Europace (2007) 9, 220–224
doi:10.1093/europace/eum025
A new alcohol provocation head up tilt protocol
in the patients with alcohol-related syncope
Katsuhiko Tateoka, Yu-ki Iwasaki*, Takuya Ono, Yoshinori Kobayashi, Takao Katoh,
and Teruo Takano
Department of Internal Medicine, Division of Cardiology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 1138603,
Japan
Received 22 December 2006; accepted after revision 26 January 2007; online publish-ahead-of-print 8 March 2007
KEYWORDS
Alcohol;
Head up tilt-test;
Provocation test;
Neurally-mediated syncope
Aims Drinking alcohol is known to be one of the triggering factors of neurally-mediated syncope. Little is
known about the diagnostic utility of the conventional and alcohol provocation head up tilt-test (HUT) in
patients with alcohol-related syncope. We investigated the effect of the alcohol provocation HUT.
Methods and results We studied 12 patients (8 males, age 51 + 19 years) who had a history of
unexplained post-alcohol ingestion syncope. An alcohol provocation protocol HUT (alcohol HUT), in
which the protocol required 350 mL of 5% alcohol beer to be drunk over 5 min followed by positioning
with the table tilted up for up to 30 min, was performed after the control and isoproterenol (ISP)
HUT. None of the subjects (0/12) exhibited a positive response in the control HUT, and only one
subject had a positive response (1/12; 8.3%) in the ISP HUT. In the alcohol HUT a positive response
(9/12; 75%) increased in the patient group, whereas there were no positive responses in the normal
control group.
Conclusion In the conventional HUT protocols, including ISP provocation, it was difficult to produce a
positive response in the patients with alcohol-related syncope. Alcohol ingestion was a useful diagnostic
provocation method in such patients.
Introduction
Syncope is a transient loss of consciousness that occurs
spontaneously and resolves naturally, with no residual
neurological abnormalities. The Framingham study in the
US found that 3.0% of males and 3.5% of females had one
or more episodes of syncope in a 26-year tracking investigation,1 indicating that syncope is not a rare disease.
Among the types of syncope of a so-called unknown cause
not coincident with any organic disease, neurally-mediated
syncope (NMS) is regarded as the most prevalent.
The head up tilt-test (HUT) has been a useful diagnostic
method for patients with NMS.2,3 Although the specificity
of the HUT has been quite high (93–100%), the sensitivity
has been relatively low (38–75%).3–6 The drug provocation
HUT such as with an isoproterenol and nitroglycerin infusion
during the HUT has increased the sensitivity without affecting the specificity.7–10 However, despite the widespread
acceptance of the HUT as a diagnostic method for syncopal
patients, it still remains unclear what the most optimal provocative agent during the HUT is. One reason is that, the
* Corresponding author. Tel: þ81 3 3822 2131.
E-mail address: [email protected]
triggers or predisposing factors of NMS have been diverse
and several pathophysiologies of NMS could be considered.
Drinking alcohol has been known to be one of the triggering
factors of NMS. There is substantial clinical experience in
post-alcohol consumption syncope. More specifically,
Dermksian et al. reported.11 that alcohol-related syncope
occurred in 10 cases (12%) with a mean age of 31.3 years.
Those patients were not always drinking so much alcohol
at the time of the syncope. It is speculated that alcohol
consumption can be regarded as one of the predisposing or
triggering factors of NMS.
However, little is known about the diagnostic utility of the
conventional and alcohol provocation HUT tests in patients
with alcohol-related syncope. The purpose of this study
was to investigate the haemodynamic response and effect
of the alcohol provocation HUT in the patients with alcoholrelated syncope.
Methods
Subjects
The study population consisted of 12 consecutive patients (8 males,
4 females; mean age 51 + 19 years) who had a history of unexplained post-alcohol consumption syncope. The amount of alcohol
& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: [email protected]
A new alcohol provocation head up tilt protocol
they drank varied from a glass of wine to two bottles of beer. Almost
all the subjects experienced a syncopal episode within 1 h after
ingesting the alcohol in a standing position. All patients underwent
a 12-lead ECG, 24-hour Holter ECG, echocardiogram, and blood
sampling, which demonstrated no abnormal findings that could be
attributed to the cause of the syncope. An electroencephalogram
and brain computed tomography were performed in selected
patients if indicated. Any cases of chronic atrial fibrillation or diabetes mellitus were excluded from the present study.
