Cerebral Blood Flow Alteration by Acetazolamide During Carotid Balloon Occlusion
Parameters Reflecting Cerebral Perfusion Pressure in the Acetazolamide Test
Background and Purpose We attempted to clarify the role of the acetazolamide-reactive mechanism in cerebral hemodynamic autoregulation and to establish a useful method of estimation using the acetazolamide test.
Methods We examined 18 patients whose cerebral hemodynamics were considered to be normal and whose cerebral blood flow (CBF) was maintained during the balloon occlusion test (BOT) of the internal carotid artery. We measured the mean stump pressure (MSTP) and the mean CBF in the middle cerebral arterial territory using a xenon-enhanced CT system during BOT with and without acetazolamide activation. We obtained the asymmetry ratio (AR=occluded CBF/contralateral CBF) and the increased CBF parameters caused by acetazolamide activation expressed as an absolute value (ΔCBF) and a percentage (%ΔCBF) for the occluded side.
Results AR during BOT with and without acetazolamide activation differed significantly (P<.001, paired t test) despite the lack of significant MSTP changes. Furthermore, although there was no significant correlation between MSTP and AR without acetazolamide activation, a positive significant correlation was detected with acetazolamide activation (r=.634, P=.005, linear regression analysis). There were significant correlations between ΔCBF and MSTP (r=.574, P=.013) and %ΔCBF and MSTP (r=.640, P=.004).
Conclusions We consider that the acetazolamide-reactive mechanism functions as autoregulation at the lower end of the autoregulatory range. The acetazolamide test, using %ΔCBF or ΔCBF as parameters (which both directly reflect MSTP), is useful for estimating the cerebral perfusion pressure decrease and presence of hemodynamic compromise.
Studies on human cerebral hemodynamics using a variety of techniques have provided a good understanding of the pathophysiology of ischemic diseases, and many patients have been treated on the basis of these results. In particular, a decrease in CPP and the presence of hemodynamic compromise are important indicators for selecting the most appropriate therapy, including surgical management, for patients with main arterial stenosis or occlusion. CBF is maintained by compensatory vasodilation, which increases CBV, in response to a drop in the CPP. A further CPP decrease may result in a decompensatory status, and under such conditions, the CBF may decrease. Furthermore, because the CBF may decrease when cerebral oxygen metabolism is low because of an organic disorder of the brain, it is impossible to estimate the CPP decrease and whether hemodynamic compromise is present by determining the resting CBF only. Therefore, it is necessary to investigate the CBV increase associated with compensatory vasodilation.1 2 3 4 5 6 7
In such circumstances, the acetazolamide test, which determines the cerebrovascular response to acetazolamide administration, has been performed to evaluate CPP decreases and hemodynamic compromise. Acetazolamide is known to inhibit carbonic anhydrase in the brain, thereby causing metabolic acidosis, dilating cerebral vessels, and increasing CBF.8 9 10 It is thought that the CBF increase induced by acetazolamide administration will be reduced if compensatory vasodilation associated with an increase in CBV has already occurred.
However, the relationship between the acetazolamide-reactive mechanism and the CBF regulatory mechanism that responds to a drop in CPP has not been clarified, and it has not been established whether the acetazolamide test can be used to estimate CPP decreases. Therefore, even if a CPP drop can be evaluated using this test, it has not been established what method of estimation (ie, which parameter, if any) directly reflects CPP changes and may be useful clinically. Several investigators have conducted studies on patients with unilateral carotid occlusion to determine whether the CBF response on the occluded side is reduced; they evaluated the difference between the CBF increases of the occluded and contralateral sides, using the latter as a standard. The authors of these studies reported that their results correlated well with the angiographic findings.11 12 13 However, this estimation would be impossible to carry out in patients with bilateral disease. We have reported that the increased value of, or percentage increase in, the CBF caused by acetazolamide activation on each side may each directly reflect the resting CBV.14
In a previous study, we performed the BOT of the ICA on patients with skull-base tumors involving the ICA and aneurysms of the ICA that could not be approached directly, and we measured CBF with a xenon-enhanced CT system and evaluated the safety of temporary occlusion, ligation, and trapping of the ICA. Furthermore, the BOT during acetazolamide activation (activated BOT) was also carried out in an attempt to confirm the definitive safety of these therapeutic procedures by determining the difference between CBFs during BOT and activated BOT.
