Is the Acetazolamide Test Valid for Quantitative Assessment of Maximal Cerebral Autoregulatory Vasodilation?
An Experimental Study
Background and Purpose—The cerebral vasodilating effect of acetazolamide (ACZ) injection has been used as an index of the autoregulatory vasodilation (or cerebral perfusion reserve). The question of whether the ACZ test assesses the maximal autoregulatory vasodilating capacity is not definitely resolved. The effects of ACZ injection on this reserve at a dose producing maximal vasodilation have never been evaluated and may help to resolve this problem.
Methods—The effect of ACZ injection on cerebral blood flow (CBF) autoregulation was tested in anesthetized rats. A pilot experiment evaluated the dose-effect relationship of injected ACZ, cumulative doses (n=4, group 1), and independent bolus doses (n=6, group 2). CBF was estimated by laser-Doppler flowmetry, and cerebrovascular resistance (CVR) was calculated from mean arterial blood pressure (MABP) and from CBF (expressed as a percentage of baseline CBF). A bolus of ACZ of 21 mg/kg produced the maximal cerebral vasodilation that could be obtained by ACZ administration. In the main experiment, MABP was lowered from 110 to 20 mm Hg by stepwise bleeding in 3 groups of 6 animals treated 10 minutes before bleeding by injection of saline (group 3), 7 mg/kg ACZ (group 4), or 21 mg/kg ACZ (group 5).
Results—The CVR-MABP relationship was linear in all groups, indicating that CBF autoregulation was still effective after ACZ administration.
Conclusions—These results indicate that maximal ACZ-induced cerebral vasodilation is not quantitatively equivalent to maximal autoregulatory vasodilating capacity in anesthetized rats.
Acetazolamide (ACZ) injection is widely used as a cerebral vasodilating stimulus for assessment of the cerebrovascular dilatory reserve in animals,1 in healthy volunteers,2 and in patients.2 3 4 Intravenous doses of 7 to 30 mg/kg ACZ in rats1 5 and 0.5 to 1 g in humans2 3 4 6 produce no or little change in blood pressure and an increase in cerebral blood flow (CBF), so that cerebral vascular resistance (CVR) decreases. In clinical investigation, this decrease in CVR in response to ACZ injection is often considered a surrogate of the decrease in CVR elicited by hypotension (ie, autoregulatory vasodilation).3 The fact that these 2 reactivities (to ACZ and to a blood pressure decrease) lead to cerebral vasodilation does not necessarily mean that they are equivalent and that the former can be considered a substitute for the latter. Indeed, these 2 cerebral vasodilations may imply different mechanisms.7 However, this question is still a matter of debate, and a recent report supports the use of the ACZ test to measure the cerebral autoregulatory capacity.8 Nevertheless, it is not certain that the results of an ACZ test provide valuable information on the brain’s capacity to adapt to hypotension or hypoperfusion. This point may be of prime importance in some clinical situations in which the ACZ test is used to check cerebrovascular reactivity, especially in cerebrovascular disease. The aim of the study was to assess the effect of ACZ injection on the cerebral autoregulatory vasodilatory capacity. We investigated the influence of an intravenous ACZ bolus on CBF autoregulation when mean arterial blood pressure (MABP) was decreased in anesthetized rats. The effects of 2 doses of ACZ (7 and 21 mg/kg) were compared with control (saline injection), with the higher dose producing the largest vasodilation that could be obtained with the drug.
Materials and Methods
A first experiment (pilot study) was designed to investigate the dose-effect relationship of injected ACZ on CBF, MABP, and CVR, to choose a dose that produced a maximal vasodilating effect on the cerebral cortical circulation, and to compare the maximal ACZ-induced vasodilation with that produced by hypercapnia.
The main study investigated the effects of ACZ administration (a low dose of 7 mg/kg and the maximal dose obtained from the pilot study, ie, 21 mg/kg) compared with saline injection on cerebral autoregulatory vasodilation.
Preparation of Animals
The experiments were performed on 28 male Sprague-Dawley rats (weight, 270 to 460 g). Principles of laboratory animal care (EEC Guideline 86/609/EEC) were followed as well as specific French laws (décret of October 19, 1987, and arrêté of October 29, 1990). Furthermore, this study was performed under license No. 92007 delivered by the French Ministry of Defense.
