Download Effect of altering conditions of the sequence method

Original article 1279
Effect of altering conditions of the sequence method on
barore¯ex sensitivity
L. Ceri Daviesa , Darrel P. Francisa,b , Adam C. Scotta , Piotr Ponikowskic ,
Massimo Piepolia and Andrew J. S. Coatsa
Background The sequence method is widely used as a
simple, non-invasive measure of barore¯ex sensitivity
(BRS). This technique, originally described in
anaesthetized cats, has been transferred virtually
unchanged to humans, without evidence that the optimal
values in cats are the same as those in patients with
cardiovascular disease.
Objective To study the effect of altering the components
of the sequence method on the measured BRS in patients
with chronic heart failure (CHF) and in normal individuals.
Methods Eighty patients with CHF [aged 62 6 12 years
(mean 6 SD)] and 40 normal control individuals [aged
38 6 15 years (mean 6 SD)] underwent measurement of
heart rate and non-invasive blood pressure. Altering only
the shift between blood pressure and R±R interval and the
required correlation coef®cient of the regression line had
no effect on the value of BRS, but had a signi®cant effect
on the number of valid sequences. Alteration of the blood
pressure or R±R interval thresholds, however, affected not
only the number of valid sequences, but also the value of
BRS in both groups. In normal controls, agreement with
the bolus phenylephrine method was improved by
increasing the blood pressure threshold, although this led
Introduction
Attenuation of barore¯ex sensitivity (BRS) predicts poor
outcome after myocardial infarction and in patients with
chronic heart failure [1±3]. The ®rst measurements of
BRS in humans [4] were performed by intravenous
injections of a pressor agent that increases blood pressure (measured intra-arterially), which in turn reduces
heart rate. Non-invasive techniques have subsequently
been developed, but acceptance of these new techniques has been limited by their relatively poor agreement with the `gold-standard' invasive method [5].
The spontaneous, or sequence method, ®rst described
in 1985 [6] is widely used as a measure of BRS. R±R
interval and beat-to-beat systolic blood pressure data
are scanned and sequences of three or more beats in
which the blood pressure and R±R interval concomitantly increase (or decrease) by more than a threshold
value are identi®ed. The BRS is de®ned as the slope of
the regression line between the data points in these
0263-6352 & 2001 Lippincott Williams & Wilkins
to a reduction in the number of valid sequences. In patients
with CHF, agreement was optimized by decreasing both
the blood pressure and R±R interval thresholds. This also
had the effect of increasing the number of valid
sequences.
Conclusion Changes should be made to this technique, to
optimize its validity in conscious humans, particularly when
applied to patients with attenuated BRS. J Hypertens
19:1279±1287 & 2001 Lippincott Williams & Wilkins.
Journal of Hypertension 2001, 19:1279±1287
Keywords: barore¯ex sensitivity, sequence method, chronic heart failure
a
National Heart & Lung Institute, Imperial College of Science, Technology and
Medicine, b Department of Cardiology, St Mary's Hospital, London, UK and
c
Department of Cardiology, Military Hospital, Wroclaw, Poland.
Sponsorship: L.C.D. is supported by the Robert Luff Fellowship, D.P.F. by the
British Heart Foundation (FS 98005), M.P. by the Wellcome Foundation and
A.J.S.C. by the Viscount Royston Trust.
Correspondence and requests for reprints to Dr L. Ceri Davies, Heart Failure
Unit, Royal Brompton Hospital, Sydney St, London SW3 6NP, UK.
Tel: ‡44 207 352 8121 ext 2708; fax: ‡44 207 351 8510;
e-mail: [email protected]
Received 31 July 2000 Revised 28 December 2000
Accepted 15 February 2001
sequences. This technique was initially developed in
anaesthetized cats [6,7]. However, the R±R interval
and blood pressure thresholds, blood pressure to R±R
interval shift and threshold correlation coef®cient of the
regression line involve essentially arbitrary constants,
which have been adopted virtually unchanged for the
study of humans. There is no evidence that these are
the optimal values.
