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Syncope
glossary
Syncope (fainting) is a reasonable starting point. In
principle, it is familiar to all of us because it is common. Nonetheless it
represents a sudden change in well-being that often encourages fear in families
and discomfort among physicians. Syncope translates from the Greek as “a
cutting short” (1). It is defined as a sudden transient loss of consciousness
with loss of postural tone and spontaneous recovery caused by impaired blood
flow to the central nervous system. Syncope may occur supine or upright and
under a wide variety of conditions. It may be due to medication, cardiac
disease, most commonly arrhythmic disease, or severe impairment of cardiac blood
flow by mechanical pump failure or obstruction. It may be due to transient
impairment of central nervous system function as in a transient ischemic attack
(mild stroke) but this is less common. However, although convulsive-like
movements may occur during syncope, it is distinct from a seizure disorder, and
is distinct from coma in which loss of consciousness is not transient at all.
(2)
glossary
Cardiac syncope is often quite serious and should be
regarded as life-threatening. Although cardiac syncope is not often closely
associated with orthostasis it may be. Causes of cardiac syncope include the
long QT syndrome, arrhythmogenic right ventricular dysplasia, cardiomyopathies,
left ventricular outflow obstruction, myocardial infarction, primary pulmonary
hypertension, and most commonly ventricular tachycardia (fast heart rate),
bradyarrhythmias (overly slow heart rate) and related arrhythmic events (3). The
first job in evaluating syncope is to evaluate the patient for possible cardiac
syncope. When specific cardiac disease is found, it is treated specifically.
Thus, for example, ventricular tachycardia is treated with antiarrhythmics,
bradyarrhythmias causing syncope are treated with a pacemaker, long QT syndrome
with medication and a defibrillator if needed, and aortic valve disease with
surgery. Cardiac syncope may first manifest during exercise, which is the best
and most physiologic stressor of the myocardial circulation and overall cardiac
function. Exercise related syncope should raise a “red flag” for underlying
heart disease (4). Nevertheless, despite flag-waving, the large majority of
exercise related syncope cases are non-cardiogenic in origin, at least for
children and adolescents. Cardiogenic syncope has been well described in
numerous texts including those already referenced and is not the central topic
for discussion here because it accounts for a small percentage of syncope in
children and of those many have previously known cardiac conditions.
glossary
Approximately 90% of syncope in children is either
“neurocardiogenic” or “unexplained”. Often the unexplained variety is
reclassified as neurocardiogenic once tilt table testing has been performed (5).
Neurocardiogenic is the current term (at least for today) for fainting mediated
through a combination of inappropriate vascular (blood vessel) and heart rate
control. It is rarely fatal – although it can be under certain unique
circumstances – but it can be injurious. There is little compelling evidence
for a primary role for the heart in neurocardiogenic syncope, once cardiogenic
syncope has been ruled out. The term is thus somewhat misleading. Synonyms for
neurocardiogenic include neurally mediated syncope and vasovagal syncope. Almost
all of neurocardiogenic syncope in children can be deemed vasovagal, an
appropriate descriptive designation coined by Sir. Thomas Lewis (6) in which the
vaso part denoted widening of blood vessels, and the vagal part denotes slowing
of the heart rate through stimulation of the vagus nerve. On the other hand
adult syncope is much more likely to be cardiogenic – about a 50/50 split with
neurocardiogenic syncope. Vasovagal syncope almost always occurs in the upright
position, which may sometimes include sitting. Therefore it is regarded as a
form of orthostatic intolerance.
