Download Defective Reflex Control of Heart Rate in Dialysis

Clinical Science (1982) 63,285-292
285
Defective reflex control of heart rate in dialysis patients:
evidence for an afferent autonomic lesion
c. Z O C C A L I ,
M. C I C C A R E L L I
AND
Q. M A G G I O R E
Centro di Fisiologia Clinica CNR, Reggio, Calabria. Italy
(Received 30 November 1981118 March 1982; accepted 6 April 1982)
Summary
1. To localize the site of autonomic abnormality in patients undergoing haemodialysis, tests
of overall autonomic function based on either
changes in blood pressure (posture, sustained
handgrip) or heart rate (Valsalva manoeuvre,
30: 15 ratio, deep breathing test) were used.
Integrity of the sympathetic efferent arc was
examined by using the cold pressor test and the
parasympathetic efferent arc by the atropine test.
Eighteen patients and 12 control subjects were
studied.
2. Changes in blood pressure on standing,
sustained handgrip and in the cold pressor test
were the same in the two groups.
3. In contrast, 1 1 patients had abnormal
results in at least two of the three heart-rate-based
tests.
4. Three of the 1 1 dialysis patients with
evidence of autonomic involvement showed abnormal responses to atropine, indicating an
efferent parasympathetic lesion, whereas the
majority had a normal response to the atropine
test, suggesting an afferent lesion only.
5. Evidence of autonomic involvement was
not associated with hypertension nor confined to
patients with dialysis hypotension.
Key words:
dysfunction.
uraemia,
dialysis,
autonomic
sufficiency undergoing haemodialysis. A number
of abnormalities have been described, such as
reduced baroreceptor sensitivity [ 11, and abnormal responses to the Valsalva manoeuvre 12-51
and diving test [41. It has been suggested that
autonomic dysfunction may result in hypertension 171 and hypotension 181 in dialysis patients.
Lilley et al. 171 attempted to locate the site of
the autonomic abnormality, and showed that
dialysis patients had blunted heart rate responses
to baroreceptor stimulation but normal rises in
blood pressure after a cold pressor test, concluding that the defect was in the afferent limb of the
autonomic nervous system. However, these
authors did not assess the integrity of the
parasympathetic efferent fibres, which form an
important part of the reflex response of heart rate
to baroreceptor stimulation 191 and, indeed, may
be affected by chronic uraemia [ 101.
In the present study we have used a comprehensive series of well-established non-invasive
procedures based on changes in either blood
pressure or heart rate in response to standard
stimuli to locate the defective part of the
autonomic nervous system in patients undergoing
regular haemodialysis. The integrity of the
parasympathetic efferent nerves was assessed by
the heart rate response to injected atropine.
Methods
Introduction
Subjects
Impairment of autonomic control of the cardiovascular system has become increasingly
recognized in patients with chronic renal in-
Eighteen males aged 22-57 years (mean 38.7
SD 9.4) maintained on chronic haemodialysis
and 12 healthy male control subjects aged 26-50
years (39.8 f 9.3) were studied. The underlying
causes of renal failure were chronic glomerulonephritis (ten), malignant nephrosclerosis (two),
Correspondence: Dr C. Zoccali, M R C Blood
Pressure Unit, Western Infirmary, Glasgow G11 6NT,
Scotland, U.K.
2
0143-5221/82/09028S-08$01.S0 0 1982 The Biochemical Society and the Medical Research Society
286
C . Zoccali, M . Ciccarelli and Q. Maggiore
polycystic disease (two), and in four patients the
aetiology was not established. Patients had
normal electrocardiograms with no evidence of
heart failure on clinical examination or chest
X-ray. None had diabetes mellitus or amyloidosis. All had been dialysed for 4-5 h three
times a week with a standard dialysis fluid (Na
138, K 1.5, C a 1.9, Mg 0.5, C1 107, acetate 36.9
mmol/l) for periods ranging from 2 to 10 years
(7.0 f 2.2) and were receiving aluminium
hydroxide and vitamin supplements. No patient
was taking anti-hypertensive drugs or other
medications known to affect autonomic nervous
system. Three patients were hypertensive with
blood pressure values above 160/90 mmHg.
