Clinical Science (1985) 68, 71-78
71
Plasma catecholamine responses to change of posture in
alcoholics during withdrawal and after continued abstinence
from alcohol
G . EISENHOFER, E. A. WHITESIDE
AND
R. H. JOHNSON
Wellington Clinical School of Medicine, Wellington Hospita!, Wellington, New Zealand
(Received 25 June 1984; accepted 24 July 1984)
Summarv
1. Plasma catecholamine, blood pressure and
heart rate responses to standing were measured in
ten alcoholics during withdrawal, ten alcoholics
after 2-7 weeks of abstinence from alcohol, six
abstinent alcoholics with orthostatic hypotension
and ten normal control subjects.
2. Withdrawing alcoholics had supine and
standing heart rates and plasma noradrenaline and
adrenaline concentrations that were higher than in
abstinent alcoholics or control subjects. Supine
blood pressures were also higher in withdrawing
alcoholics than in abstinent alcoholics or control
subjects, but on standing blood pressures in withdrawing alcoholics fell, four patients having a fall
of more than 30/5 mmHg.
3. Abstinent alcoholics without orthostatic
hypotension had higher basal and standing concentrations of noradrenaline than control subjects
but normal heart rates and adrenaline concentrations.
4. Abstinent alcoholics with orthostatic hypotension showed a wide range of basal plasma
noradrenaline concentrations and were found to
have variable plasma noradrenaline responses to
standing, three subjects having normal responses
and three subjects having no or little increase in
plasma noradrenaline on standing.
5. It is concluded that alcohol withdrawal is
associated with increased sympathetic nervous
activity, as reflected by raised supine and standing plasma concentrations of catecholamines, and
Correspondence: Professor R. H. Johnson,
Wellington Clinical School of Medicine, Wellington
Hospital, Wellington 2, New Zealand.
that even after 2-7 weeks of abstinence from
alcohol plasma noradrenaline concentrations may
be higher than in control subjects. Despite
increased sympathetic nervous responses t o standing, alcoholics during withdrawal have impaired
blood pressure control and some may exhibit
orthostatic hypotension. Orthostatic hypotension
may also be observed in alcoholics during continuing abstinence from alcohol; in some of these
patients failure of reflex noradrenaline release in
response t o standing may contribute to orthostatic
hypotension.
Key words: alcoholism, catecholamines, orthostatic hypotension.
introduction
Alcohol consumption is associated with rises in
plasma concentrations [ 11 and urinary excretion
[2-41 of catecholamines, suggesting increased
sympathetic nervous activity. Some investigators
[5] have implicated this effect in the elevation of
blood pressure associated with alcohol consumption [ 6 , 71, although one recent study has shown
that plasma concentrations of free and conjugated
catecholamines are not different between nondrinkers and drinkers with higher blood pressures
[8]. Increased plasma concentratidns of catecholamines, associated with cardiovascular
changes, have, however, been shown to occur in
alcoholics receiving disulfiram [9] and in orientals
with genetic abnormalities of aldehyde dehydrogenase [lo].
Disorders of the cardiovascular system in
alcoholism include both hypotension and hypertension. High blood pressure is particularly evident.
72
G. Eisenhofer et al.
during alcohol withdrawal [11] and may be
associated with other symptoms such as sweating,
tachycardia and tremor, ascribed to increased
sympathetic nervous activity as reflected by raised
arterial concentrations [ 121 and urinary excretion
[3, 131 of catecholamines. Orthostatic hypotension may also occur in alcoholism [14], particularly in patients with acute symptoms of Wernicke’s
encephalopathy [15, 161. This may be due to
damage to sympathetic nerves involved in reflex
vasoconstriction, analogous to the parasympathetic
neuropathy that may affect vagal control of
cardiac reflexes in alcoholic patients [17]. Abnormalities of the sympathetic nervous system may
also be involved in hypotension and impaired
blood pressure control in liver cirrhosis associated
with alcoholism [ 181.
The role of abnormalities of sympathetic
function in disturbances of cardiovascular control
in alcoholic patients has not been precisely delineated. We have examined sympathetic nervous
function in alcoholics by measuring catecholamine
responses to change of posture, in patients during
withdrawal and in patients with and without
orthostatic hypotension who had been abstinent
from alcohol for 2 or more weeks.