Orthostatic Intolerance
Defining Characteristics glossary
Orthostasis
= standing upright. Orthostatic intolerance can be defined as “the development
of symptoms during upright standing relieved by recumbency” (7). When
there is acute orthostatic intolerance it usually manifests as syncope. Many
syncopal patients have no intercurrent illness;
between faints they are well. However, chronic orthostatic intolerance also
occurs and may be confused with syncope because chronic illness can be
punctuated by acute fainting episodes. Therefore, we must rely strongly on the
history to determine chronicity. Defining symptoms of chronic orthostatic
intolerance include dizziness in all patients with a high incidence of altered
vision (blurred, ‘white outs’, ‘black-outs’), fatigue, nausea and
palpitations (8, 9). A large fraction of patients also experience headache,
tremulousness, difficulty breathing or swallowing, sweating, pallor, and other
vasomotor symptoms. Most forms of orthostatic intolerance are not typically
life threatening although circumstances can conspire to create considerable
risk. Also, people with complete autonomic failure, rarely observed in children,
may lead abbreviated lives (10).
Physiology of Orthostasis
glossary
Upright posture is a fundamental human activity
requiring rapid and effective circulatory and neurologic compensations in order
to maintain blood pressure and consciousness. If not for these defense
mechanisms the precarious positioning of the brain well above the neutral
cardiac point (roughly at the right atrium) and the presence of large venous
reservoirs below the neutral point would cause blood pressure to fall rapidly
due to gravitational pooling of blood within the dependent veins with decreased
brain blood flow and loss of consciousness. Once consciousness and postural tone
is lost the ensuing fall would render a person recumbent causing blood
remobilization and restored consciousness (11). Our primary defense against
pooling is the “muscle pump” in which contractions of leg muscles propels
sequestered venous blood back to the heart (12). This also encourages forward
flow by reducing venous pressure and increasing the pressure difference between
leg arteries and leg veins. A defective muscle pump is an important reason that
astronauts are vulnerable to orthostatic stress after exposure to low gravity;
they develop rapid leg muscle atrophy and refractory lower limb pooling (13).
The muscle pump is also partly defeated during quiet standing and is nearly
completely defeated while standing without motion. The second line of defense
against orthostatic intolerance is neurovascular adjustment which includes rapid
changes in artery resistance vessel tone (vasoconstriction) limiting flow to the
extremities and splanchnic (liver, spleen and digestive tract) vascular bed
while promoting passive emptying. The splanchnic bed is the largest venous
reservoir at least when supine. Splanchnic venoconstriction (vein contraction)
occurs further enhancing emptying (14). These reflex compensatory mechanisms are
primarily controlled by the high-pressure arterial pressure receptors also
called “arterial baroreceptors” and to a lesser degree by low-pressure
cardiopulmonary reflexes (15, 16). Later, humoral (hormonal) effects may enhance
the defense against standing through the activation of the
renin-angiotensin-aldosterone system, the release of epinephrine and vasopressin,
and by central effects (17). During quiet standing the neurovascular
compensatory mechanisms are only partly effective. While systolic blood pressure
normally does not fall and diastolic blood pressure often rises, cardiac output
decreases an estimated 25% due to impaired heart filling only partially offset
by an increase in heart rate. There is even a normal decrease in cerebral blood
flow (on the order of 6%) because cerebrovascular autoregulatory function (the
ability of the brain to maintain its blood flow constant under various blood
pressures) is essentially at the limit (18). Thus, standing is a perilous
venture and is only “easily” studied in bipeds such as man. Apes are more
reluctant experimental candidates. A corollary to all this is that dogs don’t
faint. In dogs, the heart, brain and major venous reservoirs are all at the same
level. Canines are, on the average, far more physiologically viable circulatory
specimens than man.
Patterns of Orthostatic Intolerance-Orthostatic Stress Testing
and Head-up Tilt
glossary
Patterns of orthostatic intolerance are best defined by an orthostatic
stress test – i.e. a means by which upright standing stress can be imposed in
a controlled fashion and the physiological response monitored in detail. While
standing can be used, individual differences and patient motion may make this
difficult. Therefore the standard of orthostatic assessment is the head-up tilt
table test. Although head-up tilt was used to evoke autonomic reflexes in early
NASA experiments, it was first used as a provocative agent in 1986. (19). This
device comprises a table driven by an electrical motor with a supportive
footboard enabling positioning of a patient at varying angles of upright tilt.
