Phase Relationship Between Cerebral Blood Flow Velocity and Blood Pressure : A Clinical Test of Autoregulation

Fifty healthy subjects (25 female), aged 44.7±15.0 years (mean±SD), were tested by the autoregulation test as normative controls. Twenty patients (11 female) with OCD, aged 48.7±17.9 years, and 10 patients (5 female) with intracranial AVMs, aged 34.3±15.8 years, served as samples with expected disturbances of cerebral autoregulation. In the OCD group, 12 patients had been treated with unilateral balloon occlusion of the ICA because of ICA aneurysms. Two patients had atherosclerotic occlusions of the ICA (1 unilateral, 1 bilateral), 3 patients had high-degree ICA stenoses (>70%; 2 unilateral, 1 bilateral), and 3 patients had stenoses of the MCA (2 unilateral, 1 bilateral). The 10 AVMs were mainly fed by the MCA; 5 patients had large AVMs (diameter >6 cm), and 5 patients had medium-sized AVMs (diameter 3 to 6 cm). All cerebral arterial stenoses/occlusions and AVMs were diagnosed and graded angiographically. All participants gave their informed consent.

Sinusoidal oscillations in ABP were elicited by slow breathing at a rate of 6/min for 60 seconds. Every 5 seconds subjects received instructions to breathe in or to breathe out. This test is used in clinical neurophysiology as a standardized paradigm for assessing vagally mediated heart beat variations.³ Continuous monitoring of ABP and heart rate demonstrates that slow breathing evokes sinusoidal oscillations at the respiratory frequency for both parameters. The following parameters were recorded continuously during slow breathing: (1) CBFV of both MCAs by TCD, with the use of a bilateral TCD monitor (Multidop-X, DWL); (2) continuous ABP; and (3) heart rate with noninvasive servo-controlled infrared finger plethysmography (Finapres, model 2300, Ohmeda).

In both patient groups, in addition to autoregulatory testing, CO₂ reactivity was assessed in both MCAs. Details of CO₂ testing are described elsewhere.⁴ Relative increases in CBFV during hypercapnia per increases in end-expiratory CO₂ pressure (expressed as %/mm Hg) were determined in the calculation of VMR. VMR reference values were taken from control subjects of Diehl et al⁴ (78 intracranial arteries from 15 normal subjects, aged 18 to 63 years).

Under the high-pass filter model of cerebral autoregulation, variations in ABP should be transmitted to CBFV according to the following equation:

where CBFV(f) and ABP(f) are frequency domain expressions of time courses for CBF and ABP, respectively, at a given frequency, f. HP(f) represents the gain and phase shift angle of the high-pass filter at this frequency. A high-pass filter produces a frequency-dependent phase shift angle [φ(f)] between the input signal [ABP(f)] and the output signal [CBFV(f)], which is given by the formula

where T is the time constant of the high-pass filter. φ(f) approaches 0° at very high frequencies and 90° at relatively slow frequencies, depending on the value of the time constant T. Fast Fourier transformation was used to calculate the amplitudes and phases of the recorded parameters at a frequency of 6/min during the slow breathing paradigm. Assuming a high-pass filter mechanism of autoregulation, we expected to find a positive phase shift angle (somewhere between 0° and 90°) between CBFV and ABP under normal conditions. In the case of disturbed autoregulation, the phase shift angle between both parameters should be smaller, ie, CBFV should follow ABP more passively.

Parametric data are expressed as mean±SD. Differences between groups were assessed with the use of one-sided Mann-Whitney tests for independent samples. One-sided significance levels were calculated because lower phase shift angles and lower VMR values, respectively, were expected in patients. Pearson′s correlation coefficient, r, was used to describe the correlation between quantitative variables. Significance levels were set at P=.05.

In all normal subjects and patients, slow breathing elicited a near sinusoidal oscillation in ABP at a frequency of 6/min. CBFV showed similar oscillations to ABP, with expected positive phase shift angles (Fig 1). A phase shift angle was considered reliable when it remained constant over several breathing cycles. Otherwise, subjects/patients were trained to perform the breathing test more regularly. Six control subjects and 4 patients needed training to achieve required breathing rhythms and reliable phase shift angles. In normal control subjects, CBFV of both MCAs oscillated nearly synchronously (mean absolute difference in phase shift angle, 3.2±2.9°). Further analysis was thus restricted to the right MCA. Positive phase shift angles were observed against ABP oscillations between 29.8° and 133.2° (mean±SD, 70.5±29.8°) (Table 1). Phase shift angle and age did not correlate significantly (r=.20).

In 20 OCD patients, a total of 23 MCAs were in the affected hemispheres, while 17 MCAs were unaffected. The phase shift angle in CBFV of pathological vessels was significantly reduced compared with normal values (Table 1; P<.05). For this comparison, we excluded data from the left-sided MCAs in the 3 patients with bilateral vascular pathology to achieve a sample of independent measures. Phase shift angles on unaffected sides were not significantly different from those in control subjects (P>.05). A typical example of a patient with left MCA stenosis is shown in Fig 2. Similar differences between patient data and control values were also found for VMR (Table 2).

In AVM patients, phase shift angles were strongly reduced in CBFVs ipsilateral to the AVM when compared with control values (Table 1; P<.001). CBFV of the contralateral MCA also showed significantly decreased phase shift angles compared with control values (P<.01). Comparable results were also found for VMR (Table 2).

In the two patient groups, we pooled VMR and phase shift angle data, respectively, from occluded and normal sides to calculate correlation coefficients between both parameters. A close correlation existed between the two parameters (r=.66; P<.001).

