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From the Divisions of Medical Physics and Surgery, Faculty of Medicine,
University of Leicester, Leicester, United Kingdom.
Correspondence to Dr J. Dumville, Department of Medical Physics, Leicester Royal Infirmary, Leicester LE1 5WW, UK. E-mail jd23{at}le.ac.uk
Methods—In 56 subjects the CVR was bilaterally assessed by
measurement of cerebral blood flow velocity change in response to
inhalation of 5% CO2 in air while BP was continuously
monitored. Three methods of calculating the CVR were used: the
conventional ratio between relative cerebral blood flow velocity and
end-tidal CO2, simple linear regression, and multiple
linear regression analysis (MLRA). The clinical significance of
the difference in CVR indices was evaluated. The Bland-Altman test was
applied to quantify the comparability and bias between measurements.
The magnitude and significance of a change in BP during the CVR
assessment were calculated in conjunction with an estimate of the
velocity change attributed to the BP. The statistical significance of
the data segment length on the variability and magnitude of the CVR
index was computed.
Results—The value of the CVR index was reduced by 20% and 6% in
comparison to the conventional ratio approach when MLRA and linear
regression were applied, respectively. With the use of MLRA, in 96% of
cases the value of the BP coefficient was statistically significant,
and in four patients the increase in velocity was primarily attributed
to the increase in BP.
Conclusions—The influence of BP is significant and requires
consideration when the CVR index is calculated in patients with carotid
artery disease.
Investigation of the CVR capacity by regional CBF measurements and
positron emission tomography is used to evaluate the efficiency of the
collaterals.2 Another simple noninvasive
technique is the Doppler CO2 test. Typically,
a CVR index is expressed that characterizes the response of the CBF to
a change in ETCO2 with several segments of steady
state data.3 Frequently no reference is given to
the change in systemic BP, which is inevitable from the positive
inotropic effect of CO2 on the
heart.4 However, some authors record the BP
changes and then dismiss the effect as
nonsignificant.1 5 6 In contrast, Gur et
al7 acknowledge the potential influence of the BP
by removing any large changes in BP.7
This study questions the conventional methodology of assessing the CVR
index with the purpose of highlighting the influence of BP.
Doppler Examination
BP Assessment
CVR Assessment
For each patient a 6-minute cycle of recording events took
place. The patient initially breathed ambient air to provide a 2-minute
baseline, then an equal period of elevated ETCO2
was followed by an additional 2-minute air baseline. All four signals
(right MCAV, left MCAV, BP, and CO2) were
continuously recorded onto DAT for off-line analysis.
Data Processing
Calculation of the CVR Index
Method 1
In addition, the distribution of changes in BP due to the elevation of
ETCO2 was considered.
Method 2
The second method of assessing CVR utilizes simple regression
analysis when CO2 is the independent
variable and CBFV is the dependent variable.
Method 3
The CVR indices were characterized by three categories of
CO2 reactivity: sufficient, diminished, and
exhausted.1
To identify the extent to which the three methods agree, a correlation
coefficient associated with a simple regression fit between data sets
was calculated. In addition, the Bland-Altman
procedure14 was applied to quantify the
comparability and possible bias between measurements. First, the
Bland-Altman procedure estimates a mean intermethod error (or bias),
which is the mean (Dm) of all the individual errors
(Di) within each pair of measurements of the same quantity.
Second, if a normal distribution of the differences is assumed, a 95%
confidence interval of Di is expressed by
Dm±1.96(
Further analysis was performed on the MLRA data. The magnitude
of the BP coefficients was examined. In addition, the significance of
the BP coefficient was determined by comparing the BP coefficient value
to zero and applying the t test. A value of
P
In addition, for a random subsection of patients (n=10) the
conventional approach of extracting the CVR index was further
investigated with respect to the length of the data segment utilized.
Reactive indices were extracted with the use of different data segments
(10, 20, and 40 beats), and a t test was adopted to assess
the effect of data segment length on mean CVR index and its
variability.
