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Autonomic Dysfunction
and Hypotension
Christopher J. Mathias
Classification of Autonomic Dysfunction. . . . . . . . . . . 1883
Clinical Manifestations. . . . . . . . . . . . . . . . . . . . . . . . . . 1883
Investigation of Autonomic Dysfunction . . . . . . . . . . . 1887
Description of Key Autonomic Disorders . . . . . . . . . . . 1892
Management of Postural Hypotension . . . . . . . . . . . . . 1900
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1905
T
synonymous with the Shy-Drager syndrome) and secondary
disorders associated with a clearly defi ned lesion (e.g., spinal
cord lesions), disease (e.g., diabetes mellitus), or a specific
biochemical deficit (e.g., dopamine β-hydroxylase deficiency)
(Table 88.1). A wide variety of drugs, toxins, and chemicals
result in autonomic dysfunction by their direct effects or by
causing a neuropathy. A separate category includes neurally
mediated syncope in which there is an intermittent autonomic abnormality, often associated with specific events
(Table 88.2). The postural tachycardia syndrome is a relatively recently described disorder with orthostatic intolerance without postural hypotension.
Autonomic dysfunction often results in diminished
activity leading to hypotension and bradycardia; the reverse,
overactivity, also may occur, causing hypertension and
tachycardia. In some disorders, such as neurally mediated
syncope, parasympathetic overactivity and sympathetic
underactivity may occur simultaneously.
he autonomic nervous system, especially through the
cranial parasympathetic and lumbosacral sympathetic
outflow, is closely involved in the beat-to-beat control
of systemic blood pressure, heart rate, and the regional blood
supply to skeletal muscle and vital organs. It is of major
importance in ensuring adequate tissue perfusion, in maintaining supplies of oxygen and nutrients, and in transporting
metabolic end-products in response to the demands of varying
situations. It accomplishes these actions through a complex
system of pathways that involves the brain and spinal cord,
preganglionic and postganglionic pathways, and synapses at
the target organs; the immense flexibility and capability of
the autonomic nervous system are dependent on intricate
pathways that may be damaged in a variety of conditions that
affect one or more sites with the brain, spinal cord, or periphery1 (Fig. 88.1). A key component is the baroreflex pathway,
an exquisitely sensitive mechanism that provides beat-bybeat blood pressure control (Fig. 88.2). This chapter discusses
the classification of autonomic disorders that affect the cardiovascular system, and describes the main clinical manifestations, tests of autonomic dysfunction, and features of
key major autonomic disorders. There is an emphasis on
postural (orthostatic) hypotension as it is a cardinal feature
of many autonomic disorders. It is now recognized that a
number of factors in daily life, such as food ingestion and
exercise, can themselves cause hypotension and thus worsen
postural hypotension. The pressor effect of water ingestion
in autonomic failure recently has been recognized, and has
been introduced in the management of postural hypotension.
There have been advances in the evaluation and management
of neurally mediated syncope and the postural tachycardia
syndrome. These are discussed, along with various advances
in our understanding of how the autonomic nervous system
controls cardiovascular function in humans.
Classification of Autonomic Dysfunction
Autonomic disorders may result in localized or generalized
dysfunction.4 Examples include primary disorders where
there is no clear etiologic factor (e.g., multiple system atrophy,
Clinical Manifestations
Cardiovascular Features
Autonomic dysfunction can affect the regulation of blood
pressure and heart rate and impair regional vascular control
mechanisms.
Postural Hypotension
Postural hypotension is a cardinal feature of sympathetic
vasoconstrictor failure (Fig. 88.3). It often provides the fi rst
clue to an underlying diagnosis of autonomic failure. It is
defined as a fall in systolic blood pressure of more than
20 mm Hg or in diastolic blood pressure of more than
10 mm Hg, on either standing upright or on head-up tilt to 60
degrees for 3 minutes.5,6 Normally there is no fall in blood
pressure on head-up postural change. The fall in blood pressure usually is associated with symptoms of hypoperfusion
to various organs, especially to those above the heart, such
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chapter
Sympathetic
nervous system
Mesencephalon
Tear and
salivary
glands
Superior
cervical
ganglion
Stellate
ganglion
Parasympathetic
nervous system
III
IX,VII
X
Vagus n.
Lung
Superior
mesenteric
ganglion Celiac
Liver
ganglion
Heart
Thoracic
Pons
medulla
obl.
Eye
88
Cervical
18 8 4
Stomach
Inferior
mesenteric
ganglion
Sacral Lumbar
Pancreas
Small
intestine
Large intestine
rectum
Bladder
Sympathetic trunk
Adrenal
Reproductive
organs
FIGURE 88.1. Parasympathetic and sympathetic innervation of major organs.2
as the brain7 (Table 88.3). Symptoms arising from cerebral
hypoperfusion often are the reason for requesting medical
advice. They are precipitated by sitting or standing, are
relieved by lying flat, and may vary in the same individual
at different times. Their magnitude may be independent of
the fall in blood pressure. With time symptoms of cerebral
hypoperfusion often are reduced, and this may be due to
improved cerebrovascular autoregulation.
Common symptoms of cerebral hypoperfusion include
dizziness and visual disturbances; these usually but not necessarily precede loss of consciousness (syncope, fainting).
Cognitive deficits and prolonged reaction times have been
recorded in subjects with moderately hypotension,8 and this
may apply to subjects with postural hypotension; these deficits are likely to resolve when the blood pressure is restored.
Symptoms of postural hypotension often are worse when
getting out of bed in the morning and may be enhanced by
a variety of stimuli in daily life, ranging from food ingestion
and modest amounts of alcohol, to mild exercise and a raised
environmental temperature (Table 88.4). Straining during
micturition and bowel movements that commonly are
affected in autonomic failure may induce symptoms. These
stimuli presumably raise intrathoracic pressure, result in a
Valsalva-like maneuver and thus lower blood pressure. Many
subjects recognize the association between postural change
and symptoms of cerebral hypoperfusion and therefore sit
down, lie flat, or assume postures such as squatting or stooping. Syncope may occur rapidly if the blood pressure falls
precipitously; this may be similar to a “drop” attack.
Syncope may result in injury. Seizures occasionally
occur, especially if cerebral hypoxia is prolonged. A variety
of drugs, ranging from sublingual glyceryltrinitrate to those
Arterial baroreflex
+
Muscle
symp.act.
150 mm Hg
Blood
pressure
100
2s
FIGURE 88.2. Relationship between spontaneous fluctuations of
blood pressure and muscle-nerve sympathetic activity (left) recorded
in right peroneal nerve. The baroreceptor reflex accounts for the
pulse synchrony of nerve activity and the inverse relationship to
CAR088.indd 1884
–
50
blood pressure fluctuations. Asterisk indicates diastolic blood pressure fall due to sudden atrioventricular (AV) block. Stippling indicates corresponding sequences of bursts and heartbeats. 3
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0
Normal
60-degree head up tilt
180
60-degree head up tilt
Autonomic
failure
150
Heart rate bpm
180
0
150
Heart rate bpm
Primary (etiology unknown)
Acute/subacute dysautonomias
Pure cholinergic dysautonomia
Pure pandysautonomia
Pandysautonomia with neurologic features
Chronic autonomic failure syndromes
Pure autonomic failure
Multiple system atrophy (Shy-Drager syndrome)
Autonomic failure with Parkinson’s disease
Diffuse Lewy body disease
Secondary
Congenital
Nerve growth factor deficiency
Hereditary
Autosomal dominant trait
Familial amyloid neuropathy
Porphyria
Autosomal recessive trait
Familial dysautonomia: Riley-Day syndrome
Dopamine β-hydroxylase deficiency
Metabolic diseases
Diabetes mellitus
Chronic renal failure
Chronic liver disease
Vitamin B12 deficiency
Alcohol-induced
Inflammatory
Guillain-Barré syndrome
Transverse myelitis
Infections
Bacterial: tetanus
Viral: human immunodeficiency virus infection
Parasitic: Chagas’ disease
Prion: fatal familial insomnia
Neoplasia
Brain tumors, especially of third ventricle or posterior fossa
Paraneoplastic, to include adenocarcinomas: lung, pancreas,
and Lambert-Eaton syndrome
Surgery
Organ transplantation: heart
Vagotomy and drainage procedures: dumping syndrome
Trauma
Spinal cord injury
Drugs
Neuropathy
Direct effects (see also Table 88.12)
Blood pressure mm Hg
(Portapres)
TABLE 88.1. Outline classification of disorders resulting in
cardiovascular autonomic dysfunction
Blood pressure mm Hg
(Portapres)
au tonom ic dysf u nc t ion a n d h y pot e nsion
0
0
FIGURE 88.3. Blood pressure and heart rate measured continuously
before, during, and after 60-degree head-up tilt by the Portapres
II in a normal subject (upper panel) and in patient with autonomic
failure due to multiple system atrophy (lower panel).4
associated normally with minimal cardiovascular effects,
such as levodopa (for parkinsonism), may unmask or aggravate postural hypotension. In diabetes mellitus with autonomic neuropathy, insulin may enhance postural hypotension
through it effects in causing vasodilatation or a reduction
in blood volume. Occasionally, symptoms may occur even
with a small fall in postural blood pressure, when perfusion
is compounded by impairment of the vascular supply of
the organ. An example is carotid artery stenosis in which
symptoms of cerebral hypoperfusion may be difficult to
distinguish from a transient ischemic attack caused by
thromboembolism.
Hypoperfusion of organs other than the brain may result
in a variety of symptoms. Suboccipital and paracervical pain
in a “coat hanger” distribution is probably due to reduced
TABLE 88.3. Some of the symptoms resulting from postural
hypotension and impaired perfusion of various organs
TABLE 88.2. Disorders resulting in intermittent autonomic
dysfunction that affect the circulation
Neurally mediated syncope
Vasovagal syncope
Carotid sinus syncope
Miscellaneous (situational) syncope*
Micturition syncope
Defecation syncope
Cough syncope
Laughter-induced syncope
Swallow syncope
With glossopharyngeal neuralgia
With tracheal stimulation in tetraplegics
Transient postural hypotension
Postural tachycardia syndrome
* Some examples of miscellaneous syncope.
CAR088.indd 1885
Cerebral hypoperfusion
Dizziness
Visual disturbances
Blurred—tunnel
Scotoma
Graying out—blacking out
Color defects
Loss of consciousness
Cognitive deficits
Muscle hypoperfusion
Paracervical and suboccipital (“coat-hanger”) ache
Lower back/buttock ache
Subclavian steal-like syndrome
Renal hypoperfusion
Oliguria
Spinal cord hypoperfusion
Nonspecific
Weakness, lethargy, fatigue
Falls
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chapter
TABLE 88.4. Factors that may influence postural hypotension
Speed of positional change
Time of day (worse in the morning)
Prolonged recumbency
Warm environment (hot weather, hot bath)
Raising intrathoracic pressure: micturition, defecation, or
coughing
Water ingestion*
Food and alcohol ingestion
Physical exertion
Physical maneuvers and positions (bending forward, abdominal
compression, leg crossing, squatting, activating calf muscle
pump)**
Drugs with vasoactive properties
* This raises blood pressure in autonomic failure.
** These maneuvers usually reduce the postural fall in blood pressure in
neurogenic causes of postural hypotension, unlike the others.
perfusion of head and neck muscles that tonically must be
kept active.9 Symptoms suggestive of angina pectoris may
occur even in young subjects with apparently normal coronary arteries. There may be shortness of breath and dyspnea
(platypnea) while upright.10 Oliguria while upright probably
results from renal hypoperfusion, with the reverse occurring
during recumbency.
In neurally mediated syncope, unlike postural hypotension caused by autonomic failure, hypotension often is associated with, but may be independent of, being upright. The
fall in blood pressure often is accompanied by clinical features indicative of autonomic activation that include palpitations and perspiration; this differs from subjects with
autonomic failure where these features usually do not occur.
In orthostatic intolerance due to the postural tachycardia
syndrome (PoTS), the pronounced rise in heart rate is not
secondary to a fall in blood pressure.
Hypertension
Supine hypertension (in addition to postural hypotension)
may occur in primary chronic autonomic failure. The mechanisms are not clear and include impaired baroreflex activity,
adrenoceptor supersensitivity, an increase in central blood
volume due to a shift from the periphery, and the continuing
effects of drugs used to reduce postural hypotension. Supine
hypertension may cause headache; there have been reports,
albeit rare, of papilledema, cerebral hemorrhage, aortic dissection, myocardial ischemia, and heart failure.