Rats were anesthetized with halothane in an O2/N2 mixture (4% on induction, progressively reduced to 1% for the surgery) and α-chloralose (40 mg/kg SC). Rectal temperature was maintained at 37°C to 38°C throughout the experiment with a thermostatically control blanket. All skin incisions were infiltrated with 2% lidocaine hydrochloride. First, a polyethylene catheter (ID, 0.58 mm; OD, 0.96 mm) was advanced into the abdominal aorta from the site of cannulation in the femoral artery. This catheter was used to induce a decrease in MABP by bleeding. Second, a femoral vein was cannulated (ID, 0.58 mm; OD, 0.96 mm) to perform intravenous injections. Third, a polyethylene catheter (ID, 0.38 mm; OD, 0.76 mm) was introduced into a brachial artery for MABP recordings (Statham transducer) and blood gas analysis (Pao2, Paco2, and pHa). Heparin was given intravenously to ensure patency of the catheters (6 IU/h). The rats were then tracheotomized and artificially ventilated to keep Pao2 and Paco2 within physiological ranges.
The rats were positioned in a Kopf stereotaxic frame, and the skull surface was drilled to translucency unilaterally over the frontoparietal cortex so that the pial vessels were visible. The probe (tip diameter of 0.8 mm with 3 optical fibers, 1 light emitter, and 2 collectors, interaxis distance of 0.5 mm) of the laser-Doppler flowmeter (LDF monitor, Moor Instruments England) was carefully positioned to avoid major cerebral vessels. Halothane was reduced to 0.5% to 0.2%, and α-chloralose was given hourly (20 mg/kg SC) until the end of the experiment.
After stabilization of CBF and MABP, an arterial blood gas analysis was performed. The reactivity of cerebral arterioles investigated by the laser-Doppler flowmeter was then tested by making the animals breathe an O2/N2 mixture (45%/45%) enriched with 10% CO2. Reactivity to CO2 was expressed as the percentage of increase in CBF induced by a 1-mm Hg increase in Paco2.
The experiments started approximately 2 hours after the beginning of anesthesia and 5 minutes after the end of the hypercapnic test.
In the first part of the pilot study, the animals (group 1, n=4) received increasing bolus doses of ACZ at 10-minute intervals: 7 mg/kg ACZ, 14 mg/kg ACZ, and 21 mg/kg ACZ. Since the effects of injected ACZ on CBF are sustained (at least 60 minutes in rats),1 we considered that the doses administered were cumulative, and thus the rats successively received 7 mg/kg ACZ, 21 (ie, 14+7) mg/kg ACZ, and 42 (ie, 21+21) mg/kg ACZ. The choice of a 10-minute interval was based on the fact that continuous monitoring revealed in our model that the CBF response to ACZ is maximal and stable after 7 to 8 minutes (Figure 1⇓).
In the second part of the pilot study, the rats (group 2, n=6) received a bolus injection of 42 mg/kg ACZ, and hematocrit was measured before and 10 minutes after ACZ injection. Finally, the animals inhaled an O2/N2 mixture (46.5%/46.5%) enriched with 7% CO2, and CBF was again determined. In this experiment the proportion of CO2 was limited to 7% to avoid any risk of excessive vasodilation and consecutive lethal increase in intracranial pressure due to the summation of the vasodilating effects of ACZ and CO2.
At the end of this pilot study, and on the basis of the results obtained (Table 1⇓, Results), the 21 mg/kg ACZ bolus was considered to produce the maximal cerebral vasodilation that could be obtained by ACZ injection in this model.
Three groups of rats were studied in the main experiment. In group 3 (n=6), saline (0.5 mL IV) was given to the rats. In group 4 (n=6), a low dose of ACZ was administered (7 mg/kg IV). The animals of group 5 (n=6) were injected with ACZ 21 mg/kg IV.
