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From the Departments of Neurosurgery (T.N., S.W., Y.M., K.H.) and
Neurology (T.Y.), School of Medicine, Tokyo Medical and Dental University, and
the Positron Medical Center, Tokyo Metropolitan Institute of Gerontology
(T.N., M.S., K.I., H.T.), Tokyo, Japan.
Methods—Three normal volunteers and 12 patients with an
obstruction of major cerebral arteries underwent PET measurements of
the CBF after an injection of H215O: (1) in the
resting condition, (2) during hyperventilation (HV scan), (3) 1 to 3
minutes after hyperventilation (post-HV scan), (4) during the
inhalation of 5% CO2, and (5) after an injection of
acetazolamide. Eleven patients also underwent a
15O gas study to measure CBF, oxygen extraction fraction
(OEF), and cerebral blood volume (CBV).
Results—(1) In 9 patients, the CBF value in the post-HV scan was
lower than that in the HV scan in 1 or more regions in the area of the
obstructed arteries, although the PaCO2 level
during the post-HV scan was higher than that during the HV scan in all
patients. All control regions in the patients and in the normal
volunteers showed an elevated CBF in the post-HV scan compared with the
HV scan. (2) The negative post-HV response (posthyperventilatory steal)
was prominent in 4 patients with moyamoya vessels and in another 5
patients with atherosclerotic disease who had PET evidence of
hemodynamic stress (elevated CBV or OEF). (3) The
regional pre- to post-HV change in CBF was significantly correlated
with the CBF responses to acetazolamide and
CO2.
Conclusions—Vasodilatation after the termination of
hyperventilation in the normal areas induces a steal response in the
cerebral area suffering from hemodynamic stress and may
cause profound hypoperfusion in everyday situations. This phenomenon
may be important to our understanding of the clinical symptoms and the
natural course of chronic cerebral occlusive disease bearing
hemodynamic stress.
Such hemodynamically compromised areas are exposed to a
high stroke incidence.7 9 10 11 12 An abrupt drop in
blood pressure or cardiac output has been postulated as a
hemodynamic mechanism that acts as a risk factor for
stroke evolution in the area with reduced
vasoreactivity.6 13 14 However, it has not been
determined whether a vasodilatory deficit as detected by measurement of
CO2 or acetazolamide can actually
lead to a decrease in blood flow when the blood pressure or cardiac
output falls in such? patients.
A decrease in the PaCO2 due to HV
also influences the CBF. In the present study, we focused on the
change in blood flow induced by HV because it occurs in daily
situations and because it may affect the CBF more extensively than do
changes in blood pressure or cardiac output. We hypothesized that a
disturbed vasoreactivity in patients under hemodynamic
stress may cause an abnormal response to a change in the
PaCO2. One of
the reasons we established this hypothesis is that patients with an
occlusion of a major cerebral arterial trunk with dilated
parenchymal vessels (moyamoya vessels) often present HV-induced
transient ischemic symptoms or an irreversible cerebral
infarction.15 We suspect that such symptoms may
be related to the paradoxical response to
PaCO2 alteration. Although such
HV-induced ischemic symptoms are not observed in patients with
atherosclerotic disease, the paradoxically negative blood flow response
to a vasodilatory stimulus such as hypercapnia or
acetazolamide challenge is observed in patients with or
without moyamoya vessels. Therefore, we considered that a
characteristic hemodynamic pattern may be induced by
the change in PaCO2 depending on the
degree of hemodynamic stress.
In this study, we selected patients with an occlusion of major cerebral
arteries and with minor or no permanent neurological deficit, and
examined them with repeated measurements of the CBF to identify the
changes in CBF during and right after HV. The patients were also
examined with acetazolamide/CO2
vasodilatory challenge and with an 15O gas PET
study to measure CBF, OEF, and CBV. Each of these
parameters was compared with each other to test the
hypothesis that CBF paradoxically responds to the alteration of
PaCO2 as encountered in daily
physiological conditions and that the degree of the
response depends on the severity of hemodynamic
stress.
PET H215O CBF Study
After the HV protocol, all but 1 patient (case 4) underwent an
acetazolamide challenge test in which the CBF was measured
at 10 minutes after an intravenous injection of
acetazolamide (Diamox, Lederle Japan Co). In 8 patients
(cases 1 to 3 and 8 to 12), during an inhalation of 5%
CO2 the CBF was also measured between the HV
protocol and acetazolamide scans. The percent change of CBF
caused by the acetazolamide or CO2
loading was calculated against the average resting value and termed the
"acetazolamide" or "CO2"
response.
Determination of Regional OEF and CBV
PET Data Analysis and Statistics
The data obtained are expressed as mean±SD of HV and post-HV CBFs for
each subject with the resting value set at 100. For the statistical
analysis, a general linear model was used for each subject. A
linear model was designed in which the CBF within each ROI was
expressed as (1) a sum of grand means (intercept), (2) the effect of
"condition" (whether CBF was measured at rest, HV, or post-HV), (3)
the effect of "area" (whether the ROI belongs to the control or
affected area), (4) the effect of "ROI" representing
the baseline CBF of each ROI, and (5) the interaction between
"condition" and "area" representing the difference
in the CBF response between control and affected areas, plus (6) an
error term. The "ROI" was nested within "area." The error term
was assumed to be normally distributed with an unknown uniform
variance. When the "condition-by-area" interaction was significant,
the differences in CBF between "rest" and "HV" and between
"HV" and "post-HV" for each area type (control and affected)
were then tested, making a total of 4 contrasts for each patient. For
example, a contrast between "rest" in a "control" area and
"HV" in a "control" area applies to the test for a significant
CBF increase produced by HV in the control area. In the normal
volunteer subjects, who had no affected ROIs, 2 comparisons were
examined for each subject. Bonferroni correction was applied for
multiple comparisons, and the level of significance was set at
P<0.05. This statistical analysis is similar to
performing a paired t test 4 times independently for each
patient; however, it allows a comparison when no more than 2 or 3 ROIs
belong to a specific area type, and it is more powerful because the
error is estimated from all data of the patient.
