Sissel Vorstrup

Effect of acetazolamide on cerebral blood flow and cerebral metabolic rate for oxygen.

The aim of this study was to evaluate the effect of acetazolamide on cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2). CBF, arterial and jugular venous partial O2 pressure, partial CO2 pressure, pH, and O2 saturation percentage were measured in six patients before and 3 and 20 minutes after intravenous administration of 1 g of acetazolamide. CBF was measured by the intracarotid 133xenon injection technique. In addition, changes in CBF were estimated from the arteriovenous oxygen content difference. CBF increased in all patients after acetazolamide, by approximately 55 and 70% after 3 and 20 min, respectively. The CBF changes were of the same order whether calculated from the 133Xe clearance or from the arteriovenous oxygen differences (A-V)O2. CMRO2, calculated from (A-V)O2 differences and CBF, remained constant. Except for an increase in the venous oxygen saturation, the blood gases remained constant. Acetazolamide, in a dose sufficient to inhibit the erythrocyte carbonic anhydrase (EC 4.2.1.1), thus induced a rapid and marked increase in CBF, leaving CMRO2 unchanged. This effect of acetazolamide on CBF is probably explained by a decrease in brain pH rather than by brain tissue hypoxia due to inhibition of oxygen unloading in the brain capillaries.

Cerebral blood flow in rats with renal and spontaneous hypertension: resetting of the lower limit of autoregulation.

The effect of chronic hypertension on cerebral blood flow (CBF) was studied in anaesthetised rats. CBF was measured with the intracarotid 133Xe injection method. Rats with spontaneous and renal hypertension were compared with normotensive controls. The lower limit of autoregulation was determined during controlled haemorrhage. In the normotensive rats, CBF remained constant until mean arterial pressure (MAP) had decreased to the range of 50–69 mm Hg. Thereafter, CBF decreased with each further decrease in MAP. In both types of hypertensive rats, CBF remained constant until MAP had decreased to the range of 70–89 mm Hg. Thus, a 20-mm Hg shift of the lower limit of CBF autoregulation was found in both spontaneous and renal hypertensive rats. A neuropathological study revealed ischaemic brains lesions in half of the hypertensive rats following hypotension, whereas only a single lesion was found in one of six normotensive rats. No ischaemic brain lesions were found in a control study in which CBF was shown to be stable over a 2 1/2-h period. In conclusion, hypertensive rats showed a shift of the lower limit of CBF autoregulation as well as an increased susceptibility to ischaemic brain damage during hypotension. These findings presumably reflect hypertensive structural changes in the cerebral circulation.

Regional Cerebral Blood Flow Assessed by 133Xe Inhalation and Emission Tomography: Normal Values

Regional cerebral blood flow (rCBF) in the cerebral hemispheres and the cerebellum was measured by single photon emission computed tomography with inhalation of l33Xe in 39 normal volunteers at test. The goal of this study was to assess the normal flow pattern and its variations. Five parallel tomographic slices through the brain were recorded with a resolution element of 1.7 × 1.7 × 2.0 cm (full width at half maximum). The blood flow distribution showed that the predominantly gray matter areas displayed flow approximately double that of the predominantly white matter regions. The CBF distribution was practically symmetrical with a side-to-side difference averaging 1.4 ± 1.4 ml/100 g/min. This means that a difference exceeding 4.2 ml/100 g/min (approximately 9% of mean CBF) is abnormal with a confidence level of below 5%. The measured average CBF and cerebellar blood flow were 56 ± 7 and 54 ± 6 ml/100 g/min (mean ± 1 SD), respectively. A significant correlation was found between CBF and Pco2, and between CBF and age. Repeat measurements in an additional 30 subjects showed a day-to-day variability of −0.2 ± 6.4 ml/100 g/min of the difference between the first and the second measurement. This corresponds to random methodological and biological errors of 6.4√2 = 4.6 ml/100 g/min and is a measure of the overall intraindividual variability. Xenon-133 tomography is atraumatic and affords rCBF images free of the superposition artifacts that practically invalidate the nontomographic approaches in the studies of cerebrovascular disease. The rCBF tomograms are blurred, particularly due to Compton scatter. Relative to this factor, the errors caused by local variations in the tissue: blood partition coefficient are less important.

