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(Stroke. 1999;30:1293-a.)
© 1999 American Heart Association, Inc.

Letters to the Editor

Influence of Arterial Blood Pressure on Cerebrovascular Reactivity

Ronney B. Panerai, PhD David H. Evans, PhD

Division of Medical Physics

A. Ross Naylor, MD

Department of Surgery, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom

Key Words: blood pressure • carbon dioxide

To the Editor:

In the May 1998 issue of Stroke, Dumville et al¹ showed that the classic CO₂ test to assess cerebrovascular reactivity (CVR) may produce misleading results unless simultaneous changes in arterial blood pressure (ABP) are taken into account. A similar finding has recently been reported by Hetzel et al.²

The possibility of interactions among CO₂, ABP, and cerebral blood flow (CBF) has been raised previously.^{3 4 5} The fact that 2 recent studies^{1 2} focusing on CVR arrived at similar conclusions despite significant differences in the populations studied reinforces the message that ABP has to be included as a significant covariate in any attempts to quantify the effects of CO₂ on CBF velocity (CBFV), as usually measured with Doppler ultrasound in the middle cerebral artery. Dumville et al¹ examined 56 patients with carotid artery disease (CAD) with a mean age of 67±8 years; the group studied by Hetzel et al² comprised 81 healthy volunteers with ages ranging from 19 to 74 years. CVR in the latter group was slightly higher than in the former (3.6±1.6%/mm Hg versus 3.4±1.5%/mm Hg), but multiple regression analysis has shown that when the effect of ABP is taken into account, the CVR of the CAD patients dropped to 2.76±1.2%/mm Hg.¹ Although Hetzel et al² have obtained a significant correlation between ABP and end-tidal CO₂, with a slope of 0.55 mm Hg/mm Hg CO₂, they have not reported on corrected values of CVR when the influence of ABP is removed.

By studying healthy volunteers, Hetzel et al² did not have the opportunity to observe the effects of ABP on the misclassification of subjects in relation to preestablished thresholds of CVR. In their patient population, Dumville et al¹ reported that inclusion of ABP led to 14 patients showing a compromised CVR instead of only 8 when the conventional measure of CVR was adopted. Moreover, we have shown that in 4 patients the observed increase in CBFV during the CO₂ test was primarily caused by ABP, a phenomenon that is also mentioned by Hetzel et al,² as illustrated in their Figure 3.

Different methodological approaches are probably behind the variability in CVR values observed in the literature.⁶ Attempts to quantify and to compensate for the contribution of ABP are likely to produce an even greater disparity of results unless greater care is taken by thoroughly testing differing methodological alternatives,⁶ performing sensitivity analysis of parameters,¹ and assessing reproducibility of results.² Inclusion of ABP as a covariate also requires careful consideration of dynamic changes.^{7 8} In the study of Hetzel et al² it is not clear whether a plateau in CBFV was established at each of the 4 phases of their study or whether the time delay between step changes in CO₂ and the rise in CBFV was corrected for, as described by Dumville et al.¹ Changes in ABP, either spontaneous or induced by the CO₂ test, will produce different effects on CBFV, depending on the status of cerebral pressure-autoregulation.^{8 9} Because it is not possible to exert absolute control on the time course of these variables during clinical tests, dynamic modeling of the interaction between CO₂, ABP, and CBFV is likely to play a major role in bringing further refinements to clinical applications of CVR testing.

References

1. Dumville J, Panerai RB, Lennard NS, Naylor AR, Evans DH. Can cerebrovascular reactivity be assessed without measuring blood pressure in patients with carotid artery disease ? Stroke. 1998;29:968–974.[Abstract/Free Full Text]
2. Hetzel A, Braune S, Guschlbauer B, Dohms K. CO₂ reactivity testing without blood pressure monitoring? Stroke. 1999;30:398–401.[Abstract/Free Full Text]
3. Harper AM, Glass HI. Effect of alterations in the arterial carbon dioxide tension on the blood flow through the cerebral cortex at normal and low arterial blood pressures. J Neurol Neurosurg Psychiatry
   1965;28:449–452.
4. Ackerman RH, Zilkha E, Bull JWD, Du Boulay GH, Marshall J, Russell RWR, Symon L. The relationship of the CO₂ reactivity of cerebral vessels to blood pressure and mean resting blood flow. Neurology. 1973;23:21–26.[Free Full Text]
5. Menke J, Michel E, Rabe H, Bresser BW, Grohs B, Schmitt RM, Jorch G. Simultaneous influence of blood pressure, PCO₂, and PO₂ on the cerebral blood flow velocity in preterm infants of less than 33 weeks gestation. Pediatr Res. 1993;34:173–177.[Medline] [Order article via Infotrieve]
6. Kleiser B, Scholl D, Widder B. Assessment of cerebrovascular reactivity by Doppler CO₂ and Diamox testing: which is the appropriate method? Cerebrovasc Dis. 1994;4:134–138.
7. Shapiro W, Wasserman AJ, Patterson Jr. JL. Mechanism and pattern of human cerebrovascular regulation after rapid changes in blood CO₂ and tension. J Clin Invest. 1966;45:913–922.
8. Garnham J, Panerai RB, Naylor AR, Evans DH. Cerebrovascular response to dynamic changes in pCO₂. Cerebrovasc Dis. 1999;9:146–151.[Medline] [Order article via Infotrieve]
9. Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebral autoregulation dynamics in humans. Stroke. 1989;20:45–52.[Abstract/Free Full Text]