The correlation between the post-HV responses and the
CO2 or acetazolamide response was
also examined, and statistical significance was tested in each subject
with the Bonferroni correction for multiple comparisons. The
significance level was set at P<0.05.
The regional CBFs in the HV scan and in the post-HV scan in each ROI
were expressed as a percent of the resting CBF. The average percentages
among all ROIs in the control and affected regions were calculated for
each subject and are displayed in Table 2
The CBF change in all ROIs in the affected territory was plotted for 6
representative cases and is illustrated in Figure 2
Relation of Post-HV Response to Characteristics of Ischemic
Disease
Five patients with atherosclerotic disease also showed a paradoxical
negative post-HV response in 1 or more ROIs (cases 5 to 9), although
the degree of reduction and the number of ROIs with such a negative
response were smaller than those in the patients with moyamoya
vessels. The average CBF in the affected ROIs was greater in the
post-HV scan than in the HV scan in 2 patients (cases 8 and 9). In
them, a paradoxically negative post-HV response was observed in only 1
ROI (parietal and anterior watershed ROI, respectively; Figure 2
Correlations Between the Post-HV Responses and the
Acetazolamide and CO2 Responses
The post-HV responses of all ROIs in all patients were plotted against
the acetazolamide response and the
CO2 response (Figure 8A
Correlations Between the Post-HV Responses and the OEF, CBV,
and CBV/CBF
The regional CBF/CBV values were significantly correlated with the
post-HV response (r=0.65, P<0.0001) among all
ROIs. However, among the ROIs in the affected territories, the
correlation between these parameters was less good
(r=0.33, P=0.01), and it was not possible to
determine the threshold value of CBF/CBV to classify the affected ROIs
into those with paradoxical and those with normal post-HV responses
(Figure 8D
PaCO2 Difference Between the 2 HV
Periods
Possible Pathophysiology of "Posthyperventilatory Steal
Response"
We postulate here that such a posthyperventilatory steal response may
have some role in the clinical features of patients with chronic
hemodynamic stress, because this phenomenon can be
encountered in daily physiological situations. In
the normal subjects and in the patients without impaired
vasoreactivity, the maximum decrease in CBF occurred during HV and
promptly began to recover when the HV was terminated. Homeostatic
mechanisms work to eliminate excessive changes of the
PaCO2 level, which limit excessive
cerebral hypoperfusion in normal physiological
conditions. However, in patients with a hemodynamic
problem, the maximum decrease in CBF occurred after the termination of
HV. The degree of such a decrease cannot be controlled by
physiological and intentional regulation, and
unexpected hypoperfusion can thus be encountered in daily
situations.
Clinical Relevance of the Posthyperventilatory Steal
Response
The patients with atherosclerotic occlusive disease bearing PET
evidence of hemodynamic stress also showed
posthyperventilatory steal responses. The relationship between this
phenomenon and the clinical features of atherosclerotic disease is not
clear, because ischemic attacks in atherosclerotic patients are
generally independent of HV whether or not the patients show PET
evidence of hemodynamic stress. In this group, the
reduction of CBF after HV was smaller than that observed in the
patients with moyamoya vessels, and the number of ROIs showing
posthyperventilatory steal per patient was generally small. Therefore,
a long-lasting and widespread posthyperventilatory hypoperfusion may
occur rarely in atherosclerotic patients. However, several points
suggest the contribution of posthyperventilatory steal to the clinical
course of chronic atherosclerotic disease: (1) Regions with
posthyperventilatory steal are closely correlated with the area of
chronic misery perfusion and with a negative response to a
CO2 or acetazolamide challenge. These
phenomenon have been associated with a high future stroke
rate.7 9 10 11 12 (2) In the patients with evidence of
widespread chronic hemodynamic stress as in cases 5 and
7, the most profound negative post-HV response was observed in the
frontal watershed ROI. In 6 of the 9 patients with 1 or more ROIs with
a negative post-HV response, the largest negative response was observed
in the frontal or posterior watershed ROI, where cortical infarction
most often occurs in major cerebral arterial occlusive
disease.6 13 14 30 (3) Although the CBF reduction
in the post-HV scan in atherosclerotic patients was smaller than that
in the patients with moyamoya vessels, the average post-HV CBF
value among the ROIs with a negative post-HV response was lower in the
atherosclerotic patients than in the patients with moyamoya vessels
(32.8±6.0 and 38.3±11, respectively), although not to a significant
degree (P=0.10). Although our protocol was performed by
observing the end-expiratory CO2 level carefully
to be sure not to induce too much hypocapnia, profound
hypocapnia can be induced in daily situations. A more
drastic CBF decrease below the critical level might be induced, which
could trigger a thrombotic event in the area with a
posthyperventilatory steal response. These possibilities are unproved
because we did not evaluate the natural course of the patients in this
study; a follow-up study of our subjects may provide some evidence
concerning the contribution of the posthyperventilatory steal response
to stroke evolution.