Cerebral blood flow in patients with congestive heart failure treated with captopril

The effect of captopril on cerebral blood flow was studied in five patients with severe congestive heart failure and in five control subjects. Cerebral blood flow was measured by inhalation of 133xenon and registration of its uptake and washout from the brain by single photon emission computer tomography. In addition, cerebral (internal jugular) venous oxygen tension was determined in the controls. The measurements were made before and 15, 60, and 180 minutes after a single oral dose of captopril (6.25 mg in patients with congestive heart failure and 25 mg in controls). Despite a marked decrease in blood pressure, cerebral blood flow increased slightly in the patients with severe congestive heart failure. When a correction was applied to take account of a change in arterial carbon dioxide tension, however, cerebral blood flow was unchanged after captopril administration even in patients with the greatest decrease in blood pressure, in whom a decrease in cerebral blood flow might have been expected. In the controls, blood pressure was little affected by captopril, whereas a slight, but not statistically significant, decrease in cerebral blood flow was observed. The cerebral venous oxygen tension decreased concomitantly.

Focal reductions of cerebral blood flow in amyotrophic lateral sclerosis: A [99mTc]-d,l-HMPAO SPECT study

We investigated regional cerebral blood flow (rCBF) using the [99mTc]-d,l-HMPAO technique with brain dedicated high resolution single photon emission computer tomography (SPECT) in 14 consecutive patients with amyotrophic lateral sclerosis (ALS), median age 62 years (45-77). Global CBF, expressed in % relative to the cerebellum, was significantly lower (P less than 0.05) in the ALS group (80.5 +/- 6.7%) than in the control group of 14 age-matched healthy volunteers (87.0 +/- 7.5%). Eight patients (57%) had abnormal rCBF distribution maps with reduced flow, primarily in the frontal lobes. Three of the 8 patients with abnormal rCBF had mild to moderate dementia and another one had mild aphasia. None of the patients with normal rCBF distribution maps had dementia. In the group of ALS patients as a whole rCBF was significantly reduced in the frontal cortex, the hippocampus, and the central white matter. We conclude that reduced rCBF, primarily in the frontal lobes, is a frequent finding in patients with ALS. The decreased rCBF may be associated with cognitive deficits and is most likely caused by neuronal degeneration and reduced metabolic needs.

Angiotensin converting enzyme inhibition and cerebral blood flow autoregulation in normotensive and hypertensive man.

The acute effect on the lower limit of cerebral blood flow (CBF) autoregulation of an angiotensin converting enzyme (ACE) inhibitor, captopril, was studied in normotensive volunteers and in hypertensive patients. Baseline CBF was measured using xenon-133 inhalation tomography, and changes in CBF were measured using the arterio-venous oxygen difference method. Cerebral blood flow autoregulation was studied in two separate normotensive groups, one group of 12 volunteers serving as a control, and one group of 12 volunteers studied after the administration of captopril 50 mg. In a group of seven hypertensive patients CBF autoregulation was studied before and 1 h after the administration of captopril 25 mg. In the normotensive volunteers the median lower limit of CBF autoregulation was 83 and 74 mmHg in the untreated and the captopril-treated group, respectively, with no significant difference between the two groups. In five of the hypertensive patients the lower limit of CBF autoregulation was lowered by captopril, in median by 22 mmHg. However, in two patients it was increased, by 3 and 13 mmHg, respectively. It is proposed that the shift in the lower limit of CBF autoregulation seen in some of our cases, and which has previously been documented in experimental studies, may be dependent on the activity of the sympathetic nervous system.

Regional cerebral blood flow in patients with transient ischemic attacks studied by Xenon-133 inhalation and emission tomography.

Cerebral blood flow CBF was studied in 14 patients with transient ischemic attacks TIA and arteriosclerotic neck vessel disease. CBF was measured by a rapidly rotating single photon emission computerized tomograph using Xenon-133 inhalation. This method yields images of 3 brain slices depicting CBF with a spatial resolution of 1.7 cm. Based primarily on the clinical evidence and on the angiographical findings embolism was considered the pathogenetic factor in 10 cases, whereas chronic hemodynamic insufficiency rendered symptomatic by postural factors probably accounted for the symptoms in 4 patients. Of the 14 patients, all studied days to weeks after the most recent TIA, four showed hypoperfused areas on the CBF-tomograms and with roughly the same location hypodense areas on CT-scanning, i.e. areas of complete infarction. However, an additional five patients showed reduction of CBF in areas with no abnormality on the CT-scan. The abnormal blood flow pattern was found to be unchanged after clinically successful reconstructive vascular surgery. This suggests the presence of irreversible ischemic tissue damage without gross emollition (incomplete infarction). It is concluded, that TIAs are often harmful events, as no less than 9 of the 14 patients studied had evidence of complete and/or incomplete infarction. Thorough examination and rational therapy should be instituted as soon as possible to prevent further ischemic lesions.

