(Stroke. 1997;28:2353-2356.)
© 1997 American Heart Association, Inc.
Articles |
Sex Dependency of Cerebrovascular CO2 Reactivity in Normal Subjects
From the Department of Neurology, University of Tübingen (Germany).
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Abstract |
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Background and Purpose Cerebrovascular CO2 reactivity can be assessed easily and reliably by transcranial Doppler sonography. The objectives of the present study were to evaluate sex differences in cerebral CO2 reactivity and to specify the relation between CO2 and cerebral blood flow velocity.
Methods CO2 reactivity of the circulation of both middle cerebral arteries was measured by bilateral transcranial Doppler sonography in 60 healthy volunteers (30 men, 30 women) aged 21 to 58 years. End-tidal carbon dioxide tensions (PETCO2) were elevated with the use of carbogene gas (95% O2, 5% CO2). In each subject the mean blood flow velocity (Vmean) was plotted as a function of PETCO2.
Results The best-fit curves for the relation of Vmean/PETCO2 were exponential functions, with the following basic equation: Vmean (cm/s)=aebx, where a is a theoretical quantity representing Vmean at a PCO2 of 0 mm Hg, b is the relative slope of the curve (slope divided by the value of the function) corresponding to the definition of reactivity, and x is the PETCO2 (mm Hg). The mean value of b was 0.037±0.008 in women and 0.030±0.010 in men. ANOVA demonstrated a significant difference between men and women (P<.001).
Conclusions This study demonstrates a highly significant sex-related difference in CO2-induced cerebral vasomotor reactivity. The relation between altered carbon dioxide tensions and blood flow velocities of both middle cerebral arteries in 60 healthy volunteers was found to be exponential.
Key Words: carbon dioxide • cerebral blood flow • gender • ultrasonics • vasomotor reactivity
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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During the past few years the assessment of the cerebrovascular response to changes in CO2 has increasingly been used to evaluate the hemodynamic reserve in patients with occlusive carotid artery disease and to study patients with migraine.1 2 3 4 Cerebrovascular reactivity can be measured with 133Xe or 15O2 inhalation, the nitrous oxide method, the injection of radioactive isotopes such as 85Kr, positron emission tomography, or ultrasonic methods.5 6 7 8 9
Several biological variables have to be considered when TCD is used: (1) Beginning in the sixth year of life, velocity steadily declines from 100 cm/s to approximately 40 cm/s in the seventh decade.10 11 12 (2) Women have a higher hemispheric CBF than men,13 14 reflected in a 3% to 5% higher blood flow velocity in the MCA.15 Therefore, age and sex are important sources of variance in TCD measurements and should be taken into account in all applications of TCD. (3) Blood flow velocity is considerably dependent on PaCO2. Consequently, intraindividual PaCO2 differences at rest give rise to substantial differences in blood flow velocities as measured by TCD. The reproducibility of TCD can be enhanced by the mathematical correction of the velocity for this parameter. However, the quantitative relation between local CBF and PaCO2 is not yet clear. Regarding the response of the cerebral vessels to changes in PaCO2, two parameters are of interest: (1) the shape of the curve describing the CBF velocity/PaCO2 relation, ie, the mode or quality of the reactivity, and (2) the absolute change of velocity per millimeter of mercury of PaCO2. Within physiological ranges of PaCO2, the response of the cerebral vessels to changes in PaCO2 from 20 to 60 mm Hg in both humans and animals has been described as an exponential function,6 7 8 16 17 18 19 as a linear function,5 9 20 21 22 23 24 25 and as a hyperbolic tangent function.1
The objective of the present study was to evaluate sex differences in cerebral CO2 reactivity in normal subjects by means of simultaneous bilateral Doppler sonography. Moreover, the relation between CO2 and blood flow velocity in the circulation of both MCAs was specified.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects
Sixty healthy volunteers (30 women, 30 men) aged 21 to 58 years were studied (mean age, 32.0±10 years for women and 32.3±10 years for men). Subjects were either members of the hospital staff or medical students. None of the subjects had used any medication with known vasoconstrictor or vasodilating properties for 72 hours before the examination. The volunteers were informed about the procedure, and their consent was obtained. This study was approved by the Ethics Committee of the University of Tübingen.
Methods
Recordings were performed with each subject in a
comfortable, supine position. Bilateral simultaneous flow
velocity recordings of the MCAs were obtained with the use of
Hemo Dop equipment (Medizinische Elektroniksysteme, D-Sipplingen). Two
2-MHZ transducers mounted to a fixation helmet were placed on the
temporal bone window for continuous bilateral measurement of both MCAs.