Although it would seem that an angle of 90o is most physiologic, this
usually induces too many “false positives” (patients with no history of
orthostatic intolerance who have intolerance induced during testing). Therefore
lesser angles such as 60o or 70o are customarily used
(20). Following a resting period, the patients are placed upright and their
response over a period of tilt assessed – this is usually anywhere between
30-45 minutes. At a minimum, blood pressure
and continuous electrocardiography are assessed. Typically a form of continuous
blood pressure assessment such as a finger plethysmography or an arterial
tonometer is used and respirations are also assessed on a moment to moment
basis. Other researchers have used methods to assess peripheral, thoracic
(chest), and central nervous system blood flow which are methods still consigned
to the research domain. Many adult laboratories use medications to enhance the
fainting response, often isoproterenol, which produces more “true” positive
tests (and more false positives) although the physiological underpinnings of
this use are flimsy. The central purpose of a tilt table test is to reproduce
symptoms of orthostatic intolerance in a setting in which hemodynamic variables
(blood pressure, heart rate, blood flow) can be assessed. Most often there is
correlation with changing physiological signs, but the definition of orthostatic
intolerance requires symptoms. Thus for example the incidence of false
positive faints during head-up tilt is high. If the complaining symptoms are not
reproduced but the patient has a simple faint, the test is judged as negative.
For example, my son fainted during his tenure as a HUT control patient. He has
no history of fainting and the episode bore no relation to any prior complaints.
This is a false positive and not a sign of orthostatic intolerance.
Other patterns of hemodynamic disturbance (see below) seem invariably
associated with symptoms and are more reliable indicators of chronic impairment.
glossary
The
normal response to HUT is a modest increase in heart rate (see figure,
increased heart rate by 10-20 beats/min) without a fall in systolic blood
pressure. Abnormal tilt test responses can be used to categorize patterns of
orthostatic intolerance. The overall patient assessment of chronicity and
severity of impairment should be combined with these data to reach any
conclusion concerning the nature of orthostatic intolerance in a particular
patient. In addition to the normal pattern, three typical patterns of
orthostatic intolerance are depicted in the figure, which
shows the systolic blood pressure and heart rate in-patients during tilt.
glossary
1)
Classic simple faint (Vasovagal Syncope)
This
is depicted in the figure. Typically patients easily
tolerate the early parts of tilt with little change in blood pressure or
sensorium. Following a variable period of time – on the order of 7 to 20
minutes, patients develop orthostatic symptoms of nausea, dizziness, heat, heavy
breathing, and sweatiness associated most commonly with a small initial slow
fall in blood pressure (which can be seen if the figure is
inspected closely). In short order there is an abrupt drop in blood pressure and
heart rate. The early fall in blood pressure is coincident with a decrease in
vasoconstriction (the peripheral arteries vasodilate) which normally occurs as
part of the neurovascular compensation required to maintain blood pressure with
orthostasis. Blood pressure and heart rate may plummet precipitously, and
asystole may occur. When this happens there is a rapid loss of central nervous
system activity and often a dysinhibition of peripheral neurologic responses
resulting in muscular movements mimicking a tonic-clonic seizure. This is
denoted “convulsive syncope”. That no true seizure activity is present has
been confirmed as early as the 1950’s by Gastaut and associates (21) and later
reconfirmed using HUT methods by Grubb and coworkers in the 1990’s (22). Such
episodes, while relatively uncommon, are quite dramatic and such phenomena are
periodically “rediscovered” by beginning practitioners of the HUT art. There
are several sidebar observations on simple faint that stem from the convulsive
variant:
a) If the episode occurs rapidly the patients can be
injured. It is estimated that approximately 15% of patients with simple faint
are injured overall during a faint. This can take relatively innocuous forms as
a superficial cut while falling or can be more pernicious when a car is
overturned. In the latter case it is evident that treatment for fainting is
necessary.