Although there was no clinical evidence of
autonomic neuropathy, three patients had
dialysis hypotension, defined as a mean arterial
pressure [(pulse pressure/3) + diastolic pressure]
decrease of at least 30 mmHg, requiring saline
infusion and/or sympathomimetic drug injection
at least once during more than half of their
dialysis treatments in the preceding 6 months.
They were hypotensive at the time of the study,
with mean arterial pressure frequently less than
80 mmHg. The nature of the study was explained
to all participants, who gave their informed
consent.
Tests for autonomic function and location of the
lesion
Integrity of both afferent and efferent arcs was
tested by using the response to posture, sustained
handgrip, Valsalva manoeuvre, 30 : 15 ratio and
deep breathing, with separate studies of the
efferent sympathetic arc by the cold pressor test
and the efferent parasympathetic fibres by the
injection of atropine.
Tests of overall autonomic function based on
blood pressure. 1. Change in blood pressure on
standing. Blood pressure was recorded three
times during 15 min of supine rest. The subjects
were then asked to stand, and blood pressure was
measured after 30 s. Changes in blood pressure
were calculated as the difference between the
mean resting and the standing values.
2. Sustained handgrip. The subjects exerted
maximal grip on a handgrip dynamometer,
control subjects with their dominant arm and
dialysis patients with their arteriovenous fistula
arm. Maximum voluntary contraction was taken
as the highest value of three contractions.
Handgrip was then maintained at 30% of
maximum voluntary contraction for 5 min. Blood
pressure was measured in the non-exercising arm
at 30 s intervals. The changes in blood pressure
were taken as the difference between the mean of
three resting values and the highest reading
before the release of handgrip [ 111.
Efferent arc test based on blood pressure: cold
pressor test. This was performed by placing one
hand in ice slush for 1 min and measuring blood
pressure at 30 s and 1 min. Changes in blood
pressure were calculated as in the preceding test.
This test evaluates only the efferent limb of the
sympathetic system, since fibres of its afferent arc
are somatic rather than autonomic [ 121.
Tests of overall autonomic function based on
heart rate. 1. Valsalva manoeuvre. Subjects
maintained a pressure of 40 mmHg for 15 s on an
anaeroid manometer. ECG (electrocardiogram)
was continuously recorded during the manoeuvre and the ensuing 30 s. The valsalva ratio
was calculated as the ratio of the longest R R
interval after the manoeuvre to the shortest RR
interval during the manoeuvre [13]. The test was
repeated twice and the average of the two ratios
was taken.
2. 30: 15 ratio. Heart rate was continuously
monitored electrocardiographically with the subjects supine and after standing quickly (3-4 s).
The 30 :15 ratio was calculated as the ratio of the
RR interval at beat 30 after standing to the R R
interval at beat 15 after standing [141. The test
was repeated twice and the average of the two
30 : 15 ratios was taken.
3. Deep breathing. Subjects were trained to
breathe deeply at a rate of 6 breathdmin while
supine. Heart rate was then monitored continuously on the ECG as the subjects breathed
deeply for 100 s. From the average maximum RR
interval during deep expiration (E) and the
average maximum RR interval during deep
inspiration (I), both the absolute change in heart
rate (deep breathing score) [151 and the E/I RR
ratio were calculated.
Efferent arc test based on heart rate: atropine
test. Atropine (1.8 mg) was injected intravenously in 3 min. Throughout injection and
during the next 10 min heart rate was continuously monitored with a Roche monitor. The
maximum change from the resting state was
calculated. This test evaluates parasympathetic
efferent fibre integrity [161, since sinus node
responses are related linearly to fluxes of efferent
vagal activity [ 171.
The two sets of tests were performed between
09.00 and 13.00 hours, and the patients were
investigated the day after dialysis. For measurements of blood pressure an ultrasonic sphygmomanometer was employed.
