Kroppenstedt, Stefan M.D.; Ulrich, Peter M.D.; Heimann, Axel D.V.M.; Kempski, Oliver M.D., Ph.D.
OBJECTIVE: It has been postulated that patients with a compromised cerebrovascular reserve capacity (RC), defined as cerebral blood flow (CBF) response to acetazolamide (ACZ) (by percent), are at higher risk for ischemic stroke. The value of CBF and RC for predicting the risk of hemodynamically induced impairment of cerebral function is examined.
METHODS: Both common carotid arteries were occluded in 22 Wistar-Kyoto rats. Thirty-one days later, mean arterial blood pressure was reduced to 40 mm Hg for 30 minutes. Laser Doppler scanning of CBF at resting conditions and after intraperitoneal administration of ACZ (0.1 mg/g body weight) was performed 30 minutes and 28 days after occlusion as well as before and during hypotension. Memory and motor functions were examined before and after CBF measurements.
RESULTS: After occlusion, CBF dropped significantly and ACZ did not increase CBF. Four weeks later, resting CBF had significantly improved but remained impaired, as did RC, showing a distinct interindividual variability. Hypotension reduced CBF by 57 ± 4% (P < 0.001) and significantly impaired memory and motor functions. CBF during hypotension correlated with resting CBF before hypotension (r = 0.495, P = 0.027) and with CBF before (r = 0.392, P = 0.048) and after (r = 0.476, P = 0.034) ACZ, as determined 4 weeks after occlusion. There was no correlation with RC (r = 0.091, P = 0.702). Neurological tests performed 1 day after hypotension correlated with CBF during hypotension (memory function, P = 0.03; motor function, P = 0.02) but not with RC.
CONCLUSION: In this model of chronic hemodynamic insufficiency, the risk of impairment to global cerebral function was predicted by resting CBF and CBF after ACZ but not by RC determined with ACZ.
Assessment of cerebrovascular reserve capacity (RC) by using acetazolamide (ACZ) or CO2 has become a frequent means for distinguishing patients with compromised cerebral hemodynamics from the large population of patients with cerebral ischemia (18, 25, 28). Patients with hemodynamic compromise caused by occlusion or stenosis of major arteries are thought to be possible candidates for surgical treatment (20, 30). It has been postulated that patients with a diminished RC should be prone to cerebral ischemia in hemodynamic stress situations, such as hypotensive episodes (12, 15, 30). However, clinical studies have both shown and failed to show a correlation between compromised cerebral hemodynamics and the risk of subsequent ischemic stroke (8, 11, 16, 30).
The present study was designed to examine whether RC or other parameters, such as resting and stimulated cerebral blood flow (CBF), are useful for predicting the risk of hemodynamically induced impairment of global cerebral function in a model of chronic hemodynamic insufficiency (22). To this end, 1 month after permanent bilateral carotid artery occlusion was induced in a rat model, blood pressure was reduced to 40 mm Hg for 30 minutes. CBF and RC, together with neurological functions, were assessed repeatedly.
Twenty-two male Wistar-Kyoto rats weighing 295 to 405 g were used (Charles River Wiga Co., Sulzfeld, Germany). The study was carried out in accordance with current animal protection legislation and was reviewed by the regional ethics committee.
On Day 3 of the experiment (Table 1), the rats were premedicated with 0.5 mg atropine, and anesthesia was introduced with ether and continued by intraperitoneal injection of chloral hydrate (initially, 36 mg/100 g body weight; subsequently, 12 mg/100 g body weight/h). Animals ventilated spontaneously during the entire experiment. Rectal temperature was maintained at 37°C by means of a feedback-controlled homeothermic blanket control unit (Harvard, Edenbridge, England). A polyethylene catheter was inserted into the tail artery for continuous monitoring of arterial blood pressure via a pressure transducer (Model 134615-50; Gould Co., Cleveland, OH) and for blood gas analysis. Arterial partial pressure of oxygen, arterial CO2 pressure, and pH were determined with an ABL 615 blood gas analyzer (Radiometer Analytical, Lyon, France). The peritoneum was catheterized for fluid and drug administration. After a midline incision was made, each common carotid artery (CCA) was freed from its adventitial sheath and surrounding nerves, which were carefully separated and maintained using an OP microscope (Carl Zeiss, Inc., Thornwood, NY). Occlusion was performed by double ligation with 7-0 silk sutures. The head was fixed in a stereotactic frame (Stoelting, Wood Dale, IL), and the skull was exposed by a sagittal midline skin incision. Biparietal parasagittal groove-shaped trephinations (1.5 × 4 mm) were performed with a Microtron microdrill (Aesculap Co., Tuttlingen, Germany) under microscopic guidance (OP microscope). The drill tip was cooled continuously with physiological saline to avoid thermal injury to the cortex. Special care was taken not to penetrate the dura mater, thus sparing a thin layer of the tabula interna of the calvaria (22).
