Robert L. Grubb

The Effects of Changes in PaCO2 Cerebral Blood Volume, Blood Flow, and Vascular Mean Transit Time

The relationships between cerebral blood volume (CBV), cerebral blood flow (CBF), and the cerebral vascular mean transit time (t®v) during acute changes in the PaCO2 over a range of 15 to 76 torr were investigated in vivo in rhesus monkeys by serially determining the mean transit time of a vascular tracer, 15O-labeled carboxyhemoglobin, and the mean transit time of a diffusible tracer, 15O-labeled water. Over this range of PaCO2, a significant linear relationship of CBV = 0.041 PaCO2 + 2.0 was found. For each one torr change in PaCO2, there is a change in CBV of 0.041 ml/100 gm of perfused tissue. At a normocarbic value of PaCO2 (∼37 torr), an average value of 3.5 ml/100 gm was found. A nonlinear relationship of CBV and CBF was found. This relationship is expressed in the equation, CBV = 0.80 CBF0.38. A significant linear relationship was found between CBF and PaCO2. This was described by the equation, CBF = 1.8 PaCO2 − 16.75. For each one torr change in the PaCO2, there is a 1.8 ml/100 gm per minute change in the CBF. At a normocarbic value of PaCO2(∼37 torr), an average value of CBF of 50 ml/100 gm per minute was found. The relationship of CBV and t®v was nonlinear and was expressed in the equation, t®C15O = 41 CBF−0.62.

The Effects of Arterial Blood Pressure on the Regional Cerebral Blood Volume by X-Ray Fluorescence

Cerebral blood flow (CBF) remains constant over a wide range of arterial blood pressure. This is thought to be accomplished by changes in the diameter, and therefore the volume, of the cerebral resistance vessels. To test this hypothesis, regional cerebral blood volume (rCBV) was measured in vivo in Rhesus monkeys over a range of mean arterial blood pressures (MABP) of 35 to 200 torr. Multiple measurements were made in each animal by the method of stimulated x-ray fluorescence. A significant linear relationship of rCBV = 6.26 (±0.47 SD) −0.015 (±0.004 SD) MABP was found. For each one torr change in the MABP, there is a change in rCBV of 0.015 cc/100 gm of brain tissue over a range of MABP of 35 to 200 torr. An additional observation of this investigation was that autoregulation of the cerebral blood flow (CBF) is perturbed for a period lasting up to 15 minutes after the intravenous injection of Renografin 76R.

Peripheral sympathetic regulation of brain water permeability

We have previously reported that stimulation of the locus coeruleus in chronically sympathectomized rhesus monkeys produces an increase in brain water permeability and a decrease in cerebral blood flow (CBF) 13,15. Opposite effects on brain water permeability and CBF were seen with the intraventricular administration of the alpha adrenergic blocker phentolamine. These physiological observations are consistent with the anatomical observation that some central noradrenergic fibers originating in the brain stem reach capillaries of the cerebral hemispheres 7. Noradrenergic fibers originating in the superior cervical ganglion innervate brain extraparenchymal vessels and intraparenchymal brain microvessels including arterioles down to a size of 15 #m 3. The transfer of substances, including labeled water, within the brain has been shown to occur in these vessels 9. Thus, stimulation of the cervical sympathetic chain should produce changes in brain water permeability and CBF similar in nature to changes seen with stimulation of the central noradrenergic system. To test this hypothesis, brain water permeability and CBF were measured in rhesus monkeys during and after bilateral cervical sympathetic chain stimulation. CBF and the fraction of labeled water extracted by the brain during a single capillary transit were determined by the injection of 0.2 ml of whole blood labeled with H~150 into the internal carotid artery of 8 adult rhesus monkeys (Macaca mulatta) 4. lz-14.18. The details of the animal preparation, injection procedures and the in vivo detection of the radioisotope are described elsewherO ,lz,14. The monkeys were anesthetized with phencyclidine (2 mg/kg), paralyzed with gallamine, and passively ventilated on 100 ~ oxygen. The end-tidal pC0z (p~xC02), arterial blood pressure and rectal temperature were continuously monitored. The cervical sympathetic chain was exposed bilaterally just proximal to the superior cervical ganglion and 21-gauge silver wire bipolar stimulating electrodes were placed on the sympathetic chain. The single capillary model of Renkin l° and Crone 2 was used to calculate the brain PS product (capillary permeability coefficient and surface area product) for water4,14, The relationship of CBF and the extraction fraction of labeled water (El to the brain PS product is expressed in the equation:

Intraventricular angiotensin II increases brain vascular permeability.