Paroxysmal hypertension may occur in tetanus, the
Guillain-Barré syndrome, and porphyria, when there are
rapid fluctuations in cardiovascular autonomic activity. In
high spinal cord lesions, hypertension is a major component
of autonomic dysreflexia. This can cause a throbbing headache and occasionally results in neurologic complications
such as seizures or cerebral hemorrhage. Hypertension, often
paroxysmal, is a common feature of pheochromocytoma and
may occur with other symptoms, such as sweating and palpitations. Increased sympathetic nervous activity may initiate or maintain hypertension in organ transplantees receiving
cyclosporine as immunosuppressant therapy.11 Sympathetic
CAR088.indd 1886
88
overactivity may be a factor in hypertension associated with
renal artery stenosis,12,13 and in pregnancy-induced hypotension,14 including preeclamptic toxemia.15
Cardiac Dysrhythmias
Tachycardia may occur due to increased sympathetic neural
discharge in the Guillain-Barré syndrome and tetanus. In
pheochromocytoma it is due to catecholamine release and βadrenoceptor stimulation. In PoTS, the tachycardia usually is
associated with head-up postural change and exertion. Tachycardia may result from cardiac parasympathetic (vagal) denervation, in diabetes mellitus; it may be an early sign of
autonomic dysfunction in familial amyloid polyneuropathy.
Bradycardia due to abnormal vasovagal reflex activity
may complicate tracheal suction in tetraplegics on artificial
respirators. Bradycardia due to increased cardiac parasympathetic activity may be a key feature in carotid sinus hypersensitivity and other forms of neurally mediated syncope.
The rapid rise in blood pressure in pheochromocytoma may
result in bradycardia with escape rhythms and atrioventricular dissociation. Bradycardia in high spinal injuries also may
occur during autonomic dysreflexia in response to the rise
in blood pressure.
Vascular Effects
FACIAL VASCULATURE
In orthostatic hypotension, facial pallor often occurs as the
blood pressure falls, with prompt restoration when the blood
pressure rises; similar features also occur in neurally mediated syncope. Facial pallor due to vasoconstriction may
accompany other features of excessive sympathoadrenal activation in pheochromocytoma. Facial vasodilatation accompanied by nasal congestion (Guttmann’s sign) occurs in high
spinal cord lesions in the active phase when in spinal shock;
it has also been observed in subjects receiving α-adrenoceptor
blockers and sympatholytics, such as phenoxybenzamine,
guanethidine, and reserpine. In chronic high spinal lesions,
hypertension during autonomic dysreflexia is often accompanied by flushing and sweating over the face and neck; the
mechanisms are unclear. In Horner’s syndrome, facial vasodilatation and anhidrosis with pupillary constriction may
result from lesions to sympathetic neural pathways within
the brain, spinal cord, or periphery. In the harlequin syndrome there also is facial vasodilatation and anhidrosis, but
without the ocular features of Horner’s syndrome; this suggests a preganglionic lesion below the fi rst thoracic segment,
thus sparing ocular sympathetic pathways.16 The cause is
unknown and possibilities include an immunologic process.
L IMB VASCULATURE
Raynaud’s phenomenon due to cold hypersensitivity may
occur in both hands and feet in pure autonomic failure and
multiple system atrophy.17 The blue, violaceous phase often
persists. Abnormal vascular changes, with sweating and
pain, occur in reflex sympathetic dystrophy (causalgia, the
complex regional pain syndrome), for reasons that are unclear
and could include sympathetic denervation and the effects of
neuropeptides such as substance P and calcitonin generelated peptide. In erythromelalgia, hands and feet are hot,
painful, and red; there are abnormalities in sympathetic
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au tonom ic dysf u nc t ion a n d h y pot e nsion
function and neuropeptides released from sensitized nociceptors may be responsible.18
SKELETAL MUSCLE AND SPLANCHNIC VASCULATURE
The regional vascular control of skeletal muscle and various
organs may be affected in autonomic failure and account for
various manifestations. Thus, abnormal splanchnic control
may contribute to postprandial hypotension,19 and renal oligemia while the patient is upright may contribute to oliguria. Exercise induces hypotension in autonomic failure, with
abnormal changes in many vascular regions.20 Hypoperfusion of specific areas within the brain, or their increased
sensitivity to ischemia, may cause or contribute to the symptoms of postural hypotension: in the brainstem to dizziness,
the occipital lobes to visual disturbances, and areas concerned with cognition to attention and allied deficits.21 These
usually are transient and reversible once blood pressure is
restored.
Noncardiovascular Features
The function of virtually every organ is influenced by the
autonomic nervous system with a wide variety of features,
especially in the generalized autonomic disorders (Table
88.5). Some of these also have an influence on cardiovascular
dysfunction. Sudomotor dysfunction, with overheating, can
result in cutaneous vasodilatation, which may contribute to
postural hypotension. Nocturnal polyuria is frequent and is
probably due to the raised supine level of blood pressure, fluid
shifts into the central compartment, and therefore better
perfusion of the renal vasculature. Nocturia can result in a
considerable reduction in body weight, with a presumed fall
TABLE 88.5. Some noncardiovascular manifestations of
autonomic dysfunction
Sudomotor
Anhidrosis
Hyperhidrosis
Gustatory sweating
Hyperpyrexia
Heat intolerance
Alimentary
Xerostomia
Dysphagia
Gastric stasis
Dumping syndromes
Constipation
Diarrhea
Urinary
Nocturia
Frequency
Urgency
Incontinence
Retention
Sexual
Erectile failure
Ejaculatory failure
Retrograde ejaculation
Eye
Pupillary abnormalities
Ptosis
Alacrima
Abnormal lacrimation with food ingestion
CAR088.indd 1887
18 8 7
in intravascular and extravascular fluid volume, thus contributing to worsening postural hypotension, especially in the
morning.22 Sexual dysfunction is common in the male, with
both erectile and ejaculatory failure. Drugs such as sildenafil
(Viagra) are beneficial; their vasodilator properties, however,
can worsen postural hypotension.23 In multiple system
atrophy, unlike pure autonomic failure, there often is involvement of the respiratory system, with nocturnal stridor that
may be associated with abductor cord paresis, involuntary
inspiratory, gasps and periodic apnea.24 The latter may cause
oxygen desaturation; whether hypoxia contributes to sudden
death in such subjects remains a possibility.
Investigation of Autonomic Dysfunction
The key aims of investigation of autonomic dysfunction are
as follows:
1. To determine whether autonomic function is normal
or abnormal; screening investigations to evaluate cardiovascular autonomic function are highlighted in Table 88.6.
2. If an abnormality has been observed, to assess the
degree of autonomic dysfunction with an emphasis on the
site of lesion and functional deficit.
3. To determine whether the abnormality is of the
primary or secondary variety, as the need for further investigation, along with prognosis and management, is dependent on the diagnosis; in some patients, investigations of
various systems is required.
Cardiovascular System
Postural hypotension often is a cardinal and disabling feature
of autonomic dysfunction, and investigations are designed to
confirm its presence in evaluating exacerbating factors in
daily life, so as to guide treatment strategies. In our laboratories, screening investigations include head-up tilt and
standing, with further tests to determine if postural hypotension is the result of neurogenic or nonneurogenic mechanisms.25 Consideration of the latter (Table 88.7) is of particular
importance even in neurogenic postural hypotension, as
minor changes, such as a reduction in intravascular volume
due to vomiting or diarrhea, can considerably worsen hypotension in such subjects.
The measurement of blood pressure and heart rate ideally
should be continuous and with the use of automated, noninvasive techniques. Investigation on a tilt table is advantageous in patients with severe postural hypotension or with
neurologic deficits, as they can be returned rapidly to the
horizontal, especially if they are near syncope or have lost
consciousness. In some, prolonged head-up tilt is of value,
especially with suspected neurally mediated syncope. The
use of a tilt table is of particular importance when carotid
hypersensitivity is being considered, as carotid sinus massage
also should be performed during head-up tilt, especially in
the vasodepressor forms, when blood pressure is dependent
to a greater extent on sympathetic neural activity, and its
withdrawal can have substantial effects.26
The cardiovascular responses to the Valsalva maneuver,
during which intrathoracic pressure is raised, also tests the
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chapter
88
TABLE 88.6. Outline of investigations in autonomic disease
TABLE 88.7. Nonneurogenic causes of postural hypotension
Cardiovascular
Physiologic
Low intravascular volume
Blood/plasma loss
Fluid/electrolyte deficiency
Diminished intake
Loss from gut
Sudomotor
Gastrointestinal
Renal function and
urinary tract
Sexual function
Respiratory
Eye and lacrimal
function
* Indicates screening autonomic tests used in our London Unit.
integrity of the entire baroreflex pathway (Fig. 88.4); changes
in heart rate alone, even in the absence of continuous blood
pressure recordings, provides a useful guide. Elevation of
intraoral pressure, without raising intrathoracic pressure,
can result in a falsely abnormal response. In such situations
continuous blood pressure measurements are of particular
value.
The sympathetic efferent outflow can be tested by a
variety of stimuli that raise blood pressure. These include
isometric exercise (by sustained handgrip for 3 minutes),
cutaneous cold (the cold pressor test by immersing the hand
in ice slush or a cold pack for 90 seconds), and mental arithmetic (using serial 7’s or a subtraction of 17). These activate
different afferent or central pathways (of value in subjects
with different neurologic lesions), and thus stimulate the
CAR088.indd 1888
Impaired output
Vasodilatation
Endogenous
Exogenous
Hemorrhage, burns, hemodialysis
Anorexia nervosa
Vomiting, ileostomy losses,
diarrhea
Salt losing nephropathy, diuretics
Adrenal insufficiency (Addison’s
disease)
Myocarditis
Atrial myxoma, constrictive
pericarditis
Aortic stenosis
Hyperpyrexia
Hyperbradykininism
Systemic mastocytosis
Varicose veins
Drugs such as glyceryl trinitrate
(GTN)
Alcohol
Excessive heat
sympathetic efferent outflow. Cardiac parasympathetic efferent pathways are assessed by measuring the heart rate
responses to a variety of stimuli that include postural change,
the Valsalva maneuver, breathing (sinus arrhythmia) (Fig.
88.5), and hyperventilation.
A variety of other tests should be considered in individual
cases. These include evaluation of the response to food inges160
Normal
0
160
15 seconds
80
Heart rate bpm
Endocrine
Cardiac insufficiency
Myocardial
Impaired ventricular fi lling
Blood pressure mm Hg
(Portapres)
Pharmacologic
Loss from kidney
Endocrine deficiency
Blood pressure mm Hg
(Portapres)
Biochemical
Head-up tilt (60 degrees)*; standing*;
Valsalva’s maneuver*
Pressor stimuli* (isometric exercise, cold
pressor, mental arithmetic)
Heart rate responses: deep breathing*,
hyperventilation*, standing*, head-up
tilt*, 30 : 15 R-R interval ratio
Liquid meal challenge
Exercise testing
Carotid sinus massage
Plasma noradrenaline: supine and head-up
tilt or standing; urinary catecholamines;
plasma renin activity and aldosterone
Noradrenaline: α-adrenoceptors, vascular
Isoprenaline: β-adrenoceptors, vascular and
cardiac
Tyramine: pressor and noradrenaline
response
Edrophonium: noradrenaline response
Atropine: parasympathetic cardiac blockade
Clonidine: α2-adrenoceptor agonist:
noradrenaline suppression; growth
hormone stimulation
Central regulation thermoregulatory sweat
test
Sweat gland response to intradermal
acetylcholine, quantitative sudomotor
axon reflex test (Q-SART), localized sweat
test
Sympathetic skin response
Video-cine-fluoroscopy, barium studies,
endoscopy, gastric emptying studies,
lower gut studies
Day and night urine volumes and sodium/
potassium excretion
Urodynamic studies, intravenous urography,
ultrasound examination, sphincter
electromyography
Penile plethysmography
Intracavernosal papaverine
Laryngoscopy
Sleep studies to assess apnea and oxygen
desaturation
Pupil function, pharmacologic and
physiologic
Schirmer’s test
0
100
Multiple system atrophy
Heart rate bpm
18 8 8
15 seconds
0
0
FIGURE 88.4. Blood pressure (BP) and heart rate (HR) before and
during Valsalva’s maneuver (black bar). In the upper trace, the expiratory pressure is maintained at 40 mm Hg in a patient with intact
sympathetic reflexes. The fall in BP is accompanied by a rise in HR.
