Download Neurocardiogenic Syncope, what`s the physiological explanation

Neurocardiogenic Syncope, what’s the physiological explanation
A Conceptual paper for the general public
Melina Webb
Spring 2005
Syncope is defined as a sudden and transient loss of consciousness and postural
tone1 with spontaneous recovery. It is thought that about 20% of the population will faint
at least once while 10% will faint more than once during their life time (Sheldon et al.
2003). It is estimated that about 3% of all emergency room visits are due to unexplained
syncope2 and 1% of general hospital admissions. Syncope is a condition that can affect
any age group and the onset can occur at any time during an individual’s life. All though
majority of forms of syncope are not life threatening, a synoptic episode can cause
physical injury and can also decrease the individual’s quality of life, if episodes are
reoccurring. It seems there is an understanding what physiologically happens during a
syncope episode but it is unclear why this happens and how different events and chemical
levels are related.
Neurocardiogenic syncope is one of many possible ways to give a better
understanding of why some people experience unexplained syncope even though this
condition is somewhat unexplained itself. Neurocardiogenic syncope is the most
common name for this condition but it can also be referred to as vasovagal syncope or
neurally-mediated syncope. Neurocardiogenic syncope is put in the category of a reflex
syncope3, which is related to orthostatic4 intolerance. Figure 1 shows a flow chart of
autonomic control disorders and how Neurocardiogenic syncope is categorized within.
Neurocardiogenic syncope can be defined as a sudden, transient loss of consciousness
1
due to neurally-mediated5 hypotension6 and bradycardia7 (Kinay et al. 2004). It is
thought that a wide variety of activities can cause an episode8 to take place, making this
disease relatively difficult to diagnose. Some circumstances that seem to provoke an
episode are exercise, heat, excessive standing, fear and many more. With there being
such a wide range of activities that can cause an episode there is also a wide degree of
severity that an episode can have.
Neurocardiogenic syncope is most commonly diagnosed with a tilt table test. A
tilt table test involves an individual to be strapped to a table and the place at an angle.
The degree of the angle is not standard and seems to range anywhere from 50 to 80
degrees for an amount of time varying for 20 to 45 minutes (Szufladowicz et al, 2004).
This test is used because it seems that placing the body at an angle can provoke enough
similar stress to have an episode occur. With different people having a greater tolerance
to the stress, it is possible for a drug to be given, most commonly nitroglycerin or
isoproterenol, to induce a reaction. The administration of these drugs to an individual
unaffected by this condition will not induce a synoptic episode. A tilt table test is what is
used in almost all of the studies looking at Neurocardiogenic syncope to induce a presyncope or syncope.
Multiple studies have been done to measure different physiological events that
occur in the body during and previous to a synoptic event. Preceding and during an
episode the major functions of the body that seem to be affected are heart rate and blood
pressure. The reason why the synoptic event occurs is most likely due a disturbance in
the autonomic nerves system9 which then leads to hypotension6, orthostatic intolerance4
and resulting in syncope (Blair Grubb 1999). In a normal person it is thought that about
2
25% of the body’s total circulating blood is in the thorax region10. As soon as an
individual stands up about 500mL of blood is pulled downwards, to the lower extremities
and the lower abdomen, due to gravity. Within a few seconds after standing almost 50%
of the blood is redistributed through out the body. During this process venous return11 to
the heart, cardiac filling pressure12, and stroke volume13 all decrease. The stabilization of
the body back to its normal functioning after standing, orthostatic stabilization, in a
normal person is achieved within a minute of standing. This process is thought to be
disturbed some how in a person with Neurocardiogenic syncope but it is still in question
how and why this disturbance happens.
A major factor that causes confusion with this disease is how variable the
symptoms and reactions of the body can be between each affected person. In one study
which had the goal of measuring the difference in oxygen levels within the brain, defined
the degree of the body’s reaction into four different types (Szufladowicz et al 2004). The
first classification was given the label of Type 1 or mixed. In this category heart rate falls
only at the time of syncope but the ventricular rate14 does not fall less than 40 beats per
minute for more than ten seconds. During this time the heart will become asystolic15 for
zero to three seconds. The next category is Type 2A, where cardioinhibition16 occurs
without asystole for more than three seconds. Unlike the first type, ventricular rate falls
less than 40 beats per minute for more than 10 seconds. In both Type 1 and 2A, blood
pressure falls before heart rate falls. Type 2B, is cardioinhibitory and has a ventricular
rate less than 40 beats per minute for more then 10 seconds, asystole occurs for more than
three seconds, and blood pressure falls with heart rate. The last category is Type 3 which
is vasodepressor17, in which the patient’s heart rate does not fall more than 10 percent
3
from its peak when the syncope episode occurs. This study is important in that it labeled
many of the different stages that an individual’s body could go through during an episode,
but there is never a given reason why these steps are caused.
