Download Mid- and Long-term Reproducibility of Noninvasive Measurements

AJH
1997;10:790 –797
Mid- and Long-term Reproducibility of
Noninvasive Measurements of Spontaneous
Arterial Baroreflex Sensitivity
in Healthy Volunteers
Daniel Herpin and Stéphanie Ragot
Baroreflex sensitivity (BRS) is altered in a variety
of circumstances and could be considered as a
marker for the prognosis of some cardiovascular
diseases. The present study was designed to
evaluate the reproducibility of noninvasive
measures of BRS, both at mid- and at long-term.
Fourteen healthy volunteers were examined on
three occasions (first interval 5 1 week, second
interval 5 1 year). Each recording was performed
using a noninvasive photoplethysmographic device
(Finapres 2300, Ohmeda), both in supine and
standing positions. Two different methods of
measurement were used: the sequences method
and cross spectral analysis.
The reproducibility of BRS measures was as
satisfactory at mid- as at long-term for the
sequences method (intraclass coefficient [ICC] 5
0.87 and 0.86, respectively), but it was better at
mid- than at long-term for the cross-spectral
analysis (ICC 5 0.85 and 0.54, respectively). The
measures performed in standing position were
obviously more reproducible than those made in
recumbent position (ICC 5 0.87 and 0.70 for the
sequences method, 0.85 and 0.71 for the crossspectral analysis, respectively). Due to the high
reproducibility of these noninvasive measures, the
Received September 5, 1996. Accepted January 27, 1997.
From the Service Cardiologie, Centre Hospitalo-Universitaire,
Poitiers, France.
© 1997 by the American Journal of Hypertension, Ltd.
Published by Elsevier Science, Inc.
number of patients to be included in a
pharmacological study was calculated as rather
small: for example, only 20 patients are required
for detecting a change in upright BRS of 3 msec/
mm Hg, at long-term (sequences method).
Likewise, the magnitude of the regression to the
mean, which has to be expected in patients
selected for a follow-up study, turned out to be
low: for example, <15% of the difference between
the patient group mean value and the reference
value, both at mid- and at long-term (standing
position, sequences method). We conclude that: 1)
The noninvasive measures of BRS in standing
position are reproducible enough to allow
longitudinal studies to be conducted over either a
short or a long period; 2) The long-term reliability
of the sequences method seems to be higher than
that of the cross-spectral analysis; and 3) Subtle
changes in SBR may be noninvasively detected
within small patient groups. Am J Hypertens
1997;10:790 –797 © 1997 American Journal of
Hypertension, Ltd.
KEY WORDS:
Baroreflex sensitivity, reproducibility,
repeatability, photoplethysmography.
Address correspondence and reprint requests to Daniel Herpin,
Service Cardiologie, Centre Hospitalo-Universitaire, 86021 Poitiers,
France.
0895-7061/97/$17.00
PII S0895-7061(97)00115-5
AJH–JULY 1997–VOL. 10, NO. 7, PART 1
B
aroreflex sensitivity (BRS) has been reported
to be modified in numerous circumstances:
elderly,1– 4 systemic hypertension,5–7 heart
failure,8 myocardial infarction, and ventricular arrhythmias.9,10 Plethysmographic finger blood
pressure (BP) recording has been recently used for a noninvasive determination of spontaneous cardiac BRS. The
reliability of this new method has been evaluated against
invasive methods11; to date, however, limited information
is available on its reproducibility.12–15 Of course, the prerequisite for the use of noninvasive BRS measurement in
clinical pharmacological studies is the demonstration of its
repeatability over time. Therefore, the present study was
designed to examine both the mid- and long-term reproducibilities of BRS noninvasive measurements in healthy
volunteers. An additional objective was to use these results
1) to construct a sample size table of the number of subjects
to be included in pharmacological studies; and 2) to quantify the magnitude of the regression to the mean, which has
to be expected in longitudinal studies.