The fall in BP is due to the reduction in venous return, which then
stimulates sympathetic activity; BP then partially recovers. After
release of intrathoracic pressure, there is a BP overshoot and the HR
falls below the pre-Valsalva level. In the lower trace, in a patient
with impaired autonomic function due to multiple system atrophy,
raising intrathoracic pressure lowered BP substantially, with no BP
recovery. After release of intrathoracic pressure, there was no BP
overshoot or immediate fall in HR below basal levels. The BP slowly
returned to pre-Valsalva BP levels.
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au tonom ic dysf u nc t ion a n d h y pot e nsion
80
Normal
Heart rate bpm
Blood pressure mm Hg
(portapres)
180
10 seconds of deep breathing
0
0
100
Blood pressure mm Hg
(portapres)
180
Heart rate bpm
Pure autonomic
failure
10 seconds of deep breathing
0
0
FIGURE 88.5. The effect of deep breathing on heart rate and blood
pressure in a normal subject and a patient (upper panel) with pure
autonomic failure (lower panel). There is a marked reduction in
sinus arrhythmia in the patient with autonomic failure.
tion, as postprandial hypotension can be a problem in some
patients27 (Fig. 88.6). This can be tested by recording the cardiovascular responses before and after a standard meal,
ideally liquid, and by assessing the responses to head-up
postural change both before and after food ingestion.28 Other
approaches are used in relation to exercise, another stimulus
that can lower blood pressure substantially29,30 (Fig. 88.7).
These protocols enable evaluation of responses to the stimulus while gravitationally neutral and additionally when the
patient is upright. They are used in patients with autonomic
failure, and also some with neurally mediated syncope, especially when the history favors a relationship to these stimuli.
The laboratory protocols to determine the responses to these
major stimuli in daily life also are of value in therapeutic
targeting.
Advances in noninvasive ambulatory measurement of
blood pressure and heart rate enable 24-hour recordings in a
natural setting such as at home (Fig. 88.8). It is imperative
that a suitable diary is maintained to record the responses
to key stimuli such as posture, food, and exercise. This
enables evaluation of the presence and severity of supine
hypertension, as may occur at night in autonomic failure,
and is the reverse of the circadian fall that occurs normally.
These recordings are also valuable in determining the
response to food and exercise and in evaluation of therapy.
In neurally mediated syncope a variety of investigations,
in addition to standard head-up tilt, have been introduced.31
These include the effect of prolonged tilt and in some laboratories the administration of drugs, such as isoprenaline and
glyceryltrinitrate.32,33 These do not necessarily provide a
physiologic evaluation of the problem. Some clinicians use a
combination of head-up tilt and lower body negative pressure.34 These maneuvers induce presyncope or syncope even
in normal subjects who have never fainted. In suspected
carotid hypersensitivity, it is important to ensure that carotid
artery stenosis is excluded to reduce the risk from thromboembolism and stroke, although this risk is small.35 Carotid
sinus massage should be performed while the patient is horizontal and during head-up tilt.26
The measurement of plasma catecholamine levels provides further information on the neurogenic component to
Exercise
50 W
25 W
130
120
Control subjects
110
100
90
80
70
60
50
Autonomic failure
40
Meal
15 30 45 60
90
120
180
Time (min)
FIGURE 88.6. Supine systolic and diastolic blood pressure before
and after a standard meal in a group of normal subjects (shaded area)
and in a patient with autonomic failure. Blood pressure does not
change in the normal subjects after a meal taken while lying flat.
In the patient there is a rapid fall in blood pressure to levels around
80/50 mm Hg, which remains low while in the supine position over
the 3–hour observational period.
75 W
Controls
MSA
PAF
40
30
20
10
0
–10
–20
–30
–40
0
–30 –15 0
CAR088.indd 1889
Change in systolic blood pressure (mm Hg)
Systolic and diastolic blood pressure (mm Hg)
140
3
6
9
post 2 post 5 post 10
Time (min)
FIGURE 88.7. Changes in systolic blood pressure during supine
bicycle exercise at three incremental levels (25, 50, and 75 watts) in
normal subjects (controls) and patients with multiple system atrophy
(MSA) and pure autonomic failure (PAF). The bars indicate standard
error of the mean. Unlike controls where there is a rise, there is a
fall in blood pressure in both MSA and PAF. Blood pressure returns
rapidly to the baseline in controls, unlike in the two patient groups
in whom it takes almost 10 minutes. All remained horizontal
during and for 10 minutes postexercise.
12/1/2006 3:41:35 PM
Heart rate (beats/min) Blood pressure (mm Hg)
A
200
Heart rate (beats/min) Blood pressure (mm Hg)
18 9 0
200
chapter
Systolic Diastolic
FIGURE 88.8. Twenty-four hour noninvasive ambulatory blood pressure profile, showing systolic (solid line) and diastolic (dashed line)
blood pressure and heart rate at intervals through the day and night.
(A) The changes in a normal subject with no postural fall in blood
pressure; there was a fall in blood pressure at night while asleep, with
a rise in blood pressure on waking. (B) The marked falls in blood pressure usually the result of postural changes, either sitting or standing.
Supine blood pressure, particularly at night, is elevated. Getting up
to micturate causes a marked fall in blood pressure (at “03” hours).
There is a reversal of the diurnal changes in blood pressure. There are
relatively small changes in heart rate, considering the marked changes
in blood pressure. (C) Twenty-four hour noninvasive ambulatory
blood pressure profi le, showing systolic (solid line) and diastolic
(dashed line) blood pressure and heart rate at intervals through the
day and night in a patient with the Riley-Day syndrome (familial
dysautonomia). There is considerable lability of blood pressure, with
hypotension and hypertensive episodes.
In bed
150
100
50
0
09
11
13
15
17 19 21 23 01
Sample time/24 h
03
05
07
09
11
13
15
17 19 21 23 01
Sample time/24 h
03
05
07
150
75
0
88
In bed
Systolic Diastolic
150
600
50
0
09
11
13
15
150
01
03
05
07
09
11
13
15
17 19 21 23
Sample time/24 h
01
03
05
In bed
200
150
100
300
200
100
16
18
20
22
0
2
4
6
8
Sample time/24 h
postural hypotension and in some on the underlying disorder.36 Supine norepinephrine levels often are normal in
multiple system atrophy (where the lesion is predominantly
central) and are below normal in pure autonomic failure
(where the lesion is peripheral). With head-up tilt or standing,
plasma norepinephrine levels rise in normal subjects but not
in autonomic failure (Fig. 88.9). Supine levels may provide
information on the underlying lesion, as in dopamine
CAR088.indd 1890
*
DBH
defn-1
*
DBH
defn-2
Controls
MSA
PAF
*
DBH
defn-1
*
DBH
defn-2
Controls
MSA
200
100
600
14
PAF
300
0
12
MSA
400
0
10
Controls
500
50
200
150
100
50
0
Tilt
400
600
07
Adrenaline (pg/mL)
0
Supine
500
0
Dopamine (pg/mL)
Heart rate (beats/min) Blood pressure (mm Hg)
17 19 21 23
Sample time/24 h
75
B
C
Noradrenaline (pg/mL)
100
500
400
300
200
100
0
DBH
DBH
defn-1
defn-2
FIGURE 88.9. Plasma noradrenaline, adrenaline and dopamine
levels (measured by high-pressure liquid chromatography) in normal
subjects (controls), patients with multiple system atrophy (MSA),
pure autonomic failure (PAF) and two individual patients with dopamine β-hydroxylase (DBH defn) while supine and after head-up tilt
to 45 degrees for 10 minutes. The asterisk indicates levels below the
detection limits for the assay, which are less than 5 pg/mL for noradrenaline and adrenaline and less than 20 pg/mL for dopamine.
Bars indicate ± standard error of the mean (SEM).
PAF
12/1/2006 3:41:35 PM
18 91
au tonom ic dysf u nc t ion a n d h y pot e nsion
Growth hormone (mU/l)
22
Controls (n = 27)
20
PAF (n = 19)
18
MSA (n = 31)
16
14
12
10
8
6
4
2
0
–10
A
0
15
30
Time (min)
45
60
IPD
(n = 14)
Parkinsonian
MSA (n = 15)
12
11
10
Growth hormone (mU/l)
β-hydroxylase deficiency where plasma norepinephrine levels
are extremely low or undetectable, whereas levels of the
precursor substance, dopamine, are elevated.37 In high spinal
cord lesions, paroxysmal hypertension during autonomic
dysreflexia may be mistaken for a pheochromocytoma; in the
former supine plasma norepinephrine levels are low, and
although they rise during autonomic dysreflexia, these levels
often are no higher than the basal levels in normal humans,
in contrast to the grossly elevated plasma catecholamine
levels often observed in pheochromocytoma.38
Measurement of plasma catecholamine levels in response
to various interventions are of diagnostic value in certain
conditions. Thus, in pheochromocytoma, where there is
autonomous catecholamine secretion, plasma norepinephrine and epinephrine levels are not suppressed, as they would
be after administration of the centrally acting sympatholytic
agent clonidine and the ganglionic blocker pentolinium.
This differs from the responses observed in normal subjects
and those with essential hypertension (Fig. 88.10). The α2adrenoceptor agonist clonidine has additional central effects
on central sympathetic pathways and the hypothalamus,
resulting in elevation of serum growth hormone 39; this has
been utilized to determine if the autonomic lesion is central
or peripheral.40 In multiple system atrophy with central autonomic failure, after clonidine there is no rise in levels of
serum growth hormone, unlike patients with pure autonomic failure and a peripheral lesion, where the rise in
growth hormone levels is similar to that observed in normal
subjects41 (Fig. 88.11).
9
MSA-C
(n = 16)
8
7
6
5
4
3
2
1
0
9000
–10
Plasma noradrenaline (pg/mL)
5000
3000
1000
Clonidine
500
15
30
45
60
Time (min)
FIGURE 88.11. (A) Serum growth hormone (GH) concentrations
before (0) and at 15-minute intervals for 60 minutes after clonidine
(2 μg/kg/min) in normal subjects (controls) and in patients with pure
autonomic failure (PAF) and multiple system atrophy (MSA). The
GH concentrations rise in controls and in patients with PAF with a
peripheral lesion; there is no rise in patients with MSA with a
central lesion. (B) Lack of serum GH response to clonidine in MSA
(the cerebellar form; MSA-C and the parkinsonian forms) in contrast to patients with idiopathic Parkinson’s disease (IPD) with no
autonomic deficit, in whom there is a significant rise in GH
levels.
400
300
200
100
0
30
60
90
120
Time (min)
FIGURE 88.10. Plasma noradrenaline levels in a patient with a
phaeochromocytoma (closed triangles) and in a group of patients
with essential hypertension (open triangles) before and after intravenous clonidine, indicated by an arrow (2 μg/kg over 10 minutes).
Plasma noradrenaline levels fall rapidly in the essential hypertensives after clonidine and remain low over the period of observation.
The stippled area indicates the ± SEM. Plasma noradrenaline levels
are considerably higher in the pheochromocytoma patient and are
not affected by clonidine.
CAR088.indd 1891
0
B
7000
–30
0
The measurement of other hormones such as renin (by
measuring plasma renin activity or angiotensin II levels) and
plasma aldosterone may be helpful. In diabetes mellitus,
hyporeninemia and hypoaldosteronism may contribute to
hyperkalemia. In Addison’s disease, measurement of plasma
cortisol levels before and after administration of synthetic
adrenocorticotrophic hormone determine if there is an endocrine contribution to postural hypotension.
An increasing number of investigative approaches, using
a variety of techniques, some of which are noninvasive,
address various aspects of autonomic function. A direct
technique to measure muscle and skin sympathetic nerve
activity utilizes percutaneous insertion of a tungsten microelectrode into the peroneal or median nerve42 (Fig. 88.2).