Methods
Subjects
Twenty-six male Caucasian alcoholic subjects
were investigated while undergoing treatment at
alcoholic detoxification and rehabilitation centres.
Patients were studied in three groups: one group
comprising patients undergoing withdrawal from
alcohol; a second group consisting of patients
abstinent from alcohol for more than 2 weeks; and
the third group comprising abstinent patients
investigated for orthostatic hypotension. All
patients had a history of drinking 150 g or more of
alcohol a day before admission for treatment, and
had been drinking alcohol heavily and regularly
for more than ten years and for up to 35 years.
Ten patients, with a mean age of 51 years
(range 38-60 years), who were undergoing treatment for alcohol withdrawal at an alcol~olic
detoxification centre comprised the alcohol
withdrawal group. Patients were investigated
before administration of medication, which was
not withheld for the purpose of the study. All
patients exhibited to some degree symptoms of
withdrawal, which included tremor, tachycardia,
hyper-reflexia and excessive generalized sweating.
Five patients were studied within the first day
of alcohol withdrawal, three on the second and
two on the sixth day.
Ten alcoholic patients, with a mean age of 49
years (34-62 years), admitted to a rehabilitation
centre after detoxification, comprised the
abstinent alcoholic group. Patients in this group
were in full-time residence at the rehabilitation
centre, with no access to alcohol. All had been
abstinent from alcohol for between 2 and 7 weeks
(mean 3.5 weeks) at the time of study.
Six alcoholic patients complaining of dizziness
or fainting on standing were investigated for
orthostatic hypotension and were subsequently
found to have falls in systolic and diastolic blood
pressure of greater thati 30 and 5 mmHg respectively on standing (see Table 1). These patients
had a mean age of 5 4 years (range 44-67 years)
and had been abstinent from alcohol for between
4 and 6 weeks (mean 4.3 weeks) before investigation.
The control group consisted of ten normal
male Caucasian subjects with a mean age of 59
years (range 36-64 years). Subjects included two
with a medical and one with a paramedical
working background. One of the subjects was
hospitalized at the time of investigation. Eight
of the ten control subjects were light or moderate
social drinkers of alcohol, the other two being
abstainers.
Clinical assessment
Peripheral neuropathy was assessed from the
absence of knee or ankle jerks and loss of vibration
sense (1 28 cycles/s) at the knee or ankle. Moderate
and severe neuropathy were defined as abnormalities at ankle and knee respectively. Vagal neuropathy in abstinent alcoholics with orthostatic
hypotension was assessed from heart rate
responses to standing (ratio of R-R intervals at
the thirtieth and the fifteenth beats after standing),
Valsalva’s manoeuvre, deep breathing and atropine administration [17].
Diagnosis of Wernicke’s encephalopathy in
subject 4 (see Table 1) was made on the basis of an
acute confusional state with nystagmus and ataxia.
One year after investigation this subject still had
orthostatic hypotension and exhibited memory
loss and disorientation in time and space indicative
of Korsakoff’s psychosis. Diagnosis of cerebellar
atrophy in subject 6 (Table 1) was made on the
basis o f an ataxic gait with poor co-ordination,
confirmed by a computed tomography scan
showing marked cerebellar atrophy. Evidence of
liver disease was assessed by physical examination
and raised serum concentrations of y-glutaniyl
transpeptidase, alkaline phosphatase and aspartate
and alanine aminotransferases. The extent of liver
disease was rated as moderate or severe depending
TABLE 1. Clinical data and blood pressures (BP), heart rates (HR) and plasma noradrenaline concentrations (NA) before and after change of posture
Age
(years)
Period of
abstinence
Peripheral
neuropathy
Other
nervous
damage
134/76 +6/4
118/76 +5/1
Abstinent alcoholics without orthostatic hypotension (n = 10)
Mean +SEM:
Control subjects (n = 10)
Mean k SEM:
74+3
