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(Stroke. 2003;34:2.)
© 2003 American Heart Association, Inc.

Letters to the Editor

Stages and Thresholds of Hemodynamic Failure

Edwin M. Nemoto, PhD; Howard Yonas, MD Yuefang Chang, PhD

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

To the Editor:

Derdeyn et al¹ revisited their prospective study² on oxygen extraction fraction (OEF) by positron-emission tomography to predict stroke in patients with unilateral carotid occlusion. In it, they report for the first time that high OEF predicted increased stroke risk but only when combined with high cerebral blood volume (CBV). High OEF with normal CBV did not predict increased risk for stroke. This observation is germane to the utility of cerebrovascular reserve (CVR) for the prediction of stroke risk. But first, we will comment on the stages of hemodynamic failure and the thresholds they chose to use in the prediction of stroke by OEF.

For the stages of hemodynamic failure, Derdeyn et al¹ chose to depict only stages I and II without stage III. Yet, it is well recognized that there is a stage III, as depicted by Powers³ in his classic article on the relationship of the changes in cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO₂), OEF, and CBV with a progressive fall in cerebral perfusion pressure. Stage III is important because many patients with chronic cerebral hemodynamic compromise present for care after they have suffered one, and often more, prior ischemic events. These patients frequently present with evidence of prior injury within the hemodynamically sensitive cortical and subcortical white matter. In this setting, CMRO₂ should fall as would OEF, which is CMRO₂ dependent. Thus, OEF increases in stage II but falls in stage III and is thereby biphasic as we have suggested (Figure).⁴

View larger version (22K): [in this window] [in a new window]   Illustration of the changes in cerebral variables during a progressive decrease in cerebral perfusion pressure and progression through various stages of impaired cerebral circulation modified after Powers3 by the addition of CVR and an increase in CMRO2 at the end of stage II. CBF indicates cerebral blood flow; CBV, cerebral blood volume; OEF, oxygen extraction fraction; CMRO2, cerebral metabolic rate for oxygen; CVR, cerebrovascular reserve. The stages are referenced to the changes in OEF. Stage I, OEF is unchanged. Stage II, OEF begins to increase. Whether the increase is linear is unknown. Stage III, OEF declines again. Solid lines show changes that are known and dashed lines, those that are postulated.

Powers chose to show that OEF remained maximally elevated in stage III. However, the decrease in OEF with a primary reduction in CMRO₂ has been described by several groups of investigators including Powers.^5–7 In our depiction of the different stages (Figure), we suggest that there is a decline in OEF in stage III, which provides a biphasic response in OEF with progressive hemodynamic failure. The problem created by this biphasic behavior of OEF is that in the absence of any other measure, OEF alone cannot differentiate between stages. On the other hand, CVR, unlike OEF, decreases progressively with hemodynamic failure of increasing severity.

In setting the threshold for the quantitative OEF values in the review by Derdeyn et al,¹ a value of 0.44 was used. The value of 0.44 was the upper limit of the 95% CI of the mean OEF (ie, mean+1.96xSEM) from 18 normal control subjects. It is inappropriate to use this value as the threshold to determine whether an individual OEF value is elevated or not. Rather, the upper limit of the 95% reference range (ie, mean+1.96xSD), which was 0.59, is the proper threshold. There is a distinction between the CI of the mean and the reference range. The CI of the mean refers to the estimate of the mean, while the reference range refers to the individual observation. Using the 95% reference range, only 3 of the 9 strokes were detected by OEF as opposed to 8 of 9 using 0.44. Therefore, contrary to the conclusions of the original publication,² high OEF alone is not a reliable predictor of stroke. If the 95% CI of the mean was used retrospectively to achieve a higher sensitivity, it should not be presented as a prospective study. It should also be noted that the label of the x-axis of Figure 4 in the article by Derdeyn et al¹ is not OEF in percent but rather fractional OEF.

Finally, the observation by Derdeyn et al¹ that high OEF combined with high CBV but not normal or low CBV predicted stroke is of interest. CBV should be related to CVR. In other words, as CBV increases, CVR decreases. In stage III, extreme compromise of CVR to negative values in regions dependent on pial collaterals from adjacent territories results in a true "steal" phenomenon.⁸ However, CVR may also be reduced with normal or low CBV because CVR likely tests not only vasodilatory capacity but also vascular reactivity to a vasodilatory challenge. Thus, in stage III, reduced CVR may be the result of either reduced vasodilatory capacity or reduced vascular reactivity.

In summary, acceptance of OEF alone as the gold standard for hemodynamic failure is premature based on present data. A better understanding of the relationships between CVR and OEF and how they both relate to ischemic stress is needed.

References

1. Derdeyn CP, Videen TO, Yundt KD, Fritsch SM, Carpenter DA, Grubb RL, Powers WJ. Variability of cerebral blood volume and oxygen extraction fraction: stages of cerebral hemodynamic impairment revisited. Brain. 2002; 125: 595–607.[Abstract/Free Full Text]
2. Grubb RL, Derdeyn CP, Fritsch SM, Carpenter DA, Yundt KD, Videen TO, Spitznagel EL, Powers WL. Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA. 1998; 280: 1055–1060.[Abstract/Free Full Text]
3. Powers WL. Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol. 1991; 29: 231–240.[CrossRef][Medline] [Order article via Infotrieve]
4. Nemoto EM, Yonas H, Kuwabara H, Pindzola R, Sashin D, Meltzer CC, Price JC, Chang Y. Detection of stage II compromised cerebrovascular reserve by quantitative cerebral blood flow with acetazolamide and quantitative oxygen extraction fraction by positron emission tomography. In: Senda M, Kimura Y, Herscovitch P, eds. Brain Imaging Using PET. New York, New York: Academic Press; 2002: 240–249.
5. Wise RJS, Bernardi W, Frackowiak RSJ, Legg NJ, Jones T. Serial observations on the pathophysiology of acute stroke. Brain. 1983; 106: 197–222.[Abstract/Free Full Text]
6. Powers WJ, Grubb RL, Darriet D, Raichle ME. Cerebral blood flow and cerebral metabolic rate of oxygen requirements for cerebral function and viability in humans. J Cereb Blood Flow Metab. 1985; 5: 600–608.[Medline] [Order article via Infotrieve]
7. Sette G, Baron JC, Mazoyer B, Levasseur M, Pappata S, Crouzel C. Local brain haemodynamics and oxygen metabolism in cerebrovascular disease. Brain. 1989; 113: 931–951.
8. Smith H, Thompson-Dobkin J, Yonas H, Flint E. Correlation of xenon-enhanced computed tomography-defined cerebral blood flow reactivity and collateral flow patterns. Stroke. 1994; 25: 1784–1787.[Abstract]

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