According to Aaslid et al,10 Doppler signals from the
MCA were obtained by placing the probe over the temple and adjusting
the position for a maximal reflected signal at a depth of 45 to 55
mm. The envelope of the spectra was used to determine the blood flow
velocity in the MCA. Care was taken to obtain signals with no
interference from other vessels. Vmean values were
calculated from one cardiac cycle to the next and expressed in
centimeters per second with the use of a computer-assisted
integration procedure.
The subjects used an anesthetic mask with a two-way valve to inhale normal air or carbogene gas (95% O2, 5% CO2) for induction of an artificial hypercapnia. PETCO2 was measured continuously by infrared analysis, with a sample drawn off from the mask by a line connected to a capnometer (DATEX Normocap CO2 Monitor, HoyerDy). After a 3-minute period of adaptation to the anesthetic mask and to the environment, Vmean and PETCO2 were continuously recorded over a period of 5 minutes at baseline. Thereafter, the anesthetic mask was connected to a 25-L reservoir bag that was constantly filled with carbogene gas, and hypercapnia readings were made over a period of 5 minutes. (We did not measure TCD frequencies during hypocapnia because readings during voluntary hyperventilation proved less reliable than those during carbogene gas breathing).
Blood pressure was determined in all subjects three times, ie, at baseline, during the hypercapnic stage at the highest PaCO2 level, and in the first minute of posthypercapnia.
To determine the Vmean/PETCO2 relation in each subject, we averaged the mean flow velocities and end-tidal CO2 partial pressures over a period of 20 cardiac cycles every 30 seconds and plotted Vmean as a function of PETCO2. Altogether 120 MCA territories were considered for this study. To test reproducibility we studied 10 subjects (5 men, 5 women) on 2 consecutive days. The individual coefficient of variation was calculated as percent SD of the group mean (SD/mean)x100.
Statistical Analysis
The statistical software used was SPSS (Statistical Package for
Social Sciences, release 4.0). The data were expressed as mean±SD. As
a measurement of cerebrovascular reactivity, the slope of the
Vmean/PETCO2 relation was
determined individually by exponential regression analysis. For
comparison of the cerebrovascular reactivity, an ANOVA was conducted.
We assumed statistical significance at P<.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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At rest the PETCO2 values (women, 37.54± 4.32 mm Hg; men, 38.75±4.96 mm Hg) and mean blood pressure values (women, 85±9 mm Hg; men, 89±11 mm Hg) were comparable between the study groups. Blood flow velocities of the two MCAs were averaged. Subsequently the Vmean values of each subject were plotted as a function of PETCO2. As previously described by Markwalder et al,7 the best-fit curves for the relation between Vmean and PETCO2 were exponential functions with the following basic equation: y=aebx, where y is Vmean (cm/s), a is a theoretical quantity representing Vmean at a PCO2 of 0 mm Hg, b is the relative slope of the curve (slope divided by the value of the function) corresponding to the definition of reactivity, and x is the PETCO2 (mm Hg). The Figure
gives an example of the values obtained
in two subjects with the corresponding individual regression curves.
Because of the variations in Vmean from one subject to
another and particularly between men and women, we used the individual
regression curves to calculate b, as a value of reactivity,
for each subject separately (Table 1).
The mean relative slope of the
Vmean/PETCO2 relation was
0.037±0.008 in women and 0.030±0.010 in men. ANOVA of the values
obtained for b demonstrated a significant effect for women
versus men (F=11, 18; P<.001). There were no significant
correlations between the slopes of the curves and age.
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In 10 subjects (5 men, 5 women), we measured CO2 reactivity on two consecutive days and obtained a coefficient of variation of 7.9% for b, confirming that the reproducibility of this method was satisfactory.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Methodological Considerations
Cerebral vasomotor reactivity can be assessed easily and reliably by measuring the vasodilatory response to altered CO2 tensions, but several sources of error have to be emphasized. In the present study cerebrovascular reactivity was determined during dynamic changes in PaCO2 and CBF velocities, so that the delay caused by the time it took for the blood to be transported from the lungs to the cerebral resistance vessels and the time constants in the arteriolar vascular smooth muscle were not considered. Therefore, the values reported in this study cannot be transferred without restriction to previous results obtained during steady state conditions between PaCO2 and CBF velocity.