To induce hypobaric hypotension 31 days later, the lower body portion of each animal was placed in a sealable chamber and connected to an electronically controlled vacuum pump (4, 7), by which the barometric pressure within the chamber could be reduced, thereby causing a pooling of venous blood in the lower part of the body. A catheter was inserted into the right CCA proximal to the ligation with its opening directed toward the heart for arterial blood pressure monitoring and for blood gas analysis.
Local CBF (lCBF) was measured using a laser blood flow perfusion monitor (Model BPM 403a; TSI, St. Paul, MN) with a 0.8-mm needle probe, and was expressed in laser Doppler units (LDU). The laser Doppler system has a reproducibly low biological zero (7), and, with the scanning technique described below (7, 23), permits comparison of data from individual animals and locations (10, 24). Calibration was verified using a standard-motility latex emulsion.
The lCBF data were collected from 25 locations on each hemisphere by moving the laser Doppler probe in 0.1-mm steps over the brain surface. The median of the 50 lCBF measurements from each animal is termed regional CBF (rCBF). To obtain reliable rCBF data, it is necessary to collect 25 or more local laser Doppler measurements (10), a number well surpassed in the present study. Care was taken to obtain flow readings only from areas free of large pial vessels.
The cerebrovascular RC is defined as a change in lCBF after application of the inhibitor of carbonic anhydrase, ACZ, and is expressed as a percentage of baseline flow (26). An intraperitoneal injection of ACZ (Lederle, Wolfratshausen, Germany) (0.1 mg/g body weight) was administered, and 17 minutes after the injection a bilateral laser Doppler scan was performed (Days 3 and 31). In an earlier study it was demonstrated that this dose of ACZ maximally increases CBF without causing blood pressure reduction (P Ulrich, unpublished data, 1997).
The neurological test battery was always performed between 9:00 AM and 12:00 PM. The labyrinth test (memory retention test) was administered first followed by the motor function tests, as previously described (22).
In brief, the memory retention test was performed in a four-chamber wooden maze. One of these chambers contained food pellets and was kept dark by a removable roof. The other chambers and the central compartment remained open and were illuminated whenever the rat entered to establish a passive avoidance reaction. After the rat was placed in the central compartment, the light was switched on and a stopwatch was started. Whenever the rat entered one of the three open chambers or the central compartment, these parts were immediately illuminated. The trial ended as soon as the rat entered the dark chamber, or after 300 seconds of unsuccessful exploration. Every change of location was counted, and a mean frequency of movements was computed from three trials. Exploration times from the three trials were averaged.
Motor performance was examined with an inclined screen test, a balance beam test, and the prehensile traction test according to Combs and D’Alecy (1), with minor modifications (22). In the inclined screen test, the rat was placed on a horizontal board, which was inclined to a maximum angle of 60 degrees. The rat was given a score of 3 if it spent 21 to 30 seconds on the board, 2 for 11 to 20 seconds, 1 for up to 10 seconds, and 0 if it fell down within the first 3 seconds. In the balance beam test, the rat was placed on a wooden rod. The score was 0 if the rat lost hold within 3 seconds, 1 if it was able to stay on the beam for up to 10 seconds, 2 if the time on the rod was between 11 and 20 seconds, and 3 if the animal spent 21 seconds on the beam. In the prehensile traction test, the rat was permitted to grab a rope with its forefeet, and the length of time it remained on the rope was measured. The score was 0 for 2 seconds, 1 for 3 to 4 seconds, 2 for 5 seconds without bringing a third limb up to the rope, and 3 for 5 seconds bringing one or both hind paws up to the rope. The total motor score was calculated as the sum of the scores for the three tests. The scores from three trials were averaged.
Table 1)
After a training period, rats were prepared for carotid artery occlusion, and after a stabilization period of 15 minutes, bilateral baseline lCBF scans were performed in both hemispheres. Thereafter, both CCAs were occluded, and 15 minutes after occlusion a second scan of both hemispheres was performed. Thirty minutes after occlusion, ACZ was injected intraperitoneally, and 17 minutes after the injection a third bilateral laser Doppler scan was initiated. Twenty-eight days after occlusion, lCBF was again measured before and after the application of ACZ. Three days later, mean arterial blood pressure (MABP) was reduced by hypobaric hypotension to 40 mm Hg for 30 minutes. lCBF was measured before and during hypotension. Motor and memory functions were evaluated 1 and 2 days before and 1 day after CCA occlusion, 1 day before and after the second RC test, and 1 day after MABP reduction.
