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(Stroke. 2001;32:1234-d.)
© 2001 American Heart Association, Inc.

Letters to the Editor

Revisiting the Question, "Is the Acetazolamide Test Valid for Quantitative Assessment of Maximal Cerebral Autoregulatory Vasodilation?"

Edwin M. Nemoto, PhD Howard Yonas, MD

Department of Neurological Surgery, Presbyterian University Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania

To the Editor:

The letter of Derdeyn¹ in response to the article by Demolis et al² discusses the evidence against the use of acetazolamide for maximal cerebrovascular dilation. This is important because (1) compared with CO₂, acetazolamide is safer and more easily administered in assessing cerebrovascular reserve (CVR), and (2) CVR assessed by quantitative cerebral blood flow (CBF) with acetazolamide is predictive of increased stroke risk. If CVR proves to be equivalent to oxygen extraction fraction (OEF) in detecting Powers’³ stage II compromised CVR, it would be more readily available, more easily done, and done at lower cost than PET OEF.

Demolis et al² studied "CBF" changes in rats subjected to changes in arterial blood pressure with and without acetazolamide treatment and by 7% CO₂ challenge. CO₂ caused further dilation above that induced by 42 mg/kg acetazolamide. That CO₂ causes further cerebrovascular dilation beyond that caused by acetazolamide is not surprising. Acetazolamide decreases tissue and extracellular fluid buffering capacity, thus enhancing the effectiveness of CO₂ in lowering extracellular fluid pH, which does not invalidate the use of acetazolamide in detecting stage II compromised CVR. There is more to cerebrovascular autoregulatory dilation than brain pH.

True to the title of their study, Demolis et al² studied the effect of acetazolamide on cerebrovascular autoregulation. However, it is not a model to assess the validity of acetazolamide in detecting compromised CVR. Thus, the extension of this work to the clinical realm may be questionable, but Derdeyn expressed concern about even suggesting a value of acetazolamide-based studies.

Citing Hauge et al,⁴ Derdeyn states that the vasodilatory effects of acetazolamide are complex and very likely caused by mechanisms other than PCO₂-induced vasodilation. The basis for this suggestion is purely speculative. Hauge et al noted a rapid effect of acetazolamide in causing cerebrovascular dilation, the magnitude of which they estimated would require an increase in brain PCO₂ of 2 kPa (15 mm Hg), which was thought highly unlikely since arterial PCO₂ was unchanged. Arterial PCO₂ has no bearing on whether brain PCO₂ may be elevated.

Derdeyn cites the work of Inao et al⁵ and Kazumata et al⁶ as showing striking discordances in the comparison between acetazolamide and hypercapnia. Inao et al⁵ studied 6 patients with unilateral "steno-occlusive lesion" and PET cerebral blood flow (CBF) measured during primary sensorimotor cortex activation (PSM) by bilateral hand clasping and after acetazolamide. The authors reported that with PSM activation, rCBF increased in both PSM regions. In contrast, their Figure 1 and Table 3 show that acetazolamide increased CBF markedly in the contralateral, unaffected hemisphere without increasing CBF in the ipsilateral hemisphere, suggesting that the lack of an increase with acetazolamide in the compromised region was probably due to interhemispheric steal. The comparison of PSM and acetazolamide is invalid. Indeed, in an earlier study,⁷ the same group concluded that both CO₂ and acetazolamide were correlated in CVR assessment and that acetazolamide was preferred over CO₂.

The study by Kazumata et al⁶ reported that acetazolamide identified patients with compromised CVR who had good responses to hypercapnia. However, the administration of CO₂ caused a significant increase in arterial blood pressure despite the authors’ statement that they could not find a correlation between change of blood pressure and CO₂ reactivity. Our regression analysis of their data shows that the change in blood pressure correlated linearly with the change in PaCO₂ (P=0.0128), and more importantly, that the change in blood pressure and the change in CBF was significant in the ipsilateral (P=0.037) but not in the contralateral (P=0.159) hemisphere. Thus, the discrepancy between hypercapnia and acetazolamide can be explained by the effect of hypercapnia on blood pressure. Furthermore, only 4 of the 11 patients would have been identified with compromised CVR by our previously published criteria.⁸

Derdeyn cited methodological flaws in the study by Yonas et al⁷ that we believe were not flaws. The use of a mixed patient population would be a flaw if one were to use the qualitative method of OEF estimation used by Grubb et al.⁹ It requires "normal" contralateral hemispheres and patients without bilateral carotid disease, but it is not a requirement in quantitative CBF measurement of CVR. Yonas et al retrospectively defined hemodynamic thresholds to identify normal and abnormal acetazolamide responses because it was a hypothesis building study. On the basis of this information, the study was subsequently extended in a publication by Webster et al,¹⁰ which again identified a high-risk subgroup and should logically be followed by a larger multicenter study to validate or establish the CVR thresholds.