Pao2, Paco2, and pHa were measured 10 minutes after the injection of saline or ACZ. MABP was then decreased stepwise by blood withdrawal from the arterial femoral catheter. A stable blood pressure was maintained for 1 minute after each 10-mm Hg reduction. CBF was measured during the last 30 seconds to allow autoregulatory mechanisms to be effective at each MABP level.9 MABP was reduced to 20 mm Hg, which is below the lower limit of CBF autoregulation (40 to 60 mm Hg), to ensure that the maximum of autoregulatory vasodilatation was reached. Blood was then reinfused, and the rats were killed by barbiturate injection.
Measurements and Statistical Analysis
Because CBF estimated with laser-Doppler flowmetry correlates better with relative changes in CBF rather than with absolute values,10 changes were calculated as percentages of baseline CBF (CBF0), the mean flow obtained during the minute before the injection of either saline or ACZ. Each animal was characterized by its CBF/MABP relationship. CVR was calculated as the ratio of MABP to concomitant CBF, and the CVR/MABP relationship of each rat was studied. The CVR/MABP relationship was taken as an index of autoregulatory capacity. It should be kept in mind that laser-Doppler flowmetry does not measure actual volumetric blood flows and thus does not allow the calculation of absolute CVR. Nevertheless, we have used throughout this report the classic terms of CBF and CVR to mean relative changes in CBF and CVR, respectively.
Results are expressed as mean±SD. P<0.05 was considered statistically significant.
In the pilot experiment, intragroup and intergroup comparisons resulted from distribution-free rank sign tests, paired and unpaired, respectively. In the main experiment, intergroup comparisons were performed by an ANOVA followed by a 2-sided protected least significant difference test.
Table 1⇑ shows the effects of different ACZ doses on MABP, CBF, and CVR. It appears that the cumulative 42-mg/kg injection (group 1) did not further decrease CVR compared with the decrease elicited by the 21-mg/kg dose.
To take into account the initial difference in MABP between groups 1 and 2, the intergroup comparison of changes in MABP and CVR was performed on the relative variations. It revealed that a single bolus injection of ACZ of 42 mg/kg (group 2) induced a relative decrease in CVR (−44.7±3.0%) similar to those produced by the cumulative doses of 21 and 42 mg/kg, ie, −43.0±3.9% and −43.8±5.5%, respectively. Subsequently, inhaled CO2 induced a further and significant decrease in CVR (−55.7±6.4%; P<0.01 versus pre-CO2 value). Finally, hematocrit was not modified by ACZ at 42 mg/kg (40.0±5.6% before versus 40.1±5.8% after injection, ie, a mean change of −0.07±1.77%) (P=NS).
Main Study: Control Data
The mean values of the physiological variables during the minute preceding the injection are given in Table 2⇓ for the 3 groups. There was no statistically significant difference between the groups.
Effects of ACZ Injection on CBF, MABP, CVR, and Blood Gas Analysis
ACZ injection elicited an increase in CBF in groups 4 and 5 (Figure 1⇑). In these 2 groups, the elevation in CBF was significant by 1 minute after the injection and reached a plateau 10 minutes after the injection. The rise in CBF increased with increasing doses of ACZ. ACZ injection induced a minor decrease in MABP, and this effect occurred 5 minutes after injection. The concomitant changes in CBF and MABP resulted in a decrease in CVR that was significant 1 minute after injection and that plateaued 10 minutes after injection. The reduction in CVR was greater in group 5 than in group 4. The injection of 21 mg/kg ACZ also induced an increase in Paco2 (Table 2⇑) and a decrease in pHa. The lowest dose of ACZ had a significant effect only on pHa (Table 2⇑). The injection of saline (group 3) had no statistically significant effect on any of the variables studied.
Effects of ACZ on Autoregulatory Capacity
Figure 2⇓ illustrates data obtained from each animal and pooled in each group. Interindividual variability of the lower limit of CBF autoregulation makes this limit less obvious on such a graph. The CBF values for MABP <40 mm Hg are, however, significantly lower (P<0.05) than values corresponding to higher values of MABP. Nevertheless, after ACZ injection, CBF and CVR at low MABPs were always significantly higher and lower, respectively, than CBF and CVR measured in the control group, except when MABP was maintained at its lowest level, ie, under the lower limit of CBF autoregulation. The CVR/MABP was fitted to a linear model (P<0.001) in each animal. Thus, the slope of the relationship was statistically different from zero, showing a decrease in CVR when MABP was reduced with all the injections made before bleeding.
