Can Transcranial Doppler Really Detect Reduced Cerebral Perfusion States?
Background and Purpose This study was designed to determine whether transcranial Doppler ultrasonography (TCD) may detect reduced perfusion states of the brain in patients with hypertension or diabetes mellitus with suspected cerebral atherosclerosis and arteriolosclerosis.
Methods We determined blood flow velocity with TCD in the middle cerebral artery and cerebrovascular vasodilator responses to carbon dioxide in 22 patients with or without carotid artery occlusive disease and minor stroke; we compared the results with the measurements of cerebral blood flow and oxygen metabolism by positron emission tomography (PET).
Results Blood flow velocity measured by TCD correlated with ipsilateral cerebral blood flow measured by PET in frontal, temporal, and striatal regions and throughout the entire hemisphere (P<.05 to P<.005). Relative changes in blood flow velocity and calculated cerebrovascular resistance tested by carbon dioxide inhalation both correlated closely with regional mean transit time (calculated as the ratio of cerebral blood volume divided by cerebral blood flow) in frontal, striatal, temporal, parietal, and occipital regions and also in the entire hemisphere (P<.05 to P<.0001). TCD variables did not correlate with hemispheric measurements of oxygen metabolism by PET.
Conclusions Although TCD is not useful in assessing impairments of cerebral metabolism, it is useful for detecting abnormalities of cerebral hemodynamics among patients with risk factors for cerebrovascular disease.
Hypertension and diabetes mellitus are important risk factors contributing to the occurrence and severity of stroke.1 2 3 4 5 Many studies suggest that patients with these major risk factors have decreased cerebral perfusion even in the absence of neurological symptoms or strokes.6 7 8 Thus, a reliable noninvasive technique for evaluating cerebral hemodynamics should be useful for managing such patients.
TCD, introduced by Aaslid et al,9 has been used for noninvasive evaluations of cerebral hemodynamics. Dahl et al10 11 12 reported that changes in blood flow velocity measured by TCD correlate well with changes in cerebral blood flow measured by single-photon emission computed tomography; direct comparisons of TCD measurements with estimates of cerebral perfusion and metabolism are available only in the works by Kuwert et al13 and Sitzer et al.14 PET enables reliable and simultaneous measurement of oxygen metabolism and cerebral perfusion states. However, PET is expensive and not generally available. We designed the present study to determine whether cerebral hemodynamics measured by TCD correlate with PET measurements among patients with hypertension or diabetes mellitus and whether TCD measurements correlate with PET measurements of oxygen metabolism.
Subjects and Methods
In our clinic, most patients with hypertension or diabetes mellitus routinely undergo TCD examinations. We conducted a PET study of 33 consecutive patients with hypertension or diabetes mellitus in our clinic between June 1992 and July 1994. Eleven patients were excluded from the present study because of insufficient permeability of the skull for Doppler signal (10 patients, aged 54 to 79 years) or prior history of extracranial-intracranial bypass surgery (1 patient). The remaining 22 patients were studied with both PET and TCD; 15 were men and 7 were women, with a mean age of 64 years (range, 33 to 78 years). Each patient underwent carotid color duplex examination, brain CT, and MR imaging (patient 14 did not undergo MRI because of pacemaker implantation). Conventional angiography (n=12) or MR arteriography (n=7) was performed among 19 patients suspected of having cerebral atherosclerosis. We excluded patients with cardioembolic stroke diagnosed on the basis of syndromes including (1) sudden onset of clinical symptoms with maximal focal neurological deficits at onset, (2) sharply marginated hypodense areas involving cortex by brain CT with hemorrhagic infarction, (3) evidence of embolism in other parts of the body, and (4) intracardiac thrombi demonstrated by echocardiography. Subjects were classified into four groups according to presence and size of plaques identified in the carotid arterial systems, regardless of plaque in the posterior circulation: group 1, normal findings (n=7); group 2, hemodynamically insignificant stenosis (<70%, n=6); group 3, unilateral hemodynamically significant stenosis (≥70%, n=4); and group 4, bilateral hemodynamically significant stenosis (n=5). Clinical, radiological, and vascular findings are shown in Tables 1⇓ and 2⇓.