73 f 4
95 f 8
149/81+6/5
Withdrawing alcoholics (excluding subjects 7-10 above, n = 6)
Mean +SEM:
-
101
118
98
89
102 k6
Mean HR
(beats/min)
Withdrawing alcoholics who were found to have orthostatic hypotension on investigation
1day
130/85
7
55
1day
tt
++
137/88
8
55
t
+
160/90
9
53
2 days
6 days
tt
+
140/95
10
49
Mean + SEM:
142/90 +6/2
Mean BP
(mmHg)
102
90
70
81
84
73
83t5
t
tt
t+
tt
t
Liver
disease
Supine
150/103
147/88
149/93
131177
120/56
l58/105
143/83 f 6/8
Abstinent alcoholics investigated for orthostatic hypotension
4 weeks
1
44
++
++
VN
2
52
4 weeks
+
VN
3
67
4 weeks
t+
VN, WE
4
48
4 weeks
58
6 weeks
t+
VN
5
6
57
t
CA
4 weeks
Meant SEM:
Subject
Clinical data
2.15 t0.24
3.14 f0.28
4.07 f 1.70
11.51
6.05
3.81
5.80
6.79 f 1.65
2.13
2.84
3.20
6.63
12.78
0.65
4.71 f 1.84
Mean NA
(nmol/l)
113/84 2613
124183 +5/5
135/82+8/5
100/80
76/62
130/80
l00/80
102/76 f l l / 4
60/40
60/40
110/70
98/72
85/50
90/60
84/55 f 9/6
Minimum BP
(mmHg)
87 + 4
92 + 6
115+5
120
158
120
115
128~10
133
116
81
110
100
91
105f8
Mean HR
(beats/min)
Standing
+,
3.84 f0.39
5.32 f0.30
7.06k1.60
17.26
15.03
6.85
6.49
11.4r2.75
3.28
5.56
6.62
6.89
11.42
0.85
5.77k1.49
Mean NA
(nmol/l)
~~
Individual and mean (* SEM)results are given for alcoholic subjects with orthostatic hypotension, but for all other groups mean (+ SEM) results only are
given. Abbreviations: VN, vagal neuropathy; WE, Wernicke’s encephalopathy; CA, cerebellar atrophy; -, n o evidence of damage; evidence of moderate
evidence
,
of severe damage.
damage; i+
4
w
5
2
%’
2f?.
x
2
9’
3
a
r)
2
R
2
74
G. Eisenhofer et al.
on physical examination and whether raised serum
concentrations of enzymes were reduced with
continuing abstinence. Blood samples from
patients with orthostatic hypotension were also
analysed for packed cell volume and serum
albumin.
of subjects displayed significant (P< 0.01)
increases in plasma noradrenaline at all time intervals after standing (Fig. 1). Withdrawing alcoholics
had supine plasma noradrenaline concentrations
"1
Procedure and analytical methods
Subjects were studied between 10.30 and 16.00
hours after refraining from caffeinated beverages
and cigarettes for 2 h . Subjects rested for 15-20
min in the supine position after insertion of an
intravenous forearm cannula, maintained patent
by flushing with isotonic saline. At the end of this
period two 10 ml basal blood samples were taken
at 5 min intervals and transferred to heparinized
tubes stored on ice. A further three blood samples
were taken at 2.5, 5 and 1 0 m i n after change to
the upright posture. Plasma samples were stored at
-7OOC
until measurement of catecholamine
concentrations by a radioenzymatic assay [ 191.
The intra-assay coefficients of variation determined from quality control samples within the
physiological range were 6% and 12% for noradrenaline and adrenaline respectively while the
interassay coefficients of variation were 11% and
18% for noradrenaline and adrenaline respectively.
The average sensitivity of the assay was 0.09 nmol
of noradrenaline and 0.06 nmol of adrenaline
measurable per ml of plasma.
Lying and standing heart rates were recorded
continuously with an electrocardiogram or at
intervals with a combined automatic blood
pressure/heart rate recorder (Nissei model DS
102), this instrument also being used for measurements of blood pressure. A comparison of the
automatic sphygmomanometer with a standard
mercury sphygmomanometer indicated an average
random variation in measurements between the
two instruments of If: 3.2% and f 1.9% for systolic
and diastolic blood pressures respectively. The
average variability of four consecutive measurements, made in each of six subjects with the
automatic sphygmomanometer, was f 1.5% and
+3.2% for systolic and diastolic blood pressures
respectively.
Results are expressed as mean values k SEM. The
significance of changes in values within groups was
assessed by using Wilcoxon's signed rank sum test
for related samples and the significance of
differences between groups was assessed by using
Wilcoxon's rank sum test for independent samples.