If the arbitrary constants used in the standard sequence
method are not optimal, the results from the technique
may have been unnecessarily poor. In order to optimize
this method, by identifying optimum values for these
constants, we assessed the effect on the BRS, derived
by the sequence method, of altering the R±R interval
and blood pressure thresholds, the blood pressure shift
and the regression line correlation coef®cient, in
healthy control individuals and patients with chronic
heart failure, and compared them with other conventional methods of measuring BRS.
1280 Journal of Hypertension 2001, Vol 19 No 7
Methods
Participants and measurements
Eighty patients with chronic heart failure were recruited from a specialist clinic. They were diagnosed
on the basis of clinical assessment (a history of dyspnoea and symptomatic exercise intolerance, with previous signs of pulmonary congestion or peripheral
oedema), evidence of left ventricular dysfunction from
radionucleide ventriculography or echocardiography, or
both. Patients with atrial ®brillation, permanent pacemakers, more than two ectopic beats per minute or
clinical instability within the preceding 3 months were
not eligible for the study. Forty normal control individuals were also studied; they had no signi®cant past
medical history, no abnormalities on examination, and
were not taking regular medication. All participants
gave informed consent and the study was approved by
the local ethics committee.
The individuals were studied between 1300 h and
1700 h, under standardized conditions, in a quiet room
at a comfortable temperature. All were fasted for at
least 2 h before testing and were not allowed to smoke
or drink alcohol- or caffeine-containing beverages for
24 h before the study.
On arrival to the investigation unit, the participants
rested supine for 30 min and then underwent a 10 min
recording of heart rate and non-invasive measurement
of blood pressure. Twenty-six patients and 15 controls
also underwent assessment of BRS by the bolus phenylephrine method [4].
Data collection
Blood pressure was measured non-invasively by a
Finapres device (model 2300; Ohmeda, Louisville,
California, USA), with the cuffed ®nger resting comfortably at the level of the heart. The Finapres cuff was
wrapped around the index ®nger of the left hand. The
participants underwent several minutes of accustomization to the Finapres and the servo-adjust mechanism
was turned off before recording. The electrocardiogram
was acquired from the limb lead with the largest R
wave (usually lead II). All data were sampled at
1000 Hz on a computer using an analog-to-digital converter (National Instruments, Newbury, Berkshire).
The readings were saved onto ¯oppy disk and analysed
off-line with custom software, which measured R±R
intervals and beat-to-beat blood pressure.
Barore¯ex sensitivity
BRS by the sequence method
The time series of R±R interval and systolic blood
pressure (SBP) were scanned to identify the sequences
in which R±R and SBP concurrently increased or
decreased over three or more beats. The standard
thresholds for SBP and R±R interval are 1 mmHg and
4 ms, respectively. In this study, we varied the threshold for SBP from 0 to 2 mmHg and the R±R interval
threshold from 0 to 6 ms. In the standard version of the
sequence method, there is a shift of ‡1 between the
blood pressure pulse and the R±R interval, with the
blood pressure pulse being plotted against the following
R±R interval. In this study, we assessed a blood
pressure shift from ÿ4 to ‡4 with respect to the R±R
intervals (Fig. 1).
The linear correlation between R±R and SBP was
computed for each sequence. In the standard method,
the sequence is only considered valid if the correlation
coef®cient is . 0.80. In this study, several thresholds of
correlation coef®cient were compared: 0, 0.8, 0.95, 0.96,
0.97, 0.98, 0.99 and 1.0. The average value of the
individual slopes of the valid sequences was taken as
the BRS.
BRS by the bolus phenylephrine method
This was performed according to the standard modi®cation of the method of Smyth et al. [4], which uses
phenylephrine instead of angiotensin and non-invasive
blood pressure measurements instead of intra-arterial
ones [8]. The procedure was carried out after informed
consent and with appropriate resuscitation equipment
and staff available, in 26 patients and 15 normal
individuals. Phenylephrine was injected as a bolus at a
starting dose of 2 ìg/kg, increasing by 50 ìg until the
increase in SBP was at least 15 mmHg. The bolus
Fig. 1
ECG
24
0
14
BP
Diagram showing the shifts between blood pressure (BP) and R±R
interval. ECG, electrocardiogram.