Regarding vascular risk factors, 14 of 22 patients had hypertension, 3 had diabetes mellitus, and 5 had both. None had severe anemia (hemoglobin, 10.8 to 16.0 g/dL; hematocrit, 35.2 to 48.6%; respectively). Symptomatic but not disabling small strokes were present in 7 patients (patients 8, 9, 11, 14, 15, 18, and 19). Old ischemic lesions, including white matter hyperintensities on T2-weighted MRI, were detected in 19 patients with no hemorrhagic lesions detected. Mild to moderate vascular dementia diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R15 ) was present in 4 patients (Mini-Mental State Examination, 8 to 25 points).
Informed consent was obtained from all patients before they entered the study. In patients with small strokes, cerebral hemodynamics were evaluated at least 1 month after the last stroke.
TCD examinations were performed within 1 month before PET studies using methods previously described.16 After the patient rested for 5 minutes in a supine position, a map of the circle of Willis and additional major intracranial arteries was generated by transtemporal TCD mapping with 2-MHz Trans-scan (EME Co Ltd). Sample volumes were fixed at 6 mm in diameter. Maps and sonograms were stored for later analysis on hard IBM-PC compatible disks included in the Trans-scan system. MCAs were insonated at a depth of 45 to 60 mm.
Response to Carbon Dioxide
A TCD probe was fixed on the temporal bone above the zygomatic arch with a probe holder (IMP-2, EME). Blood flow signals of the MCA were insonated and monitored. PECO2 was also monitored using Normocap 200 (Datex Co Ltd), and blood pressures were recorded every minute by a measuring device (BP-203I, Nippon Colin Co Ltd). After a stable state was reached, we recorded MCA waveforms of 15 cardiac cycles. Using a face mask, patients inhaled a mixture of 5% CO2 and 95% air for 2 minutes. Blood pressure, PECO2, and another 15 cardiac cycles of blood flow velocity were then recorded.
Calculation of Variables
We calculated the time-averaged MFV from five to seven consecutive heart beats. VMR was defined as relative changes in MFV divided by the difference in PECO2 (ΔPECO2) before versus after inhalation of CO2: VMR=(post-CO2 MFV−resting MFV)×100/resting MFV/ΔPECO2.
Slight but significant increases in blood pressure were observed in some patients after they inhaled CO2 and air. We determined percentage of change in CVRI as follows: CVRI=MABP/MFV16 and %ΔCVRI=(resting CVRI–post-CO2 CVRI)×100/resting CVRI/ΔPECO2. We used these parameters for the MCA on the side presumed to have the more severe impairment of cerebral hemodynamics. Lateralization of the lesions was judged by clinical profile, MRI and MRA, or angiography.
For PET studies, we used a Headtome–III device (Shimadzu Inc) with spatial resolutions of 8.2 mm. As described previously,17 rCBF, rOEF, and rCMRO2 were measured by the 15O steady-state technique. rCBV was determined by single inhalations of 15O-labeled carbon monoxide gas. rMTTs were calculated as rCBV/rCBF and were considered reliable indicators of cerebral perfusion pressure. Regions of interest were determined in frontal, temporal, parietal, and occipital regions; striatum; and white matter (Fig 1⇓). All values on the orbitomeatal plane plus 50 mm were averaged and used as values for entire hemispheres. PET studies were conducted blinded, without knowledge of TCD results.
Differences in TCD and PET variables between groups were assessed by ANOVA followed by Scheffé’s F test. Correlations between variables with TCD and PET were assessed by simple regression analysis. Statistical significance was assumed at a value of P<.05.
Wide ranges of resting MFVs, from 27 to 95 cm/s (mean±SD, 52.2±19.5), were observed in TCD measurements. There were no differences in average MFV among groups (Table 3⇓). No segmental increases in MFV were observed in the MCA, suggesting that MFV values were not influenced by any turbulent flows often caused by proximal or distal focal stenotic lesions nearby.
Regarding CO2 reactivity, impaired VMR (<2%/mm Hg) was found in 3 of 7 patients in group 1, in 2 of 6 patients in group 2, in 2 of 4 patients in group 3, and in 4 of 5 patients in group 4. Mean VMR values or relative changes in CVRI did not differ among groups.