Control HUT testing (control-HUT) protocol
All tilt table tests were performed between 15: 00 and 17:00 h. The
patients had abstained from any food or drink for 6 h prior to
the testing. The temperature and illumination in the room, where
the testing was performed were kept nearly constant in an effort
to exclude any factors external to the testing. During the HUT,
the electrocardiographic leads I, II, and III were monitored, and
the non-invasive blood pressure and heart rate were monitored continuously using a Finapres apparatus (Ohmeda 2300; Louisville
Colorado). The continuous data were recorded by an AcqKnowledge
multichannel data acquisition system (Biopac Systems; Santa
Barbara, CA, USA).
The subjects were made to rest in the supine position for 5 min,
after which the baseline ECG and blood pressure were recorded.
The HUT was then performed by raising the subjects, on an
electrically-driven tilt table (Minato Ikagaku, Tokyo, Japan)
equipped with a footboard, to an inclination of 808 for a
maximum period of 30 min. The positive criteria of a HUT were
defined as a systolic blood pressure of 80 mmHg or lower or heart
rate of 50 bpm or lower, accompanied by syncope or near-syncopal
symptoms. Near-syncope was defined as the sensation of prodromal
symptoms-related to syncope (lightheadedness, nausea, and
dizziness).
All patients were informed of the study and gave their written
consent. The research protocol was approved by the ethical
committee of Nippon Medical School.
HUT testing with an isoproterenol provocation
(ISP-HUT) protocol
In the case of a negative response in the control HUT, the subjects
were made to rest in the supine position for an additional 5 min,
and isoproterenol was then infused by a continuous intravenous
administration at a dose of 0.01 mg/kg/min. Thereafter, the HUT
was repeated at an 808 tilt for up to 10 min. The HUT was discontinued if the maximum heart rate reached 150 bpm or higher or the
subjects experienced palpitations or other such types of discomfort.
HUT testing with an alcohol provocation
(alcohol-HUT) protocol
On a subsequent day, the patient was made to rest in the supine position for 5 min, and then the alcohol ingestion was performed by
having the patient consume 350 mL of 5% alcohol beer (17.5 g
ethanol) over 5 min. The patient was the made to rest in the
supine position for another 5 min, and the HUT was performed at
a tilt angle of 808 for up to 30 min.
To exclude any false positive responses in the alcohol provocation
HUT, a group of five subjects (three males, mean age 35 + 9 years)
without a history of syncope in their medical history or any
structural heart disease, served as the control group.
Statistical analysis
The quantitative data were expressed as the mean + SD. An ANOVA
was used for statistical comparisons of the continuous variables
among the groups. The x2 test was used for the categorical variables. A value of P , 0.05 was considered significant.
221
Results
Results of the HUT testing
Table 1 presents the HUT test results of the subject age and
sex. None of the subjects (0/12) in the alcohol-related
syncope group had a positive response in the control-HUT.
Although only one case had a positive response (1/12, 8%)
in the ISP-HUT, the alcohol-HUT dramatically increased the
positive responses (9/12; 75%) in the alcohol-related
syncope group. These were classified as a mixed-type,
cardioinhibitory-type, or vasodepressor-type according to
the classification by Sutton et al.,12 and the composition
of the nine positive cases in the alcohol-HUT was five mixedtype, four vasodepressor-type, and no cardioinhibitory-type
cases. On the other hand, in all 5 control group patients, the
alcohol-HUT resulted in a negative response. On the basis of
those results, the sensitivity, specificity, positive predictive
value, and negative predictive value of the alcohol-HUT
testing was 75, 100, 100, and 63%, respectively.
Haemodynamic response during the HUT
We compared the change in the heart rate in the control-HUT,
ISP-HUT, and alcohol-HUT groups during the supine and tilt
positions (Figure 1). With regards to the heart rate in
the supine rest, the heart rate was higher in the ISP-HUT
group than in the control-HUT group (84.9 + 17.7 vs.