After 10 to 22 days (15.5 f 4.0), heartrate-based tests of overall autonomic function
Reflex heart rate control in dialysis patients
were repeated in seven control subjects and in
nine patients to test the reproducibilities of these
studies.
Interpretation of tests
Autonomic function was considered to be
impaired if one of the two blood pressure and/or
two of the three heart-rate-based tests of overall
autonomic function were abnormal. In patients
with abnormal overall function, the defect was
presumed to be localized to the afferent arc if
tests of the efferent arc were normal, whereas if
efferent arc tests were abnormal, it was not
possible to exclude a coexisting abnormality in
the afferent arc.
28 7
than control subjects (116.9 +_ 13-2/75.9 +_ 10- 1
mmHg), but the difference was not significant
(systolic P > 0.3, diastolic P > 0.4). Similarly,
the heart rate (74.8 f 7.7 beatslmin) was higher
than in control subjects (69.6 f 6.4 beatshin),
but again this difference was not significant (0.05
< P < 0.1).
Blood-pressure-based autonomic tests
There were no significant differences between
changes in blood pressure on standing, sustained
handgrip and cold pressor test in patients,
compared with control subjects (Table la).
Heart-rate-based autonomic tests
Statistical analysis
All results are expressed as means &- SD.The
significance of differences was calculated by
Student’s t-test and the relationship between
paired variables defined by regression analysis.
The coefficient of variation was calculated from
the formula SD/mean, where SD is
(where d is the difference between paired
measurements and n the number of pairs) [ 181.
The results of Valsalva manoeuvres and 30 :15
tests are presented as ratios, and those of deep
breathing as absolute heart rate changes. The
coefficient of variation of deep breathing score
was calculated from the E/I RR ratios.
Results
Resting blood pressure and heart rate
Dialysis patients had higher resting blood
pressure (123.3 f 19.4/79.9 f. 16.0 mmHg)
Valsalva manoeuvre ratio was significantly (P
0.01) less in patients (1.53 f 0.28) than in
control subjects (1.83 f. 0.24). Ten patients had
Valsalva ratios below 1.5 the lowest value
found in control subjects and the lower limit of
normal as defined by Levin [ 131 (Fig. 1).
The 30: 15 ratio was also significantly (P <
0.01) less in patients (1.06 f 0.06) than in
control subjects (1.26 f 0.14). Nine patients
showed values below 1.07, the 1owest.ratio of our
control subjects and the limit below which
responses were classified as abnormal. Moreover, of these patients six had ratios below 1.03,
the lower normal limit suggested by Ewing et al.
[141 (Fig. 1).
Deep breathing score was significantly (P <
0.01) reduced in patients (12.4 f 6.6) compared
with the mean value for control subjects (22.9 &6.9). Eleven subjects had scores below 13, our
lowest normal score and the limit below which
autonomic involvement is likely to be present 151
<
TABLE1. Systolic and diastolic blood pressure changes in control subjects and in dialysis patients in response to standing,
sustained handgrip and the coldpressor test
( a ) Means ? SD for control subjects (n = 12) and dialysis patients (n = 18) (N.S.,
not significant). Individual responses of (b)
hypertensive and ( c ) hypotensive patients.
ABlood pressure (mrnHg)
Standing
(a) Control subjects
Dialysispatients
(15) Patient no. 1
Patient no. 2
Patient no. 3
(c) Patient no. 4
Patient no. 5
Patient no. 6
Sustained handgrip
Cold pressor
Systolic
Diastolic
Systolic
Diastolic
Systolic
Diastolic
+4.1 ? 10.2
+3.4 f 9.4
N.S.
+7.6 f 6.0
+10.5 f 8.7
N.S.
+28.6 f 11.4
+30.0? 15.9
N.S.
~ 2 6 . 6? 7.5
+24.3 f 9.5
N.S.
+21.1 f 13.0
+22.5 12.5
N.S.
+16.9f4.9
+ 1 6 , 4 f 6.9
N.S.
