John O. Eichling

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.

Evidence of the Limitations of Water as a Freely Diffusible Tracer in Brain of the Rhesus Monkey

The extraction of 15O-labeled water by the brain during a single capillary transit was studied in vivo in 20 adult rhesus monkeys by external detection of the time course of the tracer subsequent to the internal carotid injection of 0.2 ml of whole blood labeled with H215O. The data showed that labeled water does not freely equilibrate with the exchangeable water in the brain when the mean cerebral blood flow exceeds 30 ml/100 g min−1. At the normal cerebral blood flow in the rhesus monkey (∼50 ml/100 g min−1), only 90% of the H215O is extracted during a single capillary transit. In addition, cerebral blood flow was determined with H215O and 133Xe in these monkeys using residue detection and employing the central volume principle. The data supported the hypothesis that a diffusible tracer, H215O, need not be in complete equilibrium between the phases of a system for the application of the central volume principle to be valid. Finally, the brain capillary permeability-surface area product was computed from these data; it was approximately 0.023 cm3/sec g−1.

The measure in vivo of regional cerebral oxygen utilization by means of oxyhemoglobin labeled with radioactive oxygen-15

Regional cerebral oxygen utilization rate is measured in vivo by the following method:A small volume of blood with radioactive oxygen-15-tagged hemoglobin is rapidly injected into the internal carotid artery of the patient under study. The first injection is followed by the injection carried out under identical circumstances but with blood labeled with water-(15)O. After each injection, the distribution of the radioactive label in the brain is measured and recorded, as a function of time, by six collimated scintillation probes placed over the subjects head. The recording, subsequent to the first injection, reflects (a) the arrival of the labeled oxygen into the tissues, (b) its partial conversion into water of metabolism, and (c) the washout of labeled water from the brain. The ratio of the amount of labeled water formed to the amount of oxygen perfusing the tissues, which can be derived from the recording, is a measure of fractional oxygen utilization. The second injection provides a measure of blood flow by the interpretation of the washout of labeled water from brain tissues. The product, fractional oxygen utilization x blood flow x arterial oxygen content, gives a measure of oxygen utilization rate. Some aspects of the validity of this method are tested by the injection of a nondiffusible indicator, carboxyhemoglobin-(15)O. Regional cerebral oxygen utilization rates for a series of patients with cerebral pathology are reported.

The Determination of Regional Cerebral Blood Flow by Means of Water Labeled with Radioactive Oxygen 15

THE NUMBER of methods devised for the in vivo evaluation of regional cerebral flow (rCBF) attest to the elusiveness of this parameter. One of the methods for this purpose is the injection, into the internal carotid artery of a subject, of a diffusible indicator labeled with a gammaemitting radioisotope, followed by the external measurement of the rate of washout of the indicator from various regions of the brain. This approach (1, 2), a modification of the Kety–Schmidt method (3–5), has most frequently utilized saline solutions of radioactive inert gases such as krypton 85 (1, 2) and xenon 133 (6). At this time, 133Xe appears to be the most widely used diffusible indicator despite inherent limitations which include: (a) a different solubility in lipids and in water; (b) a brain–blood partition coefficient difficult to evaluate accurately; and (c) the low–energy electromagnetic radiation of 133Xe. The first two factors render absolute flow determinations by this indicator uncertain and the third one favors...

Cerebral blood flow, oxygen utilization, and blood volume in dementia

Patients with dementia had significant decreases in cerebral blood flow and cerebral oxygen utilization and a mild, but not significant, increase in cerebral blood volume. These studies were not useful in distinguishing patients with cerebral atrophy from patients with normal pressure hydrocephalus, as similar changes in cerebral circulation and metabolism were seen in both groups. Changes in cerebral blood flow after acute decrease in the intracranial pressure also were not helpful in differentiating patients with normal pressure hydrocephalus from patients with cerebral atrophy.

In vivo determination of cerebral blood volume with radioactive oxygen-15 in the monkey.

A method for the in vivo determination of cerebral blood volume was tested in 15 adult rhesus monkeys. The technique utilized external residue detection and required the serial measurement of two mean transit times, namely, that of an intravascular tracer, CI5O-hemoglobin, and that of a diffusible tracer, H215O. In computing the mean transit time for the intravascular tracer, the conventional Hamilton extrapolation of the downslope of the recording obtained for the washout of the tracer from the brain subsequent to an intracarotid bolus injection was found to be inadequate, yielding a mean transit time that systematically underestimated that parameter. Alternatively, the use of a power law extrapolation, as proposed by Huang, allowed a more accurate prediction of the vascular mean transit time. The preliminary studies testing the method predicted that the relationship between cerebral blood volume (CBV) and cerebral blood flow (CBF) was adequately represented by the equation CBV = 0.80CBF038, with a correlation coefficient of r = 0.90 for the cerebral blood flow range of 16 to 134 ml/100 g min−1 with a normocapnic cerebral blood volume of 3.5 ml/100 g perfused brain tissue (arterial Pco2 = 37 torr, CBF = 50 ml/100 g min−).