66.9 + 11.5 bpm, P , 0.01). The alcohol-HUT group did
not demonstrate a significant difference vs. the control-HUT
group or ISP-HUT group (73.6 + 10.3 bpm vs. 66.9 +
11.6 bpm, 84.9 + 17.7 bpm, P ¼ NS). There were no significant differences in the maximum heart rate during the HUT
between the control-HUT group and alcohol-HUT group
(88.7 + 12.1 bpm vs. 99.3 + 12.4 bpm, P ¼ NS). The
heart rate was significantly higher in the ISP-HUT group
than in the control-HUT group or alcohol-HUT group
(113.3 + 15.5 bpm, 88.6 + 12.1 bpm, 99.3 + 12.5 bpm,
P ,0.01). The increased ratio of the heart rate (% increase
in the heart rate) was calculated by the following formula:
% increase ¼ maximum heart rate during the HUT/ heart
rate in the supine position 100%. The percentage increase
in the heart rate was 134.8 + 22.5% in the control-HUT,
136.6 + 24.0% in the ISP-HUT, and 136.4 + 20.2% in the
Table 1 Characteristics and results
Subjects Age
(years)
Sex
1
2
3
4
5
6
7
8
9
10
11
12
Male
Female
Male
Female
Male
Male
Female
Male
Male
Male
Male
Female
47
59
66
24
60
73
59
72
48
39
51
22
51 + 19
(þ): positive, (–): negative.
Control-HUT ISP-HUT Alcohol-HUT
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
0/12
(–)
(–)
(–)
(–)
(–)
(–)
(þ)
(–)
(–)
(–)
(–)
(–)
1/12
(–)
(þ)
(þ)
(þ)
(–)
(þ)
(þ)
(þ)
(–)
(þ)
(þ)
(þ)
9/12
222
Figure 1
K. Tateoka et al.
Comparison of the changes in the heart rate in the control-HUT, ISP-HUT, and alcohol-HUT groups in the supine and tilt positions.
The effect of the alcohol on the central nervous system
and cardiovascular system had various pathophysiological
responses. Several mechanisms of the alcohol-related
syncope could be considered.
Alcohol metabolism
alcohol-HUT, respectively. (Figure 2). There were no significant differences in the % increase in the heart rate after
the tilt-up between the ISP and alcohol administration
(136.6 + 24.0% vs. 136.4 + 20.2%, P ¼ NS).
Therefore, the alcohol provocation increased the sensitivity of the HUT without increasing the heart rate, unlike
the ISP infusion. There were no side effects associated
with the alcohol provocation except for one patient who
became intoxicated with only one beer, but recovered
within 1 h with a saline infusion.
Alcohol (ethyl alcohol C2H5OH, molecular weight 46) is
essentially a substance that causes symptoms of central
nervous system paralysis, and even low concentrations in
the blood act to inhibit the central nervous system.
Approximately 20–25% of the alcohol is absorbed by the
stomach, and the remainder is absorbed primarily by the
small intestine. Approximately 90% of the alcohol consumed
orally on an empty stomach is absorbed within 1 h.
Acetaldehyde, produced as an ethanol metabolite, is also
regarded as having a vasodilatory effect. The blood concentrations of ethanol and acetaldehyde immediately increase
after alcohol ingestion and reach a peak level within 1 h.
The ethanol concentration in the blood reflects the quantitative alcohol consumption, but the acetaldehyde varies
depending on the type of aldehyde dehydrogenase (ALDH)
present, ALDH2 1/ 2 or ALDH2 2/ 2.
Approximately 40% of Japanese individuals have a lowactivity ALDH type (ALDH2 1/ 2) or an inactive type
(ALDH2 2/ 2), and consumption of small amounts of
alcohol by those individuals causes facial flushing.13,14
Therefore, even if the alcohol ingestion is of a small
volume, the effects of the acetaldehyde on the cardiovascular system become much more prominent, especially in
Japanese rather than Europeans or Americans.
Discussion
Sympathetic nervous activity and alcohol-related
syncope
In the present study, the control and ISP provocation HUT
tests had difficulty in inducing a positive response in
the patients with alcohol-related syncope. The alcohol
HUT dramatically increased the positive responses without
producing a false positive response.