Assessment of BRS by the sequence method Ceri Davies et al. 1281
injection was repeated at least three times at the
adequate dose and the linear regression slope of R±R
and SBP was calculated for each bolus. The ®nal result
for each episode was computed as the mean of at least
three values.
BRS by the spectral analysis method
BRS was calculated by the spectral analysis method as
previously described. Brie¯y, power spectral analysis
was performed on the same R±R interval and SBP data
used for the sequence method, through the use of an
autoregressive algorithm [9], with the model order
selected according to the Akaike information criterion
[10]. A model order between 12 and 18 was found to be
appropriate in all cases. The component in the lowfrequency band (0.04±0.15 Hz) was considered. The áindex was computed as the square root of the ratio
between R±R and systolic blood pressure spectral
powers in the low-frequency band, in the presence of
an adequate coherence (. 0.5) between the R±R
interval and SBP as assessed by cross-spectral analysis
[5,6].
Statistical analysis
Numerical distributions are described by their
mean SD. Comparisons between group means were
carried out with Student's t-test and, in the case of
multiple comparisons, analysis of variance (ANOVA).
Results
Patient characteristics
The average age of the 80 patients was 62 12 years.
Fifty-three had heart failure due to coronary artery
disease, 25 had idiopathic dilated cardiomyopathy and
two had heart failure due to mitral regurgitation. The
mean ejection fraction was 0.30 0.14. Eleven patients
were in New York Heart Association class I, 46 in class
II, 23 in class III. Seventy-four of the patients were
taking an angiotensin converting enzyme inhibitor or
angiotensin II receptor antagonist, 70 were taking
diuretics, and none was receiving a â-blocker. Sixty-two
of the patients were men and 18 were women. The
average age of the 40 normal individuals was 38 15
years. Twenty-®ve were men and 15 were women.
Effect of changing blood pressure shift on measurement of
BRS
The effect of changing the blood pressure shift on the
number of valid sequences is shown in Figure 2. For
this analysis, the blood pressure threshold was set at
1 mmHg, the R±R interval threshold at 4 ms and the
correlation coef®cient threshold at 0.8. In both groups,
there was a signi®cantly larger proportion of valid
sequences (number of valid sequences divided by total
duration of recording multiplied by 100) when there
was a zero shift between the blood pressure pulse and
R±R interval (P , 0.0001 in controls and patients).
The effect of different blood pressure shifts on the
value of BRS obtained is shown in Figure 3. Again, the
maximal value for BRS was obtained with a zero blood
pressure shift, but there was no signi®cant difference in
the values obtained within the two groups (P ˆ 0.9 in
patients and P ˆ 0.1 in controls).
Effect of changing sequence correlation threshold on
measurement of BRS
The effect of changing the threshold for the correlation
coef®cient on the number of valid sequences is shown
in Figure 4. The blood pressure and R±R interval
thresholds remained unaltered from before, and the
blood pressure shift was set to the conventional 1 beat.
As the threshold correlation coef®cient was increased,
there was a large decrease in the number of valid
sequences in both patients and controls (P , 0.002 in
both groups). The largest number of valid sequences
Fig. 2
(b)
7
6
5
4
3
2
1
0
Proportion of valid
sequences (%)
Proportion of valid
sequences (%)
(a)
24 23 22 21 0
1
BP shift
2
3
4
16
14
12
10
8
6
4
2
0
24 23 22 21
0
1
BP shift
2
3
4
Effect of changing the extent and direction of blood pressure (BP) shift on the percentage of valid sequences in (a) patients with chronic failure and
(b) normal controls. For example, a blood pressure shift of ‡1 means that the blood pressure series is shifted forward 1 beat before comparison with
the R±R interval.