b) Fainting usually is short lived; upon assuming recumbence
the patient usually awakes after a few seconds. But some patients do not awake
immediately and prolonged sleep-like states have occurred. These may mimic post-ictal
(post seizure) states.
c) A patient persistently maintained upright in a severe
simple faint (for example proceeding to asystole) can potentially die. There is
no reported pediatric death during HUT. A corollary is that such testing is
potentially risky and should be performed by experienced personnel. Similar
events may also occur in the real world, so called “telephone booth
syncope’. This has decreased since telephone booths are largely anachronistic.
However, recently one of my patients with known vasovagal syncope managed to
prop herself up with impending faint and nearly required a full resuscitation.
Patients should be placed supine or allowed to fall to a recumbent position.
Recumbence invariably resolves all symptoms and signs.
glossary
Mechanisms
for Vasovagal Faint
The most popular proposed
mechanism holds that fainting results from an errant stretch reflex from the
left ventricle. The reflex is activated by an underfilled (due to reduced venous
return), overly contractile (due to sympathetic activation), left ventricle.
This results in a “paradoxical reflex” mediated by unmyelinated C-fiber
nerves coursing from the ventricle to the CNS and causing vagally mediated
bradycardia as well as vasodilation (23). Treatment increasing blood volume
should help relieve underfilling while negative inotropic (contractile) agents
should help to reduce cardiac contractility. Both hypercontractility and
decreased ventricular stretch have been called into question by recent research
(24). Also, patients receiving cardiac transplants retain the ability to faint,
which implies that the ventricular receptor theory cannot explain all simple
faints. Other theories of fainting include epinephrine or renin surges (which
would rationalize the common use of isoproterenol as adjunctive provocation)
(25). Such surges do indeed occur in those who faint and take some minutes to
develop. However, it remains unclear whether these changes are the cause of the
hemodynamic abnormalities or an attempt at compensation for decreased blood
pressure and peripheral resistance during faint. A decrease in cerebral blood
flow has also been shown to occur in syncopal patients and may precede a large
fall in blood pressure (26). However, blood flow is similarly impaired in
chronic orthostatic intolerance in which hypotension (low blood pressure)
does not usually occur (27). Other proposed mechanisms include various
changes in CNS neurotransmitters such as serotonin, norepinephrine, neuropeptide
Y and substance P. Causation has not been established. In summary it is fair to
say that we still have no precise understanding of the mechanics or the
mechanism of simple faint.
glossary
Treatment
of Vasovagal Faint
Without a clear
mechanism there is no clear treatment. Moreover, many patients with infrequent
simple faints, who do not injure themselves and who do not have convulsive
syncope, may require no specific therapy above training in aversive maneuvers.
The simplest of these maneuvers is lying down although leg crossing, bending at
the waist, squatting and other maneuvers may also be effective. Increased fluid
and salt intake is always helpful in ameliorating the initial thoracic
hypovolemia of orthostasis. Lower body exercise, particularly isometric
exercise, can be a genuine help by enhancing the muscle pump and by increasing
venous tone in the lower extremities. Elastic support hose can be useful at
times but are often unacceptable to children. Other investigators
have advocated a regimen of progressively longer quiet standing as a form
of “orthostatic training” (28). In terms of medication, often beta-1
blockade works well. This may have its basis in reducing putative
hypercontractility but other possible roles for beta-1 blockade include blunting
the release of epinephrine or renin, which are modulated by beta-1 receptors and
central effects. Other possible medications include fludrocortisone (florinef),
which retains sodium and water at the expense of small potassium wasting and has
modest if any corticosteroid side effects. In addition to its other actions,
florinef may aid in sensitizing alpha-receptors and blocking vasodilation. A
new, direct acting alpha-1 agonist, midodrine (proamatine) has been used to good
effect in many patients with assorted forms of orthostatic intolerance. Other
agents have included alpha-2 adrenergic agents (both clonidine and its obverse
yohimbine) which have been used in select patients. Disopyramide has been used
occasionally but controlled studies do not support its efficacy (30). Recently,
selective serotonin reuptake inhibitors have been used to good effect in a
variety of orthostatic disabilities. These seem to interfere with hypotensive
responses at a central level. Grubb and associates have demonstrated efficacy of
sertraline and fluoxetine in a series of controlled studies (31). The studies
were performed after careful psychiatric screening had ruled out
significant depression. Personal experience bears this out and the SSRI’s
remain a useful medication for many forms of orthostatic intolerance.