The majority of patients had sufficient CVR (
Scatterplots showing the relationships between the CVR distributions as
calculated by the three different methods are described in Figure 3
From the MLRA, the mean±SD (range) value of the pressure coefficient
was 0.49±0.34%/mm Hg (-0.14 to 1.40%/mm Hg). In 96% of cases the
value of the BP coefficient was statistically significant. The partial
CBF-MABP, CBF-ETCO2, and
MABP-ETCO2 relationships yielded
mean±SD (range) partial correlation coefficients of .41±.23 (-.41 to
.78), .71±.18 (.13 to .93), and .41±.29 (-.41 to .79), respectively.
The mean values of the partial correlation coefficients were
statistically significant (P<0.001). In addition, with the
use of the individual MLRA equations, the changes in velocity induced
by BP and ETCO2 changes are described
in Figure 5
The effect of the data segment length on the CVR index was investigated
(Table 4
When the CVR is assessed by a change in CBF relative to a change in
PCO2, the influence of BP is not
considered. Typically, a slight increase in mean BP of 7 to 12
mm Hg during CO2 inhalation is reported in the
literature.6 15 19 20 21 This is consistent
with a mean rise in BP of 7 mm Hg (range, -13 to 20
mm Hg), as reported in this study. Smielewski et
al22 reported an MABP increase of 13%; however,
in one case the MABP rose by 193% of its baseline measurement.
The relationships between MABP and CBF23 and
between CBF and
PCO224 are
extensively documented. However, it is the interplay between CBF, BP,
and PCO2 that requires further
investigation. Harper and Glass25 described a
greater reactivity in dogs with MABPs of 150 mm Hg than in dogs
with MABP of 100 mm Hg. Since canine BP is similar to that of
humans, it was translated that hypertensive patients would yield a
greater CVR index in comparison to analogous normotensive
counterparts.
To include BP in the calculation of CVR, MLRA was adopted from Menke et
al,13 who applied the technique to preterm
infants. MLRA facilitates the simultaneous evaluation of
cerebral autoregulation and CO2 reactivity.
The use of MLRA for the assessment of CVR results in a 20% mean
reduction in the CVR index. The clinical relevance of introducing the
BP must be justified. In a healthy person (no vascular disease, intact
cerebral autoregulation, intact collateral flow, normal intracranial
pressure) the CVR assessment as determined by the relative changes in
velocity and ETCO2 will be
independent of pressure provided that the pressure change is contained
within the autoregulatory plateau (of constant gradient) and the change
in ETCO2 displaces the velocity
reading along a constant gradient line. However, if any of these
conditions is violated, the influence of pressure is potentially
relevant. For example, in patients with carotid artery disease, the
resistance arteries of the brain become maximally dilated above a
critical stenosis. Breathing increased levels of inspired
CO2 may increase the CBF as a consequence of
passive autoregulation and not active
vasodilation.17 Indeed, in 4 patients in this
study the increase in velocity on breathing 5%
CO2 in air was primarily attributed to BP. In
addition, the effect of removing the influence of the MABP to the rise
in CBFV identifies an additional 6 patients at
hemodynamic risk (Table 1
The delay between end-tidal and CBFV response (4 seconds) compares
favorably with a 6-second delay described previously by Poulin et
al.29 The time delay between the pulse foot of
the MABP and MCAV cardiac cycles is due to the different sites of
variable detection: a site of synchronous detection would result in
zero delay.
From the calculations of CVR in which data segments of different
lengths were used, it was demonstrated that the longer segments reduce
uncertainty in the CVR index as a result of the smoothing of
fluctuations in the MCAV. Additionally, uncertainties in the CVR are
inevitable because of the indirect measurement of the
CBF,9 arterial
BP,30 and arterial blood
gas31 during changes in
PCO2. Although the noninvasive finger
pressure measurement was applied previously to monitor BP during
inhalation of 5% CO2 in air, its validation
during vasodilation can only be extrapolated from its accuracy during
vasoconstriction.32 Further uncertainty regarding
the value of the CVR index may be introduced if assumptions fundamental
to the accurate application of TCD are violated, ie, the angle of
incidence between the probe and directional flow remains unchanged, and
the cross-sectional area of the MCA remains constant. Intraindividual
variability would provide an estimate of the reproducibility of the
results. However, it was deemed unethical to repeat the measurement of
CVR because of patient discomfort. Method 3 may afford more
variable results as a result of the introduction of an additional
measurement. However, an increase in the degrees of freedom (
In summary, MLRA was applied to patients with carotid artery disease.