Data are expressed as mean ± standard error of the mean for physiological variables. rCBF is presented as mean ± standard error of the mean of the individual medians of 50 lCBF measurements from each animal. Neurological data, which lack a normal distribution, are given as medians, with 25th and 75th percentiles in parentheses. As a parametric test, a one-way repeated-measures analysis of variance was used, and as a nonparametric test, a repeated-measures analysis of variance on ranks was used (Sigmastat software; Jandel Scientific, San Rafael, CA). Differences were considered significant if P was <0.05.
The physiological variables are summarized in Table 2. MABP significantly increased after occlusion of both CCAs. Of the 22 animals studied, two rats died within 12 hours after bilateral CCA occlusion.
The rCBF measurements at the different time points of the experiment are shown in Figure 1. Fifteen minutes after bilateral CCA occlusion rCBF had dropped significantly (P < 0.05), from 55 ± 3 LDU to 17 ± 1 LDU. ACZ application 30 minutes after occlusion produced no significant change in rCBF (19 ± 1 LDU). Four weeks after occlusion, resting rCBF (46 ± 3 LDU) showed a significant recovery (P < 0.05) but was still impaired relative to rCBF before occlusion (P < 0.05). At that time, ACZ caused a significant (27 ± 5%) increase in rCBF, to 58 ± 3 LDU; for comparison, in sham-operated rats, the mean rCBF response to ACZ, with a 37 ± 3% increase, was significantly larger (22). Reduction of blood pressure 3 days later led to a decrease (P < 0.05) in rCBF from 42 ± 3 to 16 ± 1 LDU.
The rCBF measured during blood pressure reduction to 40 mm Hg correlated significantly with resting rCBF before hypotension (r = 0.495, P = 0.027) (Fig. 2 C), with resting rCBF (r = 0.392, P = 0.048; data not shown), and with stimulated rCBF (r = 0.476, P = 0.034) (Fig. 2B) determined 4 weeks after occlusion. No correlation was found between rCBF during hypotension and calculated RC (r = 0.091, P = 0.702) (Fig. 2A) or between the percentage of change of rCBF caused by hypotension and RC (r = 0.164, P = 0.489; data not shown).
Memory and motor functions at the different time points are shown in Figure 3. The learning effect reduced (P < 0.05) the labyrinth exploration time within the 2-day training phase before occlusion from 95 seconds (range, 50–134 s) to 35 seconds (range, 21–48 s), which is normal for trained Wistar-Kyoto rats (22). Bilateral CCA occlusion increased (P < 0.05) labyrinth exploration time to 99 seconds (range, 63–149 s). Total motor score before occlusion was 9.0 (range, 8.7–9.0) and significantly dropped 1 day after occlusion to 7.8 (range, 7.3–8.7). Four weeks after occlusion, the labyrinth exploration time and total motor score showed a significant improvement but were still impaired relative to memory and motor functions 1 day before occlusion (P < 0.05). Memory function significantly deteriorated 1 day after ACZ application; motor function remained unchanged. Hypotension increased (P < 0.05) labyrinth exploration time from 72 seconds (range, 50–163 s) to 183 seconds (range, 115–204 s) and decreased (P < 0.05) total motor score from 8.2 (range, 6.7–8.3) to 7.0 (range, 6.5–8.3).
The labyrinth exploration time and total motor function score obtained 1 day after blood pressure reduction correlated significantly (P = 0.03 and P = 0.02, respectively; Spearman rank order correlation) with rCBF during hypotension (Fig. 4 , A and B) but not with RC (Fig. 4, C and D). Because the data in Figure 4B suggested a flow threshold during hypotension below which motor function deteriorates, a sigmoidal regression was performed, which yielded a highly significant dependency between rCBF during hypotension and motor function or labyrinth time (Fig. 4, A and B).