1282 Journal of Hypertension 2001, Vol 19 No 7
Fig. 3
(a)
(b)
25
10
BRS (ms/mmHg)
BRS (ms/mmHg)
12
8
6
4
2
0
24
23
22
21
0
1
BP shift
2
3
4
20
15
10
5
0
24
23
22
21
0
1
BP shift
2
3
4
Effect of different blood pressure (BP) shifts on the resultant barore¯ex sensitivity (BRS) value in (a) patients with chronic heart failure and (b) normal
controls.
Fig. 4
4
3.5
3
2.5
2
1.5
1
0.5
0
(b)
10
Proportion of valid
sequences (%)
Proportion of valid
sequences (%)
(a)
0
0.8 0.9 0.95 0.96 0.97 0.98 0.99 1
Threshold correlation coefficient
8
6
4
2
0
0
0.8 0.9 0.95 0.96 0.97 0.98 0.99 1
Threshold correlation coefficient
Effect of altering the required correlation coef®cient on the percentage of valid sequences in (a) patients with chronic heart failure and (b) healthy
controls.
occurred when the threshold coef®cient was 0, but
there was no signi®cant difference between the number
of sequences when the correlation coef®cient was 0.8
(P ˆ 0.9 for both groups).
Changing the required correlation coef®cient had no
effect on the value obtained for BRS (Fig. 5; P ˆ 0.9
for both groups).
Effect of changing blood pressure and R±R interval
thresholds on BRS
The effect of changing the blood pressure and R±R
interval thresholds on the number of valid sequences is
shown in Figure 6, with a blood pressure shift of 0, and
a correlation coef®cient threshold of 0.8. In patients
with heart failure, increasing either the blood pressure
threshold or R±R interval threshold resulted in a
decrease in the number of valid sequences. However,
in the healthy controls, an increase in R±R interval
threshold (up to 6 ms) had very little effect on the
number of valid sequences.
The effect of different thresholds on the value of BRS
is shown in Figure 7. BRS measurement was highly
sensitive to changes in the selected thresholds for
blood pressure and R±R interval. In patients (Fig. 7a),
the average measured BRS increased from 6.2 to
12.5 ms/mmHg as the blood pressure threshold was
decreased from 2 to 0 mmHg (with an R±R interval
threshold of 4 ms). The average measured BRS increased from 7.0 to 10.6 ms/mmHg as the R±R interval threshold was increased from 0 to 6 ms (with a
blood pressure threshold of 1 mmHg). In controls (Fig.
7b), there was a marked dependence of measured BRS
on blood pressure threshold, with the mean BRS
increasing from 15.2 to 29.4 ms/mmHg as the blood
pressure threshold decreased from 2 to 0 mmHg (with
an R±R interval threshold of 4 ms). However, there
Assessment of BRS by the sequence method Ceri Davies et al. 1283
Fig. 5
(b)
30
10
BRS (ms/mmHg)
BRS (ms/mmHg)
(a)
12
8
6
4
2
0
0
0.8
0.9 0.95 0.96 0.97 0.98 0.99
Threshold correlation coefficient
25
20
15
10
5
0
1
0
0.8
0.9 0.95 0.96 0.97 0.98 0.99
Threshold correlation coefficient
1
Effect of changing the required correlation coef®cient on the value of barore¯ex sensitivity (BRS) in (a) patients with chronic heart failure and (b)
normal controls.
Fig. 6
10
18
(b)
9
8
7
6
5
4
3
0
2
1
0
0
0.8
BP threshold
1.5
(mmHg)
1
2
3
4
5 6
R–R nterval threshold (ms)
Proportion of valid sequences (%)
Proportion of valid sequences (%)
(a)
16
14
12
10
8
6
0
0.5
4
2
0
0
1
2
3
4 5
R–R interval threshold (ms)
2
1
BP threshold
1.5
(mmHg)
6
Effect of changing blood pressure (BP) and R±R interval thresholds on the percentage of valid sequences in (a) patients with chronic failure and (b)
normal controls.
was little dependence of the measured BRS on R±R
interval threshold.
