CO2 Reactivity Testing Without Blood Pressure Monitoring?
A. Hetzel, MD; S. Braune, MD; B. Guschlbauer; K. Dohms, MD
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Background and Purpose—Responsiveness to CO2 is an established test of cerebrovascular reserve capacity. Arterial
partial pressure of CO2 (PCO2) and arterial blood pressure (BP) are key parameters for cerebral blood flow. To investigate
the interaction between PCO2 and BP, we performed a study with simultaneous measurement of CO2 and BP during CO2
reactivity testing with transcranial Doppler sonography.
Methods—Eighty-one healthy volunteers, aged 19 to 74 years, underwent examination defined by a protocol with
multimodality monitoring of BP, heart rate (HR), PCO2, and Doppler frequencies (DFs) of the left middle cerebral artery
(MCA). Reproducibility was tested in a subgroup of 14 volunteers $65 years of age by CO2 reactivity testing on
different days.
Results—Increase of PCO2 was accompanied by a parallel increase of mean6SD time values of DF (3.661.6%/mm Hg
CO2). BP levels were significantly elevated after 60-second hypercapnia (mean values, 0.560.55 mm Hg/mm Hg CO2).
A significant decrease over time was seen only for pulsatility in DF but not in BP. Analysis of variance and covariance
with repeated measures revealed a highly significant effect of CO2 on MCA Doppler shift. A less-pronounced effect on
DF was seen for BP. Correlation analysis showed no significance for CO2 reactivity, but a significant correlation
between test and retest was seen in BP-related CO2 reactivity.
Conclusions—The CO2 response curve showed the known linear increase of DF. The parallel significant increase in BP
most likely results from activation of the central sympathetic nervous system. The poor reproducibility for Doppler CO2
reactivity is to some extent explainable by variability of BP. CO2-induced increases in BP can have relevant influence
on MCA Doppler shift and lead to misinterpretation of Doppler CO2 test results. (Stroke. 1999;30:398-401.)
Key Words: blood pressure n carbon dioxide n Doppler effect n ultrasonography, Doppler, transcranial
C
This study included simultaneous measurement of CO2 and
BP to assess the role of BP variability during CO2 reactivity
testing with transcranial Doppler sonography.
erebral blood flow (CBF) autoregulation and the arterial
partial pressure of carbon dioxide (PaCO2) have predominant influence on the regulation of global cerebral perfusion.1 Cerebral vessels constrict and dilate during increase
and decrease of perfusion pressure.2 Myogenic (intrinsic
response of vascular muscle to changes in stretch) and
metabolic (release of mediators during tissue hypoxia) mechanisms have been proposed as important regulatory control
systems.3,4
The potent effect of CO2 is a local action on cerebral
arterioles and appears to be mediated by extracellular H1
ions.5,6 Therefore, cerebrovascular reserve capacity is tested
by inducing changes in extracellular H1 ions (CO2 reactivity
or Diamox test).7–10
In occlusive cerebrovascular disease, not only may responsiveness to changes in extracellular pH be deranged,9,10 but
CBF autoregulation may also be impaired.11 After cerebral
ischemia, tissue becomes pressure dependent owing to loss of
CBF autoregulation.12
CO2 reactivity testing presupposes stable blood pressure
(BP). Persistent slow and rapid changes in BP interfere with
measurements of flow velocity in the MCA11,13 because of
delay in autoregulative response.
Subjects and Methods
Transcranial Doppler frequencies (DFs) under normocapnia and
hypercapnia correspond closely to other cerebral blood flow measurements,1,14 –17 accurately reflecting the relative changes in CBF
during dynamic cerebral autoregulation measurements. Noninvasive
continuous measurement of arterial BP by the Finapres method
allows accurate measurement with a maximal variation of
65 mm Hg, which is also representative for the brachial BP.18,19
End-tidal partial pressure of carbon dioxide (PETCO2) and intra-arterial CO2 were shown to correlate closely.20 PETCO2 was measured in
millimeters of mercury during expiration by an infrared capnometer
with a probe attached to 1 nostril.