Prediction of Posthyperventilatory Steal Response from Other
PET Parameters
The value of regional OEF did not correlate well with the post-HV
responses. This is not surprising because the value of OEF is based on
the uncoupling of CBF and oxygen metabolism, and the value
itself is not dependent on the vascular
response.31 However, the focal elevation of OEF
within a patient is a sign that compensation by increasing regional CBV
has already reached a maximum level,6 8 32 and in
this condition a posthyperventilatory steal was found. The use of the
absolute value of CBF/CBV also requires caution in predicting whether
an affected ROI would show a post-HV negative response. The
side-to-side ratio of CBF/CBV may be appropriate, as has been pointed
out by others.33 34 However, it imposes a
limitation on the use of CBF/CBV for evaluating the
hemodynamics of bilateral disease.
Effects of Delay and Dispersion of H215O on
CBF Measurement
Prospects for Further Investigation
Received July 9, 1997;
revision received March 31, 1998;
accepted March 31, 1998.
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© 1998 American Heart Association, Inc.
Original Contributions
Posthyperventilatory Steal Response in Chronic Cerebral Hemodynamic Stress
A Positron Emission Tomography Study
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—The
alteration of regional cerebral blood flow (CBF) during and after
hyperventilation was measured using positron emission tomography (PET)
to determine the circulatory response induced by daily respiratory
changes in the cerebral area under chronic hemodynamic stress.
Key Words: tomography, emission computed • cerebral blood flow • hyperventilation • acetazolamide • carbon dioxide • moyamoya disease
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
It has been
recognized that some patients with major cerebral arterial
occlusion are under chronic hemodynamic stress, in
which the cerebral vascular bed has reached a maximum vasodilatation to
preserve blood flow in compensation for the reduced perfusion pressure.
These areas present a reduced or even paradoxically negative blood
flow response to a vasodilatory stimulus such as hypercapnia or
acetazolamide challenge.1 2 3 4 This
state is considered to be detected by PET as "misery
perfusion"5 6 and/or increased blood
volume.7 8
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Subjects
Twelve patients with a complete obstruction of a major cerebral
artery underwent the HV protocol. The patients had either a history of
TIA without permanent deficit or a stroke with no or only moderate
neurological deficit with a good quality of life. The patients'
profiles are listed in Table 1
. All
patients except 1 (case 1) had multiple cortical and subcortical
infarctions in the territory of the obstructed artery. The study was
done at least 6 months after the stroke event. In 3 patients (cases 1,
3, and 4) such conditions lasted more than 1 year with a
consistent frequency of attack, although the study was done
while the patients were suffering from frequent reversible transient
motor or language deficits. Therefore, the study was done in the
chronic stage when the clinical condition was stable in each patient.
Three young adults (a 28-year-old male, a 22-year-old male, and a
22-year-old female) without history of neurological disease were
recruited as normal volunteers to test the reliability and
reproducibility of a PET CBF study during and after HV, which was
developed by us for the first time in the present study. The
radioactive tracers have been approved by the Radiopharmaceutical
Committee of the Tokyo Metropolitan Institute of Gerontology (TMIG)
regarding safety and efficacy for use with humans. The study protocol
was approved by the Ethics Committee of the TMIG. Written, informed
consent, in which the object of measurement, duration of study, the
number of scans and the amount of radiation exposure and blood sampling
were documented, was obtained from all volunteers and
patients.
View this table:
[in a new window]
Table 1. Profile of the Patients
The PET study was performed with a Headtome-IV scanner (Shimadzu
Corp). An arterial catheter was inserted into the radial
artery for blood sampling. The patient's head was molded and fixed on
the headrest with a customized foam head holder (Smithers Medical
Products Inc) to maintain the same head position. The transmission
data were acquired with a rotating germanium-68 rod source for
attenuation correction. The CBF was measured using the PET
autoradiographic method with an intravenous
bolus injection of 1.5 GBq of 15O-labeled water
(H215O) and a 2-minute data
acquisition starting at the time of
injection.16 17 The arterial blood
was continuously drawn, and the radioactivity concentration was
monitored with a beta detector equipped with a plastic scintillator
(Shimadzu Corp), which was then used as an input function to compute
the CBF after a correction for delay and
dispersion.18 The concentration of end-expiratory
CO2 was continuously monitored with a blood gas
analyzer (Respina, San-ei Co) to estimate the
PaCO2 during the scanning period, and
calibrated with the PaCO2 sampled
before and after each scan. The CBF was sequentially measured during
the resting state, during HV (HV scan), 1 to 3 minutes after the
termination of another 3 to 4 minutes of HV (post-HV scan), and during
a second resting state, as shown in Figure 1. The percent change of CBF in the
post-HV scan compared with that in the HV scan was termed the
"post-HV response."