glossary
2)
Dysautonomic Orthostatic Intolerance
Included
in this group are patients with true “orthostatic hypotension” defined by
the American Autonomic Society to be a persistent fall in systolic blood
pressure of >25 mmHg within 3 minutes of assuming the upright position (31).
This group harbors patients with autonomic failure. Autonomic failure includes
primary forms such as primary autonomic failure and multiple system atrophy, and
more common secondary forms occurring with Parkinson’s disease and diabetes.
Dysautonomia may also be drug induced. Pediatric causes are rare and include
familial dysautonomia as the only “relatively” common variants (32). Acute
forms may occur during infectious and inflammatory diseases or be related to
peripheral nerve disease, e.g. Guillian Barre syndrome. Using standard tests of
circulatory autonomic function such as timed breathing and the quantitative
Valsalva maneuver patients show signs of circulatory autonomic dysfunction. Also
other manifestations of dysautonomia are present including pupillary,
gastrointestinal, and sweating abnormalities. Neurological damage such as occurs
in cerebral palsy, trauma, etc may result in some autonomic dysfunction in
addition to other neurologic disability. Responses to orthostasis in such
patients differ from those in truly dysautonomic patients in that compensatory
mechanisms may adapt the patient to orthostasis (e.g. increased blood volume)
which seldom occurs in the dysautonomic.
glossary
Dysautonomic
orthostatic intolerance is depicted in the figure. Blood
pressure falls while there is no significant change in heart rate throughout the
course of the tilt. The appropriate response of the arterial baroreflex to
hypotension is tachycardia, which fails to occur in these illnesses. Patients
may be so brittle that they are hypertensive (high blood pressure) supine,
hypotensive upright, and lose consciousness due to overzealous splanchnic
vasodilation (vasoactive intestinal polypeptide?) after every heavy meal.
Treatment
modalities favor volume loading and midodrine which, as noted, often results in
recumbent hypertension. Specific therapy for chronic disease is largely
experimental and acute therapy for acute illness remains specific for the
specific disease.
glossary
3)
Chronic Orthostatic Intolerance and the Postural Tachycardia
Syndrome
The
orthostatic tachycardia syndrome is a disabling disease state described at least
since 1940 (33) and is the most common reason for referral for orthostatic
intolerance (34-40) in adults. It is an emerging form of orthostatic intolerance
in children. Patients have day-to-day disability - a feature not shared with
those with simple faint. With some exception, traditional tests of autonomic
function are normal in these patients. Patients are often unable to hold jobs or
attend schools. Dr. David Robertson of the Vanderbilt autonomic laboratories,
has stated that this is the most common form of chronic orthostatic disability,
and is present in virtually every patient with day-to-day orthostatic
intolerance (41). He has therefore
named the illness “Chronic Orthostatic Intolerance” (COI). Our understanding
of its pathophysiology remains incomplete.
The central physical finding is upright tachycardia although hypotension
and resting tachycardia may also be present. An operational definition of the
syndrome (also denoted by the acronym POTS for postural orthostatic tachycardia
syndrome) includes symptoms of orthostatic intolerance associated with an
increase in heart rate from the supine to upright position of more than 30 beats
per minute or to a heart rate greater than 120 beats per minute within 10
minutes of head-up tilt (HUT). Such a response is depicted in the figure.
