Stenosis or occlusion of the major arteries of the head and neck may cause hemodynamic impairment of the distal cerebral circulation. Hemodynamic factors may play an important role in the pathogenesis of ischemic stroke for patients with cerebrovascular disease. Several neuroimaging methods are currently available for the indirect assessment of the hemodynamic effect of atherosclerotic stenosis or occlusion on the distal cerebrovasculature. Because these methods rely on different underlying physiologic mechanisms, they are not interchangeable. Two basic categories of hemodynamic impairment can be assessed with these techniques: Stage 1, in which autoregulatory vasodilation secondary to reduced perfusion pressure is inferred by the measurement of either increased blood volume or an impaired blood flow response to a vasodilatory stimulus; and Stage 2, in which increased oxygen extraction fraction (OEF) is noninvasively but directly measured. The correlation of different Stage 1 methods with each other and with Stage 2 techniques is quite variable. Clinical studies associating different manifestations of hemodynamic impairment with stroke risk often suffer from methodologic problems. The best evidence to date for such an association is for increased OEF measured in patients with symptomatic carotid occlusion. In the absence of data demonstrating improvement in patient outcome, there is currently no role for the routine use of these tools to guide clinical management in patients with cerebrovascular disease.

Cerebral hemodynamic impairment: methods of measurement and association with stroke risk.

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.

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Effect of Acetazolamide on Cerebral Blood Flow and Cerebral Metabolic Rate for Oxygen

We have followed the time course of the effect of the carbonic anhydrase inhibitor acetazolamide injected i.v. in unanesthetized healthy human beings. The dose administered was 500 mg as a bolus. Cerebral blood flow (CBF) was measured continuously before, during and after the injection, using a pulsed ultrasound doppler system, which measured the instantaneous mean velocity across the lumen of the internal carotid artery, just below its entrance into the skull. Ventilation, heart-rate, end-expiratory PC02, arterial PC02, pH and systemic blood pressure was also measured. We found that acetazolamide caused a rise in CBF which could be detected as early as 2 min after the injection. A maximal average response of 75 % increase in CBF was seen after 25 min. The half-time of the declining phase of the response was 95 min. There were no systematic differences in the COz reactivities, given as ACBF/APAC02 in % of CBF at normocapnia, before and after acetazolamide injection, regardless of the absolute PAC02 level. The present dose of the drug caused no change in ventilation, alveolar and arterial PC02 or in arterial blood pH indicating that the carbonic anhydrase was not fully inhibited. Our observations show that acetazolamide nevertheless caused a rapid vasodilation in the brain and over a wide range of PC02’s. We suggest that this agent has a local vasodilator effect on the cerebral arterioles, unrelated to its specific effects as a carbonic anhydrase inhibitor.

Acute effects of acetazolamide on cerebral blood flow in man.

Age-related norms for the regional cerebral blood flow (rCBF) response to Diamox (acetazolamide) were based on studies of 55 normal subjects at rest and on studies of 33 of these 55 normal subjects following an intravenous injection of Diamox (22 mg/kg). After the Diamox injection, rCBF increased at all locations measured in all subjects. On average, rCBF increased 1.7 times. The following were found for rCBF in both resting and Diamox-treated subjects: 1) rCBF decreased significantly with increasing age; 2) slope and intercept for the regression of rCBF on age were largest for frontal detectors, intermediate for parietal detectors, and smallest for occipital detectors; 3) rCBF hyperfrontality was most noticeable in younger subjects; 4) in subjects of any age, 95% confidence intervals for rCBF were relatively large (expected value +/- 30%) and lower 95% confidence intervals for Diamox rCBF tended to overlap the upper 95% confidence intervals for resting rCBF; and 5) side-to-side percentage difference in rCBF did not have a significant regression on age and tended to be less than 10% to 20%. Diamox did not have an important effect on blood pressure, pulse rate, or respiratory rate. The normative data for the rCBF response to Diamox was used in evaluating 20 patients with cerebrovascular disease. Forty percent of these patients, all of whom exhibited angiographic evidence of potentially hemodynamically significant lesions, had normal rCBF at rest and after Diamox injection. Twenty percent had normal resting flows with abnormal Diamox-activated flows. Asymmetry in rCBF was the most sensitive indicator of a potential abnormality in cerebral perfusion. Thirty percent of the abnormal studies showed only significant asymmetry. It is suggested that rCBF studies at rest and after Diamox treatment, with age-related norms, may be useful in the management of patients with cerebrovascular disease.

The rCBF response to Diamox in normal subjects and cerebrovascular disease patients.

The authors studied the effects of altering global cerebral blood flow on both blood oxygen level-dependent (BOLD) response and perfusion response to finger-thumb apposition. A PICORE/QUIPSS II protocol was used to collect interleaved BOLD-weighted and perfusion-weighted images on eight finger-thumb apposition trials. Subjects were studied on a drug-free day and on a day when acetazolamide was administered between the second and third trials. After acetazolamide administration, resting cortical perfusion increased an average of 20% from preadministration levels, whereas the BOLD response to finger-thumb apposition decreased by an average of 35% in the S1M1 hand area. Contrary to predictions from the exhausted cerebrovascular reserve hypothesis and the oxygen limitation model, an effect of acetazolamide on cerebral blood flow response in the S1M1 hand area was not observed. Across the acetazolamide trials, BOLD response was inversely correlated with resting cortical perfusion for individual subject data. These results suggest that resting perfusion affects the magnitude of the BOLD response and is thus an important confounding factor in fMRI studies, and that the physiologic systems that increase cerebral blood flow in response to acetazolamide administration and systems that increase cerebral blood flow in response to altered neural activity appear to have additive effects.

BOLD and perfusion response to finger-thumb apposition after acetazolamide administration: differential relationship to global perfusion.

An experiment was designed to rule out bypoxia of cerebral tissue as a mediator of increased cerebral blood flow (CBF) due to acetazolamide (Diamox). Hypoxia might be produced by carbonic anhydrase inhibition by delaying the acidification of the red blood cell until it left the tissue capillary. Fifteen dogs were studied under pentobarbital anesthesia. CBF was estimated from the arteriovenous oxygen content difference across the brain. Cerebral tissue oxygen tension (Paco2) was measured directly on the cortical surface. CBF was altered by altering arterial Pco2 (Paco2) before and after the intravenous administration of 25 mg./kg. acetazolamide. At Paco2 = 30 mm. Hg, acetazolamide increased CBF by 69 per cent; at Paco2 = 40 mm. Hg, by 64 per cent; at Paco2 = 50 mm. Hg, by 55 per cent. This was accompanied by an increase in Po2 of 20 mm. Hg at Paco2 = 30 mm. Hg; 19 mm. Hg at Paco2 = 40 mm. Hg; 16 mm. Hg at Paco2 = 50 mm. Hg. Since Po2 increased, clinical use of the drug in association with mechanical ventilation in the treatment of chronic hypereapnia appears justified. The effect of acetazolamide on cerebrovascular tone remains unexplained.

J. Lee

Papers

The effects of acetazolamide on cerebral blood flow and cerebral tissue PO2.