The method proposed facilitates the incorporation of the BP
contribution into the assessment of CVR and removes the necessity of
having segments of steady state data. In patients with carotid artery
disease the influence of BP was statistically significant in 96% of
patients, and in 4 subjects it primarily caused the increase in
velocity. Indeed, the application of MLRA identified 6 additional
patients as hemodynamically compromised. Furthermore,
the application of MLRA would potentially allow the dissociation
between cerebral autoregulation and CO2, thus
allowing those patients most at risk of stroke and post-CEA
hypertension and hyperperfusion syndromes because of a
hemodynamic compromise to be identified and managed
accordingly.
Received October 7, 1997;
revision received January 27, 1998;
accepted February 10, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Can Cerebrovascular Reactivity Be Assessed Without Measuring Blood Pressure in Patients With Carotid Artery Disease?
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Conventional
methods of assessing cerebrovascular reactivity (CVR) omit the
influence of blood pressure (BP). This study demonstrates the
significant influence of BP during the assessment of CVR in patients
with carotid artery disease.
Key Words: blood pressure • carotid artery diseases • cerebrovascular reactivity
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Patients with a
compromised CVR are more likely to develop ischemic
events.1 These patients may benefit from
therapeutic measures improving large-vessel flow, such as CEA or other
revascularization techniques. Distal to a severe
internal carotid artery stenosis, the brain is usually able to
maintain normal CBF by recruitment of the cerebral collateral
circulation. When this fails, the brain is usually still able to
maintain perfusion by progressive dilation of low-resistance
arterioles, albeit at the expense of an increasingly compromised
CVR.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Clinical Subjects
Fifty-six patients undergoing CEA in the vascular unit of the
Leicester Royal Infirmary National Health Service Trust were included
in the study. The study was approved by the Leicester Health Authority
Ethical Committee, and informed consent was obtained from all patients.
The patients' mean age was 67±8 years, and 70% were men. From a
potential total of 112 MCAs, 85 arteries were studied. The remaining
24% of arteries were not included in the study because of the absence
of an acoustical window in the temporal bone or technical problems. The
study includes patients with unilateral and bilateral stenoses
and occlusions of the contralateral extracranial internal carotid
artery (18 stenoses with 
50% diameter reduction [non–flow
limiting], 56 stenoses with >50% diameter reduction [of
which 24 arteries had >80% stenosis], and 11 occlusions).
The grading of stenosis was based on Doppler
velocities8 in combination with B-mode
imaging.
TCD was used to assess the blood flow velocity in the
MCA9 by insonating the transtemporal
window. Ultrasonic gel was used to acoustically couple the Doppler
probe to the skin. MCA Doppler signals were identified at depths of
45 to 55 mm and characterized by flow toward the transducer.
Optimization of the Doppler signal was achieved by slight lateral
and angular shifting of the probe in the anterior direction. A
bilateral TCD examination was performed with a Sci-med Doppler
instrument with 2-MHz Doppler probes with the patient in the supine
position and head elevated. Both TCD probes were securely fixed in
position throughout the assessment with the use of separate head probe
systems (elasticized head bands attached with a hook and loop
fastener). The audio outputs of the TCD were continuously recorded
onto DAT throughout the assessment.
The arterial BP was indirectly measured throughout
the test with the noninvasive Finapres (Ohmeda
2300).10 The finger cuff was positioned on the
side of the patient common to the site of the subsequent CEA
operation.
To avoid feelings of suffocation, the patients were asked to fit
the mask tightly by themselves so that they would be able to remove it
if fearful. The face mask is characterized by two nonreturn valves that
allow the entrance of the inhalation gases and the outlet of exhaled
gas. In addition, a sampling line was attached to the front of the face
mask to enable constant monitoring of the CO2
level by an infrared CO2 analyzer (Datex
Normocap 200).