Comparison with other measures of BRS
The BRS values obtained by changing the blood
pressure and R±R interval thresholds were compared
with BRS values obtained by the bolus phenylephrine
and spectral analysis methods. The correlation coef®cients are shown in patients (Fig. 8) and normal
individuals (Fig. 9). It can be seen that, in both groups,
the agreement between the sequence method and the
other methods is highly dependent on the choice of
blood pressure and R±R interval thresholds. The
standard choice of thresholds (1 mmHg and 4 ms) did
not result in the maximum agreement for BRS between
the sequence method and the phenylephrine method
or á-index, in either groups.
Discussion
The development of risk strati®cation techniques for
patients after myocardial infarction and for patients
with chronic heart failure offers the potential to identify
those at greatest risk, so that expensive (or risk-laden)
diagnostic and therapeutic options can be targeted at
those with most to gain. The arterial barore¯ex has long
been recognized to be attenuated in these patients [1±
3], and the degree of this attenuation has been con®rmed as an important risk strati®er, independent of
1284 Journal of Hypertension 2001, Vol 19 No 7
Fig. 7
(a)
(b)
16
32
28
BRS (ms/mmHg)
BRS (ms/mmHg)
14
12
10
8
0
0.5
6
4
0
1
2
3
2
4
24
20
0
0.5
16
1
BP threshold
1.5
(mmHg)
12
0
1
2
3
4 5
6
R–R interval threshold (ms)
5 6
R–R interval threshold (ms)
2
1
BP threshold
1.5
(mmHg)
Effect of different blood pressure (BP) and R±R interval thresholds on measured barore¯ex sensitivity (BRS) in (a) patients with chronic heart failure
and (b) normal controls.
Fig. 8
(b) Seq vs α-index
Patients
0.65
0.55
0
0.45
0.5
0.35
1
0.25
0
1
1.5
2
3
4
R–R interval threshold
(ms)
5
BP threshold
(ms/mmHg)
2
6
Agreement between methods
(correlation coefficient)
Agreement between methods
(correlation coefficient)
(a) Seq vs Phe
Patients
0.65
0.55
0.45
0
0.5
0.35
1
0.25
0
1
1.5
2
3
4
5
BP threshold
(ms/mmHg)
2
6
R–R interval threshold
(ms)
Effect of different blood pressure (BP) and R±R interval thresholds on the agreement between barore¯ex sensitivity (BRS) obtained by the
sequence method (Seq) and (a) the bolus phenylephrine method (Phe) and (b) the spectral á-index method, in patients with chronic heart failure.
conventional clinical markers in patients after acute
myocardial infarction [11]. The gold-standard method
of measuring BRS, the bolus phenylephrine method, is
invasive, which has limited its widespread use in
clinical practice. The sequence, or spontaneous, method of measuring BRS is more widely used because it is
non-invasive and, unlike the spectral á-index method,
does not require the use of complicated and opaque
Assessment of BRS by the sequence method Ceri Davies et al. 1285
Fig. 9
(b) Seq vs α-index
Controls
(a) Seq vs Phe
Controls
0.3
0.2
0.1
6
3
R–R interval
threshold
(ms)
Agreement between methods
(correlation coefficient)
0.4
0
0
0
0.5
1.5
1
BP threshold
(mmHg)
2
0.7
0.6
0.5
6
R–R
interval
threshold
(ms)
Agreement between methods
(correlation coefficient)
0.8
0.5
0.4
3
0
0
0.5
1
1.5
2
BP threshold (mmHg)
Effect of different blood pressure (BP) and R±R interval thresholds on the correlation between barore¯ex sensitivity (BRS) obtained by the
sequence method (Seq) and (a) the bolus phenylephrine method (Phe) and (b) the spectral á-index method, in healthy controls.
mathematics. However, the conventional sequence
method approach has a relatively high test failure rate
in patients with attenuated BRS [12], and has been
reported to correlate only poorly with the bolus phenylephrine method [5].
In this study, we have shown that altering the conditions for acceptance of valid sequences can have
profound effects, not only on the number of valid
sequences, but also on the value of BRS and hence its
correlation with other measures of BRS. The individual
components of the sequence method that we assessed
in this study were the shift of blood pressure with
respect to R±R interval, the threshold correlation coef®cient of the regression line between blood pressure
and R±R interval, and the blood pressure and R±R
interval thresholds.