The range of the correlation coefficient and the mean slope for each group are given in Table 3⇓. A tight linear CVR/MABP relationship was found because the correlation coefficient was always >0.8. Conversely, the mean slope of the CVR/MABP curve was lowered after administration of 21 mg/kg ACZ compared with the control group.
Interestingly, the mean CVR measured 10 minutes after an injection of 21 mg/kg ACZ (0.64±0.07 mm Hg/% CBF0) was greater than the minimal CVR obtained by bleeding below the lower limit of CBF autoregulation in the control group (ie, at a MABP of 21±1 mm Hg, CVR=0.31±0.06 mm Hg/% CBF0).
The main finding of the present study is that cortical autoregulatory dilatory mechanisms are still effective after both doses of ACZ. In animals, assessments of the autoregulatory capacity are ideally based on (1) imposed acute blood pressure variations and (2) online simultaneous CBF measurements.9 Classically, decreases in MABP are obtained by administration of vasodilating drugs, although these may interfere with the autoregulatory process, or by bleeding with the use of vascular surgery.9 In experimental studies, one advantage of the ACZ test1 5 is that it only necessitates an intravenous injection. In humans, the ACZ test is safe, inasmuch as it does not induce large blood pressure variations.2 It is well tolerated, with few contraindications. In addition, the effects of an ACZ injection are long lasting, so that a high temporal resolution of the measurement is superfluous. It is thus sufficient to measure CBF twice, ie, before and after ACZ. Reactivity to ACZ varies in parallel with the mean stump pressure during carotid balloon occlusion in patients.8 It is thus tempting to consider that the simple ACZ test can be a substitute for more sophisticated procedures of CBF autoregulation assessment, especially in patients.
ACZ is a competitive inhibitor of carbonic anhydrase, and its effects on CBF are probably explained by variations in the pH of the perivascular tissues.11 This putative mechanism appears to be similar to that of the cerebrovascular reactivity to CO2.12 Changes in Paco2 affect CVR since an increase in Paco2 results in an increase in CBF. This parallelism between ACZ and CO2 effects is confirmed by a recent report13 that suggests a link between ACZ and CO2 reactivities in humans.
In contrast, there is no strong evidence allowing the assimilation of decreases in CVR induced by ACZ or CO2 to autoregulatory vasodilation. Furthermore, some studies have demonstrated that, under specific conditions, CO2 reactivity and autoregulatory vasodilation do not vary in parallel. Nemoto et al14 demonstrated that during postischemic cerebral hypoperfusion in dogs, CO2 reactivity was abolished and autoregulation was present. Lundaar et al7 established that, during cardiopulmonary bypass in 5 patients, CO2 reactivity was preserved, whereas there was no evidence of cerebral autoregulation. Florence et al15 demonstrated in anesthetized rabbits that spreading depression reversibly impairs cerebral autoregulatory vasodilation but, in contrast, induces a long-lasting decrease in the cerebrovascular reactivity to CO2. In contrast, other reports suggest that CO2 interacts with autoregulation, which can even be exhausted during hypercapnia.16 Okudaira et al8 established a correlation between ACZ reactivity and autoregulatory vasodilation in patients during a carotid balloon occlusion test. The parallelism between these 2 vasodilatory responses may only reflect the fact that they both result in a cerebral vasodilation. Certainly, it does not definitively demonstrate that they are similar.
The question as to whether or not the vasodilatory effect of ACZ injection is quantitatively similar to autoregulatory vasodilation can only be solved by comparing the maximal decrease in CVR obtained after ACZ injection with the maximal decrease in CVR obtained by bleeding and by the study of the effects of ACZ on autoregulatory vasodilation capacity. These objectives can be met by using simultaneous direct assessments of CVR variations. If the largest cerebral vasodilating effect of ACZ does not exhaust the autoregulatory vasodilation, this necessarily means that the 2 maximal vasodilations are not quantitatively equivalent.