In-house software facilitates the extraction of the peak
velocity envelope from the recorded quadrature phase signal and the
simultaneous downloading of the recorded signals from
DAT. The recorded signals were converted to a digital format at a
rate of 200 samples per second onto a microcomputer. Data were low-pass
filtered (20 Hz), and narrow spikes in the signals were detected and
removed by linear interpolation. The filtered BP signal was used to
estimate the RR interval and mark the beginning and end of each cardiac
cycle. The mean values of CBFVs and BP were calculated for each cardiac
cycle. Likewise, the ETCO2 magnitude
was estimated for each respiratory cycle. The resulting beat-to-beat
sequence of all four variables was interpolated with a third-order
polynomial and resampled at intervals of 0.2 second to produce signals
with a uniform time axis. Signals were further low-pass filtered at 0.5
Hz with the use of a Butterworth low-pass filter.
Three methods of measuring the CVR index (percentage per
millimeter of mercury) were used. All methods use the ratio between the
percent change in mean velocity relative to the air baseline velocity
and the difference in ETCO2. Common
to all methods, a pulse-seeking algorithm11 was
used to detect the foot of both the CBFV and BP waveforms. The
estimated time delay from the first 100 beats was used to realign the
signals before analysis.
The conventional ratio approach of utilizing two segments of
data (
80-second duration) at constant levels of
ETCO2 was adopted. The minimum
accepted change in ETCO2 was 3.9
mm Hg: differences below this value produced distorted results because
of the low signal-to-noise ratio.
The two additional methods of calculating the CVR index both use
the complete 6-minute data segment and use regression analysis.
This incorporates calculating cerebrovascular changes during rapid
changes in ETCO2. In addition,
Shapiro et al12 reported on the presence of
hysteresis due to the delayed response of CBFV to a step change in
PCO2. Hence, for each artery the time
delay was estimated by the cross-correlation function peak position
between CBFV and ETCO2. The estimated
time delay was used to realign the CBFV and
ETCO2 time series before
analysis was performed.
Finally, MLRA13 was performed when MABP
and ETCO2 were used as independent
variables and CBFV was used as the dependent variable. 
Di2/n)1/2.
In addition, values for interindividual variability of CVR (mean±SD)
are presented. 0.05 was adopted as the criterion for statistical
significance. In addition, the partial MABP-CBF,
ETCO2-CBF, and
MABP-ETCO2 correlation coefficients
were estimated from the data. Also, for each data segment the
contribution to the change in velocity attributed to the change in
ETCO2 was calculated as the
product of the absolute change in
ETCO2 and the
ETCO2 coefficient. A similar
calculation was performed with the use of the BP data.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
A typical data segment is described in Figure 1
. The MCAVs responded to a positive step
in ETCO2, as did the BP. The
distribution of the rise in BP resulting from the inhalation of 5%
CO2 in air is described in Figure 2 and characterized by a mean±SD (range)
increase of 7±7 mm Hg (-13 to 20 mm Hg). The CBFV
response to hypercapnia began after an estimated delay of 4 seconds.
The mean time delay between the pulse foot of the MABP and MCAV cardiac
cycles was 90±26 milliseconds when the first 100 beats in each
individual data segment were compared.
View larger version (20K):
[in a new window]
Figure 1. A typical data segment describing the cycle of
events used to characterize the CVR. The right MCAV (RMCAV), left MCAV
(LMCAV), and BP all responded to the enhancement of
ETCO2.
View larger version (9K):
[in a new window]
Figure 2. Distribution of the change in mean BP induced by
the inhalation of 5% CO2 in air relative to air. 
84%) (Table 1). When the conventional ratio was used,
8 patients had compromised CVR; however, with the introduction of BP
into the calculation, 6 more patients were identified to be
hemodynamically at risk. The 8 patients with diminished
and exhausted CO2 reactivity as assessed by the
conventional ratio all had severe carotid disease (70%
stenosis in 3 patients, 80% stenosis in 3 patients,
and 2 occlusions). The 8 patients showing diminished
CO2 reactivity from the simple regression were
not the same 8 patients showing deficient CO2
reactivity as calculated by the conventional ratio. Indeed, only 2
patients were common to each group; however, both these patients had
bilateral disease (90% stenosis).