Response

Andreas Hetzel, MD; Katharina Kempf, MD Stefan Braune, MD

Department of Neurology, University of Freiburg, Freiburg, Germany

Key Words: blood pressure • carbon dioxide

Studies by Dumville and colleagues^R1 and our group^R2 both report on the influence of CO₂ on ABP during Doppler CO₂ testing in humans. This variable CO₂ effect on CBFV and ABP can lead to a misinterpretation of the results of cerebrovascular reactivity testing. Dumville and colleagues^R1 reported 4 cases in a group of 56 patients undergoing carotid endarterectomy with false overall pictures of CO₂ reactivity, and we^R2 reported 1 case with the same phenomenon in our study. Both studies emphasize the covariance of CO₂ effects on ABP and CBFV. Therefore, Doppler CO₂ testing monitors not only the CO₂-induced vasodilation of cerebral arterioles with increase in CBFV but also the efficacy of cerebral autoregulation in maintaining stable cerebral blood flow with respect to increases in ABP. In patients and controls nonlinear fluctuations, especially rapid changes in ABP, correspond to similar changes in CBFV. This phenomenon, illustrated in Figures 2 and 3 in our article,^R2 is characteristic of a high-pass filter response.^R3 Variations in ABP of >0.1 Hz produce similar variations in CBFV.^{R3 R4} In our opinion, such variations of ABP, and not the linear increase in ABP, influence predominantly the CBFV. Multiple linear regression analysis without respect to the frequency of ABP variations will neglect this physiological fact of such a threshold-related influence. In patients with high-grade obstructions of brain-supplying arteries, cerebral autoregulation will be compromised because of missing effective collateral supply. Therefore, CO₂- and ABP-induced vasomotor response must be differentiated from passive ABP-induced changes in CBFV.

In our study neither the dynamics of ABP variations nor stable hypercapnic state were considered. Steady-state conditions could not occur with our rebreathing method. For that reason, we refrained from correcting CO₂ reactivity results for changes in ABP.

The time delay between dynamic changes in PETCO₂ and the rise and fall in CBFV is a characteristic that provides additional information about the vasomotor response.^R5 This was not considered in our study, which could explain the most pronounced increase in ABP at the end of our CO₂ test. We perform an ongoing study with respect to time delays between PETCO₂, ABP, and CBFV. First results in patients with severe carotid stenosis showed a highly significant correlation between CO₂ reactivity and time delay of the fall in CBFV at the end of hypercapnia. The realignment of this time delay as performed by Dumville et al^R1 may miss some insights into the pathophysiological dynamics of cerebrovascular responses intime. Their multiple linear regression analysis is the correct approach to consider linear interactions between the multimodal measured parameters. Contrary to the usual analysis of CO₂ reactivity, this might prevent underestimating the degree of hemodynamic compromise, especially in patients with already-diminished vasomotor response. Beat-to-beat analysis is necessary to quantify and report corrected values of CO₂ reactivity, and the analysis must also allow for a nonlinear relationship between parameters. Dynamic modeling of the interaction between the parameters will be the next step in the analysis of CO₂ reactivity with respect to the dynamics of cerebral autoregulation by considering amplitudes and time delays.

References

1. Dumville J, Panerai RB, Lennard NS, Naykor AR, Evans DH. Can cerebrovascular reactivity be assessed without measuring blood pressure in patients with carotid artery disease? Stroke.. 1998;29:968–974.
2. Hetzel A, Braune S, Guschlbauer B, Dohms K. CO₂ reactivity testing without blood pressure monitoring? Stroke.. 1999;30:398–401.
3. Blaber AP, Bondar RL, Stein F, Dunphy PT, Moradshani P, Kassam MS, Freeman R. Transfer function analysis of cerebral autoregulation dynamics in autonomic failure patients. Stroke.. 1997;28:1686–1692.[Abstract/Free Full Text]
4. Diehl RR, Linden D, Lücke D, Berlit P. Phase relationship between cerebral blood flow velocity and blood pressure: a clinical test of autoregulation. Stroke.. 1995;26:1014–1019.[Abstract/Free Full Text]
5. Poulin MJ, Liang PJ, Robbins PA. Dynamics of the cerebral blood flow response to step changes in end-tidal PCO2 and PO2 in humans. J Appl Physiol.. 1996;81:1084–1095.[Abstract/Free Full Text]

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