Sympathetic microneurography has enabled further understanding of normal sympathetic function, and of mecha-
12/1/2006 3:41:36 PM
18 9 2
chapter
nisms and disorders where there is a reduction (vasovagal
syncope), or an increase (cyclosporine-induced hypotension
and preeclamptic toxemia), in sympathetic neural activity. It
has limitations when there is sympathetic failure. Other
invasive techniques include the measurement of both
regional and total body norepinephrine spillover, to the
heart, splanchnic region, kidney, and brain.43 Noninvasive
methods now enable measurement of systemic and regional
hemodynamics in various vascular territories, enabling safe
and often continuous measurement of responses to different
autonomic stimuli. Computer-assisted approaches, using
spectral analyses, can determine parasympathetic and sympathetic contributions to both blood pressure and heart rate
control.44 Sympathetic innervation of the heart can be evaluated using relatively noninvasive techniques that include
scintigraphy (metaiodobenzylguanidine) 45,46 and positron
emission tomography (6-[18F] fluorodopamine).47
Description of Key Autonomic Disorders
Localized Autonomic Disorders
Many localized autonomic disorders effect cardiovascular
dysfunction (Table 88.8). In the Holmes-Adie syndrome, the
characteristics of the pupil often provide the clue. The typical
Holmes-Adie pupil is dilated and sluggishly responsive to
light due to parasympathetic denervation, probably of the
ciliary ganglia. Supersensitivity of the iris musculature can
be demonstrated by locally applied dilute solution of a cholinomimetic, such as pilocarpine. The cardiovascular autonomic deficits include postural hypotension and, in some,
exaggerated responses to pressor stimuli, which can cause
transient but marked hypertension. The lesion appears predominantly to involve the afferent limb of the baroreceptor
reflex. Although the Holmes-Adie syndrome is considered
benign, in some there are progressive abnormalities, with
increasing blood pressure lability and features that include
chronic dry cough, areas of anhidrosis, and compensatory
hyperhidrosis (Ross’s syndrome) and diarrhea.48
The intrinsic cholinergic plexuses to the heart and gut
are affected in Chagas’ disease. The reasons for such specific
targeting are unclear and include the effects of neurotoxins
released from parasites or an immunologic process that
selects intrinsic cholinergic plexuses.49 Abnormalities of
conduction, with bradycardia, may occur.
After heart transplantation, cardiac parasympathetic and
sympathetic pathways are severed, and the heart is incapable
of responding to stimuli that depend on integrity of the
TABLE 88.8. Localized autonomic disorders that affect
cardiovascular function
Holmes-Adie pupil and syndrome
Horner’s syndrome
Harlequin syndrome
Erythromelalgia
Reflex sympathetic dystrophy
Chagas’ disease (Trypanosomiasis cruzi)
Organ transplantation: heart
CAR088.indd 1892
88
extrinsic pathways. There are abnormal cardiac rate changes
to head-up postural change and respiratory stimuli such as
the Valsalva maneuver, deep breathing, and hyperventilation. Upregulation of cardiac adrenoreceptors may result in
enhanced responses to adrenoceptor agonists such as isoprenaline.50 Endogenous stimuli, such as exercise, that
elevate plasma norepinephrine and epinephrine levels raise
heart rate in cardiac transplantees; the response in patients
with heterotopic cardiac transplantation (with donor and
recipient atria, and their sinoatrial nodes) enable further dissection of responses.51 Mild exercise results in a similar rise
in heart rate in both denervated donor and innervated recipient atria; in the former, the rise is slower because of dependence on elevation of circulating catecholamines, rather than
reflex neural activity. The reverse, a slower return to baseline
levels, follows cessation of exercise and occurs in the denervated donor heart.
After cardiac transplantation the degree and temporal
period over which sympathetic sprouting or reinnervation
occurs varies52 and is one factor, in addition to differences
between sinus node and ventricular innervation, that may
influence heart rate variability53 and responses to exercise.54
Primary Autonomic Failure Syndromes
Acute and Subacute Dysautonomias
Acute and subacute dysautonomias are rare causes of primary
autonomic failure that present either acutely or subacutely.
The precise causes are unclear and may include a preceding
viral infection. In some there is a beneficial response to the
intravenous administration of immunoglobulin, which
favors an immunologic etiology.55–57 There are three clinical
forms. In pure cholinergic dysautonomia, parasympathetic
and sympathetic cholinergic pathways are impaired, resulting in an elevated heart rate with alacrima, xerostomia, dysphagia, large bowel atony, detrusor muscle dysfunction, and,
in men, erectile failure; anhidrosis also occurs. Postural
hypotension does not occur, as sympathetic adrenergic function is not affected. There is a response to cholinomimetic
agents, such as bethanechol, indicating preservation of postsynaptic cholinergic receptor function and suggesting a presynaptic lesion. In the pandysautonomias, the parasympathetic
and sympathetic nervous systems are affected, either without
(pure pandysautonomia), or with additional neurologic
lesions, often involving peripheral nerves. In the latter, sural
nerve biopsy indicated a reduction in both myelinated and
unmyelinated fibers. Cardiovascular dysfunction with postural hypotension often is a prominent problem.
Management in the acute/subacute neuropathies largely
consists of supportive therapy. Postural hypotension often
impedes rehabilitation and usually entails a combination of
nondrug and drug therapy as described further. Hyperthermia should be prevented, especially when there is widespread
anhidrosis. Adequate fluid intake and nutrition is of importance, particularly if there is a paralytic ileus. The investigation of dysphagia, especially in acute cholinergic dysautonomia
must not include the use of barium, as this can result in
deposition in the large bowel; a recent case needed, in due
course, a hemicolectomy with a colostomy. Blurred vision
can be prevented with low-dose pilocarpine eye drops. Arti-
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18 9 3
au tonom ic dysf u nc t ion a n d h y pot e nsion
ficial tears, such as hypromellose, are needed to prevent
ocular complications. Artificial saliva is helpful. Cholinomimetics such as bethanecol and carbachol, which can be given
either orally or parenterally to improve bowel and bladder
activity, are helpful. The prognosis in the early stages is
largely dependent on establishing an early diagnosis and on
supportive management to prevent complications.
In Guillain-Barré syndrome, there may be a variety of
cardiovascular changes from hypertension and tachycardia
to hypotension and bradycardia. There are differences
between the axonal and myelinated forms of the GuillainBarré syndrome.58 Autonomic disturbances affecting the circulation contribute to both morbidity and mortality.
TABLE 88.9. Some clinical manifestations in patients with
primary autonomic failure
Chronic Autonomic Failure Syndromes
Other neurologic deficits
These disorders clinically fall into two major categories,
those without (pure autonomic failure, PAF), and those with
neurologic deficits (Fig. 88.12). The former, pure autonomic
failure, encompass idiopathic orthostatic hypotension, a
term that does not indicate the possible autonomic involvement of sweat glands, pupils, and urinary bladder, bowel, and
sexual function. When primary chronic autonomic failure is
associated with other neurologic abnormalities (Table 88.9)
and without a defi ned cause or association, the term ShyDrager syndrome was used after the first neuropathologic
description; multiple system atrophy (MSA) now is used.62 It
is a sporadic, progressive disorder characterized by autonomic dysfunction, parkinsonism, and ataxia in any combination.63 There are three major clinical forms of MSA, based
on the additional neurologic features: parkinsonian (MSA-P),
cerebellar (MSA-C), and mixed (MSA-M).
The parkinsonian features may predate autonomic failure
in MSA and may be difficult to differentiate from idiopathic
Parkinson’s disease, especially in the early stages. Distinguishing the two disorders is important because the prognoMSA
P
C
M
PAF
PD
PD+AF PSP
LBD
Autonomic
Parkinsonian
Cerebellar/
pyramidal
Dementia
FIGURE 88.12. The major clinical features in parkinsonian syndromes and allied disorders with autonomic failure. These include
the three major neurologic forms of multiple system atrophy; the
parkinsonian form (MSA-P, also called striatonigral degeneration),
the cerebellar form (MSA-C, also called olivopontocerebellar
atrophy), and the multiple or mixed form (MSA-M, which has features of both other forms), pure autonomic failure (PAF), idiopathic
Parkinson’s disease (IPD), Parkinson’s disease with autonomic
failure (PD+AF), progressive supranuclear palsy (PSP), and diffuse
Lewy body disease (LBD).
CAR088.indd 1893
Cardiovascular system
Sudomotor system
Alimentary tract
Urinary system
Reproductive system
Respiratory system
Ocular
Postural hypotension
Anhidrosis, heat intolerance
Xerostomia, oropharyngeal dysphagia,
constipation, occasionally diarrhea
Nocturia, frequency, urgency,
incontinence, retention
Erectile and ejaculatory failure (in the
male)
Stridor, involuntary inspiratory gasps,
apneic periods
Alacrima, anisocoria, Horner’s
syndrome
Parkinsonian, cerebellar and
pyramidal signs
Note: Oropharyngeal dysphagia, incontinence and respiratory features, along
with additional neurologic features indicative of multiply system atrophy.
sis is considerably poorer in MSA, and the frequency and
nature of complications and the management of the conditions differ.64–66 Differentiation of the two groups is important in relation to drug trials and interventional studies (e.g.,
as with substantia nigra implantation) because those with
MSA are unlikely to respond favorably. Furthermore, there
is accumulating evidence of autonomic nervous system
involvement in idiopathic Parkinson’s disease, although the
extent and degree of dysfunction varies and is dependent on
factors that include age and duration of disease.67,68 There is
a smaller group with apparent idiopathic Parkinson’s disease
in whom substantial cardiovascular autonomic failure may
occur, often as a late complication. These patients usually
are elderly and have been successfully treated with l-dopa
and other antiparkinsonian drugs for many years. They thus
differ clinically from those who have the parkinsonian forms
of MSA.
The extent and degree of autonomic dysfunction varies
in the different parkinsonian syndromes. Cardiovascular
autonomic failure is an exclusionary feature in progressive
supranuclear palsy.69 In diffuse Lewy body disease, orthostatic hypotension and autonomic failure may be severe and
an early manifestation, even before the onset of parkinsonian features.70,71 Autonomic deficits have been described in
patients with the Guam Parkinsonian dementia complex72
and in Wilson’s disease.73,74
Drug treatment of neurologic deficits in parkinsonian
syndromes, especially multiple system atrophy, idiopathic
Parkinson’s disease, and diffuse Lewy body disease, has
the potential to lower blood pressure. These hypotensive
effects may be compounded, especially in the presence of
autonomic failure, and may substantially worsen postural
hypotension. Whether potentially neuroprotective agents
such as selegiline contribute to sudden death in Parkinson’s
disease, because of their cardiac and vascular actions, remains
speculative.75,76
Secondary Autonomic Disorders
Autonomic dysfunction secondary to cerebral and spinal disorders is described, along with some other conditions.
12/1/2006 3:41:36 PM
Spinal Cord Lesions
In cervical and high thoracic spinal cord lesions, the majority
of autonomic pathways to the heart and blood vessels are
separated from cerebral control.82 The baroreceptor afferents,
however, are preserved and cardiac parasympathetic efferents to the heart remain intact and functional. Thus, hypotension occurs during postural change because of the inability
of the brain to activate peripheral sympathetic efferent83
pathways, and the heart rate rises because of baroreceptor
activation and withdrawal of cardiac vagal tone (Fig. 88.13).
With time, compensatory mechanisms, which include activation of the renin-angiotensin-aldosterone system and an
improvement in cerebrovascular autoregulation, help reduce
postural hypotension and its symptoms. The reverse, hypertension followed by bradycardia, may occur during autonomic dysreflexia when isolated spinal cord sympathetic
pathways are activated by stimulation of skin, skeletal
muscle, or viscera below the level of the lesion82 (Fig. 88.14).
Thus, the presence of bedsores, skeletal muscle spasms,
urinary tract infection, a blocked urethral catheter, or an
anal fissure can result in a severe and paroxysmal elevation
of blood pressure, often with a compensatory bradycardia.
The segmental level is important, as autonomic dysreflexia
does not occur in spinal lesions below level T5. The precise
reasons are not known; the large splanchnic vascular bed is
supplied below this level and may provide an explanation. A
key component in the management of autonomic dysreflexia
is identifying the cause and alleviating it; drugs acting on
various components of the reflex may be used (Table 88.10).