Results
With the exception of the abstinent alcoholics
with orthostatic hypotension (Table l), all groups
I
I
10-
s
:
v
42
e
8-
6-
0
5
4-
is
2-
0
1
I
I
I
0
2:5
5
10
Time (min)
FIG. 1. Plasma catecholamine concentrations
( r n e a n f s ~ ~in) the supine position (v)and
in response to standing ( 7 ) in ten withdrawing
alcoholics (o), ten abstinent alcoholics without
orthostatic hypotension (A) and ten control subjects (.). Withdrawing alcoholics had supine and
standing noradrenaline and adrenaline concentrations which were significantly (P< 0.05)
higher than abstinent alcoholics or control subjects.
Abstinent alcoholics had supine noradrenaline
concentrations which were significantly (P<
0.05) higher than control subjects. Plasma
adrenaline concentrations 10 min after standing
were significantly (P< 0.01) higher than supine
concentrations in all groups.
Plasma catecholamines in alcoholism
(mean k SEM) of 5.1 1 f 0.83 nmol/l, which were
significantly higher than those of abstinent alcoholic subjects without orthostatic hypotension
(3.14f 0.28 nmol/l, P < 0.05) or control subjects
(2.15 f 0 . 2 4 nmol/l, P < 0.01). Ten minutes after
standing, plasma noradrenaline concentrations in
withdrawing alcoholics had risen to 10.43 f 1.64
nmol/l. These were significantly higher than the
standing plasma noradrenaline concentrations in
both abstinent alcoholics (6.08 k 0.68 nmol/l, P <
0.05) and control subjects (4.63 f 0.47 nmol/l,
P < 0.02). Abstinent alcoholics had significantly
(P < 0.05) higher supine plasma noradrenaline
concentrations than control subjects.
In abstinent alcoholics without orthostatic
hypotension and in control subjects, plasma
adrenaline concentrations rose significantly (P <
0.01) from supine values of 0.28 k 0.04 nmol/l and
0.32 k 0.02 nmol/l respectively to standing values
(at 10 min) of 0.38 f 0.04 nmol/l and 0.44f 0.04
nmol/l respectively (Fig. 1). In withdrawing
alcoholics, plasma adrenaline concentrations
showed significant increases from supine values
of 0.60 f 0.09 nmol/l to 0.94 k 0.12 nmol/l (P <
0.02) at 5 min after standing and 1.02 f 0.16
nmol/l (P < 0.01) at 10 min after standing. Withdrawing alcoholics had plasma adrenaline concentrations that were significantly higher than in
abstinent alcoholics or control subjects in both
supine (P < 0.05) and standing (P< 0.005)
positions. No differences in supine and standing
plasma adrenaline concentrations between control
subjects and abstinent alcoholics were found.
Heart rates in withdrawing alcoholics rose from
a mean of 97 f 5 beats/min to 123 k 5 beats/min
at 10 min after standing and were significantly
(P < 0.01) higher than in control subjects or
abstinent alcoholics in both supine and standing
positions (Fig. 2). No differences in supine and
standing heart rates were found between abstinent
alcoholics without orthostatic hypotension and
control subjects, who had supine heart rates of
73 f 4 beats/min and 74 f 2.5 beats/min rising to
9 4 f 6 beats/min and 88 k 3.5 beats/min at 10 min
after standing respectively.
Abstinent alcoholics without orthostatic hypotension had a group mean supine blood pressure of
134/76 mmHg which, although higher for the
systolic component, was not significantly different
from that of control subjects, who had a group
mean supine blood pressure of 118/76mmHg
(Fig. 3). Withdrawing alcoholics had a group
mean supine blood pressure of 146/84 mmHg,
which was higher than in control subjects and
abstinent alcoholics, this being significant for
systolic (P < 0.005) and diastolic (P < 0.02) blood
pressures in control subjects only. On standing,
75
130-
120-
110-
I
I
I
h
.5
E
2
100-
8
eal
C
E 90-
C
I
m
G
80 70 I
I
I
i
215
Time (min)
k
I
10
FIG. 2. Heart rate ( m e a n f ~ ~
in ~the
) supine
position (0-) and in response to standing ( ) in
ten withdrawing alcoholics (o), ten abstinent
alcoholics without orthostatic hypotension (A)
and ten control subjects (m). Withdrawing alcoholics had supine and standing heart rates which
were significantly (P < 0.01) higher than abstinent
alcoholics or control subjects.