View larger version (31K):
[in a new window]
Figure 1. Time course of end-tidal CO2 during
the HV and post-HV protocols in 1 representative
subject. The end-expiratory percent concentration of CO2
sampled at the nostril was continuously monitored during protocol. This
value was converted to PaCO2 by calibration
with the sampled arterial blood gas (indicated with A and
arrows; the numbers indicate the value of PaCO2
in each test in this sampling). The first resting scan (Rest 1), a HV
scan during the first HV, a post-HV scan 1 to 3 minutes after the
second HV, and a second resting scan (Rest 2) were performed in that
order. A post-HV scan was performed while the
PaCO2 was recovering to the resting
level.
All patients but 1 (case 1) underwent an
15O-gas study within 2 months before or after the
H215O-PET study. No patients
presented any change in clinical symptoms between the 2
studies. The gas study was designed to examine the
flow-metabolism uncoupling and to evaluate the compensation
by increased blood volume. The regional CBF and OEF were measured using
continuous and consecutive inhalations of
C15O2 and
15O2 gas with continuous
arterial blood sampling, and using a table-lookup technique
as described previously.19 20 In brief, the
subject inhaled C15O2 and
15O2 consecutively, each
for 9 minutes. Regional cerebral activity was measured for 8 minutes
starting 30 seconds after the commencement of tracer inhalation. The
arterial blood was continuously drawn with a pump into a
fraction collector, and the arterial whole blood activity
was monitored using a beta detector equipped with a plastic
scintillator (Shimadzu Corp). The plasma radioactivity curve was
obtained from the sequentially collected blood samples. The regional
CBF and OEF were calculated with the lookup tables that were created
from the arterial whole blood and plasma radioactivity
curves and were corrected for delay and
dispersion.18 The CBV was measured by a 3-minute
inhalation of C15O and a 6-minute PET scan, with
blood sampling after the equilibration of the radioactivity within the
circulating blood.21 The OEF was corrected for
the effect of regional CBV.22 23
All of the PET data were analyzed using the image
analysis software system, "Dr. View" (Asahi Kasei Co,
running on workstations, Indigo2 and Indy, Silicon Graphics Inc). All
of the PET images of each patient were coregistered with one another
using a locally developed image registration
program.24 25 They were also coregistered to the
subject's MRI to obtain the morphological information for placing the
ROIs in noninfarcted areas. The arterial territory was
defined using a brain atlas.26 The "affected
area" was defined as the arterial territory without or
with only poor antegrade perfusion in the arteriogram. When the
territory of the MCA was affected, 9 ROIs (each of which consisted of a
series of 1-cm-diameter circles along the cortical rim) were placed
over the frontal convexity, temporal cortex, medial occipital cortex,
and parietal cortex on each side and the cerebellum. When an ACA or PCA
was affected, additional symmetrical ROIs (frontal interhemisphere,
occipital convexity, anterior or posterior watershed) were placed on
the PET images. The ROIs were examined on the coregistered MRI to
confirm their anatomic localization and the exclusion of the infarcted
area.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Results of HV Protocol
The results of the HV protocol are summarized in Table 2. The
PaCO2 in the resting scans was 37.5
to 45.6 mm Hg (mean±SD, 41.1±2.4), which was reduced by 5.0 to
20.3 mm Hg (mean±SD, 11.7±4.6) in the HV scans. In the post-HV
scans, performed 1 to 3 minutes. after the termination of HV, the
PaCO2 was significantly elevated by
3.6 to 13 mm Hg (mean±SD, 7.7±3.5) from the HV scan values, but
was still significantly lower than the resting values by 0.7 to 10.8
(mean±SD, 4.0±3.4). Therefore, the post-HV scan in this study was
generally performed while the PaCO2
was recovering from the HV value to the resting value (Figure 1
).
View this table:
[in a new window]
Table 2. Summary of Hyperventilation Protocol Results in
Patients and Normal Controls . All subjects showed a
significant reduction of CBF by HV and a significant elevation of CBF
by the termination of HV in the nonaffected region (control region of
patients and all regions in volunteers). However, in the affected
territory, the reduction of CBF seen by the HV study was smaller than
that in the control region in all but 1 patient (case 11). The
reduction was not significant in 5 patients. The CBF did not increase
significantly during the recovery from HV in the affected area of 11 of
the 12 patients. Moreover, in 4 patients (cases 1, 3, 4, and 7), the
CBF in the post-HV scan was significantly smaller than that in the HV
scan. In another 3 patients (cases 2, 5, and 6), the averaged CBF in
the post-HV scan was smaller than that in the HV scan, although not to
a significant degree. . As shown, the pattern of CBF change
was different both among the patients and among the ROIs in individual
patients. Even when the CBF averaged across the affected ROIs did not
show a significant reduction when the post-HV scan value was compared
with that from the HV scan, the post-HV CBF was lower than the HV CBF
in 1 or more regions in the affected area (cases 5, 8, and 9; Figure 2). All of the ROIs in the control region of patients and those in the
normal volunteers showed higher CBFs in the post-HV scan than in the HV
scan. Some ROIs in the territory of the obstructed artery, which showed
a reduction in CBF, presented an increase in CBF during the
recovery from HV to the same degree as the control. In general, the
post-HV reduction of CBF after the termination of HV was encountered in
the regions with a poor reduction of CBF during HV. In cases 1 to 7, 1
or more ROIs in the affected territory even showed paradoxically
elevated CBFs in the HV scan as compared with the resting scan (Figure 2). The post-HV reduction in CBF after the termination of HV was most
prominent in such regions (Figure 2; cases 1, 4, 5, and 7).