In this study, we attempted to clarify the role of the acetazolamide-reactive mechanism in autoregulation by investigating whether the correlation between the intra-ICA pressure and the magnitudes of the CBF decrements during BOT and activated BOT differed, and we tried to establish a useful method of estimation that directly reflects CPP based on the correlations between the intra-ICA pressure and the acetazolamide test parameters.
Subjects and Methods
In the early phase of the BOT study, we attempted to investigate the safety of ICA occlusion with a comparison of the CBFs during BOT and at rest. However, we considered this to be difficult because the CBF values varied among the examined patients even under resting conditions, as the absolute value of CBF has been demonstrated to be age-dependent and subject to interindividual variation even in healthy subjects.11
Therefore, in the late phase we attempted to investigate the safety of ICA occlusion on the basis of new evaluation methods. In the first method, based on the finding that no significant change in CBF on the contralateral (unoccluded) side occurred during BOT,15 the CBF ratio of the two sides (AR, calculated as AR=CBF on the occluded side/CBF on the contralateral side) was evaluated to determine whether ICA occlusion would reduce CBF as described below.
We calculated AR for resting CBF in 30 patients who had all undergone the CBF measurements during BOT and at rest in the early phase of the BOT study (13 with ICA aneurysms, 17 with skull-base tumors; mean±SD age, 56.1±10.4 years; 9 men and 21 women) and had no ischemic lesions, evidence of increased intracranial pressure confirmed by angiography, CT, or MRI, or history of hypertension. The mean AR was obtained as the control (0.95±0.09 in the middle cerebral arterial territory). Any patient whose AR during BOT was within ±2SD of this resting value was considered to be one whose CBF was not decreased by BOT.
The second method used was acetazolamide activation, conducted to investigate the reserve compensatory potential during BOT.
From the 24 patients who underwent not only BOT but also activated BOT in the late phase, those with no evidence of ischemic lesions, increased intracranial pressure, or a history of hypertension and whose CBF was considered not to be decreased by BOT were selected; the main purpose in this study was to clarify the role of the acetazolamide-reactive mechanism in autoregulation and to determine the usefulness of acetazolamide challenge for investigating the decline in CPP or the presence of hemodynamic compromise. The subjects comprised 18 patients (3 men and 15 women; age, 53.9±11.7 years), of whom 11 had skull-base tumors and 7 had ICA aneurysms (Table⇓). Six of the 18 patients were among the 30 patients in whom AR for resting CBF was obtained. Informed consent was obtained from each patient.
Before testing, the patients were premedicated with intramuscularly injected atropine sulfate (0.01 mg/kg body wt), hydroxyzine HCl (1 mg/kg body wt), and pentazocine (0.6 mg/kg body wt). A balloon catheter with a double lumen (CPVL4.8-110-SGA; Cook, Wedge 4F JC212; Argon) was inserted through the catheter sheath into the femoral artery and advanced into the ICA under adequate heparinization, with 20 U/kg heparin sodium injected intravenously every 30 minutes. The intra-ICA pressure was measured continuously (MacLab, AD Instruments), and the mean intra-ICA pressure during BOT, measured distal to the inflated balloon, was used as the MSTP. In patients who developed no clinical symptoms during BOT for 15 minutes, the CBF during BOT was measured. The CBF and MSTP during BOT were measured simultaneously; the occlusion was then discontinued, and the CBF during activated BOT was measured 20 minutes after the intravenous administration of 20 mg/kg body wt acetazolamide. The CBF measuring technique used has been described elsewhere.14
Mean CBF in either the white or gray matter located in the middle cerebral arterial territory (in which CBF has been found to reflect MSTP directly15 ) was measured, and the AR was obtained. The MSTPs and ARs during BOT and activated BOT were compared using Student’s t test for paired data. In addition, the correlations between AR and MSTP for BOT and activated BOT were analyzed using linear regression analysis; any differences between the two correlations were investigated.