Immediately after bilateral CCA occlusion, rCBF fell by 68% and was not increased by ACZ administration. Memory and motor functions were impaired 1 day after occlusion. Four weeks after occlusion, resting CBF showed an incomplete recovery, as did RC. Memory and motor functions remained impaired. These results are in good accordance with previously published data (22), showing that permanent occlusion of both CCAs in a rat model reproduces the clinical picture of chronic hemodynamic insufficiency. Likewise, other experimental studies (3, 9) have shown a secondary improvement of RC after occlusion of major cerebral arteries. Concerning the cause of the improvement of RC, Coyle and Panzenbeck (2) found that basilar-carotid anastomosis significantly widens during the first 6 weeks after unilateral permanent CCA occlusion, a finding that was confirmed in a clinical study (27). In the majority of patients with uni- or bilateral carotid stenosis and occlusion, initially impaired cerebrovascular RC improved spontaneously during the first few months.
A hemodynamic stress situation was induced by MABP reduction to 40 mm Hg, which is below the lower autoregulation threshold of approximately 50 mm Hg in Wistar-Kyoto rats (7). MABP was reduced by using hypobaric hypotension, a method that has been shown to be excellent for blood pressure manipulation (4, 7). Reduction of blood pressure to 40 mm Hg decreased CBF by more than 50%, to an rCBF of less than 20 LDU, indicating severe cerebral hypoperfusion (7, 21, 22). Memory and motor functions were severely impaired 1 day after hypotension, as additional proof of the severe hypoperfusion encountered during the hypotension phase.
In the present study, RC, defined as a change in rCBF after ACZ administration, showed distinct variability among individual animals, ranging from -23%, indicating intracerebral steal, to +82%. According to the common opinion that patients with diminished RC in hemodynamic stress situations are at increased risk for cerebral ischemia and thus stroke (11, 12, 30), animals with diminished RC should have either a lower CBF during blood pressure reduction or a larger percentile decrease of CBF relative to animals with a higher RC. However, CBF measured during hypotension as well as the percentile change of CBF caused by hypotension did not correlate with RC but rather with resting CBF and CBF after ACZ application. In addition, CBF measured during hypotension, but not RC, correlated with memory and motor functions 1 day after hypotension. Because the present study has shown that resting CBF might be a better parameter than RC to assess the risk for hemodynamic stroke, the benefit of CBF stimulation to determine RC might need to be reevaluated. Neurological deterioration after ACZ application, as found in the current study, is certainly unwanted and has been reported earlier (13, 22). It is probably due to a steal phenomenon and is a known side effect of ACZ on ischemic tissue (13, 17).
How do the present findings compare with those in clinical studies? In a prospective study by Kleiser and Widder (11) with patients who had internal carotid artery occlusion and impaired RC, an increased risk for stroke was demonstrated by transcranial Doppler CO2 test. Similar findings were obtained by Yonas et al. (30), who used xenon computed tomography to show that only the CBF response to ACZ was predictive of stroke; however, patients with stroke also had a significantly lower resting flow. This is in contrast to the positron emission tomography study of Powers et al. (16) that failed to show an increased stroke risk in patients with hemodynamic cerebral ischemia. Similarly, Yokota et al. (29) could not find an enhanced risk of stroke in patients with a reduced vasodilatory response to ACZ. Ishikawa et al. (8), using xenon single-photon emission computed tomography and ACZ, were unable to find a correlation between RC and stroke risk, whereas resting CBF had prognostic significance. The relationship between a low resting flow and subsequent stroke has also been reported earlier (19). In a study using positron emission tomography, Grubb et al. (6) recently found an enhanced stroke risk in a group of patients with Stage II hemodynamic failure, as proved by an increased oxygen extraction fraction distal to the symptomatic carotid artery occlusion. Because oxygen extraction fraction may have increased in these patients in compensation for a reduced baseline flow, these clinical data are in good agreement with the current results obtained in animal experiments.
The assumption that resting CBF is a more reliable parameter than RC, moreover, is indirectly supported by the results of extracranial-intracranial (EC/IC) bypass surgery studies. Surgery restored RC but failed to raise resting CBF or to decrease the risk of further ischemic stroke (8, 14). The multicenter EC/IC bypass study conducted from 1977 to 1985 (5) could not prove stroke prevention by EC/IC bypass surgery. However, at that time there was no reliable method for identifying a subgroup of patients in whom hemodynamic factors were of primary pathophysiological importance (6). Today, measurement of oxygen extraction fraction by positron emission tomography (6) could be such a method. Empirical trials are required to ascertain whether patients with established hemodynamic insufficiency can profit from EC/IC bypass surgery (6).