blood pressures in withdrawing alcoholics fell
from 146/84mmHg when supine to 126/83
mmHg at 10 min in the standing position, a level
that was not significantly different from that in
abstinent alcoholics (129/87 mmHg) * or control
subjects (120/88 mmHg). When the lowest
standing blood pressure was compared with the
mean supine blood pressure for each subject it
was found that withdrawing alcoholics had a maximum fall (mean f SEM) in systolic blood pressure
of 25.0 f 5.3 mmHg that was significantly greater
than in abstinent alcoholics (1 1.3 f 4.78 mmHg,
P < 0.05) or control subjects (4.7 f 2.4 mmHg,
P < 0.01). Withdrawing alcoholics exhibited a
maximum mean fall in diastolic blood pressure on
standing of 3.7 2 3.4 mmHg, which was significantly different from the mean increases in diastolic blood pressure observed in abstinent alcoholics (7.1 k 2 . 9 mmHg, P < 0.05) or control
subjects (7.6 f 2.5 mmHg, P < 0.05). A fall in
blood pressure on standing was a common feature
in withdrawing alcoholics, and in four patients
this involved mild to severe orthostatic hypo-
G. Eisenhofer et al.
76
2
5
2
a-
Control subjects
Abstinent alcoholics
Withdrawing alcoholics
150-
I
I
I
I
I
I
I
I
I
140-
I
I
I
I
lf
130-
25
3
+
R
co
120-
110-
44y-t
I
I
I
+&-I
I
I
I
0
I
I
I
I
I
I
I
I
I
I
I
5
10
0
5
10
0
5
10
Time (min)
FIG. 3. Systolic and diastolic blood pressure (mean k SEM) in the supine position (w)
and in response to standing ( 7 ) in ten withdrawing alcoholics (o), ten abstinent
alcoholics (A) and ten control subjects (m). Withdrawing alcoholics had significantly
(P < 0.02) higher supine systolic and diastolic blood pressures than control subjects.
Withdrawing alcoholics showed impaired systolic and diastolic blood pressure
responses to standing which were significantly (P < 0.05) different from the responses
of abstinent alcoholics or control subjects.
tension (Table 1). All four withdrawing alcoholics
with orthostatic hypotension exhibited increases
in plasma noradrenaline upon standing.
In the group of six abstinent alcoholics complaining of dizziness on standing and found to
have orthostatic hypotension, three patients
(subjects 1-3) showed increases in plasma noradrenaline after standing while the other three
(subjects 4-6) had absent or reduced noradrenaline
responses (Table 1). In the three patients with
normal noradrenaline responses, supine noradrenaline concentrations were within the range of
control subjects (1.22-3.49 nmol/l) and abstinent
alcoholics without orthostatic hypotension (2.005.17 nmol/l). In the three patients with abnormal
noradrenaline responses, supine plasma nor-
adrenaline concentrations were outside these
ranges, with one subject having low noradrenaline
concentrations and the other two having high
noradrenaline concentrations. All three patients
with abnormal noradrenaline responses had
evidence of nervous damage which included
peripheral neuropathy, some degree of vagal
neuropathy, cerebellar atrophy and Wernicke’s
encephalopathy. All patients with orthostatic
hypotension showed heart rate increases of greater
than 10 beats/min after standing and all had
normal packed cell volumes (range 37-50%, mean
45%, normal range 38-52%) and serum albumin
concentrations that were below or within the
normal range (range 25-42 g/l, mean 35 g/l,
normal range 37-48 g/l).
Plasma catecholamines in alcoholism
Discussion
Findings of increased catecholamines and catecholamine metabolites in the cerebrospinal fluid [20221, blood [12, 231 and urine [13, 221 of withdrawing alcoholics have indicated that increased
central and peripheral adrenergic nervous activity
may be the basis of many of the symptoms of
alcohol withdrawal such as high blood pressure,
tachycardia, hyperhidrosis and tremor. This view
is supported by our findings that withdrawing
alcoholics have raised plasma concentrations of
noradrenaline and adrenaline in supine and standing positions. These concentrations varied widely,
probably reflecting variation of the withdrawal
reaction [ 121.