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Figure 2. Changes in the CBF during the HV and post-HV
protocols in 6 representative patients. The CBF values
in the HV and post-HV scans are expressed as the percent of the average
of 2 resting scans. Each plot represents an ROI in the affected
region (obstructed arterial territory) and in the control
region. The mean PaCO2 during each scan is also
shown. The degree of reduction in CBF at post-HV compared with the HV
scan was large in cases 1 and 4, who each showed dilated parenchymal
vessels in an angiography (moyamoya vessels). In these 2 patients,
most of the regions in the territory of the obstructed artery showed a
profound negative post-HV response (see the PET images of cases 1 and 4
in Figures 3 and 4). Cases 5, 7, 8, and 9, who had obstructions of a
vessel with an atherosclerotic origin, also showed such a paradoxical
response in some regions, although the reduction rate was smaller than
those of cases 1 and 4 who had moyamoya vessels. It should also be
noted that many regions in the territory of the obstructed artery
showed a positive post-HV response and only a few regions showed a
negative post-HV response. Also, note that the negative post-HV
response was closely associated with a poor reduction of CBF by HV. The
regions with the largest reduction of CBF in the post-HV scan showed no
reduction or even showed a paradoxical increase in the CBF by HV.
Among the ROIs with a negative post-HV response, the average CBF
values in the resting scan, the HV scan, and the post-HV scan were
47.9±16.0, 44±14.3, and 36.6±19.2 mL ·
min–1 · 100 g–1,
respectively. Therefore, the lowest CBF occurred during the post-HV
scan rather than during the HV scan. Such a paradoxical negative
post-HV response in the affected area was prominent in the 4 patients
with angiographically visualized dilated parenchymal vessels
(moyamoya vessels; cases 1 to 4). Both the degree of reduction in
CBF and the number of ROIs with a post-HV paradoxical response were
large in these patients compared with those without moyamoya
vessels (Figure 2). Therefore, even the average CBF in all affected
ROIs was lower in the post-HV scan than in the HV scan (Table 2). The
CBF maps of 2 patients suffering from occlusion of a unilateral major
cerebral artery with moyamoya vessels clearly indicated that in the
area supplied by the occluded artery the most profound hypoperfusion
occurred not during HV but after HV, although the
PaCO2 levels in these post-HV scans
were higher than those in the HV scan (Figures 3 and 4).
These 2 patients (cases 1 and 4) noticed by themselves that their
frequent transient hemipareses are closely related to the events that
cause HV. The most prominent negative post-HV response was observed in
anterior and posterior watershed ROIs (47.2% and 47.7% reduction
after HV, respectively). Another patient (case 3) complained that he
could not speak well when he felt fatigue after daily hard work; the
most prominent negative post-HV response was observed in his left
temporal cortex (34.8% reduction after HV). In the other patient with
moyamoya vessels (case 2), there was no clear trigger that induced
her transient hemiparesis.
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Figure 3. PET images of a 20-year-old female with
an occluded left ICA with moyamoya vessels (case 1). She often
presented transient weakness of the right upper extremity that
was generally initiated by HV or fatigue, for more than 4 years. The
area of the left MCA and bilateral ACA was angiographically fed via a
leptomeningeal collateral through the left PCA and right MCA. All PET
images were obtained with an H215O PET study
and were coregistered with the patient's own MRI (shown in the first
column from the left). As is indicated in the second, third, and fourth
columns, prominent hypoperfusion occurred in the post-HV scan rather
than the HV scan, and the lowest perfusion was noted in the left
frontal watershed area. When we obtained a subtraction image (post-HV
minus HV), the area with a paradoxical steal response after HV was
clearly visualized. The subtraction images representing the
CO2 or acetazolamide response also clearly
indicated the area with a paradoxical negative response by such
vasodilatory stimuli. The area of negative post-HV response
corresponds well to the area with impaired response produced by
CO2 or acetazolamide. The unit of the scales is
milliliters per minute per 100 grams.
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Figure 4. PET images of a 41-year-old female with
an occluded MCA, patent accessory MCA, and narrow
peripheral ACA and PCA on the left side (case 4). Dilated
parenchyma vessels (moyamoya-like vessel) are observed at the
origin of the obstructed MCA. The territory of the affected artery is
mainly supplied via a leptomeningeal collateral through the patent left
accessory MCA. She often presented transient weakness of the
right upper and lower extremities (usually initiated by HV or fatigue)
for several years. The CBF image and subtraction images were obtained
by a H215O PET study. The OEF and CBV images
were obtained with a 15O-gas PET study with
C15O2, 15O2, and
C15O. All PET images were coregistered with the patient's
own MRI (shown in the first column from the left). As indicated in the
second, third, and fourth columns, prominent hypoperfusion occurred
after the termination of HV rather than during the HV, and the most
profound hypoperfusion occurred in the left posterior-watershed ROI.
When we obtained a subtraction image (post-HV minus HV), the
area with a paradoxical negative response after HV was clearly
visualized. The OEF and CBV obtained in the 15O-gas PET
study are also shown. The area with an elevated OEF value corresponded
well to that displaying the maximum post-HV steal response. The left
cerebral hemisphere showed an elevated CBV value despite decreased
resting blood flow, which is also a sign of hemodynamic
compromise. Units are milliliters per minute per 100 grams for the CBF
and subtraction images, percent for the OEF images, and milliliters per
100 grams for the CBV images. ).