CAR088.indd 1894
Normal
150
10 min of 60-degree head up tilt
0
180
Spinal
injury
0
150
Heart rate bpm
180
Heart rate bpm
Autonomic failure may result from specific lesions, especially in the brainstem. Posterior fossa tumors and syringobulbia may cause postural hypotension by ischemia or
destruction of brainstem cardiovascular centers. Demyelination or plaque formation in multiple sclerosis may cause a
variety of autonomic defects of cerebral origin, although it is
difficult to exclude a spinal contribution.77,78 Autonomic
failure in the elderly may be largely central, due to widespread neuronal degeneration, although peripheral neural
and target organ deficits may contribute.79
Certain cerebral disorders cause a pathologic increase in
autonomic activity. In bulbar poliomyelitis, hypertension
has been associated with damage to the lateral medulla. In
cerebral tumors, distortion or ischemia of specific pressor
areas, which have been defined experimentally and termed
Cushing-sensitive areas, may raise blood pressure by increasing sympathetic activity. Similar mechanisms may also
account for increased sympathetic activity, hypertension,
and cardiac dysrhythmias associated with subarachnoid
hemorrhage, although the local effects of various chemicals
from extravasated blood also may influence cerebral centers.80
In tetanus, hypertension may result from increased sensitivity of brainstem centers through retrograde spread of tetanus
toxin along the nerve fibers. In fatal familial insomnia, a
prion disease predominantly involving the thalamus, abnormalities of autonomic function include an increase in blood
pressure, heart rate, lacrimation, salivation, sweating, and
body temperature, along with altered hormonal circadian
rhythms in the presence of intact target organ function.81
Blood pressure mm Hg
(portapres)
Cerebral Disorders
88
Blood pressure mm Hg
(portapres)
chapter
3 min of 60-degree head up tilt
0
0
FIGURE 88.13. Blood pressure and heart rate measured continuously with the Portapres II in a patient with a high cervical spinal
cord lesion. There is a fall in blood pressure because of impairment
of the sympathetic outflow disrupted in the cervical spine. Heart
rate rises because of withdrawal of vagal activity in response to the
rise in pressure.
Patients with high cervical lesions (above the diaphragmatic innervation at the fourth and fifth cervical segments),
require artificial respiration. They are prone to severe bradycardia and cardiac arrest, especially in the early phases
after injury when they are in a state of “spinal shock”85,86
(Fig. 88.15A). In this phase isolated spinal cord sympathetic
reflexes often are absent and therefore autonomic dysreflexia does not occur. Disconnection of the respirator and
tracheal suction, as for intermittent tracheal toilette, activates vagal afferents that then increase vagal efferent activity (Table 88.11). This is not opposed by sympathetic activity,
as normally would occur. Furthermore, the cardiac effects
Plasma
NA and A
IVP
BP
HR
(ng/mL) (mm Hg) (beats/min) (mm Hg)
18 9 4
200
0
100
0
100
Bladder stimulation
0
0.20
0.00
Time (min)
FIGURE 88.14. Blood pressure (BP), heart rate (HR), intravesical
pressure (IVP), and plasma noradrenaline (NA) and adrenaline (A)
levels in a tetraplegic patient before, during, and after bladder stimulation induced by suprapubic percussion of the anterior abdominal
wall. The rise in BP is accompanied by a fall in heart rate as a result
of increased vagal activity in response to the rise in blood pressure.
Level of plasma NA (open histograms), but not A (filled histograms),
rise, suggesting an increase in sympathetic neural activity independently of adrenomedullary activation.
12/1/2006 3:41:36 PM
18 9 5
au tonom ic dysf u nc t ion a n d h y pot e nsion
TABLE 88.10. Drugs used in the management of autonomic
dysreflexia with their major site of action
Target organ
Blood vessels
Sweat glands
Anal sphincter
Skeletal muscle
BP (mm Hg)
Sympathetic efferent
200
Topical lignocaine
Clonidine
Reserpine
Spinal anesthetics
Ganglia: hexamethonium
Nerve terminals: guanethidine
α-Adrenoceptors: phenoxybenzamine
Glyceryl trinitrate, nifedipine
Anticholinergics: probanthine
Botulinumtoxin
Dantroleine sodium
The Riley-Day Syndrome (Familial Dysautonomia)
The Riley-Day syndrome is an autosomal recessive disorder
predominantly affecting autonomic and sensory neurons.87
100
0
6 h post atropine
(0.6 mg i.v.)
A
Time (min)
BP (mm Hg)
200
0
HR (beats/min)
of vagal nerves cannot be reversed by the inflation “reflex”
because of respiratory paralysis. Hypoxia secondary to a
variety of causes, from respiratory infections to pulmonary
emboli, also may sensitize the vagus nerve. Thus, activation
of vagal afferents can result rapidly in severe bradycardia
and hypotension with potentially disastrous sequelae. The
importance of the final efferent pathway is emphasized by
the effectiveness of the muscarinic cholinergic blocker
atropine in preventing bradycardia and cardiac arrest
(Fig. 88.15B).
A key factor in preventing excessive vasovagal reflex
activity is adequate oxygenation. If bradycardia occurs, intravenous atropine may be necessary. Cholinomimetics, such
as neostigmine and carbachol, which may be used to reverse
urinary bladder and bowel paralysis in spinal shock, should
be avoided or used with caution. The β-adrenoreceptor agonist
isoprenaline may be used to raise heart rate, but it can reduce
blood pressure because of enhanced vasodilatation due to
vascular β2-adrenoceptor stimulation. Temporary cardiac
demand pacemakers may be of value. Similar problems may
occur in chronic tetraplegics undergoing general anesthesia
when vagal afferents are stimulated during intubation, especially when there is inadequate cardiac vagal blockade. Such
patients should be administered atropine, ideally intravenously, before intubation.
Off respirator
0
HR (beats/min)
Afferent
Spinal cord
Atropine
0.6 mg i.v.
Off respirator
for suction
100
0
20 min post atropine
Time (min)
(0.6 mg i.v.)
FIGURE 88.15. (A) The effect of disconnecting the respirator (as
required for aspirating the airways) on the blood pressure (BP) and
heart rate (HR) of a recently injured tetraplegic patient (C4/5 lesion)
in spinal shock, 6 hours after the last dose of intravenous atropine.
Sinus bradycardia and cardiac arrest (also observed on the electrocardiograph) were reversed by reconnection, intravenous atropine,
and external cardiac massage.85 (B) The effect of tracheal suction, 20
minutes after atropine. Disconnection from the respirator and tracheal suction did not lower either heart rate or blood pressure.86
B
It occurs mainly in Ashkenazi Jews with a history of consanguinity. In a newborn infant, absent fungiform papillae,
lack of corneal reflexes, decreased deep tendon reflexes, and
a diminished response to pain in a child of Ashkenazi Jewish
TABLE 88.11. The major mechanisms contributing to bradycardia and cardiac arrest in recently
injured tetraplegics in spinal shock during tracheal suction and hypoxia
Tracheal suction
Normal
Tetraplegics
CAR088.indd 1895
Hypoxia
Increased sympathetic nervous activity
Bradycardia is the primary response
causes tachycardia and raises blood
opposed by the pulmonary (inflation)
pressure
vagal reflex, resulting in tachycardia
There is no increase in sympathetic
The primary response, bradycardia, is
nervous activity, so there is no rise
not opposed by the pulmonary
in heart rate or blood pressure.
(inflation) vagal reflex, because of
Vagal afferent stimulation may lead
disconnection from respirator or
to unopposed vagal efferent activity
“fi xed” respiratory rate
Increased vagal cardiac tone
Bradycardia and cardiac arrest
12/1/2006 3:41:36 PM
extraction should point to the diagnosis. An abnormal intradermal histamine skin test (with an absent flare response)
and pupillary hypersensitivity to cholinomimetics confirms
the diagnosis. The chromosome abnormality is linked to
9Q31 and there is a mutation in the gene IK-BKAP in 99%
of cases; there is sufficient sensitivity in genetic probes to
ascertain whether the fetus is affected.88,89
Clinical features result from autonomic underactivity
and overactivity. These include a labile blood pressure (with
hypertension and postural hypotension), parasympathetic
abnormalities (with periodic vomiting, dysphagia, constipation, and diarrhea), and urinary bladder disturbances. Neurologic abnormalities, psychometric abnormalities, associated
skeletal problems (scoliosis), and renal failure may occur.
The prognosis is dependent on anticipating complications and on supportive therapy. The average life expectancy
has steadily risen; previously 50% died before the age of 5
years. Many now reach adulthood, with 50% reaching the
age of 30 years. Many lead independent lives and some have
married and had normal offspring. In the past, many would
have been dead by the early second decade. Death is often
sudden and may be the result of cardiorespiratory arrest;
cardiac pacemakers may be of value.90
The management of patients includes control of blood
pressure, which can be difficult because of its lability.
Impaired thermoregulation can occur with extremes of temperature and requires appropriate therapy. Reduced food
intake because of periodic vomiting and impaired gastroesophageal motility may impair growth and result in anemia;
a gastrostomy is often helpful.
Diabetes Mellitus
Peripheral and autonomic neuropathy often complicates diabetes mellitus, especially in patients who are poorly controlled and on insulin therapy. Their morbidity and mortality
is considerably higher than those without a neuropathy. The
vagus initially may be involved, with characteristic features
of cardiac vagal denervation.91 In conjunction with partial
preservation of the cardiac sympathetic, this may predispose
diabetics, many of whom have ischemic heart disease, to
sudden death from cardiac dysrhythmias. In some, sympathetic failure may cause postural hypotension; additional
nonneurogenic factors that include dehydration (as may
occur with hypoglycemia-induced osmotic diuresis and
watery diarrhea), anemia, and at times even insulin itself can
lower blood pressure further. In diabetics insulin may
enhance postural hypotension; it causes hypotension even
when supine when given intravenously to patients with
primary autonomic failure even when blood glucose is maintained by a euglycemia clamp (Fig. 88.16).
Although vagal denervation (synonymous with cardiac
autonomic neuropathy) often is an initial feature, there is
evidence that sympathetic impairment occurs at an early
stage in type 2 diabetics in whom there are subnormal vasoconstrictor responses to cold.92 Sympathetic denervation may
predispose to excessive gravitational blood pooling, either in
the legs or splanchnic circulation, and lower blood pressure,
with a tachycardia. Compensatory tachycardia, often attributed to impaired vagal function in diabetes, therefore, may
have an alternative cause, and be associated with intermit-
CAR088.indd 1896
88
160
300
120
200
80
40
100
56 u
S–C
48 u
S–C
Blood glucose (mg%)
chapter
BP (mm Hg)
18 9 6
8 am 10 am 12 pm 2 pm 4 pm 6 pm 8 pm 10 pm
Time
FIGURE 88.16. Diurnal variation of lying and standing blood pressure in a 48-year-old man with severe autonomic neuropathy. Insulin
was given subcutaneously (SC) at times shown by the vertical
arrows. The unhatched area shows supine blood pressure, the
hatched area the standing blood pressure, and the continuous line
the blood glucose.91
tent episodes of hypotension. Factors such as anemia, sometimes secondary to renal impairment, may contribute.
In the later stages of diabetes, impairment of baroreceptors and sympathetic denervation of the heart and blood
vessels, among other factors, can result in severe postural
hypotension. In some the capacity to maintain blood pressure is further compromised by damage to innervation of the
renal juxtaglomerular apparatus, leading to hyporeninemic
hyperaldosteronism.
Awareness of hypoglycemia is dependent in part on sympathetic activation, and may be diminished with autonomic
nerve damage. There also may be involvement of the gastrointestinal tract (gastroparesis diabeticorum and diabetic
diarrhea), urinary bladder (diabetic cystopathy), and sexual
organs (in the male causing impotence with erectile and
ejaculatory failure). Sudomotor abnormalities include gustatory sweating. There is no known means to prevent the
neuropathy except by strict glycemic control. Pancreatic
transplantation may reverse some of the features.
Amyloidosis
Autonomic dysfunction may occur in systemic amyloidosis
or familial amyloid polyneuropathy.93 Amyloid deposition
may be focal or generalized and (in AL amyloidosis), derived
from monoclonal light chains, and in the hereditary amyloidosis from mutations in the genes for transthyretin, apolipoprotein A-1, and gelsolin.
Primary amyloidosis due to immunoglobulin light chain
(AL) amyloid deposition may occur in multiple myeloma,
malignant lymphoma, Waldenström’s macroglobulinemia,
and nonmalignant immunocyte dyscrasia. It may occur in up
to 10% with a benign monoclonal gammopathy. Autonomic
manifestations include postural hypotension, gastroparesis,
diarrhea, and distal anhidrosis, with motor and sensory
symptoms. In amyloidosis, which complicates chronic infections and inflammatory disorders, there is deposition of the
protein AP, derived from a serum protein, SAP.