Direct measurement of PaCO2 requiring arterial puncture was avoided in favor of continuous on-line, noninvasive monitoring of PETCO2 by means of infrared analysis. Burki and Albert26 have shown that these values are a close approximation of the PaCO2. Young et al27 studied cerebrovascular reactivity in 68 anesthetized patients using arterial and end-tidal estimations of CO2 tensions and found a high correlation (r=.91, P=.0001) between cerebrovascular reactivity and changes in CO2 when calculated from either arterial PaCO2 or PETCO2 values.
PCO2 response curves depend on arterial blood pressure.2 18 23 28 In our study hypercapnia raised the mean arterial blood pressure 5 to 15 mm Hg, indicating relatively stable cardiovascular conditions. Moreover, there was no statistical correlation in the group of 60 subjects between CO2 reactivity and initial blood pressure. A rise of mean arterial blood pressure of 5 to 10 mm Hg has also been observed by Tominaga et al,18 Markwalder et al,7 Hauge et al,29 and Widder et al.2 The latter authors found no variations in CO2 reactivity in three healthy volunteers during hypotension and hypertension for systolic blood pressures from 110 to 180 mm Hg. Therefore, physiological changes of blood pressure are most unlikely to influence CO2 reactivity.
Relevance of Our Results
The present study was performed to measure the possible sex
differences in cerebral vasomotor reactivity to CO2. We
also wanted to specify the relation between
PaCO2 and blood flow velocity in both MCAs.
Within physiological ranges of
PaCO2, the response of the cerebral vessels to
changes in PaCO2 from 20 to 60 mm Hg
in both humans and animals has been described as an exponential
function,6 7 8 16 17 18 19 as a linear
function,5 9 20 21 22 23 24 25 and as a hyperbolic tangent
function.1 When extreme PaCO2
values were included, the shape of the
CBF-PaCO2 curve in animal experiments was found
to be sigmoid.30 A possible explanation for the divergent
results found in the literature may be the use of different methods to
determine CBF or CBF velocity and the comparison of results between
different animals and humans. The data of the present study,
correlating PETCO2 values with absolute
Vmean values individually, indicate that in the
physiological range of
PaCO2, CO2 reactivity is well
described by an exponential curve. Averaging all of our values obtained
in men and women results in an overall CO2 reactivity of
3.4%/mm Hg. This value is identical to that reported by Markwalder et
al7 and Widder et al2 and is close to the value
of 3.3%/mm Hg found by Maeda et al16 in mixed populations
of men and women (Table 2). Izumi et
al,32 studying CO2 reactivity in 20 men and
only 5 women, reported a value of 2.9±0.6%/mm Hg, which is similar to
the value of our male study population. Olesen et al,8 who
studied 25 patients with various intracranial diseases, reported a mean
CO2 reactivity of 4±1%/mm Hg, whereas Tominaga et
al,18 who studied nine hypertensive patients among others,
found a value of 6±1%/mm Hg, but these results are not
representative of healthy individuals.
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The present study demonstrates a highly significant sex-related difference in CO2-induced cerebral vasomotor reactivity. Our results suggest that women have a stronger vasodilatory response to changes in PaCO2 than men. Recently, Karnik et al33 found significantly increased vasodilatory responses to acetazolamide in 18 women compared with 18 men, a fact that indirectly supports our findings, since Ringelstein et al34 found a highly significant correlation of CO2-induced and acetazolamide-induced cerebrovascular reactivity in 47 patients, indicating a strong similarity of the vasodilative effect of these two methods. The mechanisms and the biological significance of increased vasomotor reactivity in women are unclear. An increased frequency of subclinical atherosclerosis with loss of elasticity of the cerebral vessels in men could theoretically contribute to the reduced vasodilatory capacity. However, the majority of our subjects were between 20 and 40 years old, and there were no significant difference in the subgroups aged 21 to 27 and 28 to 58 years. Increased vasomotor reactivity in women may also reflect their increased susceptibility to migraine.
In conclusion, the relation between altered CO2 tensions and blood flow velocities of both MCAs in 60 healthy volunteers was found to be exponential. There was a significantly higher (P<.001) vasodilatory capacity to CO2 in women than in men.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the Deutsche Forschungsgemeinschaft (DFG Scha 374/3–1). We thank the volunteers for their participation in the study.
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Footnotes |
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Reprint requests to Andreas Kastrup, MD; Department of Neurology, University of Tübingen, Hoppe-Seyler Str 3, 72076 Tübingen, Germany.
Received July 8, 1997; revision received August 18, 1997; accepted August 29, 1997.
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