A study by Szufladowiz et al, states that the most widely accepted physiological
explanation that occurs during Neurocardiogenic syncope is a disturbance in the
regulation of blood pressure and heart rate with a secondary effect being hypoperfusion18
of the brain. It is thought that a low total blood volume, which causes a negative pressure
on the lower part of the body is what results in a synoptic episode. A term used to
explain the proposed process that causes Neurocardiogenic syncope is the Bezold-Jarish
reflex (Szufladowicz et al. 2004). It is thought that this reflex is an extreme version of
the reflex that is used to respond to hypotension. This reflex causes bradycardia, dilation
in peripheral blood vessels, which results in a lowering of blood pressure. In Figure 2
done by Fang et al it can be seen how blood pressure and heart rate are effected through
out the episode. The overall idea presented is that as the heart slows and blood pressure
decreases there is a lack of oxygen getting to the brain, which in the end results in
syncope.
There are a variety of causes and different mechanisms that occur before and
during a syncope episode. The major organ monitored in most of Neurocardiogenic
syncope testing in the heart (see Figure 3 and 4 for a detailed picture of the heart). In one
theory, it is thought that the heart will go through four major phases before a synoptic
event (Julu et al 2003). It has been measure that as a tilt table test begins the body goes
in the first phase which was labeled as “full compensation.” During this stage, there is a
brief decrease in blood pressure. There was an increase in forearm vascular resistance19
4
which stayed high for the remainder of the stage. During this first stage both cardiac
vagal tone (CVT) 20 and cardiac sensitivity to baroreflex (CSB) 21 decreased. Since
cardiac vagal tone is associated with the parasympathetic nervous system, a decrease in
CVT will cause an increase in heart rate. The second phase that Julu et al identified was
labeled as tachycardia22. At the start of tachycardia, heart rate and blood pressure
increase until they become unstable or hit a peak and level off for the rest of the phase.
The reported systolic blood pressure23 decreased but there was not a significant change in
diastolic blood pressure24. CVT and CBS seem to stay fairly constant to the values in the
first phase, which are considerably lower than the baseline readings. The third stage is
identified as instability. The defining characteristic of this stage is the oscillations of
arterial blood pressure25 and heart rate. Heart rate seemed to decrease compared to the
other two previous stages. Again, both CVT and CBS were much lower then baseline but
their values were not different from the two preceding phases. The final stage is labeled
as pre-syncope and recovery. During this stage there was a quick decrease in arterial
blood pressure and heart rate. In majority of the patients being tested in this experiment,
lower blood pressure occurred before bradycardia while in some others, both occurred at
this same time or opposite. This phase was ended in the experiment by putting the
subject back into a supine position and not allowing a synoptic episode to occur. CVT
and CBS were very low through out all of the phases but then increase dramatically once
placed in the supine position before dropping back to a resting lever. If CVT had a quick
and extremely large increase, asystole was associated with it. This study clearly shows
what changes are occurring in the body but never addresses why this could be happening.
5
Another idea involving the cause of Neurocardiogenic syncope is related to
exercise. In dynamic or isotonic exercise the muscle length changes to compensate for
the added tension put on the muscle. Due to the need for more oxygen to the muscle,
cardiac output26, stroke volume, heart rate, and mean arterial pressure27 are increased, and
pulmonary vascular resistance28 is decreased. In a study done by Kosinski et al, it is
thought that the beginning event in Neurocardiogenic syncope is vigorous ventricular
contraction29 which causes the baroreceptors30 to respond improperly. In exercise an
individual wants an increased cardiac output but it seems that this could result in a
decreased filling pressure which would cause a rapid change in stroke volume. This
would then be related to orthostatic stress which then would lead to a synoptic episode
(Kosinski et al). Even though the above idea seems to be an explanation, Kosinski et al,
also reviewed a couple studies finding no relationship between VO2 max32 and
orthostatic tolerance. This still leaves the exact relationship between exercise and an
episode unclear but still can lead to an overall understanding of what occurs within the
body due to the fact that exercise is a purposed cause. During exercise it is thought that a
vigorous myocardial contraction31 can cause a synoptic response (Kosinski et al).
One other important factor in determining the exact cause of Neurocardiogenic
syncope could be related the plasma levels of β endorphin32, norepinephrine33, and
epinephrine34. It is known that endogenous opioids35 and catecholamines36 are connected
to autonomic activity. It was seen that β endorphin and epinephrine levels were increased
greatly in a tilt-table induced synoptic episode and in an episode induced with
nitroglycerin, but they also observed no significant increase in these levels in the episode
was induced with isoproterenol or if the patient had a negative response, this data is
6
shown in Table 1 and Figure 5. The conclusions that Takase et al found could be a direct
or secondary cause of neurally-mediated syncope. The major problem with this study is
that it is thought that nitroglycerin and isopropterenol induce Neurocardiogenic syncope
but if there are differences in the chemical levels in the body between the two, then this
testing method can be found unreliable. Many of the other studies would use
isoproterenol to induce syncope in many subjects who did not have a synoptic episode
within 20 to 30 of being placed at an angle. The changes in endogenous opioids35 and
catecholamines36 could be an underlying cause of Neurocardiogenic syncope but further
research is needed to confirm this.