However, in 2 atherosclerotic patients (cases 5 and 7) who had complete
obstruction of a unilateral ICA with poor cross circulation through the
circle of Willis, the area with paradoxical post-HV response was
observed in the whole territory supplied by the occluded artery
(Figures 2, 5, and 6). In these 2 patients, the largest
post-HV negative response was observed in the anterior watershed ROI
(7.8% and 10.0% reduction, respectively; Figures 5 and 6). There was
no trigger inducing their transient hemiparesis. In the remaining
patient (case 6), a negative post-HV response was observed in only a
temporal ROI. All ROIs in the affected areas of the other patients
(cases 10 to 12) (Figure 7), all control
ROIs in all patients, and all ROIs in the normal volunteers showed
increased CBFs during the recovery of the
PaCO2 level.
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Figure 5. PET images of a 48-year-old male with
occlusion of a distal portion of the right ICA (case 5). Since this
artery is tortuous and irregular from its origin, it was presumed to
have an atherosclerotic origin. The territory of the affected artery
was fed via a leptomeningeal collateral through the right PCA. He once
presented with transient left-sided weakness and was found to
have multiple cerebral infarctions on MRI. The CBF, CBV, and OEF images
were obtained with a 15O-gas PET study using
C15O2, 15O2, and
C15O, and subtraction images were obtained from a CBF study
within a H215O PET study. All PET images were
coregistered with each other. The CBV in the affected side was elevated
despite the decreased CBF. Subtraction images to show the post-HV
response (post-HV minus HV) visualized well the area with a paradoxical
negative response after HV. The maximum negative response was observed
in the anterior watershed ROI. The area with a negative post-HV
response corresponded well to the nega- tive response produced
by acetazolamide loading, as was shown with the subtraction
image (acetazolamide minus Rest). Units are milliliters per
minute per 100 grams for the CBF and subtraction images, percent for
the OEF images, and milliliters per 100 grams for the CBV images.
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Figure 6. PET images of a 60-year-old male with
occlusion of the right ICA (case 7). The territory of the right ACA and
MCA was fed through an only poorly developed anterior communicating
artery from the left side. Since the right PCA was not visualized by
vertebral angiography, the occluded right ICA was thought to have had a
fetal-type posterior communicating artery. The patient once
presented with transient left-sided weakness and was found to
have multiple cerebral infarctions on an MRI. The CBF, CBV, and OEF
images were obtained with a 15O-gas PET study using
C15O2, 15O2, and
C15O, and subtraction images were obtained from a CBF study
within an H215O PET study. All PET images were
coregistered with each other. The OEF in the affected side was markedly
elevated in comparison with the other side. The subtraction images
presenting a post-HV response (post-HV minus HV) indicated that the
area with a paradoxical steal response after HV corresponded well to
that of the elevated OEF. The maximum negative response was
observed in the anterior watershed ROI. The area with a
posthyperventilatory negative response also corresponded well to the
area with no or a negative response by acetazolamide
loading, which is indicated in the subtraction image
(acetazolamide minus Rest). Units are milliliters per
minute per 100 grams for the CBF and subtraction images, percent for
the OEF images, and milliliters per 100 grams for the CBV images.
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Figure 7. PET images of a 67-year-old male with
occlusion of the left cervical ICA (case 12). He presented with
right hemiplegia and total aphasia. A cerebral infarction in the right
frontal and parietal watershed portion was found. The PET examination
was done at 6 months after the stroke event, when the patient's motor
function was completely recovered and only motor aphasia remained. An
angiogram of the right ICA revealed that the territory of the left MCA
was fed through a poorly developed anterior communicating artery. The
CBF, CBV, and OEF images were obtained with a 15O-gas PET
study using C15O2,
15O2, and C15O, and subtraction
images were obtained with a CBF study and an
H215O PET study. All PET images were
coregistered with each other. There was no apparent laterality in the
OEF or CBV. The subtraction images with the post-HV response (post-HV
minus HV), acetazolamide response
(acetazolamide minus Rest), and CO2 response
(CO2 minus Rest) indicated that most of the portions on
both the affected side and control side showed positive
responses. Units are milliliters per minute per 100 grams for the CBF
and subtraction images, percent for the OEF images, and milliliters per
100 grams for the CBV images.
The PET subtraction images representing the post-HV
response (equal to the CBF in the post-HV scan minus that in the HV
scan) had a distribution pattern similar to the CBF images of the
CO2 or acetazolamide response (equal
to the CBF in CO2 or acetazolamide
challenge minus rest) by visual inspection in all cases, as shown in
representative cases (Figures 3 and 5 through 7). In
the ROI analysis, the regional post-HV increase was
significantly correlated with the acetazolamide or
CO2 response, with a high correlation coefficient
in the cases with a paradoxically negative post-HV response (cases 1 to
9) (Table 2). However, in the patients without a paradoxical response
and in the normal volunteers, the correlation coefficient was small and
less often significant (Table 2). and 8B). Both the
acetazolamide response and the CO2
response were significantly correlated with the post-HV responses among
all ROIs and among the affected ROIs (P<0.0001). In
accordance with these plots, the acetazolamide or
CO2 response magnitude could be used as an
indicator to distinguish regions with a paradoxically negative post-HV
response from those with a normal positive post-HV response. Among
regions with less than a 10% response to acetazolamide, 33
of 40 (83%) regions showed a negative post-HV response. Among regions
with more than a 10% response to acetazolamide, 13 of 18
(72%) regions showed a positive post-HV response. Among regions with
less than a 5% response to 5% CO2, 27 of 33
(82%) regions showed a negative post-HV response. Among regions with
more than a 5% response to 5% CO2, 11 of 15
(73%) regions showed a positive post-HV response.