In the familial disorder, abnormalities result from deposition in peripheral nerves of mutated amyloid protein,
mainly produced in the liver. Classification of FAP is now
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au tonom ic dysf u nc t ion a n d h y pot e nsion
Neurally Mediated Syncope
In neurally mediated syncope, there is an intermittent abnormality of the autonomic nervous system, resulting in a fall
in heart rate due to increased cardiac vagal activity, and
hypotension due to withdrawal of sympathetic neural tone.
Autonomic causes of syncope and presyncope are common,
once cardiac and nonautonomic neurologic causes have been
excluded.95 There may be increased cardiac parasympathetic
activity resulting in bradycardia (the cardioinhibitory form),
diminished sympathetic vasoconstrictor activity resulting in
hypotension (the vasodepressor form), or a combination of
the two (Fig. 88.17A). It is essential to exclude disorders with
a prolonged QT interval such as the Brugada syndrome.
There are three major causes of neurally mediated
syncope: vasovagal syncope, carotid sinus hypersensitivity,
and miscellaneous causes, often referred to as situational
syncope.
Vasovagal Syncope
This is the most common form of neurally mediated syncope.
Episodes in children may be accompanied by anoxia and
seizures, hence the term reflex anoxic seizures or syncope.96
A greater degree of vagotonia in children may predispose to
the cardioinhibitory form; a cardiac demand pacemaker is of
value.
In those presenting as teenagers there often is a strong
family history, and episodes have been associated with attacks
in friends of the patient.97–99 Whether this indicates an
acquired or genetic predisposition, or both, is unclear. Fainting often is associated with a postural component, such as
standing still at assembly. Precipitating stimuli include
blood, needles, and pain. An emotional component has
resulted in the term emotional syncope. Even the sight of a
CAR088.indd 1897
160
Start of presyncopal symptoms
Heart rate bpm
Blood pressure mm Hg (portapres)
140
0
A
60-degree head up tilt
140
0
160
Start of presyncopal symptoms
Heart rate bpm
Blood pressure mm Hg (portapres)
based on the chemical and molecular nature of the constituent proteins and not on clinical presentation. There are
various forms: transthyretin (TTR30) FAP, FAP Ala 60 (Irish/
Appalachian), FAP Ser 84, and His 58. Diagnosis is based on
biopsy and detecting TTR and other mutations. The latter
can be performed using blood, thus enabling detection and
diagnosis before onset of symptoms. This is of particular
value in screening families. Amyloid deposits and overall
load can be mapped using scintigraphy following iodinated
(123I) or technetium (99mTc) radiolabeled SAP obtained from
donor serum.94 The cardiovascular system, gut, and urinary
bladder can be affected at any stage. Motor and sensory neuropathy often begins in the lower limbs. The disease relentlessly progresses but at a variable speed. There is increasing
evidence of differences in autonomic dysfunction in the
various mutations. There may be dissociation of autonomic
symptoms from functional deficits; this is of importance, as
evaluation of cardiovascular autonomic abnormalities is
essential in preventing morbidity and mortality especially
during hepatic transplantation, which is the only way currently to reduce levels of variant transthyretin and its deposition in nerves. This prevents progression and may reverse
some neuropathic features. It may be of greater value if performed before substantial nerve damage, or cardiac deposition, occurs.
0
B
60-degree head up tilt
0
FIGURE 88.17. (A) Blood pressure and heart rate with continuous
recordings from the Portapres II in a patient with the mixed (cardioinhibitory and vasodepressor) form of vasovagal syncope.5 The arrow
indicates the start of symptoms during head-up tilt. (B) Atropine
raises heart rate but has no effect on vasodepression induced again
by head-up tilt despite maintenance of heart rate.
needle or mention of venepuncture may induce an attack.
There may be difficulties in diagnosis and management when
vasovagal syncope occurs along with pseudosyncope.99
The investigation of vasovagal syncope includes tilt table
testing, often with a provocative stimulus, which in recent
studies has included venepuncture and even pseudovenepuncture.95 In the mixed form, where the role of bradycardia
is not clear and a cardiac demand pacemaker is being considered, an atropine test often is useful. Atropine for a short
period maintains an elevated heart rate; a reduction in symptoms and signs with repeat head-up tilt favors a beneficial
effect of cardiac pacing. A lack of effect despite an elevated
heart rate, indicates that vasodepression is the predominant
component and that a cardiac demand pacemaker is unlikely
to be of benefit (Fig. 88.17B). However, there is unpredictability in inducing an episode with head-up tilt tests. This
has led to combining additional physiologic and pharmacologic stimuli to induce an attack, such as by lower body
negative pressure, or drugs such as isoprenaline and glyceryltrinitrate. Such testing may result in false positives.100
The management of vasovagal syncope includes reducing
or preventing exposure to precipitating causes, although
these may be unclear. In some, especially with a phobia,
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18 9 8
Miscellaneous Causes
There are a variety of situations, often referred to as situational syncope, which can cause intermittent bradycardia
120
Heart rate bpm
Blood pressure mm Hg (portapres)
160
20 seconds of left
carotid sinus massage
0
0
FIGURE 88.18. Continuous blood pressure and heart rate measured
noninvasively (by Finapres) in a patient with falls of unknown
cause. Left carotid sinus massage (RCSM) caused a fall in both heart
rate and blood pressure. The fi ndings indicate the mixed (cardioinhibitory and vasodepressor) form of carotid sinus hypersensitivity.
CAR088.indd 1898
BP (mm Hg)
Food
200
100
0
250
125
0
SV (mL)
50
0
LVET (ms)
TPR (MU)
Carotid Sinus Hypersensitivity
The incidence of carotid sinus hypersensitivity increases
with advancing age and is more common than previously
thought, especially in older patients with unexplained falls.107
Some give a history of attacks induced by neck movements
or fastening of the collar. The provocative stimulus of carotid
sinus massage should be performed in the laboratory when
upright during head-up tilt (Fig. 88.18), which is when there
is a greater dependence on autonomic activity. There are
three major forms: the cardioinhibitory form, with marked
bradycardia; the rarer vasodepressor form, with hypotension;
and the common mixed form, with a combination of bradycardia and hypotension. A cardiac demand pacemaker often
is of benefit, especially in the cardioinhibitory form; in the
mixed and vasodepressor forms, the use of vasopressor drugs
may be necessary.108,109 Denervation of the carotid sinus has
been used especially in unilateral hypersensitivity.
88
100
CO (L/min)
cognitive behavioral psychotherapy is helpful. A combination of nonpharmacologic approaches should include a high
salt diet, fluid repletion, exercise especially to strengthen
lower limb muscles, measures that activate the sympathetic
nervous system such as sustained handgrip, the use of the
calf muscle pump to prevent pooling, and various maneuvers
that include leg crossing.101–104 The ideal approach, when
there are symptoms suggestive of an oncoming attack, is to
sit or lie down, if needed, with the legs up. Drugs are used
especially when there is a low supine blood pressure and
nonpharmacologic measures alone are not successful. They
include low-dose fludrocortisone, and sympathomimetics
such as ephedrine and midodrine. The 5-hydroxytryptamine
uptake release inhibitors have been used with varying
success. There is a limited role for beta-blockers. In the cardioinhibitory form, a cardiac demand pacemaker initially
was found to be of value,105 although this was not clearly so
in a later study.106 The long-term prognosis is favorable.
HR (bpm)
chapter
10
5
0
10
5
0
500
250
0
10:00
10:05
10:10
10:15
10:20
10:25
Time
FIGURE 88.19. Continuous measurement of heart rate (HR), blood
pressure (BP), stroke volume (SV), cardiac output (CO), total peripheral vascular resistance (TPR), and left ventricular ejection time
(LVET) before, during, and after a solid meal eaten after an overnight
fast. After completion of the food there is a fall in blood pressure,
stroke volume, and cardiac output, and then a fall in heart rate. The
patient collapsed at this point, hence the change in the record. On
recovery from syncope, while the patient was lying flat, the heart
rate recovered, but stroke volume, cardiac output, and blood pressure remained low. A cardiac pacemaker was avoided.
and hypotension. Syncope has been reported with swallowing (Fig. 88.19); in some this is associated with glossopharyngeal neuralgia. In some, instrumentation, even during
anesthesia, may result in cardiac arrest. It may occur during
pelvic and rectal examination, during micturition and defecation, and in trumpet blowers and weight lifters. Changes
in intrathoracic pressure may contribute in cough and laughter-induced syncope and trumpet blowing. The “fainting
lark” (voluntary syncope) is due to a combination of the
Valsalva maneuver and gravity lowering blood pressure, with
hyperventilation causing hypocapnia and cerebral vasoconstriction. It is induced by squatting, overbreathing, standing
up suddenly, and blowing against a closed glottis (Fig. 88.20).
Bradycardia and cardiac arrest may occur in high spinal cord
injuries, especially in tetraplegics on artificial respirators,
where increased vagal activity not opposed by sympathetic
activity may result from tracheal stimulation (see Fig. 88.15
and Table 88.11). In “commotio cordis,” where there is cardiac
12/1/2006 3:41:37 PM
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au tonom ic dysf u nc t ion a n d h y pot e nsion
Middle cerebral artery ETCO2 (%)
blood flow velocity
(cm·s–1)
Blood pressure
(mm Hg)
250
200
150
100
50
Squatting
Standing
0 hyperventilation straining
10
Lying
5
0
200
150
100
50
0
Time (s)
10 sec
FIGURE 88.20. Finger arterial blood pressure at heart level, endtidal carbon dioxide concentration (ETCO2) and middle cerebral
artery blood flow velocity in a normal patient during squatting and
hyperventilating, followed by standing and straining. There is a
rapid fall in blood pressure and the patient can readily lose consciousness. This is the basis of the “fainting lark” as used by
children.
spaceflight. In a family with identical twins, a genetic basis
with a defect in the noradrenaline transporter system has
been described, which accounted for the raised basal noradrenaline levels; mutation of the gene encoding the noradrenaline transporter was thought to be responsible.119 The
possibility of immunologically mediated autonomic neuropathy has been raised. Antibodies to autonomic ganglia have
been observed and related to the autonomic deficits.120 In
some it appears to follow a viral infection. Predominantly
lower limb autonomic denervation, affecting vascular and
sudomotor function, occurs.121–123 Venous pooling may be a
problem.124 There is a strong association with the joint hypermobility syndrome (Ehlers-Danlos type III)125 (Fig. 88.22).
Psychogenic components also need to be evaluated, especially when hyperventilation is thought to contribute.
In PoTS, the symptoms may warrant use of drug
approaches similar to those used for orthostatic hypotension,
and include fludrocortisone and midodrine. Correcting hypovolemia and contributory factors (such as hyperventilation)
is important. Beta-blockers, especially those that are cardioselective, may reduce tachycardia. As in neurally mediated
syncope, use of nonpharmacologic measures should be introduced. With time some recover spontaneously. The complications of associated disorders, such as the joint hypermobility
syndrome, need to be addressed.
Drugs, Poisons, and Toxins
The term instantaneous or transient postural hypotension
has been used to describe children with normal autonomic
function who have appropriate vasoconstrictor responses to
gravitational stimuli.113,114 Whether this may be an exaggeration of the initial transient fall in blood pressure often
observed in normal adults is not known.115 Impaired cerebral
hemodynamics may contribute to dizziness, but does not
explain all the findings.116
Postural Tachycardia Syndrome
This disorder is characterized by orthostatic intolerance
(lightheadedness and other manifestations of cerebral hypoperfusion), often with palpitations but without orthostatic
hypotension (PoTS).117 The symptoms occur on standing and
during even mild exertion. Investigations exclude orthostatic
hypotension and autonomic failure; during postural challenge heart rate increases by over 30 beats per minute, or
rises above 120 bpm (Fig. 88.21). It has been observed predominantly in young women between the ages of 20 and 50.
There are similarities to syndromes initially described by Da
Costa and by Lewis (also known as soldier’s heart or neurocirculatory aesthenia). There is an association with mitral
valve prolapse, chronic fatigue syndrome, and deconditioning following prolonged bed rest and microgravity during
CAR088.indd 1899
140
200
60-degree head up tilt
Normal
0
200
0
140
60-degree head up tilt
0
200
AF
0
140
Heart rate bpm
Transient Orthostatic Hypotension
These may impair cardiovascular function either by a direct
action on neural pathways and receptors, or by causing an
autonomic neuropathy (Table 88.12). They include drugs that
are successfully used in the therapy of hypertension; these
drugs may act centrally (clonidine, methyldopa, moxonidine), or peripherally (β-adrenoceptor blockers). They may
cause marked bradycardia and hypotension even when used
locally; examples are xylometazoline hypochloride used
Blood pressure mm Hg (portapres)
arrest and sudden death during blunt impact to the chest,
such as during sports activities, the cause may be excessive
vagal activity in the presence of apnea.112 The first-dose hypotensive effect of certain drugs may be neurally mediated, via
the Bezold-Jarisch reflex.