This experimental study assessed the value of resting CBF and CBF stimulation in predicting functional impairment after hemodynamic challenge using a rat model that reproduced the clinical picture of chronic hemodynamic insufficiency. The risk of impairment of global cerebral function could be predicted by resting CBF and not by RC. These findings suggest the need for caution when using RC to assess the risk for hemodynamic cerebral ischemia.
We thank Andrea Schollmayer, Michael Malzahn, and Laszlo Kopacz for their excellent technical help and support.
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The authors created hemodynamic cerebral insufficiency in a rat model by ligating both common carotid arteries and then by challenging the animals through the induction of hypobaric hypotension (the lower part of the animals was placed in a sealed chamber to which suction was applied, causing pooling of venous blood and controllable hypotension). Blood pressure, cerebral blood flow (CBF) (measured by means of a laser flow probe), and, afterward, neurological functioning of the rats were the variables assessed. Four weeks after ligation, the results were considered in relation to a state of “chronic” hemodynamic insufficiency.
Acetazolamide (ACZ) infusion causes cerebral vasodilation and therefore an increase in CBF under normal conditions, and failure of CBF to increase in response to ACZ is generally regarded as a sign of compromised CBF despite a baseline study within normal limits. Response to ACZ is quantified as reserve capacity, defined as CBF response as a percentage of baseline flow. In this experimental study, it was found that CBF during hypotension correlated with baseline CBF as well as with CBF after ACZ infusion, but not with reserve capacity. The cause of this was a little confusing to this reviewer but appears to have been due to a great deal of interanimal variability in ACZ response. If these results can be extrapolated to the clinical setting (a significant step, indeed), the authors make the point that the value of CBF stimulation in the assessment of cerebral hemodynamics is questionable.
J. Max Findlay
Edmonton, Alberta, Canada
Kroppenstedt et al. used a unique rodent model of chronic hemodynamic insufficiency to investigate the relationship between the risk of future neurological injury and cerebrovascular reserve capacity. In the context of current attempts to reevaluate the role of extracranial-intracranial bypass surgery with the use of contemporary radiological techniques, it is extremely important to recognize that whereas an absolute CBF reduction predicts neurological dysfunction, reserve capacity does not, at least in this specific experimental model. Although it remains to be seen whether these findings are valid in the clinical setting, the hypothesis should not be difficult to test. We look forward to further work from this group using this model and can only speculate about the feasibility of performing similar experiments using positron emission tomography, single-photon emission computed tomography, or xenon computed tomography.
E. Sander Connolly Jr.
New York, New York
The work by Kroppenstedt et al. is an admirable attempt to take an important clinical problem to the laboratory to address the question of whether the assessment of cerebrovascular reserve (CVR) capacity with ACZ is a sensitive means of identifying patients at increased ischemic risk for stroke after carotid occlusion. These authors investigated this topic by occluding both carotid arteries in the rat and studying the alteration of CBF and CVR by measuring laser Doppler flow velocity changes in response to intraperitoneally administered ACZ. They concluded that whereas baseline and post-ACZ CBF values are related to the response to subsequent hemodynamic compromise, CVR is not.
This is an important observation, because despite the results of the extracranial-intracranial bypass study that concluded that no subgroup of patients benefited from bypass surgery, many have continued to believe that a significant subgroup that could benefit does exist. As with all studies, the results hinge on studying the correct patients. For bypass surgery, the subgroup is one that has a severe compromise of hemodynamics. Although recent literature suggests that the measurement of oxygen extraction fraction is able to identify this subgroup, an extensive literature search also provides support for the conclusion that a measure of CVR identifies the same subgroup (3–7, 11–13). This study by Kroppenstedt et al., however, suggests that only activated flow values (CBF after ACZ) can detect the group at increased ischemic risk.
Before we can accept the conclusions of the authors, it is important to examine the validity of their conclusions as well as whether they can be taken directly to the clinical realm. Animal models always raise two areas of concern. One is whether the animal model being studied recreates the clinical disorder, and the other is whether the variable being examined is a valid measure assessed with the appropriate method. The authors used laser Doppler pial scanning as a measure of relative CBF values. Although they made observations that could have significant clinical relevance, their work unfortunately suffers from both errors.