PET revealed wide ranges of hemodynamic and metabolic states, but no differences in PET measurements were found among the four groups (Table 3⇑). Positive correlations between rMTT and rOEF were seen in temporal, parietal, and striatal regions and for entire hemisphere (r=.44, r=.60, r=.54, and r=.53, respectively [P<.05 to P<.005]). rMTT negatively correlated with rCMRO2 in parietal, striatal, and white matter regions (r=.42, r=.52, and r=.70, respectively [P<.05 to P<.0005]).
Comparison of TCD and PET
Since TCD or PET measurements did not differ significantly among groups 1 through 4, analyses were performed by combining all four groups. Relationships between TCD and PET measurements are shown in Table 4⇓. MFV correlated with rCBF by PET for entire hemisphere (P<.05), frontal region (P<.01), and in the territory of the MCA of temporal and striatal regions (P<.05; Fig 2⇓). In temporal and striatal regions and for entire hemisphere, MFV also correlated with rMTT (P<.05). MFV also correlated with rOEF in frontal and striatal regions.
VMR demonstrated good correlation with rMTT in territorial areas of the anterior, middle, and posterior cerebral arteries (P<.05 to P<.0005; Fig 3⇓). Relative changes in CVRI also correlated well with rMTT in each region of gray matter (P<.02 to P<.0001; Fig 4⇓).
For entire hemisphere, VMR and relative changes in CVRI correlated with rMTT (Fig 5A⇓ and 5B⇓). Relationships between VMR and oxygen metabolism for entire hemisphere are shown in Fig 5C⇓ and 5E⇓. As VMR decreased, rOEF subsequently increased and rCMRO2 declined. These trends achieved significance only in frontal region. Relative changes in CVRI did not correlate with rOEF or rCMRO2 for entire hemisphere (Fig 5D⇓ and 5F⇓) or other regions.
We could not evaluate blood flow velocity in 10 of 32 patients because of poor permeation through bone of the Doppler signal. Itoh and his coworkers18 examined rates of successful detection of MCA blood flow signals by TCD in 597 patients (16 to 89 years old) and found that the rate was 82% in men and 61% in women aged 50 years or older. Our rate of successful TCD evaluation in this study was only 69% (22/32) because stable and sufficient signals are required to measure CO2 responsiveness.
MFV and rCBF
MFV by TCD slightly but significantly correlated with rCBF measured by PET in some carotid arterial territorial regions and also throughout the entire hemisphere. Bishop et al19 also demonstrated weak but statistically significant correlations between blood flow velocity by TCD and CBF measured by 133Xe among patients with or without carotid occlusion.
Van der Zwan et al20 demonstrated that territorial distributions of human basal cerebral arteries correlate with vascular diameters. Thus, the diameter of the MCA trunk and the size of the area perfused by the MCA may be assumed to correlate. MFV should have applications for estimating rCBF in a standardized area, since relationships between rCBF and MFV can be expressed as follows: rCBFSTD×PAMCA=MFV×LAMCA, where rCBFSTD indicates rCBF in a standardized area; PAMCA, perfusion area of the MCA; and LAMCA, luminal area of the MCA trunk. These assumptions, however, can only be reasonably applied to patients without significant stenosis or a collateral circulation, such as in groups 1 or 2.
VMR or CVRI Changes Versus Perfusion State
Patients in our study had differing degrees of cerebral atherosclerosis or arteriolosclerosis. Heistad et al21 demonstrated that responsiveness of the cerebral arteries to CO2 is impaired in monkeys with extracranial atherosclerosis. Clinically, MCA responses to vasodilatory stimuli are reduced among patients with severe carotid occlusive disease.22 23 24 25 26 27 28 Some patients with severe carotid atherosclerosis show compromised intracranial hemodynamics as measured by PET.29 Maeda and associates30 reported that CO2 reactivity was reduced among patients with lacunar infarctions, ie, by intracranial arteriolopathy. Similarly, Meguro et al31 showed reductions in CBF and CBF-CBV ratios in patients with severe periventricular hyperintensities by MRI, presumably indicating arteriolopathy.