The isoproterenol HUT has been widely used as a provocation
drug in patients with syncope, in whom the control HUTexhibited a negative response. Isoproterenol exaggerates the
sympathetic activity producing vigorous contractions. The
vigorous contractions in a hypovolemic ventricle might
Figure 2 Effect of tilt up on the heart rate in the control, ISP and
alcohol HUT.
A new alcohol provocation head up tilt protocol
stimulate mechano-receptors that might trigger hypotension
and bradycardia. Isoproterenol has a vasodilator effect
derived from the b2 sympathomimetic action in addition to
the cardiac systolic-enhancing effect derived from the b1
sympathomimetic action. In the present study, however, the
ISP administration did not increase the sensitivity of the
ISP HUT, however, the alcohol ingestion did increase it.
Moreover, the maximum heart rate during the HUTwas significantly higher with the ISP administration as compared to the
alcohol ingestion, indicating that the b1 and b2 stimulation
might not play a major role in the development of syncope
in patients with alcohol-related syncope.
223
Limitations
There were several limitations to the present study. Our
study had a small study population, especially for the
control subjects, which might have resulted in an insufficient specificity for the calculations. Although this study
demonstrated a dramatic result of the alcohol-HUT, we
could not confirm the exact mechanism of the alcoholrelated syncope. We moreover did not evaluate the ALDH
typing or concentration of ethanol and acetaldehyde in
this study. However, the amount of alcohol at the time of
the syncope was almost equal to the amount of the use in
the alcohol HUT study. Further study will be needed to
clarify these problems.
Haemodynamic effects of alcohol
In addition to the effect of alcohol on the central nervous
system, the peripheral vasodilatory effect of acetaldehyde
also plays an important role in alcohol-related syncope. In
an alcohol and placebo experiment using healthy individuals
as subjects,15 the heart rate was increased in the alcohol
group vs. the placebo group after alcohol consumption,
both in the supine and standing positions and the effect
was prolonged beyond detection of the blood alcohol concentration. A report by Narkiewicz et al. 16 stated that the
blood pressure was unchanged after vs. before the alcohol
consumption, but the heart rate was significantly increased.
In the present study, there were no significant differences in
the blood pressure before and after the alcohol administration in the supine position. The vasodilatory effect of
alcohol may not have a prominent effect at the level of
the limb arteries. Alcohol ingestion increases the gastrointestinal blood flow, which creates a change in the distribution of blood pooling. Therefore, as we have already
reported,17 the systemic vascular resistance is reduced by
alcohol ingestion which decreases the venous return
leading to an empty left ventricle. Unfortunately, we
could not measure the peripheral vascular resistance or
other such parameters that would have substantiated the
vasodilatory effect. Drinking water or other types of water
infusion has been reported to improve the orthostatic tolerance in the HUT.18,19 In our research, the orthostatic tolerance was not improved even by the infusion of 350 mL of
an alcoholic beverage; rather, the positivity became higher
with the alcohol-HUT than it did with the isoproterenol infusion. Therefore, the alcohol infusion has a more potent
effect than a water infusion on the improvement in the
orthostatic tolerance.
Alcohol and serotonin
Some of the patients with NMS exhibited a significant
improvement in their symptoms after treatment with a serotonin reuptake inhibitor. Serotonin is known to be a central
nervous system neurotransmitter that regulates many functions, including the blood pressure and heart rate. It has
been speculated that the serotonin in the central nervous
system plays a crucial role in the pathogenesis of NMS. On
the other hand, alcohol ingestion increases the extracellular
levels of the forebrain serotonin, which might overstimulate
the post-synaptic serotonin receptors leading to hypotension
and bradycardia. Therefore, the mechanism of the alcoholrelated syncope might involve the serotonin in central
nervous system.
Conclusions
Drinking alcohol was considered to be a natural provocation
method and could reproduce a similar situation as that at
the time of the syncope without causing any side effects
as a provocation agent might. The alcohol HUT was a
useful and safe diagnostic provocation method in the
patients with alcohol-related syncope.
Acknowledgements
We thank Mr John Martin for his linguistic assistance.
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