Eighty-one healthy volunteers, aged 19 to 74 years, underwent
examination defined by a protocol with continuous measurement of
digital BP and heart rate (HR) (Finapres), unilateral DF of the middle
cerebral artery (MCA; EME TC2– 64), and PETCO2 (infrared capnometer, Normocap, DATEX). For analysis of reproducibility, an
additional group of 14 volunteers, aged $65 years (range, 65 to 82
years) and without ipsilateral relevant atherosclerosis, was examined
twice with the same protocol.
After a resting period of sufficient length to obtain stable baseline
values, with the patients in supine position, a CO2 reactivity test was
Received March 9, 1998; final revision received August 6, 1998; accepted October 30, 1998.
From the Department of Neurology, University of Freiburg, Freiburg, Germany.
Correspondence to Dr Andreas Hetzel, Department of Neurology, University Clinics, Breisacherstr 64, D-79106 Freiburg, Germany. E-mail
[email protected]
© 1999 American Heart Association, Inc.
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398
Hetzel et al
February 1999
399
performed with rebreathing in a 50-L bag filled with 7% CO2enriched air.
Five phases were defined during CO2 reactivity testing: baseline
(phase 0) and the increase of PETCO2 divided into steps of approximately 4 mm Hg CO2 during rebreathing (phase I, beginning; phase
II, 4 to 5 mm Hg CO2; phase III, 8 to 9 mm Hg CO2; and phase IV,
12 to 13 mm Hg).
The changes in DF were calculated as percentage of baseline
values and the remaining parameters as differences from baseline.
Data were reported as mean6SD.
Data evaluation was carried out by standard statistical techniques
(nonparametric Mann-Whitney test and nonparametric Wilcoxon’s
test for paired samples). Analysis of variance and covariance with
repeated measures were performed to investigate the interaction
between the parameters measured. Spearman correlation coefficients
were calculated for estimation of retest variability.
Results
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Increasing PaCO2 during CO2 reactivity testing provoked a
significant increase in DF. The time-mean of DF increased by
3.661.6%/mm Hg CO2 (P,0.001), and pulsatility measured
by Gosling’s pulsatility index decreased significantly after
reaching 8 mm Hg PaCO2.
During hypercapnia mean BP values increased significantly
(see upper panel of Figure 1); mean values of BP were positively
correlated to PETCO2 (0.5560.50 mm Hg/mm Hg CO2,
P,0.001). HR (not shown in Figure 1) was significantly
elevated by 4.667.8 bpm only during phase 4 (P,0.01).
ANOVA with repeated measures showed that CO2 as
independent variable was the most relevant parameter for the
variable MCA-DF but interacted closely with the covariables
BP and HR.
A significant correlation was found between the covariables CO2 (P,0.001), BP (P,0.05), and HR (P,0.01).
Multifactor variance analysis revealed that CO2 was not the
only relevant covariable.
The retest variability of 14 volunteers was quantified with
Spearman correlation coefficients. The time-mean values of
all measured parameters did show significant correlation (DF,
0.67, P,0. 01; BP, 0.66, P,0. 05; and CO2, 0.70, P,0. 01),
but CO2 reactivity itself showed only a poor correlation (0.36,
P50.20).
The correlation analysis for the BP-related CO2 reactivity
(CO2 reactivity per mm Hg change in BP) revealed a significant Spearman correlation coefficient (0.73, P,0. 01).
Not only could the reproducibility be increased by additional BP measurements, but the interpretation of individual
results of CO2 reactivity testing could also be improved as
shown in following cases.
In the first case, that of a 53-year-old migraineur, breathdependent oscillations of BP induced amplified amplitudes of
oscillation of DF under normocapnia. During hypercapnia, a
significant increase of BP occurred, and changes in BP
predominantly determined changes in DF. Steady-state hypercapnia was reached after 20 seconds and induced continuous increase of MCA blood flow velocity and BP over a
period of 40 seconds. The relevance of changes in BP are
plainly recognizable at the end of hypercapnia. Rapid changes
due to arrhythmia led to parallel changes in DF (see Figure 2).
This demonstrates that BP oscillations may interfere with
CO2 reactivity testing and result in limited reproducibility,
even under physiological conditions in healthy people.