A parameter indicating the decline in vasoreactivity on the occluded (ipsilateral) side, based on the difference between the magnitude of the CBF increased on both sides and using the contralateral (unoccluded) CBF as a standard, was obtained as follows: AE=([contralateral CBF during activated BOT−ipsilateral CBF during activated BOT]/contralateral CBF in activated BOT)×100−([contralateral CBF during BOT−ipsilateral CBF during BOT]/contralateral CBF during BOT)×100.12
Furthermore, as a parameter of the CBF increase due to acetazolamide activation on the occluded side independent of the contralateral side, the acetazolamide vasoreactivity was obtained as follows: ΔCBF=(CBF during activated BOT−CBF during BOT) and %ΔCBF=([CBF during activated BOT−CBF during BOT]/CBF during BOT)×100.14
We evaluated the relationships between AE, ΔCBF, and %ΔCBF and MSTP during BOT by linear regression analysis and obtained correlation and regression coefficients.
CBF and MSTP During BOT and Acetazolamide-Activated BOT
In our 18 patients, the respective mean CBFs for the occluded and nonoccluded sides during BOT were 36.6±7.4 and 40.1±7.2 mL/100 g per minute, whereas those during activated BOT were 39.1±10.0 and 53.6±12.3 mL/100 g per minute, respectively.
The mean intra-ICA pressure before balloon occlusion was 97.3±10.4 mm Hg. The MSTPs during BOT and activated BOT were 56.2±12.3 and 55.7±10.8 mm Hg, respectively, and did not differ significantly. The ARs during BOT and activated BOT were 0.91±0.08 and 0.74±0.15, respectively, showing that acetazolamide-activation reduced the AR significantly (P<.001).
Relationships Between AR and MSTP During BOT and Acetazolamide-Activated BOT
During BOT, the ARs were essentially constant, and the relationship was represented as a horizontal line, showing that there was no significant correlation (r=.156, P=.505) between AR and MSTP (Fig 1⇓, left). However, during activated BOT, a positive correlation (r=.634, P=.005) with a significant slope was detected despite no significant change in the MSTP, which indicated that AR was dependent on MSTP (Fig 1⇓, right).
Correlations Between AE, ΔCBF, %ΔCBF, and MSTP
There was a significant negative correlation between AE and MSTP, which could be expressed by the following formula: y=65.3−0.8x (r=−.636, P=.005), where y=AE and x=MSTP (Fig 2⇓, left). Significant positive correlations between ΔCBF and MSTP (y=ΔCBF; x=MSTP; y=−17.6+0.4x; r=.574, P=.013) and between %ΔCBF and MSTP (y=%ΔCBF; x=MSTP; y=−54.6+1.1x; r=.640, P=.004; Fig 2⇓, right) were observed. Eight patients had negative %ΔCBF; in particular, 2 patients with the lowest MSTP (33 and 35 mm Hg) had the greatest extent of negative %ΔCBF.
Because our patients’ background characteristics, such as age, sex, occluded side, and absolute CBF value, were not uniform, we considered that it might not always be appropriate to evaluate them using only the absolute CBF values on the assumption that all patients require similar CBF levels. Therefore, in the late phase of the BOT study, we investigated the CBF decreases caused by BOT by obtaining AR as a CBF reduction parameter to standardize the patients’ backgrounds, as well as investigating the threshold for neurological dysfunction using the absolute CBF value of each individual.15 From the results of the examinations described above, for the purpose of the present study, 18 patients whose CBFs on the occluded side were found to be maintained (ie, their CPPs were within the autoregulatory range during BOT) were selected from among 24 patients in whom both BOT and activated BOT were performed.
The relationship between AR and MSTP during BOT was represented as a horizontal line, showing that there was no significant correlation between the two. This suggested that the CPPs of the 18 patients were within the autoregulatory range,16 17 even during BOT. We consider that the lower autoregulatory limit for CBF maintenance is an MSTP of approximately 40 mm Hg in patients with almost normal hemodynamics,15 18 which is in agreement with the results reported by Fitch et al.19
However, the AR decreased significantly during activated BOT despite the lack of change in MSTP, showing that AR was MSTP dependent. This suggested that acetazolamide activation produced a fall in AR because of a decrease in CBF, the magnitude of which depended on that of the MSTP decrease on the occluded side.
Acetazolamide passes through the blood-brain barrier by diffusion, decreases the cerebral pH, and dilates cerebral blood vessels, resulting in an increase in CBF via a chemical regulatory mechanism similar to that evoked by CO2.8 9 20 21
In the light of the results of the previous studies that investigated the relationship between blood pressure and CO2 vasoreactivity and autoregulation,17 22 23 24 25 it was considered that the chemical regulatory mechanism that reacts to CO2 may be implicated in the function of CBF maintenance that responds to a fall in CPP (ie, so-called autoregulation), especially at the lower end of its range. Consequently, the reactivity to CO2 may decline depending on the magnitude of the compensation achieved by such a mechanism.