-3
+I7
+27
+35
+28
+29
+21
+40
0
+2
+9
+2
+22
+I7
+29
+15
+25
+7
0
+7
+9
+27
+22
+26
+28
+23
+28
+3 1
+ 30
+ 17
+ 18
+ 29
+
+I
+I5
+35
+30
C. Zoccali, M . Ciccarelli artd Q. Maggiore
28 8
Deep breathing score
3 0 : 15 ratio
Valsalva ratio
l
o
00
1.3
12
1 .
1
1 .o
0
P4
i
--QQ
-
-
4 1
FIG. 1. Tests of overall autonomic function based on heart rate in normal subjects (0)and in
dialysis patients: normotensives (o), hypertensives (a, 1, 2, 3), hypotensives (0,4, 5 , 6). The
lowest value for control subjects used for classifying patients' response (normal or abnormal) is
shown as a broken line.
Dialysis patients
I
I
I
I
'
-
Atropine test
I
I
I
I
I
1 .
I
tI
6 0
0 4
0
0
0
0
3.
-130
I
I
0
I
I
I
I
I
0 0
1.
I
I
I
I
0
1
1
(Fig. 1). When the results were re-expressed as
E/I ratios, these 11 patients only were again
found to have abnormal values.
2
1
3
Abnormal results
FIG. 2. Heart rate change after atropine injection.
Patients are grouped according to the number of
abnormal heart-rate-based tests of overall autonomic
function and were considered to have autonomic
involvement if at least two of the three tests gave
abnormal results. Symbols are as identified in Fig. 1.
In the atropine test, heart rate changes in
dialysis patients (34.2 f 8) were significantly (P
< 0.05) less than in control subjects (40.8 f 7).
However, when these patients were grouped, by
using the results from the heart-rate-based tests of
overall autonomic function, into those with
overall normal autonomic function (no, or at
most one, abnormal test) and overall abnormal
autonomic function (at least two out of three
abnormal tests) and their response to atropine
was re-examined (Fig. 2) and their results
compared with those of normal subjects, it can be
seen that those regarded as having overall normal
autonomic function had heart rate changes (39-4
f 7.8) similar to those of control subjects,
whereas the others with abnormal overall autonomic function had significantly reduced heart
rate changes (30.8 f 0.3) compared with those
of control subjects (P < 0.01) and the patients
with normal autonomic function (P < 0.025).
Moreover, there was a linear inverse correlation
between the atropine response and the number of
abnormal test results ( r - 0-56,
P < 0.01).
In only three patients were the heart rate
changes in response to atropine less than 30, the
lowest value of our control subjects and the lower
limit of normal as reported by Duncan et al. [ 191
(Fig. 2). These three patients had abnormal
function in all three tests of overall autonomic
function based on heart rate (Fig. 2).
Reflex heart rate control in dialysis patients
TAELE2. Correlations between the results of heart rate
based tests and resting heart rate
P values are not significant.
Test
Control subjects
r
P
0.25
0.05
0.36
>0.3
>0.7
>0.2
0.24
>0.4
289
TABLE3 . Agreement between heart rate based tests of
overall autonomicfunction
N, normal; A, abnormal.
Dialysis patients
Valsalva
ratio
P
r
Deep
No.of
ratio breathing patients
score
30:15
~~
Valsalva ratio
30 : 15 ratio
Deep breathing
Atropine test
0.25
-0.01
-0.15
0.21
>0.3
>0.7
>0.5
>0.4
No relationship was found between the results
of heart-rate-based tests and resting heart rate, in
normal subjects or in dialysis patients (Table 2).
All test results normal
N
One test result abnormal
A
N
N
"
"
A
N
N
A
2
0
0
0
2
3
Two test results abnormal
A
A
N
A
N
A
N
A
A
All test results abnormal
A
A
A
Total
5
6
18
Hypertensive and hypotensive dialysis patients
There was no difference in blood pressure
between the eleven patients (122.2 f 21.3/77.4
f 14.7 mmHg) with autonomic dysfunction (at
least two abnormal heart-rate-based tests of
overall autonomic function) and the seven
patients (125.3 f 14.8/82.1 k 19-0 mmHg)
without (at most one abnormal test). Individual
results from the three hypertensive patients and
the three hypotensive dialysis patients were
included in the above calculations, but these are
shown separately in Table 1 and in Figs. 1 and 2.