Figure 1. Multimodality monitoring during CO2 reactivity testing
with simultaneously recorded BP (in mm Hg), MCA-DF (kHz),
heart rate (bpm) and PETCO2 (mm Hg). Relative changes compared with baseline values were calculated for all parameters.
Data are reported as mean6SD. The symbols indicate significant differences between phases in Wilcoxon’s test for paired
samples (1P,0.01, *P,0.001).
In the second case, a 69-year-old man presented with
symptomatic high-grade carotid stenosis on the left side. The
preoperative CO2 reactivity testing is shown in Figure 3. No
side-to-side differences were seen under normocapnia. A
relevant increase of DF during hypercapnia on the left side
was not observed. Vasomotor reactivity was exhausted on the
left side. The MCA-DF, however, increased with the rise of
BP at the end. CO2 reactivity at the beginning of steady-state
hypercapnia was 0%/mm Hg CO2 and increased as a result of
BP increase by 0.8%/mm Hg CO2. Therefore, despite maximal vasodilatation, a falsely indicated partially maintained
CO2 reactivity was evoked by a CO2-induced increase of BP.
Discussion
The CO2 response curve confirmed the known linear correlation between PaCO2 and MCA flow velocity.7–10,21 Recently,
Kastrup et al22 observed an increase of BP during hypercapnia that reached values similar to ours but did not reach
significance in the t test. The parallel increase of BP more
than HR is induced by activation of the central sympathetic
nervous system.23 In some individuals the effect of BP
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CO2 Reactivity Testing Without BP Monitoring?
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Figure 2. Individual multimodality monitoring during CO2 reactivity testing in a 53-year-old migraineur with simultaneously recorded BP
(in mm Hg), bilateral MCA flow velocity (mean time of MCA velocity in cm/s), and PetCO2 (in mm Hg). See text for further details.
Figure 3. Patient with 90% stenosis of the left internal carotid artery with multimodality monitoring during CO2 reactivity test: hypercapnia demonstrates exhausted vasomotor reactivity. Significant increase of MCA-DF on the left side is not visible despite hypercapnia
(compare first and second bars that indicate periods of measurements). MCA-DF did not increase, however, until BP rose (third bar).
Calculation of CO2 reactivity revealed 0%/mm Hg CO2 at the beginning of hypercapnic steady state. CO2 reactivity increased at the end
of hypercapnia because of BP increase from 0% to 0.8%/mm Hg CO2 (see text for further details).
Hetzel et al
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reaches the level of CO2-induced changes. The differentiation
of normal from pathological findings can be difficult because
of large SDs of changes in BP and CO2 during CO2 reactivity
testing (Figure 1). Therefore, the common Doppler CO2 test
should be interpreted very carefully, as recommended by
Widder et al.9 In their opinion, only exhausted CO2 reactivity
is a significant finding. The problem of variable CO2 effects
on DF and BP can lead to misinterpretation of CO2 test results
if not all relevant parameters are monitored (see Figures 2 and
3). The effect of BP on MCA Doppler shift is not linear. This
might be explained by the high-pass filter properties of
cerebral autoregulation. Depending on the frequency of BP
oscillation, a phase displacement and potentially a rise of
amplitudes of DF oscillation was observed by Diehl et al.24
Therefore, simple mathematical methods are not able to
extract the irregular variations in DF due to BP variations. In
the present study, only individual phase-related data exist,
with no opportunity of performing time-series analysis to
exclude the individual effect of BP on CO2 reactivity. An
ongoing study of BP increase during CO2 reactivity measurements in patients with carotid stenoses will provide such data.
Parallel measurement of BP increases the individual reliability of CO2 reactivity testing. Correlation of test and retest
of CO2 reactivity related to BP changes showed a moderately
significant correlation, whereas the correlation of the Doppler
CO2 test alone was poor. We conclude that the consideration
of changes in BP improves the prognostic value and minimizes false-negative results of CO2 reactivity testing.
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CO2 Reactivity Testing Without Blood Pressure Monitoring?
A. Hetzel, S. Braune, B. Guschlbauer and K. Dohms
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Stroke. 1999;30:398-401
doi: 10.1161/01.STR.30.2.398
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Copyright © 1999 American Heart Association, Inc. All rights reserved.
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