Our results suggested that CBF could not be maintained in response to a fall in CPP in the lower autoregulatory range, resulting in CPP dependency of the CBF, if the potential for chemical control or regulation had been eliminated by preadministration of acetazolamide. Therefore, we consider that the acetazolamide-reactive mechanism plays a role in autoregulation at the lower end of the autoregulatory range, and that within this range the role of this mechanism becomes more significant as CPP declines and the CBF is maintained.
When cerebral hemodynamics were examined by means of the acetazolamide test, CBF increased normally when MSTP was high (about 80 mm Hg or more), whereas the CBF increase was reduced in an MSTP-dependent manner at the lower end of the autoregulatory range (below 80 to over 40 mm Hg), and no CBF increase occurred at the lower autoregulatory limit (about 40 mm Hg). Therefore, the method of estimation used when performing the acetazolamide test should be one that directly reflects MSTP if MSTP is considered to be a direct indicator of CPP.
In this study, a significant negative correlation between MSTP and AE, which has been reported to be a useful parameter in patients with unilateral ICA occlusion, was observed. This finding indicated that enlargement of the difference between the CBFs of the two sides induced by acetazolamide administration, using the contralateral unoccluded CBF as a standard and expressed as a percentage of the latter, would increase as the drop in MSTP increased. In other words, the CBF increase on the occluded side would be smaller than that on the nonoccluded side. Consequently, these results reconfirm that AE may be a useful acetazolamide test parameter for investigating CPP in patients with unilateral ICA occlusion. However, under conditions in which the bilateral CPPs are assumed to be decreased to similar extents (eg, in patients with moyamoya disease), it is impossible to estimate the decreased CPP using this parameter, and each hemisphere of the brain should be evaluated separately.
In the present study, significant positive correlations between %ΔCBF and ΔCBF and intra-ICA pressure, which was assumed to be a direct indicator of CPP, were found, and we clarified that the CBF increase induced by acetazolamide could be reduced directly by a drop in CPP. Some patients had low %ΔCBF despite a relatively high MSTP. We consider that high vascular resistance, perhaps due to arteriosclerotic changes not detected by routinely performed neuroradiological examinations, reduced the CPP, resulting in low %ΔCBF. In the 2 patients with the lowest MSTP, a large negative %ΔCBF was recognized, and this was assumed to indicate intracerebral steal. At or below the lowest limit of the autoregulatory range, we consider that the lack of further vasodilation produced this phenomenon, since full compensation had already occurred. Therefore, in such cases, CBF during BOT was considered to be maintained by exhausting the autoregulatory potential completely.
In a previous study conducted on the basis of the correlation between the acetazolamide vasoreactivity and CBV, %ΔCBF and ΔCBF were found to be potentially useful because they both directly reflected the CBV, which was considered to be sensitive to CPP change, enabling the CPP drop in each hemisphere to be assessed separately.14 Therefore, in this study we have confirmed the validity of estimation with the acetazolamide test using %ΔCBF or ΔCBF as a parameter.
The acetazolamide test is considered a useful examination for investigating CPP decreases and demonstrating the presence of hemodynamic compromise in each cerebral hemisphere separately in patients with various diseases, as well as those with unilateral ICA occlusion. The acetazolamide activation in BOT has the potential to yield important information about reserve autoregulatory potential, thus making ICA ligation, trapping, or temporary occlusion safer, regardless of the maintenance of CBF.
Selected Abbreviations and Acronyms
|AE||=||asymmetry enhancement; ([contralateral CBF during activated BOT−ipsilateral CBF during activated BOT]/contralateral CBF during activated BOT)×100−([contralateral CBF during BOT−ipsilateral CBF during BOT]/contralateral CBF during BOT)×100.|
|AR||=||asymmetry ratio; CBF in occluded side/CBF in contralateral side|
|BOT||=||balloon occlusion test|
|CBF||=||cerebral blood flow|
|ΔCBF||=||(CBF during activated BOT−CBF during BOT)|
|%ΔCBF||=||([CBF during activated BOT−CBF during BOT]/CBF during BOT)×100|
|CPP||=||cerebral perfusion pressure|
|CBV||=||cerebral blood volume|
|ICA||=||internal carotid artery|
|MSTP||=||mean stump pressure|
We thank S. Ohtsuki of the Biostatistics Group, Kureha Chemical Industry Co Ltd, for support with statistical analysis.