Central Noradrenergic Regulation of Brain Microcirculation

Earlier studies, as well as anatomical findings of others, led to the development of a working hypothesis that the central noradrenergic system is analogous to the peripheral sympathetic system except that it is specialized, in part, for performing specific functions related to brain microvasculature. This hypothesis has been tested in adult rhesus monkeys with chronic bilateral superior cervical ganglionectomies in whom stereotaxically placed cannulae were permanently located in the locus coeruleus for electrical stimulation using concentric bipolar electrodes passed through the cannulae. Cerebral blood flow and brain permeability for water (H2 15O) were simultaneously measured as previously described. The results demonstrated that electrical stimulation of the locus coeruleus produced a prompt increase in brain water permeability and a reduction of cerebral blood flow. Transient increase in water permeability and a decrease in cerebral blood flow was also induced by intracarotid infusion of hypertonic urea. Neurally mediated mechanism for regulation of brain water permeability is proposed which would account for changes in permeability induced by electrical stimulation and by mechanical distortion.

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:

Risk of radiation induced skin injuries from arrhythmia ablation procedures

Catheter guided ablation of cardiac arrhythmias is an effective and safe procedure for the treatment of most supraventricular and selected ventricular tachycardias. Because catheter manipulation is fluoroscopically guided, there is risk of radiation induced injury, especially during prolonged procedures. The Food and Drug Administration has recently issued a bulletin warning of the risks of acute skin injury occurring during fluoroscopically guided procedures that result in an exposure level exceeding 2 Gray units (Gy). This study was performed as an investigation into the risk of radiation induced skin injury during arrhythmia ablation procedures. The amount of radiation exposure for 500 patients who underwent ablation was calculated based upon fluoroscopy times and the entrance dose of radiation (0.02 Gy/min). The mean radiation exposure was 0.93 ± 0.62 Gy. Although 5.6% of patients (n = 28) received enough radiation exposure to reach the threshold dose (2 Gy) for early transient erythema, no clinical manifestations of acute radiation induced skin injury were observed. No patients achieved the threshold dose for irreversible skin injury. Patients undergoing AV node ablation or modification received significantly less radiation (0.39 ± 0.40 Gy and 0.79 ± 0.44 Gy, respectively) than patients undergoing other ablation procedures (0.94–1.45 Gy, P < 0.05). There was no association between the magnitude of radiation exposure and the presence of underlying heart disease. Patients undergoing ablation of accessory pathways were exposed to more radiation if there was a right‐sided pathway (1.69 ± 0.93 Gy) compared to other sites (0.87–1.24 Gy, P < 0.05). This study demonstrates that the risk of significant radiation induced skin injury during arrhythmia ablation procedures is low provided that precautions are taken to minimize radiation exposure.

Radiation exposure to family and household members after prostate brachytherapy.

PURPOSE Patients with localized prostate cancer frequently seek alternatives to radical surgery and external beam radiation therapy. Permanent prostate brachytherapy is an acceptable option. However, fears of radiation exposure to family members may deter some individuals from choosing this treatment option. A direct measurement was performed to determine the expected lifetime exposure from the patient with a brachytherapy prostate implant to family members and the household. METHODS AND MATERIALS After a permanent brachytherapy implant with (125)I or (103)Pd, patients and their family members were provided radiation monitors to measure direct radiation exposure at home. Each patient was given two monitors to wear, and each member of the household, including the spouse, children, and pets, was given a single monitor. In addition, four rooms in the house frequently occupied by the patient were monitored. Based on the reading from the dosimeters measured at the first follow-up visit, the lifetime exposure to each individual or room was calculated. Forty-four patients, along with their families, agreed to participate and complied with the use of the dosimeters. Twenty-nine patients received a (125)I implant and 15 a (103)Pd implant. Assays were obtained on 272 monitors: 78 worn by patients, 52 worn by household members, and 142 posted in rooms. RESULTS Exposures measured by patient dosimeters were within the expected range for the type of implant received. Exposures to family members were low. Based on dosimeter readings, the calculated mean lifetime dose to a spouse from her husband was 0.1 (range: 0.04-0.55) mSv for a (125)I implant and 0.02 (range: 0.015-0.074) mSv for a (103)Pd implant. Other family or household members had 0.07 (range: 0.04-0.32) mSv or 0.02 (range: 0.015-0.044) mSv for (125)I and (103)Pd implants, respectively. The calculated lifetime exposure did not exceed the annual limit set by the U.S. Nuclear Regulatory Commission in any of the cases. The majority of room dosimeters (94%) had no detectable radiation exposure. CONCLUSIONS Radiation exposure to family members from a patient receiving a permanent prostate brachytherapy implant with radioactive (125)I or (103)Pd is very low and well below the limits recommended by the U.S. Nuclear Regulatory Commission. Radiation exposure to members of a patients family or to the public should not be a deterrent to undergoing this procedure.