METHODS
Subjects
Data were obtained from 14 normotensive
subjects: seven women and seven men, mean age 31 (610
years [range, 23 to 51 years]), who gave their informed
consent for the study. Each subject supplied a medical
history and underwent a physical examination in order to
exclude those with diabetes, heart disease, or acrosyndrome, and those taking medications known to interfere
with BP and heart rate (HR) control.
Experimental Protocol Each subject underwent three
noninvasive plethysmographic recordings (Finapres model
2300E, Ohmeda Monitoring Systems, Englewood, CT).
Two recordings were performed 1 week apart, and the
third was performed 1 year later. The cuff was fitted to the
third finger of the right hand and located at heart level. All
recordings were performed by the same operator and were
started only when clinic systolic BP differed from plethysmographic measure, by ,10 mm Hg, after a 10-min rest in
supine position. Each recording consisted of two 15-min
periods, the first in supine and the second in standing
position. Both periods took place after an adaptation period
of about 3 min, in order to obtain a stable situation. Data
recordings were performed between 9 am and 11 am, with
each subject examined at the same time for all of his or her
recordings, in order to exclude changes related to diurnal
sympathovagal variations.
BRS Estimation The analogue BP signal was sampled at 200 Hz and digitized at 12 bits by a personal
computer (model 486DX2/33, Advantech PC-Labcard
718, IBM Corporation, Lexington, MA) using ISN software (Grenoble, France) to obtain values for SBP, DBP,
and HR. The signal was displayed by an interactive
software to detect and eliminate morphologic aberrations of BP tracing. BRS was estimated using two
BAROREFLEX SENSITIVITY REPRODUCIBILITY
791
different methods: the sequences method and crossspectral analysis.
The sequences method16 computed sequences of three or
more beats in which SBP and pulse interval progressively
increased (SBP1/RR1 sequences) or decreased (SBP-/RRsequences). The threshold change was set at 1 mm Hg for
SBP and at 4 msec for pulse interval. For each sequence the
correlation coefficient between the two values was verified
not to be ,0.95. The slope was taken as a measure of the
BRS, as done when changes in BP and HR are induced by
intravenously administered boluses of vasoactive drugs.
The cross-spectral analysis of SBP and HR has been
validated by Robbe et al17 and De Boer et al.18 The
spectral characteristics of the stationary segments of
the whole recording were calculated by a direct fastFourier transform algorithm for discrete time series of
256 points (periodogram method). The modulus of the
transfer function between SBP and RR intervals was
examined in midfrequency band (66 to 127 MHz) and
was considered as an index of BRS when the coefficient of coherence was .0.5.
Statistical Analysis The data obtained at the first
visit (D1) were plotted against those obtained at the
second visit (W1), as well as against those recorded at
the third visit (Y1); the correlation coefficients were
calculated by using the Spearman test, and the intervisit differences were evaluated by both a paired
Wilcoxon test and an analysis of variance.
According to the recommendations of Bland and
Altman,19 the intervisit differences (W1 2 D1 and
Y1 2 D1) were plotted against the average values
[(W1 1 D1)/2 and (D1 1 Y1)/2], in order to investigate any possible relationship between the measurement error and the estimated true value. The 95%
confidence intervals of the differences were then calculated. In addition, the repeatability coefficients were
estimated as recommended by the British Standards
Institution (square root of the sum of the squares of
the differences, divided by the number of subjects),
allowing the 95% confidence intervals of the expected
intervisit differences to be calculated.20
The intraclass correlation coefficient (r) was calculated as follows:
r 5 ~BMS 2 WMS!/~BMS 1 WMS! (formula 1)
where BMS and WMS denote between-subject mean
squares and within-subject mean squares, respectively. Arbitrarily,21 a value of r in the range 0 to 20
indicates slight reliability; 0.21 to 0.40, fair reliability;
0.41 to 0.80, moderate reliability; and 0.81 to 1.00,
strong reliability.