In the case shown, the patient became immediately symptomatic following the
start of HUT and required the table to be put down within a very few minutes.
Although this patient was not hypotensive, hypotension may follow or occur with
tachycardia. Often it is delayed beyond the onset of the symptoms and of the
tachycardia, and therefore only shows up during the artificially sustained
orthostasis enforced during HUT. Onset of symptoms often follows an infectious
disease and may be related to inflammatory mediators (42). We reported the first
pediatric cases of POTS. Our data showed that POTS physiology underlies
orthostatic intolerance in the large majority of adolescents with the chronic
fatigue syndrome (CFS) (43-46). POTS is common, affecting an undisclosed number
of patients mostly in the age range of 12 to 50 years, mostly female
(approximately 80%). There is an as yet undetermined but increasing apparent
prevalence in children and adolescents (43).
glossary
Patients
with the syndrome display an unusual amount of pooling in the lower extremities
often associated with acrocyanosis. The literature contains a number of
potential explanations for abnormal venous pooling and fluid collection in POTS
including impaired innervation of the veins or in their response to sympathetic
stimulation (35). One such explanation favors an autonomic neuropathy that
predominantly affects the lower extremities (36,37). "1-adrenergic
denervation hypersensitivity results. A second explanation invokes decreased $1-
receptor sensitivity (2); a third, "1-receptor
supersensitivity (35); a fourth altered venoconstriction (36), while a fifth
(47) suggests increased capillary filtration as an explanation. However, "1-adrenergic
control of venous filling in response to baroreflex stimulation during
orthostasis is important only in skin and splanchnic circulations in humans
(16,17) while involvement of skeletal muscle $1-receptors remain controversial (17,18). "-adrenergic
effects may also alter venous filling, but only indirectly through arterial
vasoactivity (18) and this mechanism may be most important during exogenous
beta-agonist administration (isoproterenol) or during endogenous epinephrine
release later during HUT. It is uncertain how important active venoconstriction
is to the orthostatic response. Finally, venous capacitance properties in POTS
could be abnormal because of altered vascular structure, altered muscle tone or
both. A link with antecedent inflammatory disease is the chronic elaboration of
cytokines with potent vasoactive consequences such as IL-1, IL-6 and TNF. Such a
link seems established in the chronic fatigue syndrome in which POTS and so
called “neurally mediated hypotension” (actually POTS) occur with high
frequency (42, 48). Finally, most recently Dr. Robertson and associates have
isolated an aberrant gene for the norepinephrine reuptake transporter protein
producing alternations between hypertension and hypotension in the same patient
(and her twin sister) dependent on norepinephrine stores (49). This gene seems
[for now] confined to a single family. Such results, however, point to the
likelihood of different types of vascular abnormalities resulting in a common
pathway of postural tachycardia associated with symptoms of orthostatic
intolerance.
glossary
Our
preliminary data (50) suggest the hypothesis that blood pooling in POTS always
results from a defect in arterial vasoconstriction during orthostasis causing
increased venous filling and enhanced microvascular filtration (leaking from the
capillaries). Blood is redistributed peripherally and redistribution is enhanced
during orthostasis producing increased microvascular filtration and dependent
edema. Central hypovolemia (low blood volume) causes reflex tachycardia, reduced
cerebral blood flow and often hypotension. POTS results in a circulation at high
risk for simple fainting by virtue of a depleted thoracic vascular bed. In many
ways it resembles hemorrhage or hypovolemia in that tachycardia and malperfusion
are noted first which may then proceed to hypotension or loss of consciousness
or both.
Effective
treatment for chronic orthostatic intolerance is being developed but will depend
on specific etiologies as these are discovered. For the moment we continue to
use some of the medications outlined in the vasovagal section. Of these florinef
and midodrine seem to be most effective with an emerging use of SSRI’s.
Beta-blockers and clonidine are rarely tolerated and may point to a very
different origin for COI from syncope.
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Fainting and Related Phenomena a Lay Review