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Figure 8. Correlations between the regional post-HV
responses and the acetazolamide response (A),
CO2 response (B), CBV (C), and CBF/CBV (D). All ROIs from
all patients were plotted using filled (affected area) and open
(control area) circles. Among all regions, all 4 parameters
were highly correlated with the post-HV responses. Among the affected
regions, the acetazolamide response (A), CO2
response (B), and CBV (C) were highly correlated with the post-HV
responses, but CBF/CBV (D) was not. The most appropriate threshold
value for the acetazolamide response, CO2
response, CBV, and CBF/CBV to predict a negative post-HV response was
investigated as was described in the text. The horizontal lines in
panels A, B, and C indicate threshold values. No useful threshold value
was found for CBF/CBV.
The visual inspection of the CBF, CBV, and OEF images obtained by
the 15O-gas PET study, coregistered with each
other, indicated that when a focal difference of OEF or CBV was clear,
paradoxical post-HV responses were encountered (Figures 4 through 6).
When such a focal abnormality in OEF or CBV was not noted, post-HV
paradoxical responses did not occur (Figure 7). However, when the OEF
values in all ROIs from all patients were analyzed, the
correlation between the OEF value and the post-HV responses was found
to be small (r=0.2, P=0.03). Moreover, there was
no significant correlation between these parameters in the
affected regions (r=0.01, P=0.93). The regional
value of CBV was significantly and highly correlated with the post-HV
response among all ROIs and among the affected ROIs (r=0.530
and r=0.537, respectively, and P<0.0001 and
P<0.0001, respectively) (Figure 8C). In accordance with
this plot, the CBV value could be used as an indicator to distinguish
regions with a paradoxical post-HV response from those with a normal
post-HV response. Among regions with CBV values greater than the
mean+SD of the normal volunteers,27 30 of 36
(83%) regions showed the paradoxical negative post-HV response. Among
regions with CBV of less than the mean+SD, 14 of 22 (64%) regions
showed a positive post-HV response (Figure 8C). ). The regional value of CBF/CBV seems to be influenced by
the resting CBF and to have limited value in predicting the degree of
post-HV response of the affected territory, which bore significantly
lower resting CBF values compared to the control areas (34.2±7.1
versus 40.4±7.7 mL · min–1 · 100
g–1, P<0.0001)
The post-HV scan was done after the second period of HV, and the
HV scan was done during the first HV. This procedure was necessary
because we needed at least a 10-minute interval between the 2 PET scans
to allow for isotope decay and to avoid continuing the HV for more than
10 minutes. Although we attempted to maintain similar levels of
PaCO2 during the 2 HVs by adjusting
the rhythm of ventilation, the possibility that different
PaCO2 levels between the 2 HV periods
might have affected the result was not ruled out. Thus, we reexamined
and compared the PaCO2 levels during
the HV protocol between 2 groups of subjects: the patients who had 1 or
more regions with an apparent negative post-HV response (cases 1 to 9)
and the patients without a negative post-HV response and the normal
volunteers (cases 10 to 12 and the 3 volunteers). There was no
significant difference between the 2 groups, either in the value of
PaCO2 during the various scans or in
the PaCO2 differences from the
resting values (Table 3). There was also
no significant difference in PaCO2
between the 2 HV periods in either group (Table 3).
View this table:
[in a new window]
Table 3. PaCO2 (in mm Hg) During Each Scan
in Subjects With or Without ROIs With a Negative Post-HV Response
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
In the present study, the cerebral area under chronically
reduced perfusion pressure, which was expressed by elevated CBV,
elevated OEF, or impaired vasoreactivity, showed a paradoxical response
in CBF during and after HV. As a result, a profound hypoperfusion
occurred not during the HV but rather after the HV. The post-HV
response was strongly correlated with the vascular responses to the
vasodilatory stimuli of CO2 and
acetazolamide. We speculate that the termination of HV acts
like a vasodilatory stimulus because the reduced
PaCO2 recovered to the baseline level
during that period. Thus, a paradoxically negative response was
observed in the post-HV state and in the
CO2/acetazolamide loading tests in
almost identical regions.
These negative responses to vasodilatory stimuli could be
explained as a "steal phenomenon" because normal vessels, which are
a main source of blood supply to the impaired area through
leptomeningeal collaterals or through poorly developed collaterals of
the circle of Willis,8 promptly dilate in
response to a stimulus, which reduces the blood supply to the area with
an impaired vascular response. As was shown in this study, a
paradoxical increase in CBF produced by reducing the
PaCO2 and a paradoxical decrease in
CBF produced by increasing the PaCO2
often occur in the territory of an obstructed artery. However, it is
not reasonable to speculate that the vessels in such a region dilate by
themselves in response to the reduced
PaCO2 or that they constrict in
response to the increased PaCO2. It
is more reasonable to consider this a passive phenomenon caused by the
vascular response in the control region by the same
arterial source. Therefore, in this paper we will refer to
the paradoxically negative response in CBF after the termination of HV
as the "posthyperventilatory steal response."