The number (n) of patients to be included in a study
aimed at detecting a given variation in BRS, (parallel
design), was calculated by using the formula:
n 5 M * ~ § 2 /~D 2 ! (formula 2!
792
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HERPIN AND RAGOT
TABLE 1. BRS VALUES (msec/mm Hg)
Supine Position
SBP1/RR1
SBP2/RR2
MF Gain
Standing Position
SBP1/RR1
SBP2/RR2
MF Gain
Day 1
Week 1
Year 1
21.31 6 15.54
17.71 6 6.44
12.8 6 5.0
16.36 6 10.43
16.21 6 9.72
11.1 6 4.7
18.61 6 13.80
16.84 6 9.22
10.1 6 3.7
8.58 6 3.73
8.43 6 3.45
9.7 6 2.8
8.03 6 3.78
7.94 6 3.72
9.5 6 2.5
8.16 6 3.92
7.87 6 3.75
9.2 6 1.5
All differences (Day 1 v Week 1, Day 1 v Year 1): not significant.
SBP1/RR1, SBP2/RR2, sequences method (see text for explanation).
MF Gain, cross-spectral analysis in mid-frequency band.
where § denotes the standard deviation of the intervisit differences and D denotes the absolute change
in BRS to be detected. M is given by the usual tables
[unilateral test: M 5 2(z12a 1 z12b)2, bilateral test: M
5 2(z12a/2 1 z12b)2].
Finally, the expected regression to the mean (R) was
quantified according to the formula:
R 5 ~1 2 r! * ~S 2 N! (formula 3)
where S denotes the BRS values of the patient group selected for a given study and N, those of a reference group;
r is the ratio between subject variance/total variance, as
provided by an analysis of variance with repeated measures (random-effects model, nested design).22,23
All analyses were performed using BMDP software
(BMDP Statistical Software Inc., Los Angeles, CA)
(programs 1D, 3D, 2R, 4F, 2V, and 8V). The null hypothesis was rejected when P . .05.
RESULTS
Table 1 shows that BRS values did not significantly
differ from one examination to the other, especially in
standing position, whatever the method of measurement and the interval between the two measures. The
correlation coefficients between each pair of data,
which measure the strength of the relation, were
higher in standing position (mid-term: 0.81 to 0.84,
P , .001; long-term: 0.64 to 0.81, P , .01) than those
observed in supine position (mid-term: 0.62 to 0.73,
P , .02; long-term: 0.46 to 0.49, P 5 NS). No significant
differences were found between men and women with
respect to either the BRS values or the reproducibility
of the measures.
According to the method of Bland and Altman,19
Figures 1 to 3 plot the differences between the pairs
of data against their means. It can be seen that:
1) The mean difference was close to zero (at least not
significantly different from 0; thus, we were able to
use the data to assess repeatability); 2) There was no
obvious relation between the differences, which
reflect the measurement error, and the mean, which
is likely to be close to the true value; thus our
data had not to be log-transformed; and 3) the degree of agreement (inversely related to the width of
the 95% confidence interval of the differences) was
greater in standing position than in recumbent position.
Values of the coefficients of repeatability, as well
as those of the 95% confidence intervals of the expected intervisit differences, are shown on Table 2.
The intraclass correlation coefficients are displayed
on Figure 4. Once again, measurements performed
in standing position turned out to have the highest
repeatability.
TABLE 2. REPEATIBILITY COEFFICIENTS (RC)
OF BRS MEASUREMENTS AND 95%
CONFIDENCE INTERVAL (CI) OF THE EXPECTED
ERROR (msec/mm Hg)
Mid-term (1 week)
Supine position
SBP1/RR1
SBP2/RR2
MF gain
Standing position
SBP1/RR1
SBP2/RR2
MF gain
Long-term (1 year)
Supine position
SBP1/RR1
SBP2/RR2
MF gain
Standing position
SBP1/RR1
SBP2/RR2
MF gain
Abbreviations as in Table 1.