TCD has been previously demonstrated to be a valuable tool for quantifying dynamic cerebral autoregulation.^{1 2 5} While the test paradigm of the Aaslid/Newell group needs a special device for stepwise decreases in ABP, the slow breathing test presented here requires only the patient’s capability to breathe at a constant slow rate. After some training, all subjects/patients succeeded in producing sinusoidal oscillations in blood pressure at a breathing frequency of 6 cycles per minute. These fluctuations were transmitted to CBFV. As expected from the high-pass filter model of autoregulation, CBFV oscillations showed a positive phase shift angle against ABP of approximately 70°, with a lower normal limit of approximately 30°.

The methodical validity of our autoregulation test may be questioned by the fact that we did not prove the constancy of the MCA diameter during the breathing test. This is a critical point, because in principle CBFV changes can be elicited by fluctuations in MCA diameter at the insonation site. However, since even the strong blood pressure step used by the Aaslid/Newell group obviously did not significantly change the MCA diameter² (see introductory paragraph), it is unlikely that oscillations in MCA diameter will be induced by the slight ABP waves in our paradigm.

We tested the clinical validity of the phase shift angle in CBFV as a measurement of cerebral autoregulation in two groups of patients known to be prone to autoregulatory disturbances. Patients with OCD have increased cerebrovascular resistance at proximal vessel sites (ICA or MCA). Peripheral cerebral resistance vessels dilate under such conditions to compensate for the cerebral perfusion pressure drop caused by the proximal increase in resistance. Since maximal dilatory capacity of arterioles is limited, counter regulation against blood pressure variations becomes more and more difficult with increasing proximal resistance. In consequence, VMR to vasodilating stimuli such as hypercapnia diminishes, as demonstrated by ¹³³Xe CBF measurements⁶ and by TCD.^{7 8 9} This could also be shown in our OCD patients who exhibited a significant VMR decrease in the affected MCA. As predicted by the high-pass model, the phase shift angle was also significantly reduced in the affected vessels. In extreme cases phase shift angles were equal to 0° (Fig 2), and CBFV showed a blood pressure–passive behavior. In common with the VMR results, phase shift angles of nonaffected MCAs did not differ from normal values.

Two different mechanisms are responsible for disturbed autoregulation in AVM patients. In AVM feeders, a large part of nonnutritional flow supplies the AVM nidus, which does not contain the arteriolar bed necessary for autoregulation.^{4 10 11 12 13} Nonfeeders (eg, the contralateral MCA) may demonstrate autoregulatory failure when the AVM produces a strong drop in cerebral perfusion pressure at the level of the circle of Willis that exceeds the lower limits of autoregulation (steal phenomenon).^{4 14} Pathological autoregulation in AVM feeders—and also, to a lesser degree, in nonfeeders—has been proven by several TCD studies with the use of the CO₂ test.^{4 15 16} In our sample of AVM patients, feeders showed a strong and nonfeeders a moderate reduction in VMR. Again, phase shift angles of feeding and nonfeeding MCAs showed decreases comparable to VMR.

Phase shift angles and VMR values were more affected in AVM patients than in OCD patients. Since 12 of the 20 OCD patients had balloon occlusions of one ICA, these data cannot be generalized to a population with exclusively atherosclerotic OCD.

In addition to subgroup analysis, we compared VMR and phase shift angle by calculating correlation coefficients between both variables in pooled patient groups. A substantial correlation of r=.66 was found. This indicates that these different tests of hemodynamic responsiveness (VMR, static response to an increase in arterial CO₂; phase shift angle, dynamic autoregulation) measure essentially the same cerebrovascular property.

This does not, however, prove the equivalence of metabolic regulations of CBF (a part of which is the CO₂-dependent H⁺ activity) and autoregulation. Several authors consider cerebral autoregulation an intrinsic myogenic mechanism that is unrelated to metabolic or neuronal control of CBF.^{17 18} On the other hand, Aaslid et al^{1 5} have suggested that the same feedback loop is involved in metabolic regulation and dynamic autoregulation of CBF, because the time responses of blood flow changes to functional stimuli and to blood pressure steps are practically identical. Diehl et al¹⁹ recently presented a cybernetic model of metabolic regulation that predicts a low-pass filter response in CBF to functional stimuli and a high-pass filter response to blood pressure variations, using the same metabolic feedback loop. However, this model does not exclude the existence of an additional myogenic component in cerebral autoregulation.

Irrespective of the exact mechanism of autoregulation, the hemodynamic state in OCD and AVM patients is caused primarily by a disturbance of autoregulation due to a drop in cerebral perfusion pressure and not to an uncoupling of metabolism and CBF. Thus, the measurement of dynamic autoregulation seems to be more appropriate than the assessment of CO₂ responsiveness in these patients. Furthermore, in contrast to CO₂ stimulation, the deep breathing test is totally without stress for patients. However, the TCD CO₂ test is a well-established tool in the management and monitoring of patients with OCD.^{7 8 9} Further studies will be needed to demonstrate the clinical usefulness of dynamic autoregulation testing, for example, in deciding whether an OCD patient may profit from extracranial-intracranial bypass surgery.

In conclusion, deep breathing at a constant rate elicits sinusoidal oscillations in blood pressure at the respiratory frequency that are transmitted to CBFV. In accordance with our high-pass filter model of autoregulation, a positive phase shift angle occurs between CBFV and ABP oscillations. This phase shift angle is significantly reduced in patients with a presumed disturbance of autoregulation. Phase shift angle and VMR as assessed by CO₂ stimulation are significantly intercorrelated. Further studies will show whether dynamic autoregulation testing is an equivalent or even a better alternative to TCD CO₂ testing.