The model of ischemia that Kroppenstedt et al. have developed does appear to create a state of compromised hemodynamics. However, what kind of hemodynamic compromise was created? The model they used is a standard paradigm for inducing global as opposed to focal cerebral ischemia. Furthermore, the mechanism by which a young rodent responds to bilateral cervical carotid occlusion is unlikely to be the same as that of a 60-year-old man with internal carotid artery occlusion and no significant anterior or posterior communicating vessels to recruit. Does the rodent become dependent on pial collaterals, as most commonly occurs in symptomatic patients with a severe compromise of cerebral hemodynamics (10)? Vasodilation of resistance vessels associated with an increase in cerebral blood volume is the reason that the middle cerebral artery (MCA) territory can become dependent on perfusion pressure for maintaining function (1, 7–9). This state of maximal cerebral blood volume, decreased CBF, and increased oxygen extraction fraction identifies the most severe hemodynamic condition before ischemic deficits would occur if perfusion were to be further compromised. This degree of hemodynamic compromise is associated with a predisposition for ischemic injury within the transcortical white matter border zone and with typical symptoms of ischemia, such as blood pressure-related transient episodes of limb shaking (i.e., “ischemic claudication”) (2). The usefulness of examining the quantitative CBF response to ACZ is based on the observation that ACZ, by blocking carbonic anhydrase, induces a local tissue acidosis and thereby causes maximal vasodilation of neighboring vascular territories, providing collateral supply (usually via pial vessels) to the area at risk, namely, the MCA territory. By maximally dilating the surrounding normal regions, and with the MCA territory already partially or maximally dilated, the ACZ challenge lowers perfusion pressure to the MCA territory. The CBF response within the MCA territory may be blunted, ranging from slightly less than the norm of a 30% increase to a 30% or more decrease of CBF; that is, a steal phenomenon. Only a significant negative response of CBF has been predictive of the subgroup at greatest hemodynamic stroke risk (12, 13). It is the transition from positive reactivity to negative CVR that has correlated with a significant risk of oxygen extraction fraction (3, 5, 7).
Unfortunately, there is no evidence presented to support the notion that the rodent model examined by the authors recreates the above physiological responses of hemodynamic compromise. As presented, and in the responses observed, the model resembles global rather than focal cerebral ischemia, and the hemodynamics and response to ACZ are likely to be completely different. In global cerebral ischemia, as induced in this model, the “steal phenomenon” is unlikely. Because intracranial collaterals are not normally occluded in young rats, the creation of a dependence on pial vessels is far less likely. No pathological information is presented to support the belief that the transcortical border zone is predisposed to infarction with this model of compromised hemodynamics. Although it is an interesting study question, there is no reason to believe that an acute decrease of perfusion pressure by 40 mm Hg in the rat duplicates the clinical situation of moderate blood pressure alterations causing primarily subcortical ischemia. Thus, although the authors present an interesting experimental model, direct translation of this work to the clinical world has to be made with caution.
The second question is whether Doppler measurement of velocity alterations within pial vessels measures CBF within the depths of ischemia, as is most commonly observed in patients with a severe compromise of hemodynamics. It is clear that laser Doppler technology does not measure CBF; although CBF may vary in a positive relationship to pial volume flow rates, the relationship deviates from linearity at the extremes. Therefore, Doppler velocity measurements are not equivalent to CBF measurements. The important question for this study is whether pial velocity measurements are able to accurately record negative alterations of CBF that are most striking deep within the hemisphere. We recently examined this question in patients with symptomatic carotid occlusion (n = 26) and in asymptomatic patients 1 week after subarachnoid hemorrhage (n = 68). Xenon computed tomography CBF studies accompanied by transcranial Doppler measurement within the MCA territory were obtained before and immediately after intravenous ACZ administration. Whereas MCA transcranial Doppler values did correlate with positive changes of CBF, Doppler measurements were not sensitive to 80% of the occurrences of negative reactivity (unpublished data). From these studies, one would have to doubt that laser Doppler technology would be sensitive to negative tissue flow changes even if they occurred in the rats that they studied.
Another concern is whether the tissue acidosis induced by ACZ had a direct vasodilatory effect on pial vessels and thus may have significantly altered velocity profiles of the pial microcirculation. Although the tone and thereby the size of the basal vessels are only slightly altered by changes of acid-base balance, the microcirculation should be maximally altered. Clearly, an examination of laser Doppler and quantitative CBF is still needed to better understand the relationship of pial flow velocity and quantitative CBF changes that occur after ACZ.
Although this is an interesting experimental study, I believe it is premature to disregard the vast literature concerning the efficacy of quantitative CBF studies accompanied by hemodynamic stress as a means of identifying those patients with an acute or chronic compromise of cerebral hemodynamics.
Howard Yonas
Pittsburgh, Pennsylvania
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Key words: Cerebrovascular reserve capacity; Hemodynamic cerebral ischemia; Hypobaric hypotension