Despite raised plasma concentrations of catecholamines and normal or increased catecholamine and heart rate responses to standing, withdrawing alcoholics as a group showed a fall in
blood pressure on standing and significant impairment of blood pressure control. Four patients
in this group had significant orthostatic hypotension. It should be noted that these patients
were not specifically chosen for study because of
orthostatic hypotension. Thus orthostatic hypotension and impaired blood pressure control may
be common, although not often recognized,
features of the alcohol withdrawal syndrome.
A number of possible factors may cause impaired blood pressure control and orthostatic hypotension during withdrawal. Reduced a-adrenoceptor mediated responses have been shown to
occur in human alcoholic subjects during withdrawal [24] and, in the rat, a-adrenoceptor
densities have been found to be reduced both
centrally [25] and peripherally [26] after chronic
alcohol administration and during withdrawal
from alcohol. Impaired a-adrenoceptor mediated
vasoconstriction despite normal or increased
sympathetic nervous release of noradrenaline may
be one cause of impaired blood pressure control
during withdrawal. Also, alcohol withdrawal has
been shown to be associated with increased p
adrenoceptor activity in the rat heart preparation
[27] and, in man, 0-adrenoceptor antagonists have
been found to be useful in the treatment of
alcohol withdrawal [28, 291. Increased P-adrenoceptor mediated vasodilatation may be another
factor causing impaired blood pressure control
during alcohol withdrawal. A role of contracted
blood volume should also be considered, although
evidence indicates that alcohol withdrawal is
associated with overhydration and raised blood
volume rather than dehydration [30].
In unselected alcoholics who had been
abstinent from alcohol for 2-7 weeks, orthostatic
77
hypotension was not observed. These patients had
supine and standing plasma noradrenaline concentrations that were higher than those of agematched control subjects. The period of
abstinence from alcohol varied from 2 to 7 weeks
and it remains to be determined whether plasma
noradrenaline concentrations fall to normal values
after a more protracted period of abstinence.
Other investigators have found increased supine
and standing plasma catecholamine concentrations
associated with cirrhosis [18, 311. Liver disease in
the alcoholics that we have studied may therefore
contribute to raised plasma noradrenaline concentrations in both withdrawing and abstinent alcoholics.
We also measured the catecholamine and heart
rate responses to standing in six abstinent alcoholics who were selected for investigation because
of dizziness on standing and subsequently found
to have orthostatic hypotension. Three of these
(subjects 4-6) displayed normal heart rate
responses but had no significant postural increase
in plasma noradrenaline. This indicates that failure
of noradrenaline release contributed to orthostatic
hypotension in these three subjects. One of the
alcoholics with failure of noradrenaline responses
to standing had low plasma noradrenaline concentrations, which suggests the presence of a postganglionic lesion. The two other patients had high
plasma noradrenaline concentrations, which
excludes a post-ganglionic lesion [32]. The other
three abstinent alcoholics with orthostatic hypotension (subjects 1-3) displayed noradrenaline and
heart rate responses to standing that were comparable with those observed in the abstinent
alcoholics without orthostatic hypotension. In two
of these patients (subjects 1 and 2), who showed
large falls in blood pressure but noradrenaline
responses that were not greater than in control
subjects, a lesion affecting the release of noradrenaline cannot be ruled out. Contracted blood
volume or impaired vasoconstriction responses are
other factors that may have contributed to orthostatic hypotension in these patients.
In conclusion, alcohol withdrawal is associated
with raised supine and standing plasma concentrations of noradrenaline and adrenaline. Despite
this increased sympathetic nervous activity, withdrawing alcoholics show impaired blood pressure
control and some may exhibit orthostatic hypotension. With continuing abstinence from alcohol,
plasma noradrenaline concentrations may remain
elevated as compared with normal subjects but
orthostatic hypotension is not commonly
observed. In some abstinent alcoholics, in whom
orthostatic hypotension is observed, there may be
failure of noradrenaline release.
78
G. Eisenhofer et al.
Acknowledgments
This work was supported by the Alcoholic Liquor
Advisory Council and the Medical Research
Council of New Zealand. Thanks are also extended
to Dr David Lambie for helpful discussion.
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