other 34 dogs were not subjected to hemodilution; 26 of these underwent temporary arterial occlusion and eight had a sham operation only. In each group the animals were about equally divided into 1) an acute protocol with regional cerebral blood flow measurements by a radioactive microsphere technique and sacrifice at the end of the acute experiment, and 2) a chronic protocol with survival for 1 week to permit daily neurological assessment and final histopathological examination but without blood flow measurements. Isovolemic hemodilution was performed about 1 hour after the arterial occlusion or sham operation and was accomplished by phlebotomy and infusions of low molecular weight dextran to bring the hematocrit to a level of 30% to 32%. This treatment resulted in a very significant reduction in viscosity and fibrinogen levels. The decrease in hematocrit lasted throughout the week in the animals in the chronic protocol. The decrease in viscosity correlated almost linearly with the decrease in hematocrit. There was a slight decrease in systemic arterial pressure with hemodilution but there were no significant changes in central venous pressure or in pulmonary arterial or wedge pressure. There was a slight decrease in cardiac index in both the hemodilution and control groups, which may have been due to the effects of barbiturate anesthesia. There was a slight increase in the measured blood volume in both groups, which was probably artifactual and related to the method of calculation. Intracranial pressure increased significantly with time in all animals subjected to arterial occlusion, but this increase was less severe in the hemodilution group. There was no significant change in intracranial pressure in sham-operated animals, whether hemodiluted or not. The results of cerebral blood flow measurements, assessment of neurological condition, and measurement of infarct size are given in Part 2 of this report.

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Isovolemic hemodilution in experimental focal cerebral ischemia

Part 2: Effects on regional cerebral blood flow and size of infarction

Yong-Kwang Tu, Roberto C. Heros, Dimitris Karacostas, Ted Liszczak, Akio Hyodo, Guillermo Candia, Nicholas T. Zervas, and Karen Lagree

✓ Seventy-six splenectomized dogs were entered in a study of the value and effects of isovolemic hemodilution. Of these, seven were not included in the analysis because of technical errors. Of the remaining 69 dogs, 35 were treated with hemodilution; 28 were subjected to a 6-hour period of temporary occlusion of the distal internal carotid artery and the proximal middle cerebral artery, and seven underwent a sham operation only, with arterial manipulation but no occlusion. The other 34 dogs were not subjected to hemodilution; 26 of these underwent temporary arterial occlusion and eight had a sham operation only. In each group the animals were about equally divided into 1) an acute protocol with regional cerebral blood flow measurements by a radioactive microsphere technique and sacrifice at the end of the acute experiment, and 2) a chronic protocol with survival for 1 week to permit daily neurological assessment and final histopathological examination but without blood flow measurements. The general experimental protocol, the hemodynamic and rheological measurements, and the changes in intracranial pressure are described in Part 1 of this report.

In the animals with arterial occlusion, blood flow decreased significantly in the territory of the ischemic middle cerebral artery. This decrease was partially reversed by hemodilution in the animals so treated. When the changes in blood flow before and after hemodilution in treated animals are compared with the changes at equivalent times in animals without hemodilution, the increases in flow in the gray matter of the ischemic hemisphere brought about by hemodilution are statistically significant. The neurological condition of the animals in the chronic protocol (sacrificed 1 week after occlusion) with hemodilution, as evaluated by daily neurological assessment, was significantly better than that of the control animals.

In the animals sacrificed acutely (8 hours after arterial occlusion), the volume of infarction as estimated by the tetrazolium chloride histochemical method was 7.36% of the total hemispheric volume in the control animals and 1.09% in the hemodiluted animals, showing a statistically significant difference (p < 0.005). In the chronic animals these values were 9.84% and 1.26%, respectively (p < 0.005), as calculated by fluorescein staining. By histopathological examination the volume of infarction in the chronic animals was calculated as 10.92% in the control animals and 1.20% in the hemodiluted animals (p < 0.005). There was good correlation between the size of infarction and the decrease in hematocrit and viscosity, and excellent correlation between the size of infarction estimated by fluorescein and that determined by histopathological examination in each animal in the chronic group.

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Vassilios G. Varsos, Theodore M. Liszczak, Dae Hee Han, J. Philip Kistler, Juan Vielma, Peter McL. Black, Roberto C. Heros, and Nicholas T. Zervas

✓ Angiographic spasm of cerebral arteries was produced in dogs by successive injections of cisternal blood 48 hours apart. Angiograms were taken before and after each cisternal injection. There was progressively greater angiographic vasospasm of the basilar artery. Intravenous aminophylline, 10 mg/kg/hr, reversed vessel constriction on the 1st and 3rd day after one injection of cisternal blood. On the 5th day after two blood injections (on Day 1 and Day 3), intravenous aminophylline, nifedipine (1 mg/kg), and intra-arterial bolus injection of 2 mg/kg papaverine failed to reverse the constriction. The intractable constriction produced in this model resembles that found in patients. The calcium antagonist, nifedipine, is as ineffective as the more traditional vasodilators in reversing vasospasm in this model.