Anderson, Robert E.

Background and Purpose The use of intermittent reperfusion versus straight occlusion during neurovascular procedures is controversial. This experiment studied the effects of intermittent reperfusion and single occlusion on intracellular brain pH (pH i ), regional cerebral or cortical blood flow, and nicotinamide adenine dinucleotide (NADH) fluorescence during temporary focal ischemia. Methods Twenty fasted rabbits under 1.0% halothane anesthesia were divided into four groups: (1) nonischemic controls, (2) 60 minutes of uninterrupted focal ischemia, (3) 2×30-minute periods of focal ischemia separated by a 5-minute reperfusion, and (4) 4×15-minute periods of focal ischemia separated by three 5-minute reperfusion periods. Focal ischemia was produced by occlusion of both the middle cerebral and ipsilateral anterior cerebral arteries. After the final occlusion, there was a 3-hour reperfusion period in all groups. Regional cerebral and cortical blood flow, brain pH i , and NADH fluorescence were measured with in vivo panoramic fluorescence imaging. Results During occlusion, regional cerebral and cortical blood flows and NADH fluorescence values were not different among the groups. Brain pH i was significantly lower in the 4×15-minute group compared with the 1×60-minute group (6.57±0.02 versus 6.73±0.06; P <.03) but not significant when compared with the 2×30-minute group. During the short reperfusion periods, all parameters returned to normal except for NADH fluorescence levels, which remained elevated. During the postischemic final reperfusion period, there was a mild brain alkalosis of approximately 7.1 in all groups. There were no significant differences in NADH fluorescence among groups during the final reperfusion. Regional cerebral and cortical blood flow returned to near normal values in all groups. Conclusions This study demonstrates that intermittent reperfusion during temporary focal ischemia has different effects on the intracytoplasmic and the intramitochondrial compartments: worsening of brain cytoplasmic pH i but no significant differences in the oxidation/reduction level of mitochondrial NADH.

Abstract Perturbations in cerebral hemodynamics at the time of ablation of an arteriovenous shunt have been regarded as important in the pathogenesis of swelling and hemorrhage complicating resection of arteriovenous malformations (AVMs). A carotid-jugular fistula model in the rat had previously been investigated and found to simulate in part the nonhemorrhagic pathophysiology of a large cerebral arteriovenous fistula. Utilizing this model and measuring cerebral blood flow in 14 regions with a [14C]iodoantipyrine autoradiographic technique, the effects of hypocapnea on the cerebral circulation in opened and closed fistulas were investigated. Regional cerebral blood flow (rCBF) in control animals ranged from a median of 53 to 64 ml/100 g/min at a partial arterial carbon dioxide pressure (PaCO2) of 28 ± 2 mm Hg and 85 to 112 ml/100 g/min at a PaCO2 of 40 ± 5 mm Hg. In animals with an open carotid-jugular fistula created 12 weeks before the study, these median rCBF values at comparable PaCO2 levels ranged, respectively, from 15 to 39 ml/100 g/min and 50 to 68 ml/100 g/min (the 25th percentile for the open fistula in the hypocapneic group was 15 ml/100 g/min in 5 of the 14 regions studied). In contrast, median rCBF in the closed fistula group ranged from 73 to 100 ml/100 g/min in hypocapneic animals and from 118 to 187 ml/100 g/min in normocapneic animals. These results demonstrate the preservation of CO2 reactivity; hypoperfusion in the presence of a carotid-jugular fistula, hyperemia on fistula occlusion, and the potential to induce cerebral ischemia with hyperventilation in this model of a cerebral arteriovenous fistula. These data caution against the use of hyperventilation during surgery in patients with cerebral arteriovenous malformations.