60-degree head up tilt
0
0
FIGURE 88.21. Blood pressure and heart rate measured continuously before, during, and after 60-degree head-up tilt by the Portapres II in a normal subject (top panel), from a patient with orthostatic
hypotension due to autonomic failure (middle panel) and in patient
with the postural tachycardia syndrome (PoTS) (bottom panel).
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chapter
88
B
A
FIGURE 88.22. (A,B) Joint hyperextensibility as demonstrated by a patient with the joint hypermobility syndrome and postural tachycardia
syndrome (PoTS).
TABLE 88.12. Drugs, chemicals, poisons, and toxins causing
autonomic dysfunction affecting the cardiovascular system
Decreasing sympathetic activity
Centrally acting
Clonidine
Methyldopa
Moxonidine
Reserpine
Barbiturates
Anesthetics
Peripherally acting
Sympathetic nerve ending (guanethidine, bethanidine)
α-Adrenoceptor blockade (phenoxybenzamine)
β-Adrenoceptor blockade (propranolol)
Increasing sympathetic activity
Amphetamines
Releasing noradrenaline (tyramine)
Uptake blockers (imipramine)
Monoamine oxidase inhibitors (tranylcypromine)
β-Adrenoceptor stimulants (isoprenaline)
Decreasing parasympathetic activity
Antidepressants (imipramine)
Tranquilizers (phenothiazines)
Antidysrhythmics (disopyramide)
Anticholinergics (atropine, probanthine, benztropine)
Increasing parasympathetic activity
Cholinomimetics (carbachol, bethanechol, pilocarpine,
mushroom poisoning)
Anticholinesterases
Reversible carbamate inhibitors (pyridostigmine, neostigmine)
Organophosphorous inhibitors (parathion, sarin)
Miscellaneous
Alcohol, thiamine (vitamin B1. deficiency
Vincristine, perhexiline maleate
Ciguatera toxicity
Jellyfish and marine animal venoms
First dose of certain drugs (prazosin, captopril)
Withdrawal of chronically used drugs (clonidine, opiates,
alcohol)
CAR088.indd 1900
intranasally as a decongestant, and timoptolol used intraocularly for glaucoma. Drugs may raise heart rate either through
increasing sympathetic activity (e.g., amphetamines), or by
reducing cardiac parasympathetic activity. Drugs that
increase cholinergic activity can lower heart rate. Reef fish
containing ciguera toxin may cause bradycardia through
increased vagal tone. Alcohol and perhexiline maleate may
affect cardiovascular function by causing an autonomic
neuropathy.
Certain antihypertensive agents such as the angiotensinconverting enzyme inhibitors (captopril and enalapril), and
α-adrenoceptor blockers (prazosin) may cause syncope, especially after the first dose. The postulated mechanisms include
activation of cardiac C-fiber afferents, an increase in cholinergic activity, and a withdrawal of sympathetic activity
similar to the Bezold-Jarisch reflex, resulting in bradycardia
and vasodilatation.
Management of Postural Hypotension
Postural hypotension may cause considerable disability and
there is the potential risk of serious injury. The key aims in
management, therefore, are to provide low-risk therapy,
ensure appropriate mobility and function, prevent falls and
associated trauma and maintain a suitable quality of life,
depending on the underlying disorder and individual priorities. In nonneurogenic postural hypotension, the underlying
problem often needs to be rapidly resolved. It may be an
indicator of substantial blood and fluid loss, or a serious
underlying disorder such as adrenal insufficiency. This may
include reducing fluid loss, replacing blood and fluids, correcting the endocrine deficiency, improving cardiac function,
and preventing vasodilatation. In neurogenic orthostatic
hypotension, cure is less likely, and long-term management
usually needs to be considered. This in part is dependent on
12/1/2006 3:41:37 PM
au tonom ic dysf u nc t ion a n d h y pot e nsion
TABLE 88.13. Some of the measures used in the management of
neurogenic postural hypotension
Nonpharmacologic measures
To be avoided
Sudden head-up postural change (especially on waking)
Prolonged recumbency
Straining during micturition and defecation
High environmental temperature (including hot baths)
Severe exertion
Large meals (especially with refi ned carbohydrate)
Alcohol
Drugs with vasodepressor properties
To be introduced
Head-up tilt during sleep
Small frequent meals
High salt intake
Judicious exercise (including swimming)
Body positions and maneuvers
To be considered
Elastic stockings
Abdominal binders
Water ingestion
Pharmacologic Measures
Starter drug: Fludrocortisone
Sympathomimetics: ephedrine, Midodrine
Specific targeting: octreotide, desmopressin, erythropoietin
the pathophysiologic processes and the primary disease
responsible. It should be emphasized that the management
of associated nonneurogenic factors, such as those resulting
from fluid and blood loss, is essential, as they can considerably exacerbate neurogenic postural hypotension.
This section focuses on the management of neurogenic
postural hypotension. The main therapeutic strategies
include both nonpharmacologic and pharmacologic measures126 (Table 88.13). The former is an essential component
of management, even when drugs are used. Education is of
importance because an appropriate implementation of nonpharmacologic approaches, in particular, is especially dependent on the cooperation of the patient and caregivers.
Reducing the postural blood pressure fall alone is not the
singular aim as there may be dissociation between symptoms and the level of blood pressure.
Nonpharmacologic Measures
These measures can be divided into factors that should be
avoided, introduced, and considered (Table 88.13). Simple
explanations often suffice in enabling motivated patients to
avoid stimuli that are known to worsen postural hypotension, such as rapid changes from lying down and sitting to
the head-up position. However, the reason for some of the
measures to be introduced may not be obvious and require
further explanation. Head-up tilt, especially at night, by
raising the head end of the bed by 20 to 30 inches probably
acts by reducing renal perfusion pressure and activating nonneural mechanisms such as the renin-angiotensin-aldosterone system, which then reduce recumbency-induced diuresis
and help maintain blood pressure; it is particularly effective
in combination with low-dose fludrocortisone.128 When headup tilt is impractical, or the degree of tilt achieved inadequate, nocturnal polyuria and nocturia can be reduced with
CAR088.indd 1901
19 01
the antidiuretic agent desmopressin.129 Straining during micturition and bowel movements should be avoided. In hot
weather the elevation of body temperature, because of impairment of thermoregulatory mechanisms such as sweating,
may further increase vasodilatation and worsen postural
hypotension. Ingestion of alcohol or large meals, especially
those containing a high carbohydrate content, may cause
postprandial hypotension and aggravate postural hypotension.130,131 Determining the appropriate degree and type of
exercise is important and the advice requires individual tailoring. Exercising in a more horizontal position, such as
swimming and the use of a rowing machine, is less likely to
lower blood pressure. The use of various body positions and
physical maneuvers (Fig. 88.23), which include leg crossing,
squatting, sitting in the knee-chest position, and abdominal
compression, together with appropriate aids, such as lightweight portable chairs, is of value.132,133
Antigravity suits often are difficult to apply, having been
designed mainly for the physically able; they are of limited
value as the compensatory mechanisms that must be
recruited to induce postural hypotension are not activated
when the suit is not in use. Elastic stockings, compression
binding of the lower limbs,134 and abdominal binders may
help.135 However, for some patients, such as those with amyloidosis with accompanying hypoalbuminemia, positive
gravity suits may be the last resort as often it is impossible
to maintain intravascular volume without causing tissue
edema. Cardiac pacemakers have no place in the management of chronic neurogenic hypotension, except in unusual
circumstances.136,137 In such patients the lack of sympathetic
vasoconstriction results in peripheral pooling, reducing
venous return and thus ventricular filling and cardiac output.
Raising heart rate neither affects the underlying defect nor
provides benefit.
Recent observations indicate that drinking 500 mL of
water raises blood pressure substantially in patients with
primary autonomic failure138,139 (Fig. 88.24). A rise in blood
pressure also occurs after a similar amount of water in older,
but not younger, normal subjects. The reasons for this remain
unclear. In normal subjects, the pressor response begins
within 5 minutes, peaks between 30 and 35 minutes, and
wanes after 90 minutes. Plasma noradrenaline levels rise and
there is an increase in muscle sympathetic nerve activity
measured by microneurography, suggesting a role for the
sympathetic nervous system in the pressor response in
normal patients140 ; however, in a later study there was a
transient pressor response and increase in muscle sympathetic nerve activity only while drinking.141 It seems unlikely
that this is the predominant mechanism in primary autonomic failure, whether due to pure autonomic failure or
multiple system atrophy. In these patients there is a marked
rise in blood pressure, within 6 minutes in the former and
14 minutes in the latter group.142 As sympathetic nerve activation alone seems an unlikely explanation in patients with
sympathetic denervation, other possibilities include the
release of various vasoconstrictor neurohumoral substances,
and repletion of intravascular and extravascular fluid
volume.143 Regardless of the mechanism there are potential
benefits, especially in the morning soon after waking, when
patients with autonomic failure often are relatively dehydrated because of nocturnal polyuria.22
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19 0 2
chapter
88
Finap (mm Hg)
150
75
0
0
30
60
0
30
62 yrs PAF
FIGURE 88.23. Physical countermaneuvers using isometric contractions of the lower limbs and abdominal compression. The effects
of leg crossing in standing and sitting position, placing a foot on a
chair, and squatting on fi nger arterial blood pressure in a 54-year-old
Continuous finger blood pressure (mm Hg)
140
Water
120
100
80
60
40
20
0
0
5
10
15
20
25
30
35
42
45
50
55
Time (minutes)
FIGURE 88.24. Changes in blood pressure before and after 500 mL
distilled water ingested at time 0 in a patient with pure autonomic
failure. Blood pressure is measured continuously using the Portapres II.
CAR088.indd 1902
0
30
60
Time (s)
man with pure autonomic failure and incapacitating postural hypotension. The patient was standing prior to the maneuvers during
which there is an increase in blood pressure and the pulse
pressure.
Pharmacologic Measures
PAF subject
160
–5
60
Drugs are needed when nonpharmacologic approaches are
not completely successful. They raise blood pressure in
various ways (Table 88.14). The starter drug is the mineralocorticoid fludrocortisone, which acts by reducing salt and
water loss and may increase α-adrenoceptor sensitivity. Previous reports include its use in diabetes and levo-dopa–
induced hypotension.144,145 A low dose of 100 to 200 μg may
be used at night, when there is the greatest natriuresis and
diuresis. Side effects are minimal with these doses. With
higher doses, hyperkalemia and excessive fluid retention
may occur. Its benefits may not be realized until it is
stopped.
Drugs that mimic the deficient neurotransmitter norepinephrine should be considered next. Ephedrine has both
direct and indirect actions and is of value in central autonomic disorders such as multiple system atrophy, at dosages
of 15 to 45 mg thrice daily. It ideally is taken on waking, with
further doses before lunch and dinner. It is not recommended
at night when its pressor effects are not needed and when it
may cause insomnia. Other side effects, especially in higher
12/1/2006 3:41:38 PM
au tonom ic dysf u nc t ion a n d h y pot e nsion
TABLE 88.14. Outline of the major actions by which a variety of
drugs may reduce postural hypotension
Reducing salt loss/plasma volume expansion
Mineralocorticoids (fludrocortisone)
Reducing nocturnal polyuria
V2-receptor agonists (desmopressin)
Vasoconstriction: sympathetic
On resistance vessels (ephedrine, midodrine, phenylephrine,
noradrenaline, clonidine, tyramine with monoamine oxidase
inhibitors, yohimbine, l-dihydroxyphenylserine)
On capacitance vessels (dihydroergotamine)
Vasoconstriction: nonsympathomimetic
V1 receptor agents: terlipressin
Ganglionic nicotinic-receptor stimulation
Anticholinesterase inhibitors
Preventing vasodilatation
Prostaglandin synthetase inhibitors (indomethacin, flurbiprofen)
Dopamine receptor blockade (metoclopramide, domperidone)
β2-adrenoceptor blockade (propranolol)
Preventing postprandial hypotension
Adenosine receptor blockade (caffeine)
Peptide release inhibitors (somatostatin analogue: octreotide)
Increasing cardiac output
Beta-blockers with intrinsic sympathomimetic activity
(pindolol, xamoterol)
Dopamine agonists (ibopamine)
Increasing red cell mass
Erythropoietin
doses, include tremulousness, reduction in appetite, and
urinary retention in males due to its effects on the urethral
sphincter. In patients refractory to ephedrine, as in those
with peripheral lesions such as pure autonomic failure and
diabetes mellitus, a directly acting sympathomimetic should
be introduced. An example is the prodrug midodrine, which
is converted to desglymidodrine and stimulates α1-adrenoceptors.146–148 It is used in dosages of 2.5 to 10 mg, thrice daily.