Regarding relationships between cerebral vasodilatory responses and perfusions, Herold et al32 compared PET parameters with CO2 reactivity measured by intravenous 133Xe techniques among patients with carotid artery occlusive disease and found significantly linear relationships between CBF-CBV ratio and CO2 reactivity. Hirano et al33 also found that vasomotor reactivity to acetazolamide correlated with the CBF-CBV ratios. Our results indicate that decreases in perfusion pressure due to atherosclerosis or arteriolosclerosis are compensated by vasodilatory reserves. Thus, VMR and relative change in CVRI become reduced in states of compromised cerebral hemodynamics.
CO2 response of the MCA correlated with rMTT in the anterior and posterior cerebral arterial territories; this is probably because the MCA influences maintenance of blood flow to other territories, through bone and degrees of arteriosclerosis (and also vasodilatory response) may not differ significantly within territories of the MCA and anterior and posterior arteries in patients without embolic strokes.
Changes in VMR or CVRI and Metabolism
We failed to show the expected contributions of decreased CO2 responses to the presence of elevated rOEF and decreased rCMRO2, as reported previously.32 33 34 35 In addition to the small sample size of this study, the following causes would explain the results.
Although 1 patient with extracranial-intracranial bypass surgery was excluded from the present study and all brain lesions present in our patients were in chronic stages, PET revealed heterogeneous relationships between hemodynamics and metabolic states. The “misery perfusion pattern” (a decreased rCBF with an increased rOEF greater than 48%) was seen in only 2 patients (Table 3⇑; patients 16 and 18), and 6 patients demonstrated the “matched hypoperfusion”; rCMRO2 was 1.8 mL/100 mL per minute or less, and rOEF was below 48% (patients 4, 14, 15, 19, 21, and 22). Metabolic conditions of the brain are altered according to the severity and stages of ischemia.36 For example, in patients with unilateral carotid artery occlusive disease, asymptomatic patients do not show an increase in OEF, suggesting efficient compensatory mechanism of hemodynamics,13 whereas symptomatic patients (ie, those with advanced stages of occlusive disease) tend to have exhausted vasodilatory capacity and elevated OEF.36 Thus, it seems likely that the ischemic brain lesions were in different stages, even in the same group.
We included 8 diabetic patients (patients 1, 8, 10, 12, 16, 18, 19, and 22). Diabetes mellitus is known to decrease vasodilatory responses37 38 and is involved in progression of arteriolosclerosis and atherosclerosis.39 Grill et al40 observed that global cerebral productions of lactate and pyruvate are higher in diabetic than nondiabetic subjects, and they proposed that a larger fraction of glucose is anaerobically metabolized in diabetic patients. Diabetes mellitus, therefore, influences both vasodilatory responses and cerebral metabolism of glucose and oxygen.
The perfusional states and the oxidative metabolic conditions appear not to be correlated in a simple manner among patients with different stages of brain ischemia, particularly among diabetic patients.
TCD is a reliable method to evaluate decreases in the cerebral circulation in patients with hypertension or diabetes mellitus. TCD promises to be useful for the management of such patients when used in combination with noninvasive morphological imaging such as MR arteriography and carotid duplex examinations.
Selected Abbreviations and Acronyms
|CVRI||=||cerebrovascular resistance index|
|MABP||=||mean arterial blood pressure|
|MCA||=||middle cerebral artery|
|MFV||=||mean flow velocity|
|PECO2||=||partial pressure of end-tidal CO2|
|PET||=||positron emission tomography|
|rCBF||=||regional cerebral blood flow|
|rCBV||=||regional cerebral blood volume|
|rCMRO2||=||regional metabolic rate for oxygen|
|rMTT||=||regional mean transit time|
|rOEF||=||regional oxygen extraction fraction|
The authors are grateful to Dr Yuichi Ichiya for performing the PET examinations. We also thank Drs Katsumi Irie and Kentaro Takano for important advice on this study.
Reprint requests to Hiroshi Sugimori, MD, Second Department of Internal Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan.
- Received May 15, 1995.
- Revision received July 20, 1995.
- Accepted July 27, 1995.
- Copyright © 1995 by American Heart Association
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