Although Derdeyn cited the study by Yokota et al¹¹ as also indicating the lack of utility of acetazolamide as a cerebrovascular challenge, this study was flawed. They used the ratio of the affected side to that of the "normal" side for an asymmetry index or (AI) based on qualitative SPECT measurements. As shown by Yonas et al, ¹² a CBF ratio approach fails to identify 50% of the patients with compromised CVR. Use of an average AI index from a normative curve for comparison is an inferior statistical design that eliminates the power of repeated measures analysis. Quantitative CBF assessment makes no assumptions and simply assesses compromised CVR for a given region in response to acidosis induced by acetazolamide.

Finally, the relationships between changes in CBF, OEF, CMRO₂, and cerebral blood volume, to which we would add CVR, as illustrated by Powers,³ is based on the normal brain, and even then partly on speculation. We know little about the changes in these variables in the hemodynamically stressed brain. Despite the belief of Derdeyn et al¹³ that only OEF provides a measure of stage II hemodynamic stress, the use of the interhemispheric relative OEF ratio provides a view of only a highly select subgroup of patients, which may not be generalizable to the greater universe of patients with symptomatic occlusive vascular disease.

References

1. Derdeyn CP. Is the acetazolamide test valid for quantitative assessment of maximal cerebral autoregulatory vasodilation? Stroke. 2000;2000:2271–2272. Letter.
2. Demolis P, Florence G, Thomas LJ, Tran Dinh YR, Giudicelli JF, Seylaz J. Is the acetazolamide test valid for quantitative assessment of maximal cerebral autoregulatory vasodilation? An experimental study. Stroke. 2000;31:508–515.[Abstract/Free Full Text]
3. Powers WJ. Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol. 1991;29:231–240.[Medline] [Order article via Infotrieve]
4. Hague A, Nicolaysen G, Thoresen M. Acute effects of acetazolamide on cerebral blood flow in man. Acta Physiol Scand. 1983;117:233–239.[Medline] [Order article via Infotrieve]
5. Inao S, Tadokoro M, Nishino M, Mizutani N, Terada K, Bundo M, Kuchiwaki H, Yoshida J. Neural activation of the brain with hemodynamic insufficiency. J Cereb Blood Flow Metab. 1998;18:960–967.[Medline] [Order article via Infotrieve]
6. Kazumata K, Tanaka N, Ishikawa T, Kuroda S, Houkin K, Mistumori K. Dissociation of vasoreactivity to acetazolamide and hypercapnia: comparative study in patients with chronic occlusive major cerebral artery disease. Stroke. 1996;27:2052–2058.[Abstract/Free Full Text]
7. Gambhir S, Inao S, Tadokoro M, Nishino M, Ito K, Isigaki T, Kuchiwaki H, Yoshida J. Comparison of vasodilatory effect of carbon dioxide inhalation and intravenous acetazolamide on brain vasculature using positron emission tomography. Neurol Res. 1997;19:139–144.[Medline] [Order article via Infotrieve]
8. Yonas H, Smith H, Durham SR, Pentheny SL, Johnson DW. Increased stroke risk predicted by compromised cerebral blood flow reactivity. J Neurosurg. 1993;79:483–489.[Medline] [Order article via Infotrieve]
9. Grubb RL, Derdeyn CP, Fritsch SM, Carpenter DA, Yundt KD, Videen TO, Spitznagel EL, Powers WJ. Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA. 1998;280:1055–1060.[Abstract/Free Full Text]
10. Webster MW, Makaroun MS, Steed DL, Smith HA, Johnson DW, Yonas H. Compromised cerebral blood flow reactivity is a predictor of stroke in patients with symptomatic carotid artery occlusive disease. J Vasc Surg. 1995;21:338–345.[Medline] [Order article via Infotrieve]
11. Yokota C, Hasegawa Y, Minematsu K, Yamaguchi T. Effect of acetazolamide reactivity and long-term outcome in patients with major cerebral artery occlusive diseases. Stroke. 1998;29:640–644.[Abstract/Free Full Text]
12. Yonas H, Pindzola RR, Meltzer CC, Sasser H. Qualitative versus quantitative assessment of cerebrovascular reserves. Neurosurgery. 1998;42:1005–1012.[Medline] [Order article via Infotrieve]
13. Derdeyn CP, Grubb RL, Powers WJ. Cerebral hemodynamic impairment: Methods of measurement and association with stroke risk. Neurology. 1999;53:251–259.\.[Abstract/Free Full Text]

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