Hemodilution increases cerebral blood flow in acute ischemic stroke.

We measured cerebral blood flow in 10 consecutive, but selected, patients with acute ischemic stroke (less than 48 hours after onset) before and after hemodilution. Cerebral blood flow was measured by xenon-133 inhalation and emission tomography, and only patients with focal hypoperfusion in clinically relevant areas were included. Hemodilution was done according to the hematocrit level: for a hematocrit greater than or equal to 42%, 500 ml whole blood was drawn and replaced by the same volume of dextran 40; for a hematocrit between 37% and 42%, only 250 ml whole blood was drawn and replaced by 500 cc of dextran 40. Mean hematocrit was reduced by 16%, from 46 +/- 5% (SD) to 39 +/- 5% (SD) (p less than 0.001). Cerebral blood flow increased in both hemispheres by an average of 20.9% (p less than 0.001). Regional cerebral blood flow increased in the ischemic areas in all cases, on an average of 21.4 +/- 12.0% (SD) (p less than 0.001). In three patients, a significant redistribution of flow in favor of the hypoperfused areas was observed, and in six patients, the fractional cerebral blood flow increase in the hypoperfused areas was of the same magnitude as in the remainder of the brain. In the last patient, cerebral blood flow increased relatively less in the ischemic areas. Our findings show that cerebral blood flow increases in the ischemic areas after hemodilution therapy in stroke patients. The marked regional cerebral blood flow increase seen in some patients could imply an improved oxygen delivery to the ischemic tissue.

CBF before and after extracranial-intracranial bypass surgery in patients with ischemic cerebrovascular disease studied with 133Xe-inhalation tomography.

Cerebral blood flow (CBF) was studied by 133Xenon inhalation tomography in 22 patients with symptoms of ischemic cerebrovascular disease before and after establishment of an extracranial-intracranial bypass shunt. Selection of patients for shunting was based on angiographically demonstrated arterial occlusions and on the finding of focal low flow areas corresponding to the clinical symptoms, that consisted mainly of minor stroke with good remission and with or without subsequent TIAs. It was required that the area of low flow should clearly exceed the CT lesion present in practically all cases. Following surgery, the permanent neurologic deficits remained unchanged, while the TIAs stopped in all but one case. Two patients showed a definite increase of CBF in the low flow area while another two showed a questionable increase. All the other cases, 18 of the 22, showed an unchanged tomographic flow map with no trend towards diminution in extension or severity of the focal hypoperfused area. A persistent low flow in areas with no corresponding CT lesion following alleviation of a possible flow impediment is interpreted to represent an incomplete infarction or diaschisis.

Neuronal pH Regulation: Constant Normal Intracellular pH is Maintained in Brain during Low Extracellular pH Induced by Acetazolamide—31P NMR Study:

The intracellular pH in the brain was studied in six healthy volunteers before and immediately after the administration of 2 g of acetazolamide. Phosphorus-31 nuclear magnetic resonance spectroscopy by a 1.5 tesla whole-body scanner was used. The chemical shift between the inorganic phosphate and the phosphocreatine resonance frequencies was used for indirect assessment of the intracellular pH. The mean baseline intracellular pH was 7.05 ± 0.04 (SD). The mean pH changes obtained at 15-min intervals within the first hour of acetazolamide administration were −0.03 ± 0.04 (SD), −0.02 ± 0.03 (SD), and 0.00 ± 0.04 (SD), i.e., no statistically significant pH decrease was observed during the period where extracellular pH is known to drop markedly. Although several factors contribute to the lack of change of the intraneuronal pH, we will discuss that this observation in addition might suggest a direct intracerebral effect of acetazolamide.