RC
95% CI of
Expected Error
10.42
7.37
3.75
620.42
614.44
68.17
1.94
1.69
1.55
64.19
63.65
63.38
12.01
6.61
4.66
625.94
614.28
610.25
2.03
1.84
2.23
63.98
63.61
64.37
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793
FIGURE 1. Relationship between average BRS values and intervisit differences in BRS measures, according to the SBP1/RR1
sequences (sequences of three or more successive beats in which SBP and pulse interval increased).
From the preceding data, we constructed Table
3, which gives the number of subjects to be included
in pharmacological studies, and Table 4, which
displays the value of the 1st term of formula 3,
allowing for an easy calculation of the magnitude
of the regression to the mean, which has to be
TABLE 3. NUMBER OF SUBJECTS TO BE
INCLUDED IN A FOLLOW-UP STUDY (STANDING
POSITION; PARALLEL DESIGN; a 5 0.05, b 5 0.10,
BILATERAL TEST)
Mid-Term (1 week)
Long-Term (1 year)
D
Sequences
Method
Cross-Spectral
Analysis
Sequences
Method
Cross-Spectral
Analysis
1
2
3
4
5
150
38
16
10
6
100
26
12
6
4
178
44
20
12
8
210
52
24
14
8
D, change in BRS to be detected (msec/mm Hg).
anticipated in follow-up studies. Investigators will
only have to multiply this value by the difference
(S 2 N).
DISCUSSION
The salient findings of our study are the following:
1) The measures performed in recumbent position
were by far, less reproducible than those made in
standing position; 2) The reproducibility of noninvasive measures of BRS was roughly the same at
mid- as at long-term for the sequences method,
whereas it was higher at mid- than at long-term for
the cross-spectral analysis; and 3) Due to the high
reproducibility of noninvasive BRS measures in
standing position, very few subjects are needed for
detecting a slight change in this parameter. Likewise, the magnitude of the expected regression to
the mean is likely to be low.
BRS Measures Several invasive methods have been
proposed for activating or deactivating baroreceptor
reflexes: intravenous injection of vasopressor (such as
794
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HERPIN AND RAGOT
FIGURE 2. Relationship between average BRS values and intervisit differences in BRS measures, according to the SBP-/RRsequences (sequences of three or more successive beats in which SBP and pulse interval decreased).
angiotensin or phenylephrine) or vasodepressor (such
as nitroglycerin) drugs, which allows the vagal control
and, to a lesser extent, the sympathetic control of HR
to be studied; neck chamber technique, which allows
for a simultaneous investigation of BP and HR control;
and low body negative pressure technique, which is
the reference method for investigating the role of the
cardiopulmonary receptors. More recently, computerassisted processing of BP signals has allowed accurate
measures of BRS to be noninvasively obtained from
spontaneous variations of BP and HR. Of course, non-
invasive BRS measures have some drawbacks, as compared with the classic phenylephrine method: the
measuring period has to be longer for the noninvasive
than for the invasive method (5 to 20 min, according to
the different investigators, versus ,1 min following
intravenous injection). In addition, more computing
power is required and stationary time series are
needed. However, the advantages of noninvasive
measures over phenylephrine method have to be emphasized: 1) No rise in BP is induced; 2) The shortterm BP regulation and the BRS are not affected by the
TABLE 4. ESTIMATION OF THE REGRESSION TO THE MEAN: VALUES OF (1-R) (SEE TEXT FOR
EXPLANATION)
Mid-Term (1 week)
Supine
Standing
Long-Term (1 year)
SBP1/RR1
SBP2/RR2
MF Gain
SBP1/RR1
SBP2/RR2
MF Gain
0.30
0.13
0.40
0.11
0.29
0.15
0.32
0.14
0.34
0.13
0.55
0.46
Abbreviations as in Table 1.