All had normal results of tests based on blood
pressure change (Tables lb, lc). Autonomic
involvement was present in the first hypertensive
patient (patient 1) and in two hypotensive
patients (patients 4 and 5). The hypertensive
patient had three and the hypotensive patients
had two abnormal responses in the heart rate
based tests of overall autonomic function (Fig. 1).
The second hypertensive (patient 2) and the
remaining hypotensive patient (patient 6) had
normal results in these tests. The third hypertensive patient (patient 3) had only one abnormal
test. The atropine response was normal in all but
one hypertensive patient (patient 1) (Fig. 2). As
shown in Figs. 1 and 2, responses of hypertensive and hypotensive dialysis patients to the
heart-rate-based tests were scattered uniformly
throughout the results of the patient group.
Agreement and reproducibility of heart rate
based tests of overall autonomicfunction
Eleven patients had abnormal results in at least
two of three heart-rate-based tests of overall
autonomic function, and six of them in all three
tests (Table 3). Table 3 shows there was a good
agreement between 30 : 15 ratio and deep breathing test, with only two cases having normal
30 : 15 ratio when the deep breathing scores were
abnormal. However, in five cases the results of
Valsalva manoeuvre were discordant with those
of the other tests. In two patients Valsalva
manoeuvre was abnormal when their 30:15
ratios and deep breathing scores were normal,
and in three patients it was normal when both
other results were abnormal.
As expected from the good agreement between
30: 15 ratio and deep breathing test, the
reproducibilities of these were good (coefficient of
variation 3.2 and 3.5% respectively; that for
Valsalva manoeuvre results was less satisfactory:
14.2%). However, when we sought the diagnostic
precision of the combined test criterion (i.e.
abnormal autonomic function, at least two out of
three abnormal tests) among the nine patients
who had repeated the tests, none had his class
changed on second testing (Table 4). Furthermore, on second testing the control subjects
again had normal ratios and scores throughout.
Discussion
The changes in blood pressure of our patients in
response to standing, sustained handgrip and the
cold pressor test were similar to those of control
subjects, suggesting that autonomic control of
blood pressure is not impaired in patients
undergoing haemodialysis. These findings are in
keeping with the results of others [4, 20, 211,
though impairment of the blood pressure response to sustained handgrip has been reported [3,
51. In the latter studies there were no control
subjects and the authors did not state the time at
which their autonomic tests were carried out in
relation to the period of dialysis. In our study all
patients were tested the day after haemodialysis,
C . Zoccali, M . Ciccarelli and Q. Maggiore
290
TABLE4. Diagnostic precision of the combined test criterion (i.e. abnormal autonomic control of heart rate, ar least two out of
three abnormal tests)
Heart-rate-basedtests of overall autonomic function were repeated (second testing) after 10-19 days (14.8 f 3.7). The results
shown are for dialysis patients only. N, normal; A, abnormal.
Patient
no.
First testing
Second testing
Valsalva
ratio
30: I5
ratio
Deep
breathing
score
Valsalva
ratio
30: I5
ratio
Deep
breathing
score
A
N
A
N
A
N
N
A
A
N
A
2
3
5
A
N
N
A
N
N
N
A
A
N
A
6
N
N
N
N
I
A
A
A
N
A
A
A
N
A
A
A
N
A
A
A
N
N
A
N
A
A
A
N
1
8
9
10
when the effects of the unphysiological cycling of
body composition during dialysis on cardiovascular function are minimized [221.