There seems to be multiple factors that cause Neurocardiogenic syncope. There
are multiple studies that monitor basic functions of the body but never question why these
reactions occur. The next step that needs to be taken to get a better understanding of
what causes the body to physiological respond the why it does is to perform a study that
measures multiple factors and then purpose there connections. Through the above
knowledge it seems that all of the different factors are related but it does not seem that
anyone has put everything together and found a clear conclusion to this condition. This is
an important topic since Neurocardiogenic syncope affects a large number of people.
After looking at what is known about Neurocardiogenic syncope, it can be concluded that
it is still unknown what causes the body to react in the way it does and further research
needs to be done.
Although there are many possible physiological explanations that seem to give a
reason for Neurocardiogenic syncope, there are still many unexplained aspects of this
condition. It seems that since a few different treatments have been discovered to help
7
people with this condition, doctors are content with using them without having a clear
understanding about what is occurring with in the body. Through looking at the multiple
studies that give a physiological reason to Neurocardiogenic syncope it seems that this
condition is related to a change blood pressure, heart rate, and vagal tone. The next step
that needs to be taken before a definite treatment can be decided is more research to
understand what causes this reaction in the body. If an understanding of cause and
mechanism are obtained then different treatments to correct the problem can take place,
resulting in the best way to manage a condition that affects a large number of people.
8
1. postural tone: the tone that is in the muscles and the body that allows the body to
have posture, the positioning of the limbs and body
2. unexplained syncope: syncope that occurs for an unexplained reason, the person
that experiences this has no structural heart disease, arrhythmia, or neurological
disease
3. reflex syncope: syncope that is cause from an involuntary reaction within the
body
4. orthostatic: related to or caused by standing up
a. orthostatic intolerance: inability to compensate for pressure change when
one stands up
5. neurally-mediated hypotension: low blood pressure due to Neurocardiogenic
syncope
6. hypotension: low blood pressure
7. bradycardia: decreased heart rate (>60beats/min)
8. synoptic episode: an episode beings when an individual gets pre-synoptic
symptoms and ends after the person has fainted
9. autonomic nervous system: is divided into two subdivisions, the sympathetic and
parasympathetic nervous system
a. sympathetic nervous system: the part of the nervous system used in the
“flight or fight” response, this response can increase heart rate, constrict
blood vessels and raise blood pressure
b. parasympathetic nervous system: the part of the nervous system used in
more relaxing situations, this response decreases heart rate, increases
intestinal and gland activity and relaxes sphincter muscles
10. thorax region: the area of the body that is above the diaphragm but below the neck
11. venous return: the amount of blood that is returning to the heart from the veins
12. cardiac filling pressure: the pressure within the heart as the blood flows into the
heart before the it contracts
13. stroke volume: the amount of blood pumped out of the ventricles of the heart with
each beat
14. ventricular rate:
15. asystolic or asystole: absence of heart rate and electrical activity with in the heart
16. cardioinhibition: the heart is being blocked or prevented from performing
correctly
17. vasodepressor: a reduction of tone in a blood vessel due to vasodilatation causing
blood pressure to lower
a. vasodilatation is when a blood vessels passage in the middle is widened
due to the smooth muscle relaxing
18. hypoperfusion: a decrease blood flow through an organ, in this context the brain,
this then results in a lowered oxygen level
19. forearm vascular resistance: the amount of resistance to blood flow in the blood
vessels of the forearm
20. cardiac vagal tone (CVT): the parasympathetic nervous system controls vagal
tone which has the role of decreasing heart rate
9
21. cardiac sensitivity to baroreflex (CSB): the baroreceptors are used to detect any
pressure changes with in the blood vessels, so this measures the amount of change
that occurs in the heart when there is a pressure change
22. tachycardia: an increase in heart rate
23. systolic blood pressure: tells you the amount of pressure that is being put on the
walls of the arteries while the heart is contracting. This is the top number when
given a blood pressure and is normally considered high if above 150 mmHg
24. diastolic blood pressure: tells you the amount of pressure that is being put on the
walls of the arteries while the heart is at rest (not contracted or between heart
beats). This is the bottom number when blood pressure is talked and is normally
considered high if it is above 90 mmHg
25. arterial blood pressure:
26. cardiac output: is the measurement of the amount of blood flowing through the
heart to the rest of the body
27. mean arterial pressure: mean arterial pressure is the average pressure being
exerted in the arteries walls, to calculate this the systolic and diastolic pressures
are added together and then divided by 2
28. pulmonary vascular resistance
29. ventricular contraction
30. baroreceptors: These are pressure sensitive receptors that can be found on the wall
of the atrium of the heart, in the vena cava, the aortic arch and in the carotid sinus.