Abstract Modern aneurysm clips with newer metallurgic properties and state-of-the-art designs have evolved through the years. Regretfully, manufacturers are still not required to provide product information regarding clip strength, and when such information is supplied, there is no interbrand consistency to how it is obtained. This experiment compares the closing pressures of 5 commonly used brands of aneurysm clips: Yasargil, Sugita, Sundt-Kees, Vari-Angle McFadden, and Heifetz. Interclip comparison is also made of opening pressures, that is, the arterial pressure required to open an aneurysm clip. Findings show a distinct difference in closing forces among these brands of aneurysm clips. The study of opening forces indicates that the important factors determining clip release or displacement were the failure of the clip to cross the vessel completely and intrinsic characteristics of the vascular wall. (Neurosurgery 26:80-85, 1990)

We report that regional CBF determined by the initial slope technique using 133 Xe and 85 Kr in cats and rabbits can be significantly influenced by the size of the field of measurement. The clearance curves of umbelliferone, a lipid-soluble intracellular pH fluorescent indicator, from a visually avascular 80-fm field were used to cross-correlate rCBF with focal cortical perfusion. Our findings indicate that in the cat, as the gamma or beta detector's field of volume was reduced, regional CBF (rCBF) measured by intraarterially injected 133 Xe or 85 Kr decreased in value by 33% and 28%, respectively, and the slope of the rCBF-P a co 2 response curve became less steep by 56% and 45%, respectively. Umbelliferone, measuring a much smaller volume of tissue, showed a lower normocapnic flow and a more oblique P a co 2 response curve. In the rabbits studied, the normocarbic rCBFs and the rCBF-P a co 2 response curves measured with the three techniques corresponded to those measured in the cat. These results suggest that large field/volume measurements assess a measure of flow that is a weighted average of several distinct flow compartments and that these compartments differ in their response to changes in P a co 2 .

Zomepirac sodium (ZS) (5 mg/kg i.v.) was used to evaluate the effects of preischemia cyclooxygenase inhibition on CBF (as assessed by 133 Xe clearance), CBF–P a CO 2 responsiveness, and electrophysiologic (EEG) parameters before and after a 15-min period of complete global ischemia produced by four-vessel occlusion and mild hypotension. During the 15-min period of ischemia, CBF was essentially zero. Following reflow all groups displayed an initial hyperemia as compared with control (92 ± 11 vs. 141–146 ml/100 g/min). Saline-treated animals during reflow displayed a delayed hypoperfusion (26 ± 3 ml/100 g/min), which showed no improvement during the 2-h reflow period prior to death. In contrast, ZS-treated animals during reflow displayed significantly higher flows during the hypoperfusion phase (72 ± 9 ml/100 g/min). The CBF–P a CO 2 response displayed an approximately sevenfold reduction in slope at 2 h after reflow in saline-treated animals. This decrease in P a CO 2 reactivity was not observed in the ZS-pretreated animals. With regard to EEG, all animals showed a total flattening during the 15 min of ischemia. In saline-treated animals only one of seven showed any sign of even marginal recovery. In ZS-treated animals EEG activity showed prominent recovery in seven of seven. Brainstem auditory evoked potentials were monitored and showed prominent recovery of amplitude and latency in ZS but not saline-treated animals during reflow.

The effects of the N-methyl-d-aspartate (NMDA) antagonist MK-801 on capillary beds and CBF following 1 h of transient incomplete focal cerebral ischemia were studied by examining 133 Xe CBF, capillary diameter, and area of perfused vasculature. Capillary diameter increased from a control of 5.24 ± 0.37 to 8.62 ± 0.57 μm (p < 0.001) and area of perfused vasculature from 20,943 ± 1,151 to 30,442 ± 1,691 μm 2 /×10 magnification field (p < 0.001) with MK-801 1.0 mg/kg administered 30 min prior to ischemia. After flow restoration in control animals, there was a relative hypoperfusion with eventual normalization of CBF over 60 min. Alternatively, in MK-801 1.0 mg/kg animals, there was rapid normalization of CBF upon flow restoration without the postischemic hypoperfusion observed in controls. On histological analysis, there was consistently less neuronal edema in MK-801-treated animals. These results support the hypothesis that hypoperfusion following incomplete focal cerebral ischemia may be due in part to NMDA-mediated cellular edema with subsequent extravascular capillary bed compression.