In our series, the patients with moyamoya disease (cases 2 and
3) or unilateral cerebral arterial occlusive disease with
angiographically demonstrated moyamoya vessels (cases 1 and 4)
exhibited a marked posthyperventilatory steal response. It may explain
why such patients often present a long-lasting but reversible TIA
after a condition that leads to HV (eg, crying, eating a hot meal, or
playing a wind instrument).15 In our series, the
transient motor or language symptoms seen in 3 patients (cases 1, 3,
and 4) could be triggered by HV. It should be noted that the reduction
of CBF at post-HV was very large in these patients. A milder post-HV
steal was observed in the other patient with moyamoya vessels (case
2) and in the atherosclerotic patients in whom the ischemic
attack was not associated with HV. Therefore, it may be reasonable to
hypothesize that the profound posthyperventilatory steal response,
which may cause rather long-lasting posthyperventilatory hypoperfusion,
is 1 of the triggers of well-known HV-induced ischemic
symptoms. It would be worthwhile to examine the correlation between the
posthyperventilatory steal response and the HV-induced abnormal
electroencephalogram observed in patients with moyamoya
disease.28 29 It should also be noted that such
uncontrollable hypoperfusion may be closely correlated with the
progressive deterioration and ischemic damage of the cerebral
cortex that occurs in moyamoya
patients.15
From the standpoint of clinical practice, our HV/post-HV protocol
is difficult to apply to patient diagnosis in daily clinical
situations, because it requires serial quantitative measurements of CBF
in short intervals with PET. Therefore, we compared the post-HV
response with other parameters that can be obtained more
easily. Through this analysis, we showed the possibility that
the optimum threshold value for acetazolamide and
CO2 responses and regional CBV could be settled
to predict post-HV steal response, although the study of more patients
is necessary to calculate the sensitivity and specificity of such
threshold value. Because the CO2 or
acetazolamide response can be measured with
133Xe single- photon emission computed tomography
or cold Xe-CT, and the CBV can be imaged with
99mTc red blood cell single-photon emission
tomography, these parameters may be substituted for the
HV/post-HV test.
In the present study, the regions supplied by obstructed
arteries may be perfused by collateral circulation from other arteries,
and may have a different delay and dispersion of tracer from other
regions when CBF is measured with
H215O
PET.18 35 36 37 38 To evaluate the effects on our
results of regional differences in delay and dispersion, a simulation
was performed using an arterial time-activity curve
obtained in the present study (data not shown). Since the
arterial mean transit time is related to the CBV/CBF ratio
measured in this study, its within-subject regional difference was
calculated for each patient (1.7 to 6.8 seconds; mean±SD, 4.4±1.5
seconds). This simulation indicated that an arterial mean
transit time of +6.8 seconds, which is the maximum value of the
within-subject difference, induces an error of 15% in CBF values. As
for CBF changes (either an increase or a decrease), an arterial mean
transit time of +6.8 seconds induces an underestimation of 3 percentage
points when the CBF is changed by 20%. Therefore, the finding of a
smaller CBF response to CO2 change in the
affected regions than in the control regions in the present study
may be partly but not totally explained by the regional difference in
the delay and dispersion of tracer.
We reported here that the focally impaired vascular response may
cause a posthyperventilatory steal response. We also proposed that this
phenomenon may explain the clinical symptoms initiated by HV in
selected populations of patients with obstructive cerebrovascular
disease. Since the present study was done in selected patients who
were screened with a PET 15O-gas study, we are
still not sure how far the contribution of posthyperventilatory steal
response would be seen among a whole population of patients with
obstructed cerebral artery. We need to examine an extended group of
patients using this protocol to further clarify this phenomenon.
Another subject of further study concerning the posthyperventilatory
steal response should be the correlation of this phenomenon with the
risk of future stroke evolution, as we postulated. It is also important
to determine whether this condition can be treated or controlled with
treatment to increase the CBF by surgical
revascularization. Whether or not patients are
treated surgically, a follow-up study with the PET HV/post-HV protocol
together with neurological examination and CT scan or MRI should
provide more evidence to help clarify the nature of the
posthyperventilatory steal response.
Selected Abbreviations and Acronyms
ACA
=
anterior cerebral artery
CBF
=
cerebral blood flow
CBV
=
cerebral blood volume
HV
=
hyperventilation
ICA
=
internal carotid artery
MCA
=
middle cerebral artery
OEF
=
oxygen extraction fraction
PCA
=
posterior cerebral artery
PET
=
positron emission tomography
ROIs
=
regions of interest
TIA
=
transient ischemic attack
Acknowledgments
We thank Keiichi Oda, Shin-ichi Ishii, and Miyoko Ando for their
excellent technical assistance in data acquisition and
analysis.
Footnotes
Address correspondence and reprint requests to Tadashi Nariai, MD, Department of Neurosurgery, Tokyo Medical and Dental University, 1–5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
1.
Muhonen MG, Greene GM, Heistad DD, Loftus CM.
Mechanism of redistribution of cerebral blood flow during hypercarbia
and seizures. Am J Physiol. 1994;266(5, pt
2):H2074–H2081.
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