These receptors can detect when the walls of the above structures begin to stretch
due to an increase in pressure
31. myocardial contraction: contractile action of the heart
32. VO2 max: The maximal rate of oxygen an individual can consume
33. β endorphin: a chemical within the body that is involved in autonomic activity
34. norepinephrine: chemicals within the body that is involved in autonomic activity
35. endogenous opioids: chemicals within the body that is involved in autonomic
activity
36. catecholamines: chemicals within the body that is involved in autonomic activity
10
Figure 1: This is a flow chart from an article done by Blair P. Grubb, 1999. It shows how
Neurocardiogenic syncope is related to other disorders of the autonomic control
associated with orthostatic intolerance
11
Figure 2: These two graphs show the result from the Fang et al study. The top graph
shows the average systolic blood pressure (SBP) at baseline (the patient was in the supine
position for 5 minutes and then SBP was taken), at endpoint (when the patient
experienced syncope or pre-synoptic symptoms), at supine position for 1 minute, at
supine position for 2 minutes, and at supine position for 4 minutes (this was after the
endpoint and the patients were returned to there baseline position). The second graph
shows heart rate at the same five points that SBP was measured. The top graph, showing
SBP, shows that there is a dramatic decrease in SBP at the point of syncope or presyncope and then once the patient is placed back in to a supine position SBP begins to
rise to the normal resting or base line level. The second graph shows heart increase
during syncope or pre-syncope and then still rising after the episode but then returning to
baseline.
12
Figure 3. This is a picture of the heart with all of the major structure labeled.
Figure 4. This is a second picture of the heart with only the main blood vessels being
labeled.
13
Table 1. This table is from Takase et al., 2003. This table lays out each group that was
test; it shows the average and the standard deviation (SD) of the test groups.
Figure 5. This shows the results of the Takase et al study of the beta-endorphin levels.
They are shown in the four different test groups that are described in the above table (1).
14
Fang, B., Kuo, L. (2000). Usefulness of Head-Up Tilt Test in the Evaluation and
Management of Unexplained Syncope or Pre-syncope. Jpn Heart J, 41; 623-631
Kinay, O., Yazici, M., Nazli, C., Acar, G., Gedikli, O., Altinbas, A., Kahraman, H.,
Dogan, A., Ozaydin, M., Tuzun, N., Ergene, O. (2004). Tilt Training for
Recurrent Neurocardiogenic Syncope. Jpm Heart J, 45; 833-843
Grubb, Blair P. (1999). Pathophysiology and Differential Diagnosis of Neurocardiogenic
Syncope. The American Journal of Cardiology, 84; 3Q-9Q
Eltrafi, A., King, D., Silas, J., Currie, P., Lye, L. (1999). Role of carotid sinus syndrome
and neurocardiogenic syncope in recurrent syncope and falls in patients referred
to an outpatient clinic in a district general hospital. Postgrad Med Journal, 76;
405-408
Szufladowicz, E., Maniewski, R., Kozluk, E., Zbiec, A., Nosek, A., Walczak, F. (20040.
Near-infrared spectroscopy in evaluation of cerebral oxygenation during
vasovagel syncope. Institution of Physics Publishing. 823-836
Calkins, H., Shyr, Y., Frumin, M., Schork, A., Morady, F. (April 1995). The value of the
clinical history in the differentiation of syncope due to ventricular tatycardia,
atrioventricular block, and neurocardiogenic syncope. The Journal of Medicine,
96; 365-373
Julu, P., Cooper, S., Hansen, S., Hainsworth, R. (2003). Cardiovascular regulation in the
period preceding vasovagal syncope in conscious humans. The physiological
society. 549.1; 299-311
Sheldon, R., Rose, S., Connolly, S. (2003). Prevention of syncope trial (POST): a
randomized clinical trial of beta blockers in the prevention of vasovagal syncope.
Europace, 5; 71-75
Bloomfield, Daniel (2002). Strategy for the management of vasovagal syncope. Drugs
Aging, 19; 179-202
Takase, B., Matsushima, Y., Umeda, E., Satomura, K., Katsushika, S., Ohsuzu, F., Sato,
T., Kurita, A. (2003). Endogenous Opioids and Epinephrine in Nitroglycerin
Provocation Tilt Test in Patients with Neurally Mediated Syncope. Jpm Heart J,
44; 493-503
Kosinski, D., Grubb, B., Kip, K., Hahn, H. (1996). Exercise induced neurocardiogenic
syncope. American Heart Journal, 132; 451-452
15