The effects of severe hypoglycemia on brain pH, cerebral blood flow (CBF), and other physiologic and metabolic parameters were studied in 26 cats subjected to insulin hypoglycemia. Two groups were utilized to compare the effects of anesthesia. The halothane group was composed of 14 animals and the barbiturate group contained 12 animals. Insulin was administered by both the intravenous and intramuscular routes until there was a severe electroencephalographic (EEG) change or until 6 h had elapsed. The cerebral responses to hypoglycemia demonstrated the following: CBF was unaffected by severe hypoglycemia in normotensive animals with or without EEG changes; brain pH was essentially constant in all groups regardless of glucose levels, CBF, or EEG; and the EEG abnormalities corresponded closely to brain glucose levels. Cerebral adenosine triphosphate and phosphocreatine levels were lowest in the animals with isoelectric EEGs. We conclude that CBF and brain pH in the normotensive cat under general anesthesia are relatively unaffected by insulin hypoglycemia despite the presence of severe EEG changes and cerebral energy reserves. The study suggests that the P a co 2 –CBF response curve is not dependent upon the metabolic integrity of cerebral tissue and is mediated by pathways separate from those of autoregulation.

CBF, as measured by the clearance of 133 Xe or 85 Kr in the pentobarbital-anesthetized cat, displays a monotonic increase as the P a co 2 is elevated over a range of 20–60 mm Hg (slope Xe, 1.65 ± 0.14 ml/100 g/min/mm Hg; slope Kr, 1.40 ± 0.11 ml/100 g/min/mm Hg). Clonidine (20 μg/kg i.v.), a centrally acting, α 2 -preferring agonist, reduced the slope of the P a co 2 -CBF response functions for Xe and Kr by 70 and 64%, respectively. Clonidine reduced normocarbic CBF-Xe by 36%, but had no effect on normocarbic CBF-Kr. ST-91, a polar structural analog of clonidine that does not cross the blood–brain barrier, did not reproduce the effects of clonidine when administered at an equivalent dose. This indicates that the effects of clonidine observed were secondary to its action on central rather than peripheral sites. In addition to the effects on the clearance of CBF markers, clonidine reduced the increased MABP otherwise evoked by elevated P a co 2 . Reduction in the MABP response to P a co 2 did not account for the lowering of CBF during hypercarbia. In separate experiments where MABP was elevated to correspond with the P a co 2 -MABP response observed in the absence of clonidine, a comparable reduction in the slope of the P a co 2 response was also observed. In addition, the pressure autoregulatory response was unaltered after clonidine treatment. These observations suggest that the central action of α 2 -receptors on the CBF-CO 2 response cannot be attributed to an altered perfusion pressure.

Intracellular brain pH was measured with a lipid-soluble, pH-sensitive fluorescent indicator in 16 squirrel monkeys. Eight of these were under halothane anesthesia and eight under barbiturate anesthesia. Measurements were taken before, during, and after focal incomplete ischemia. Brain pH following 3 h of cerebral focal ischemia changed from a normal value of 7.0 to 6.5 and 6.2 in animals studied under barbiturate and halothane anesthesia, respectively. Brain pH returned toward normal after flow was restored in animals under barbiturate anesthesia but continued to deteriorate in animals under halothane anesthesia.

Abstract A simple and reproducible method of quantitating the amount of hematoporphyrin derivative by fluorescence microscopy in biopsies of tumors from patients undergoing photoradiation therapy is presented, substantiated by laboratory studies of experimental central nervous system tumors and normal rat tissues. The literature regarding the quantitation of hematoporphyrin is reviewed, and implications of this study for the future application of photoradiation therapy and the design of laboratory studies are discussed.