Blood pressure shift
In the original description of the sequence method [6],
the shift between blood pressure and R±R interval was
set at 1 beat, with the R±R intervals being paired with
the systolic pressure peak occurring within the preceding R±R interval (Fig. 1). However, previous work with
bolus injections of phenylephrine [13] showed that,
when blood pressure is transiently disturbed, the temporal relationship between the R±R interval sequence
and the systolic blood pressure sequence depended on
the heart rate, with a shift of 0 being optimal for
individuals with heart rates of 75 beats/min or less and
‡1 for those with faster heart rates. Others have used
the shift that produced the largest number of valid
sequences (in most cases a shift of 0) [14,15]. In our
study, altering the shift between ÿ4 and ‡4 had a
profound in¯uence on the number of valid sequences
obtained both in patients with heart failure and in
normal controls. In both groups, the shift that gave the
greatest number of valid sequences was 0. In our study,
the mean heart rate of the patients with heart failure
was 76 14 beats/min and the mean heart rate of the
normal controls was 66 10 beats/min. However, the
value for BRS was unaffected by the blood pressure
shift in both groups, as described previously [15]. In
the control group, the value of measured BRS peaks at
blood pressure shifts of zero and ‡1, which may
represent `true' barore¯ex sequences. The valid sequences obtained at the other blood pressure shifts
correspond to the relative change between R±R interval and blood pressure from other modulatory systems.
In patients with CHF, BRS is attenuated and so other
cardiovascular re¯exes (such as the chemore¯ex) play a
more prominent role in blood pressure and R±R
interval control. As a result, the relationship between
the changes in blood pressure and R±R interval is less
dependent on their shift. It would seem optimal, therefore, to use the blood pressure shift that produces the
1286 Journal of Hypertension 2001, Vol 19 No 7
largest number of sequences, as this maximizes the
opportunity to measure the BRS successfully, and does
not bias the overall result.
Correlation coef®cient threshold
Studies investigating BRS by the sequence method
have used different threshold correlation coef®cients to
select valid sequences of beats, ranging from no speci®ed threshold correlation coef®cient [16] to a correlation coef®cient threshold of more than 0.95 [17]. In this
study, it can be seen that an increase in the threshold
correlation coef®cient results in a small decrease in the
number of valid sequences, but has no effect on the
value of BRS obtained. In fact, the number of
sequences obtained with a threshold of 0.8 was not
signi®cantly different from that obtained with no correlation coef®cient requirement. This is because the
initial selection of sequences of three successive points
with blood pressure and R±R interval moving consistently in the same direction results in sequences that
have very high correlation coef®cients (nearly all greater than 0.90). Therefore, excluding sequences with
lower correlation coef®cients has little impact on the
number of valid sequences.
We suggest, therefore, that it would be optimal to place
no condition at all on the correlation coef®cient, as this
maximizes the number of valid sequences without
introducing bias into the BRS value.
Blood pressure and R±R interval thresholds
The original description of the sequence method in
cats included sequences in which the blood pressure
increased or decreased by 1 mmHg and the pulse
interval either lengthened or shortened [6]. In a fuller
description of the technique, the same authors proposed thresholds of 1 mmHg in blood pressure and
4 ms in R±R interval [7]. These thresholds are now
very widely used in clinical research, although alternative values have ranged from 6 ms [18] down to no
threshold [14].
The ®ndings in our study are that altering the blood
pressure and R±R interval thresholds has a profound
effect, not only on the number of valid sequences, but
also the measured value of BRS. In the healthy control
group, alteration of the R±R interval threshold had no
effect on the number of valid sequences, the value of
BRS or the correlation between either the bolus
phenylephrine or spectral analysis BRS. As these individuals have a normal BRS, there is a large change in
R±R interval for a small change in blood pressure. If,
for example, an individual has a BRS of 15 ms/mmHg,
an increase in blood pressure of 1 mmHg (required to
attain the blood pressure threshold) will, on average,
lead to a lengthening of R±R interval by 15 ms, easily
exceeding the R±R interval threshold. In persons with
a normal BRS, therefore, it is not necessary to include
an R±R interval threshold.