In contrast, impairment of the Valsalva manoeuvre, 30: 15 ratio and deep breathing tests
indicate defective autonomic control of heart rate,
as reported previously by others [2-61. It has
been suggested that the blunted reflex heart rate
responses in these tests are explained by the high
resting heart rate of patients undergoing dialysis
when compared with that of control subjects
[211. In the present study we also found that
dialysis patients tended to have faster resting
heart rates than do control subjects. However,
when resting heart rates were correlated with the
results of the tests of autonomic function in both
patients and normal subjects, no relationship
could be found.
We also used the atropine test to characterize
the abnormality of heart rate response found in
our study. The normal response to atropine in
most of the patients, together with abnormal
heart responses to overall autonomic function
tests, suggest that most patients have an afferent
lesion. Autonomic neuropathy of dialysis patients
is unusual in sparing efferent function. Other
autonomic neuropathies, such as the alcoholic
I191 and the diabetic [231, commonly involve
parasympathetic efferent fibres.
Various factors have been proposed to explain
the tachycardia of dialysis patients, including
myocardial damage, anaemia and the presence
of arteriovenous fistulas or shunts [241. Autonomic dysfunction may also have a role. Sympathetic tone is enhanced in dialysis patients [7,201,
who show a greater decrease in heart rate than
normal subjects after beta-blockade 1251. Efferent
parasympathetic damage could contribute to the
N
A
A
N
N
tachycardia in some patients. In this regard we
found an inverse relationship between heart rate
increase after atropine and severity of autonomic
dysfunction, which implies that involvement of
the parasympathetic efferent nerves increases as
autonomic function declines. The three patients
with a clearly impaired response to atropine had
abnormal results in all heart-rate-based tests.
Abnormal reflex heart rate control may be
explained by subclinical heart failure. However,
patients with heart failure have a markedly
impaired response to atropine, but an entirely
normal response to /3-adrenoreceptor-blocking
drugs [261.
The functional relevance of the observed defect
in autonomic control of heart rate is not clear.
Heart rate is normally an important determinant
of cardiac output. Patients unable to vary their
heart rate must rely on changes in stroke volume
to increase cardiac output [27, 281; failure to
compensate for defective autonomic control of
heart rate by increasing stroke volume would
result in impairment of cardiac reserve.
It has been suggested that afferent baroreceptor nerve damage may cause hypertension
in dialysis patients [71. Although McGrath et al.
were able to implicate an abnormality of autonomic control in the high peripheral vascular
resistance of hypertensive patients on chronic
dialysis, baroreceptor function assessed by the
haemodynamic changes during Valsalva manoeuvre was identical in hypertensive and normotensive patients [291. Similarly we found no
difference in blood pressure between patients with
and without autonomic dysfunction. Our observations do not support an important role of
baroreceptor dysfunction in the cause of hypertension in dialysis patients. Abnormal baro-
ReJex heart rate control in dialysis patients
receptor function is unlikely to have a primary
role in long-term blood pressure regulation [301.
In the present study we did not find an
association between autonomic dysfunction, as
shown by abnormal heart rate responses to
formal testing and dialysis hypotension. Reflex
heart rate changes in response to baroreceptor
stimulation do not predict simultaneous blood
pressure changes [3 11, which may help to explain
previously contrasting claims [7,211.
Our results in uraemic patients and previous
reports in diabetic patients [321 indicate that
defective autonomic regulation of heart rate is
more common than disturbance of reflex blood
pressure control. Therefore, when screening for
autonomic neuropathy it seems advisable to
perform heart-rate-based tests of overall autonomic function first. Both the deep breathing test
and the 30: 15 ratio appeared satisfactory, but
the deep breathing test was apparently more
sensitive. The Valsalva ratio was less reproducible and agreed poorly with the two other
tests. The atropine test can be reserved for those
in whom two or more of the tests of overall
autonomic function are abnormal.
Dialysis patients, without symptoms of autonomic nerve damage, exhibit defective reflex
control of heart rate, which in the majority of
patients is due to an afferent autonomic lesion.
This defect is not associated with hypertension,
nor is it confined to patients with hypotension
during dialysis.
Acknowledgments
We thank Dr S. G . Ball and Dr P. F. Semple for
revising and Mrs C. V. Sadler for typing the
manuscript.
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