View this table:
[in a new window]
Table 1. Classification of CO2 Reactivity and characterized numerically in Table 2. The Bland-Altman test was applied to
compare methods (Figure 4). The resultant
mean error and confidence intervals are described in Table 3. MLRA and the conventional ratio were
the least comparable methods: replacing the conventional ratio by the
MLRA could decrease the CVR index by -0.67%/mm Hg (mean). The mean
error values reflect the change in the mean CVR from the three
analysis methods: conventional ratio (3.43±1.50%/mm Hg),
simple linear regression analysis (3.22±1.28%/mm Hg), and
MLRA (2.76±1.20%/mm Hg). The use of simple linear regression and
MLRA resulted in a 5% and 19% reduction in the resultant CVR index,
respectively.
View larger version (29K):
[in a new window]
Figure 3. Comparison of CVR as estimated by three different
methods: (A) MLRA vs conventional ratio, (B) simple regression vs MLRA,
and (C) simple regression vs conventional ratio. All CVR indices
describe the change in relative velocity per unit change of
ETCO2 (%/mm Hg).
View this table:
[in a new window]
Table 2. Comparison of the Three Tests by Simple Regression
Fit and Correlation Coefficient
View larger version (29K):
[in a new window]
Figure 4. Three different analysis methods are
considered: conventional ratio (M1), simple regression (M2), and MLRA
(M3). Data obtained from the different analysis methods are
compared with the Bland-Altman test: methods M3 and M1 (A), methods M2
and M3 (B), and methods M2 and M1 (C).
View this table:
[in a new window]
Table 3. Comparison of the Three Tests to Assess CVR . A mean±SD (range) increase
in velocity of 19±11% (2% to 70%) was induced by the change in
ETCO2, whereas the increase in BP
contributed a mean±SD (range) velocity increase of 4±5% (-6% to
20%). The velocity increase introduced by the different mechanisms was
significantly different (P=0.0000). Some of the BP effects
were negative (Figure 5). In 4 patients the increase in velocity was
primarily attributed to the BP increase: 3 patients had bilateral
disease (85% stenosis both sides), and 1 patient was
characterized by a unilateral stenosis of 80%.
View larger version (22K):
[in a new window]
Figure 5. Comparison of the relative velocity changes (%)
induced by a change in ETCO2 and BP. Relative velocity
changes were calculated as the product of the absolute change and
the associated coefficient from the MLRA divided by the mean baseline
CBFV and expressed as a percentage. The graph describes patients with
sufficient ( 
) and deficient (
) CO2 reactivity.). The duration of the data
segment did not affect the CVR index magnitude (P0.66) but
did influence the variability. An extension of the data segment from 10
to 40 beats significantly reduced the variability of the CVR index
(P=0.02).
View this table:
[in a new window]
Table 4. Mean CVR and Cumulative Variance for Measurements
With the Same Data Segment Length
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Typically, it is the relationship between CBF and
ETCO2 that characterizes the CVR.
Impairment of the collateral blood supply,15 16
status of pressure autoregulation,17 and
intracranial pressure18 all affect the
physiological response to a change in
ETCO2. The contribution of the BP to
the CVR index is considered below. 
). The distinction between
active vasodilation and passive autoregulation would identify patients
at risk of hypoperfusion and stroke in the face of reductions in
arterial BP.26 In addition, the
status of pressure autoregulation and CVR would aid the comprehension
of post-CEA hypertension and hyperperfusion syndromes, which are a
cause of postoperative morbidity.27 Indeed, the
influence of BP can define the condition. After traumatic brain injury,
the influence of BP on CO2 reactivity was used to
distinguish between ischemia and
hyperperfusion.28 100) has
considerable influence in the reduction of intraindividual
variability.
Selected Abbreviations and Acronyms
BP
=
blood pressure
CBF
=
cerebral blood flow
CBFV
=
cerebral blood flow velocity
CEA
=
carotid endarterectomy
CVR
=
cerebrovascular reactivity
DAT
=
digital audiotape
ETCO2
=
end-tidal CO2
MABP
=
mean arterial blood pressure
MCA
=
middle cerebral artery
MCAV
=
middle cerebral artery blood velocity
MLRA
=
multiple linear regression analysis
TCD
=
transcranial Doppler ultrasonography
Acknowledgments
Dr J. Dumville is a research associate sponsored by the
Stroke Association.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
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