Laser-Doppler flowmetry allows rapid, instantaneous measurements of blood flow variations by measuring red cell flux. Since results can vary with hematocrit changes, in the pilot study we monitored the absence of any significant short-term effect of ACZ on hematocrit. Intergroup comparisons of CBF variations are thus valid with respect to this parameter.
In our study, blood pressure was modified by bleeding. Arterial bleeding induces hypovolemia, hypocapnia, and alkalosis,9 but it produces rapid and controlled hypotension. Anesthesia obtained by α-chloralose plus halothane allows studies of the cerebrovascular reactivity inasmuch as its effects on this reactivity are only transient.17
When compared with saline (group 3), both doses of ACZ produced a slight hypotension and the classically described decrease in CVR.2 It appeared from continuous monitoring that, in our model, ACZ effects on CBF or CVR plateaued 7 to 8 minutes after the injection (Figure 1⇑). We thus chose to start measurements 10 minutes after ACZ injection. This time is similar to that observed by Kawata et al in rats,5 slightly shorter than that of 10 to 15 minutes measured by Bickler et al in rabbits,12 and slightly shorter than that of 10 to 20 minutes measured by Postiglione et al in rats.1 The effects of ACZ on Paco2 and pHa are well known11 and probably explain in part the mechanism by which ACZ affects CVR.
One major finding of our study is that a dose of 7 mg/kg of ACZ does not produce a maximal decrease in CVR. A dose of 21 mg/kg results in a greater (1.5-fold) effect on CBF and CVR and does not further decrease blood pressure. The results of our pilot study also established that injection of 42 mg/kg ACZ (cumulative or bolus doses) did not produce significantly larger effects than 21 mg/kg.
The CVR/MABP relationship during blood withdrawal describes the autoregulatory capacity. In the case of a nonautoregulated cerebral circulation, blood pressure variations induce proportional changes in CBF, with CVR remaining unchanged. Under these conditions, the CVR/MABP relationship would appear as a straight horizontal line. In contrast, perfect autoregulation will ideally result in a straight linear CVR/MABP relationship with a slope that significantly differs from zero and that reflects the autoregulatory capacity. In our animals, CBF is expressed as a percentage of baseline flow. If it remains unchanged, its value is thus by definition 100%. In the case of a perfectly efficient autoregulation, the CVR/MABP relationship is described by a line with a slope of 1/100, ie, 0.01. The slope of the CVR/blood pressure obtained from the autoregulation testing in the control group (Table 3⇑) is 0.0084±0.0019 and does not significantly differ from the “theoretical” slope of 0.01.
Another important point is that the minimal values of CVR obtained after the injection of both doses of ACZ and before bleeding (0.80±0.15 and 0.64±0.07 mm Hg/% CBF0, groups 4 and 5, respectively) are not as low as the CVR measured after lowering blood pressure under the limit of CBF autoregulation in controls (0.31±0.06 mm Hg/% CBF0 at a MABP of 21±1 mm Hg). This comparison is limited by the fact that it does not take into account the variations of intracranial pressure. This pressure may increase after ACZ-induced cerebral vasodilation, leading to an overestimation of CVR, especially before bleeding. At the lowest MABP values, maximal autoregulatory vasodilation probably makes this intergroup difference negligible.
Carbonic anhydrase inhibition produced by ACZ is reversible and thus surmountable. ACZ-induced accumulation of CO2 is probably limited compared with that obtained by CO2 inhalation, as is the resulting increase in CBF. This hypothesis was confirmed by the results of our pilot study showing that a 7% CO2 inhalation resulted in a further cerebral vasodilation in rats that were given a maximal vasodilating dose of ACZ.