The situation is, however, very different in those with
attenuated BRS, such as the patients in this study who
had CHF. In this group, there is a much smaller
increase in R±R interval for a given increase in blood
pressure and therefore alterations in the R±R interval
threshold will have an impact on the number of valid
sequences. This is clearly seen in Figure 6a where, as
both thresholds increase, the proportion of valid sequences decreases. The measured value of BRS itself
increases as the blood pressure threshold decreases and
the R±R interval threshold increases. Measured BRS is
effectively the change in R±R interval divided by the
blood pressure change. Therefore, if the R±R interval
threshold is high and the blood pressure threshold is
low, the validity thresholds will select sequences which
yield a high measured BRS. These sequences are rare
in patients with a low BRS and may represent artefact,
rather than true barore¯ex phenomena.
Agreement between sequence and other methods of
measuring BRS
In the healthy controls, the correlation coef®cients
increased with increasing blood pressure threshold,
although there was a slight decrease in correlation
coef®cient with the phenylephrine method at the greatest blood pressure threshold. The agreement between
the different methods could therefore be optimized by
increasing the blood pressure threshold above the
standard of 1 mmHg, although this would result in a
decrease in the number of sequences. Doing this would
remove the small, artefactual, sequences that are not
barore¯ex-mediated. In patients with attenuated BRS,
the method with the largest body of evidence for its
prognostic usefulness is the bolus phenylephrine technique. Agreement between non-invasive measures of
BRS and the phenylephrine technique is poor and this
has led some authors to conclude that `the results
obtained by means of non-invasive BRS assessments
should not be used in clinical practice as an alternative
to those obtained by the phenylephrine method' [5].
However, against this point of view, several arguments
can be offered. First, the reproducibility of the bolus
phenylephrine method in patients with low BRS is far
from excellent [12], which places an upper limit on
how closely it can agree with any other method [19].
Second, it is likely that the phenylephrine method and
sequence method do not assess the same part of the
barore¯ex arc and would therefore not be expected to
agree. The changes in blood pressure are greater and
sustained for longer with the phenylephrine method
and may therefore explore the saturation point of the
baroreceptors. In addition, the choice of an increase in
blood pressure of 15 mmHg and a blood pressure shift
of 1 beat are as arbitrary as the choices of threshold in
Assessment of BRS by the sequence method Ceri Davies et al. 1287
the sequence method, and phenylephrine may have
direct pharmacological actions, unrelated to its effect
on the baroreceptors. However, it can be seen that
altering the thresholds in the sequence method also has
an effect on agreement with the á-index BRS, which is
calculated from the same blood pressure and R±R
interval data, although this is more profound in the
normal controls.
Study limitations
The patients with heart failure and healthy controls
were not age-matched and it is possible that normal
elderly patients with a depressed BRS will show a
pattern similar to that in the heart failure group.
Conclusion
Modi®cation of the arbitrary thresholds of the sequence
method of BRS assessment in patients with heart
failure and normal controls has a profound effect on the
number of valid sequences obtained and on the value
of BRS. Altering the blood pressure shift, whilst having
no effect on the measured value of BRS, can dramatically increase the number of valid sequences. In both
groups, a blood pressure shift of 0 gave the greatest
number of sequences. Varying the threshold correlation
coef®cient of the regression lines affected the number
of valid sequences, but had no effect on the measured
value of BRS. Finally, we found that altering the blood
pressure and R±R interval thresholds away from their
standard values affects not only the measured values of
BRS, but also their agreement with other BRS measurement techniques.
The clinical implications of these ®ndings are that the
optimal thresholds vary, depending on whether the
individual has normal or attenuated BRS, that a single
threshold may not be applicable to both groups, and
that values of BRS from different centres or studies,
obtained using different threshold criteria, may not be
directly comparable.
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