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FIGURE 3. Relationship between average BRS values and intervisit differences in BRS measures, according to the cross spectral
analysis in the mid-frequency band (66 to 127 MHz).
measuring method itself; 3) Measures can be applied
repeatedly; and 4) Computation of modulus or sequences results in stable and high correlated values.16 –18
Recently, good short-term reproducibility has been
demonstrated for the sequences method, 24 h apart,14
even during the Valsalva maneuver15; likewise, crossspectral analysis has been shown to provide reproducible results at a 1-week interval.12 Our study is the
only known study comparing the reproducibilities of
both methods.
The higher reproducibility of standing recordings,
as compared with that of supine measures, has already been reported by Iellamo et al,14 who found a
lower variation coefficient for the former than for
the latter (13.9% v 15.0%), despite a lower average
value (9 v 22 ms/mm Hg). We may speculate that
the greater reproducibility of standing measures
is mainly linked to the orthostatism-induced stimulation of sympathetic activity, resulting in a substantial decrease in BRS and, above all, in a lesser
influence of the internal (or even external) stimuli
on the sympathovagal balance. Eventually, intervisit variations are of lesser magnitude in standing position than in supine position, because 1) the
baseline BRS level is lower, and 2) the subject is
more stationary.
Clinical Implications Changes in BRS may occur
with different pharmacological drugs: b-blockers,24,25
angiotensin converting enzyme inhibitors,26 centrally
acting antihypertensive agents,27 a1-blockers,28 calcium antagonists,29 and digitalis.30,31 Our data clearly
show that long-term reproducibility of noninvasive
BRS measures is satisfactory enough, for allowing
pharmacological studies to be conducted over a long
period (up to 1 year), provided that: 1) the sequences
method (rather than the cross-spectral analysis) is
used, and 2) the recordings are performed in standing
position. Of course, this assumption may be extrapolated to a shorter follow-up period of 1 to 3 months;
however, a 6-month interval would probably not be
adequate because of a possible seasonal rhythm in
autonomic activity.32 When a pharmacological study
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AJH–JULY 1997–VOL. 10, NO. 7, PART 1
HERPIN AND RAGOT
FIGURE 4. Values of the intraclass correlation coefficient and of the corresponding reliability, according to the method of BRS
measurement, the recording position, and the between-visit interval.
is designed to evaluate the mid-term effect of a drug,
both methods seem to have an equivalent reliability,
once again with the clear evidence that the standing
position provides the most reproducible results. Furthermore, our findings should help the design of a
pharmacological study to be more precisely established: slight changes in BRS may be detected within a
small patient group, even at long-term, as long as the
recording is made in upright position (for example, 20
patients, for detecting a drug-induced change of 3
msec/mm Hg). Finally, the quantification of the regression to the mean should allow the results of an
open, noncontrolled study to be properly analyzed. It
is worth noting that the magnitude of the regression
toward the mean is much greater in supine than in
standing position, whereas it is of the same extent at
mid- as at long-term, at least for the sequences
method. Interestingly, the value of the expected regression to the mean is proved to be substantially
lower (250%), than that calculated for the measure of
left ventricular mass index.33
Study Limitations By design, the standing observation period followed the supine period, raising the
question of a possible “order effect.” This issue has not
been specifically addressed in the literature. However,
the lack of training effect with noninvasive recordings
has been clearly demonstrated.13 Furthermore, Robbe
et al17 emphasized that an adaptation period of about
1 min should usually be enough to obtain a stationary
situation. Hence, the influence of the timing of the
recordings on their reproducibility should be of limited importance, as opposed to the preeminent role of
orthostatism-induced changes in autonomic activity.
Our study was conducted within a healthy population. However, the variability we found in our subject
group should not be higher in diseased patients, as
long as no pathological status has been found to be
associated with a significant increase in baseline levels
of BRS. Of course, further studies are required within
selected populations, especially hypertensive patients
and the elderly, to determine whether the noninvasive
measurements of spontaneous BRS may prove to be
valuable in clinical practice.
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