Angiotensin II (All) has several important actions when injected into the brain. Included among these actions are the stimulation of drinking behavior, increased sodium appetite and the release of antidiuretic hormone t-3, phenomena which appear designed to effect changes in body water and electrolyte balance. Although the brain is clearly involved in these responses and may, in fact, possess its own intrinsic renin-angiotensin system 19,23, no one has yet investigated the possibility that All might have a specific effect on brain water and electrolyte balance. Because the normal functioning of the brain is dependent upon the precise adjustment of water and electrolyte content and, hence, volume 7, often in the face of fluctuating osmotic and hydrostatic force imposed by the incoming blood, it seems reasonable to ask whether All has a specific effect on any aspect of brain water and electrolyte homeostasis. Previous studies reported by us and others have called attention to anatomical and functional features of brain capillaries which suggest that they might play an important and active role in the maintenance of brain water and electrolyte homeostasis (for annotated bibliography see ref. 12). Based on these data and the known effects of centrally administered All we inquired in these experiments whether All administered into the anterior third ventricle of rhesus monkeys could produce a change in brain capillary permeability. Our data indicate that All can produce a transient increase in brain capillary permeability, as measured by 150-labeled water, in the absence of any other hemodynamic disturbances. This finding is consistent with the hypothesis that AII has a role in brain fluid and electrolyte homeostasis that may be distinct from its role in overall body blood volume regulation. Our experiments were performed on 7 adult rhesus monkeys (Macaca mulatta). The monkeys were anesthetized with phencyclidine (2 mg/kg), paralyzed with galla-

The Effects of lodinated Contrast Agents on Autoregulation of Cerebral Blood Flow

The effects of an iodinated contrast agent, Renografin-76® upon cerebral autoregulation was studied in rhesus monkeys. This was done by measuring the effects of an intravenous injection of Renografin-76 upon: (1) the response of baseline CBF as measured by the washout of a carotid bolus of H215O during and after the injection of Renografin-76, (2) the response of CBF monitored continuously by a Doppler flow probe technique to changes in the mean arterial blood pressure (MABP) before and after an injection of Renografin-76, and (3) the response of the regional cerebral blood volume (rCBV) as measured by stimulated x-ray fluorescence. An intravenous injection of Renografin-76 can disturb cerebral autoregulation in the rhesus monkey for as long as 15 minutes after the beginning of the injection. After the intravenous in jection of Renografin-76, transient rises in both CBF and MABP lasting from 2 to 12 minutes occurred on an average of 23% and 16%, respectively, over control values.

Extracranial-intracranial bypass for ischemic cerebrovascular disease: what have we learned from the Carotid Occlusion Surgery Study?

Extracranial-intracranial (EC-IC) arterial bypass has been used in the treatment of various neurosurgical pathologies including skull base tumors requiring sacrifice of a large intracranial artery; complex intracranial aneurysms requiring trapping; and distal revascularization, moyamoya disease, and symptomatic cerebrovascular stenoocclusive disease. The latter indication has been the subject of intense investigations in several large randomized controlled trials, most recently the Carotid Occlusion Surgery Study (COSS). In the present literature review and synthesis, the authors examine the current evidence available for EC-IC arterial bypass for the treatment of ischemic cerebrovascular disease including both extracranial carotid artery occlusive disease and intracranial atherosclerotic disease. They focus particular attention on EC-IC arterial bypass for the treatment of symptomatic hemodynamic cerebral ischemia and how lessons learned from the COSS might guide future investigations into the treatment of this disease.

Cerebral Hemodynamics and Stroke Risk in Patients with Complete Carotid Artery Occlusion: Is There a Role for Cerebral Revascularization?

Patients with complete carotid artery occlusion comprise approximately 15% of those with carotid territory transient ischemic attacks or infarction [1, 2, 3]. Prevention of subsequent stroke in patients with carotid artery occlusion remains a difficult challenge. The overall risk of subsequent stroke is 7% per year and the risk of stroke ipsilateral to the occluded carotid artery is 5.9% per year [4]. These risks persist in the face of platelet inhibitory drugs and anticoagulants [5]. The importance of hemodynamic factors in the prognosis of carotid occlusion and the role of surgical re-vascularization in the treatment of these patients has been a subject of controversy for many years. The technique of extracranial-intracranial (EC/IC) arterial bypass surgery was developed in the late 1960’s and applied to patients with carotid occlusion in an attempt to prevent subsequent stroke by improving the hemodynamic status of the cerebral circulation distal to the occluded vessel. The results of an international multicenter randomized trial to determine the efficacy of EC/IC arterial bypass for the prevention of subsequent stroke was reported in 1985. Among 808 patients with symptomatic carotid occlusion who were randomized, no benefit of superficial temporal artery — middle cerebral artery (STA-MCA) bypass surgery could be demonstrated [6]. Based on the results of this trial, EC/IC bypass was generally abandoned as a treatment for symptomatic carotid artery occlusion.