Reprint requests to Yojiro Okudaira, MD, Department of Neurosurgery, Tokyo Metropolitan Hiroo General Hospital, 2-34-10 Ebisu, Shibuya-ku, Tokyo 150, Japan.
- Received August 7, 1995.
- Revision received December 18, 1995.
- Accepted December 18, 1995.
- Copyright © 1996 by American Heart Association
Baron JC, Bousser MG, Rey A, Guillard A, Comar D, Gastaigne P. Reversal of focal ‘misery-perfusion syndrome’ by extracranial-intracranial arterial bypass in hemodynamic cerebral ischemia: a case study with 15O positron emission tomography. Stroke. 1981;12:454-459.
Powers WJ, Raichle ME. Positron emission tomography and its application to the study of cerebrovascular disease in man. Stroke. 1985;16:361-376.
Lassen NA, Olsen TS, Hojgaard K, Skriver E. Incomplete infarction: a CT negative irreversible ischemic brain lesion. J Cereb Blood Flow Metab. 1983;3(suppl 1):602-603.
Metter EJ, Mazziotta JC, Itabashi HH, Mankovich NJ, Phelps ME, Kuhl DE. Comparison of glucose metabolism, X-ray CT, and postmortem data in a patient with multiple cerebral infarcts. Neurology. 1985;35:1695-1701.
Severinghaus JW, Cotev S. Carbonic acidosis and cerebral vasodilatation after Diamox. Scand J Clin Lab Invest. 1968;1(suppl 102):E. Abstract.
Vorstrup S, Henriksen L, Paulson OB. Effect of acetazolamide on cerebral blood flow and cerebral metabolism rate for oxygen. J Clin Invest. 1984;74:1634-1639.
Vorstrup S, Brun B, Lassen NA. Evaluation of the cerebral vasodilatory capacity by the acetazolamide test before EC-IC bypass: surgery in patients with occlusion of the internal carotid artery. Stroke. 1986;17:1291-1298.
Okudaira Y, Bandoh K, Arai H, Sato K. Evaluation of the acetazolamide test: vasoreactivity and cerebral blood volume. Stroke. 1995;26:1234-1239.
Okudaira Y, Bandoh K, Ito M, Sato K, Cho N. Correlation of the regional cerebral blood flow and the mean stump pressure during a balloon occlusion test of internal carotid artery and the collateral flow determined by cerebral angiography, and the ischemic threshold or a cerebral functional impairment [in Japanese]. Jpn J Neurosurg. 1993;2:110-120.
Lassen NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev. 1959;39:183-238.
Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, Patterson JL Jr. Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol. 1978;234:H371-H383.
Fitch W, Ferguson GG, Sengupta D, Garabi J, Harper AM. Autoregulation of cerebral blood flow during controlled hypotension in baboons. J Neurol Neurosurg Psychiatry. 1976;39:1014-1022.
Severinghaus JW, Lassen N. Step hypocapnia to separate arterial from tissue Pco2 in the regulation of cerebral blood flow. Circ Res. 1967;20:272-278.
Harper AM, Glass HI. Effect of alternation in the arterial carbon dioxide tension on the blood flow through the cerebral cortex at normal and low arterial blood pressure. J Neurol Neurosurg Psychiatry. 1965;28:449-452.
Sengputa D, Harper M, Jennet B. Effect of carotid ligation on cerebral blood flow in baboons, I: response to altered arterial PCO2. J Neurol Neurosurg Psychiatry. 1973;36:736-741.
Pistolese GR, Faraglia V, Spartera C, Tata MV, Lauri D, Agnoli A. Relationship between different levels of CBF and reactivity to physiological stimuli (CO2 and MABP). In: Langfitt TW, ed. Cerebral Circulation and Metabolism. New York, NY: Springer-Verlag; 1975:272-275
Paulson OB, Olesen J, Christensen MS. Restoration of autoregulation of cerebral blood flow by hypocapnia. Neurology. 1972;22:286-293.