ACZ injection thus appears to limit the efficiency of the autoregulatory process inasmuch as, after both doses, CBF slightly decreased during blood withdrawal. Nevertheless, even after the maximal dose of 21 mg/kg, ACZ administration did not exhaust the cortical autoregulation. The main effect of ACZ, a dose-dependent decrease in the CVR/MABP slope, is probably nonspecific and due to the cerebral vasodilating properties of ACZ that impair the ability of the cerebral arterioles to further dilate. This may explain the correlation found between autoregulatory capacity and ACZ effects in humans.8
In summary, the effect of ACZ injection on CVR is not maximal at doses as low as 7 mg/kg in rats. Even the maximal ACZ-induced decrease in CVR obtained with the 21-mg/kg dose does not suppress CBF autoregulation. The CBF reactivities to ACZ injection and to hypotension are quantitatively different since exhausting the former does not suppress the latter, probably because ACZ does not produce maximal acidosis. The decreased CVR/MABP slope after ACZ administration is probably only a nonspecific consequence of the vasodilating properties of the drug. This demonstrates that the maximal vasodilating effect of ACZ (classically designed as the “cerebral vasodilatory reserve”) is not an accurate index of maximal autoregulatory capacity. Assessments of CBF autoregulation must be based on the study of the relationship between CBF and blood pressure in animals and in humans. The ACZ test is of special interest, for example, when it is performed in patients with cerebrovascular disorders in a preoperative context. This test gives valuable information on cerebrovascular reactivity, but its capacity to forecast cerebrovascular adaptation to hypotension or low flow is at the least questionable.
This study was supported by grants from the National Center of Scientific Research, the University of Paris VII, and the French Military Health Service. We are grateful to Dr Richard Sercombe for assistance with the English language.
- Received August 5, 1999.
- Revision received October 19, 1999.
- Accepted November 15, 1999.
- Copyright © 2000 by American Heart Association
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The response of cerebral blood flow (CBF) to acetazolamide, an inhibitor of carbonic anhydrase, is frequently used in clinical settings to evaluate cerebrovascular reserve capacity (CVRC). Inhibition of carbonic anhydrase is thought to induce vasodilation by a mechanism similar to that of CO2-induced dilation. Reduced CVRC has been used to identify patients with compromised hemodynamics who may be at increased risk of cerebral ischemia. In patients with carotid artery occlusion, impaired CVRC has been associated with increased stroke risk.R1 R2 It is not clear, however, whether the acetazolamide test is a good indicator of cerebrovascular autoregulatory capacity, the ability of the cerebral circulation to dilate in response to hypotension. The authors examined the effect of acetazolamide at a dose determined to provide maximal dilation on the ability of the cerebral circulation to further dilate in response to hemorrhage-induced hypotension. Autoregulation was attenuated, but otherwise remained intact, after administration of acetazolamide, which led the authors to conclude that the mechanism of acetazolamide-induced dilation is different and independent form that of autoregulatory dilation in response to hypotension, and thus is not a valid measure of autoregulatory reserve capacity.
The study addresses a clinically relevant question of how accurate the acetazolamide test is in identifying patients with impaired autoregulation. The finding of the study that CBF response to acetazolamide is not a good indicator of autoregulatory capacity is in contrast to the finding of Nishimura et al,R3 who observed with positron-emission tomography (PET) in patients with occlusive cerebral artery disease that impaired autoregulation was associated with diminished CO2 reactivity. A dissociation between hypercapnic and acetazolamide vasoreactivities has been reported in subpopulations of patients with occlusive cerebral artery disease.R4 These contradicting reports indicate that further studies are necessary to address this issue and assess the ability of cerebrovascular reactivities to CO2 and acetazolamide to predict autoregulatory impairment and risks of cerebral ischemia in patients with hemodynamically compromised cerebral circulation.
- Received August 5, 1999.
- Revision received October 19, 1999.
- Accepted November 15, 1999.
Yokota C, Hasegawa Y, Minematsu K, Yamaguchi T. Effect of acetazolamide reactivity and long-term outcome in patients with major cerebral artery diseases. Stroke.. 1998;29:640–644.
Nishimura S, Suzuki A, Hatazawa J, Nishimura H, Shirane R, Yasui N, Yoshimoto T. Cerebral blood-flow responses to induced hypotension and to CO2 inhalation in patients with major cerebral artery occlusive disease: a positron-emission tomography study. Neuroradiology.. 1999;41:73–79.
Kazumata K, Tanaka N, Ishikawa T, Kuroda S, Houkin K, Mitsumori K. Dissociation of vasoreactivity to acetazolamide and hypercapnia: comparative study in patients with chronic occlusive major cerebral artery disease. Stroke.. 1996;27:2052–2058.