Side effects include cutis anserine (goose bumps), tingling of
the skin, pruritus (especially of the scalp), and, in the male,
urinary hesitancy and retention. Midodrine appears more
effective than ephedrine,149 although this may depend on the
disorder studied. Sympathomimetics should be avoided or
used with caution in patients with coexisting ischemic heart
disease, cardiac dysrhythmias, and peripheral vascular
disease.
Other therapeutic attempts to raise blood pressure have
concentrated on pre- and postsynaptic α2-adrenoceptor mechanisms. They have limited application in practice. Clonidine
is mainly an α2-adrenoceptor agonist, which predominantly
lowers blood pressure through its central effects by reducing
sympathetic outflow.150 It also has peripheral actions on postsynaptic α-adrenoceptors, which may raise blood pressure in
the presence of pressor supersensitivity. These peripheral
vasoconstrictor effects probably account for its modest
success in severe, distal sympathetic lesions.151 Yohimbine
blocks presynaptic α2-adrenoceptors, which normally suppress the release of noradrenaline and may be of benefit
especially in incomplete sympathetic lesions.152
β-adrenoceptor blockers, such as propranolol, may be
successful when postural hypotension is accompanied by
CAR088.indd 1903
19 0 3
tachycardia; the combination of blocking β2-adrenoceptor
vasodilatation and β1- adrenoceptor–induced tachycardia may
account for the benefit. Certain β-adrenoceptor blockers,
such as pindolol, with a high degree of intrinsic sympathomimetic activity, may increase cardiac output and through
this, or other less well-understood mechanisms, raise blood
pressure. Cardiac failure may complicate treatment.
Xamoterol, another agent with similar properties, had limited
success and was withdrawn because of deleterious effects.
If the combination of fludrocortisone and a sympathomimetic does not produce the desired effect, selective targeting,
depending on the underlying pathophysiologic abnormalities, is needed. In postprandial hypotension, the somatostatin analogue octreotide is effective presumably because it
inhibits the release of vasodilatory gastrointestinal peptides.153,154 Importantly, it does not enhance nocturnal hypertension.155 It also may reduce postural and exercise-induced
hypotension.156,157 A dose of 25 to 50 μg subcutaneously 30
minutes before a meal reduces postprandial hypotension.
Side effects include nausea and abdominal colic. The combination of octreotide and midodrine is more effective than
either drug alone.158 Desmopressin, a vasopressin analogue,
acts on renal tubular vasopressor-2 receptors to reduce nocturnal polyuria and improve morning postural hypotension.
It is used as a nasal spray (10–40 μg) or in tablet form (100 to
400 μg) nocturnally.132 Side effects include hyponatremia and
water intoxication. Erythropoietin is beneficial in anemic
patients,159–161 especially in diabetes mellitus and amyloidosis
with complicating renal failure. It raises the red cell mass
and hematocrit and presumably improves cerebral oxygenation. A dose of 50 μg per kg body weight three times a week
for 6 to 8 weeks is used, sometimes with oral iron.
To prevent vasodilatation, prostaglandin synthetase
inhibitors, such as indomethacin and flurbiprofen, have been
used with some success. They may act by blocking vasodilatory prostaglandins, by causing salt and water retention
through their renal effects, or both.162,163 They have potentially serious side effects, however, such as gastrointestinal
ulceration and hemorrhage. The dopamine antagonists metoclopramide and domperidone are occasionally of value when
an excess of dopamine is contributory. Whether preventing
the vasodilator effects of nitric oxide will be of value remains
speculative.164 The anticholinesterase inhibitor pyridostigmine presumably by resulting in stimulation of nicotinic
acetylcholine receptors in ganglia, has been found recently
to reduce postural hypotension.165,166
Supine hypertension may occur in chronic autonomic
failure and may be worsened by treatment (Fig. 88.6). It occasionally may result in cerebral hemorrhage, aortic dissection,
myocardial ischemia, or cardiac failure. This may be a greater
problem with certain drug combinations, such as tyramine
(which releases noradrenaline) and monoamine oxidase
inhibitors (such as tranylcypromine and moclobemide),
which prolong its actions. Supine hypertension may increase
symptoms of cerebral ischemia during subsequent postural
change, probably through an unfavorable resetting of cerebral
autoregulatory mechanisms. To prevent these problems,
head-up tilt, omission of the evening dose of vasopressor
agents, a pre-bedtime snack to induce postprandial hypotension, and even nocturnal use of short-acting vasodilatators
have been suggested.
12/1/2006 3:41:38 PM
19 0 4
chapter
CH
NH2
COOH
HO
Tyrosine hydroxylase
HO
Dopa
CH
CH2
HO
NH2
COOH
HO
HO
CH
HO
HO
CH2
CH2
NH2
OH COOH
Dopa decarboxylase
Dopamine
CH
DL–DOPS
NH2
Dopamine β-hydroxylase
HO
Noradrenaline
CH
CH2
NH2
OH
HO
HO
Adrenaline
Phenylethanolamine
N-methyltransferase
CH
OH
HO
CH2
NH
CH3
FIGURE 88.25. Biosynthetic pathway in the formation of adrenaline and noradrenaline. The structure of dihydroxyphenylserine
(DL-DOPS) is indicated on the right. It is converted directly to noradrenaline by dopa decarboxylase, thus bypassing dopamine
β-hydroxylase.
To overcome the problems with lability of blood pressure,
a subcutaneous infusion pump, as in the control of hyperglycemia with insulin in diabetes mellitus, has been used,
infusing the short-acting vasoconstrictor noradrenaline. Previous studies with a pilot device had been successful,167 but
with a number of practical problems, including accurate
monitoring of blood pressure without an intraarterial catheter. Some of these have been overcome successfully.168 This
may benefit the severely hypotensive patient who is refractory to the combination of nonpharmacologic and conventionally administered drug therapy.
there are undetectable plasma norepinephrine and epinephrine concentrations, the ideal therapy is the prodrug l-threodihydroxyphenylserine, which is similar in structure to
norepinephrine except for a carboxyl group; the enzyme
dopa-decarboxylase coverts it into norepinephrine 36,169 (Fig.
88.25). In addition to its particular value in DBH deficiencies
(Fig. 88.26), l-DOPS has been of value in neurogenic postural
hypotension due to primary autonomic failure,170,171 familial
amyloid polyneuropathy,172,173 and hemodialysis-induced
hypotension.174,175
In Parkinson’s disease, postural hypotension occurs in a
substantial number of patients.176,177 There are many causes
of postural hypotension in patients with parkinsonian features (Table 88.15), including the effect of antiparkinsonian
and coincidental drugs, and an erroneous diagnosis, as parkinsonism may be the presenting feature of the primary
autonomic failure syndrome multiple system atrophy. Effective treatment, therefore, is dependent on the causative and
contributory factors. Management of postural hypotension
in elderly patients may be a problem as multiple factors contribute, including dementia.178,179 Lack of adherence to advice
and poor drug compliance are additional factors that complicate their management. In a recent study of elderly patients,
55% had postural hypotension and antihypertensive drug
treatment was considered to be causative.180
In some disorders, the prevention of progression, or
reversal, of the underlying pathophysiologic mechanisms
CAR088.indd 1904
110
70
30
Therapy in Specific Disorders and Situations
L
Noradrenaline/dopamine (pg/mL)
In secondary autonomic failure, modifications to therapy
often are needed to encompass the different pathophysiologic
processes, the effects of the underlying disease, and the interactions of drugs used to treat this disorder. In diabetes
mellitus, insulin therapy itself may lower blood pressure.
Furthermore, in diabetics there may be a fine line between
reducing postural hypotension with its attendant symptoms,
and enhancing supine hypertension, as the latter may impair
renal function and accelerate renal failure. In high spinal
cord injuries, the balance between paroxysmal hypertension
induced during autonomic dysreflexia and hypotension when
upright must be considered. In systemic amyloidosis, excessive proteinuria and hypoalbuminuria result in a low intravascular volume and peripheral edema; this often is worsened
by fludrocortisone and compounded by refractoriness to
sympathomimetic agents because of amyloid deposits in
blood vessels. In disorders with specific enzymatic defects,
such as dopamine β-hydroxylase (DBH) deficiency, where
DBH deficient (1)
150
Blood pressure (mm Hg)
CH2
Tyrosine
88
800
T
No drugs
L
T
DL-Dops
L
T
L-Dops
600
400
200
*
L
T
L
L
T
T
FIGURE 88.26. Blood pressure (systolic and diastolic) while the
patient is lying down (L) and during head-up tilt (T) in one of two
siblings with dopamine β-hydroxylase (DBH) deficiency (1) before,
during, and after treatment with DL-DOPS (racemic mixture;
DOPS, dihydroxyphenylserine) and L-DOPS (levo form). The levo
form causes a greater rise in blood pressure and a greater reduction
in postural hypotension than the racemic mixture.
0
*
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19 0 5
au tonom ic dysf u nc t ion a n d h y pot e nsion
TABLE 88.15. Possible causes of orthostatic hypotension in a
patient with parkinsonism
Side effects of anti-parkinsonian drugs
l-dopa, bromocritine, pergolide
l-dopa and COMT inhibitors (tolcapone)
MAO-b inhibitor: selegeline
Coincidental disease causing autonomic dysfunction
Diabetes mellitus
Drugs for allied conditions
Hypertension: antihypertensives
Prostatic hypertrophy: α-adrenoceptor blockers
Ischemic heart disease: vasodilators
Cardiac failure: diuretics
Erectile failure: sildenafi l
Autonomic failure
Multiple system atrophy
Parkinson’s disease with autonomic failure
Diffuse Lewy Body disease
may reduce postural hypotension. Thus, in acute dysautonomia, intravenous γ-immunoglobulin may be of value. It
remains to be determined whether transplantation of the
pancreas in diabetes mellitus and of the liver in familial
amyloid polyneuropathy, which appear to improve somatic
and probably halt autonomic nerve damage, will reduce postural hypotension in these conditions. After pancreaticrenal transplantation, motor and sensory conduction
increased; however, there was no clear improvement in
autonomic testing, although progression was halted.181
Whether this was due to maintaining euglycemia or the
effect of immunosuppression was unclear.182 After hepatic
transplantation, despite a 50% reduction in amyloid deposits when assessed by serum amyloid scintigraphy, disturbances affecting the gastrointestinal tract are unchanged,
but cardiomyopathy is more common and cardiac dysrhythmias still occur.183,184
Various therapeutic approaches have been used when
stimuli in daily life, such as food and exercise, induce hypo-
Exercise
Blood pressure (mm Hg)
160
25 W
50 W
tension or exacerbate postural hypotension, especially in
patients with autonomic failure. In postprandial hypotension, caffeine may act by blocking vasodilatory adenosine
receptors. A dose of 250 mg, the equivalent of two cups of
coffee, may be of benefit. The prodrug l-dihydroxyphenylserine (l-DOPS), presumably through adrenoceptor-induced
vasoconstriction, reduces postprandial hypotension in
primary autonomic failure.185 The somatostatin analogue
octreotide, which inhibits release of a variety of gastrointestinal tract peptides, including those with vasodilatory properties, has been successfully used to prevent postprandial
hypotension; 24-hour recordings of blood pressure indicate
that it does not enhance nocturnal (supine) hypertension.155,156
The need for subcutaneous administration is a drawback and
the development of an oral preparation will be a substantial
advance in therapy. Exercise-induced hypotension in autonomic failure is difficult to treat. In some, activation of the
calf muscle pump is successful, especially in the postexercise phase (Fig. 88.27). Water drinking reduces exerciseinduced hypotension and syncope186 ; whether it will be of
value in autonomic failure is not known. Exercise-induced
hypotension in autonomic failure is reduced by octreotide
and midodrine.157,187
Summary
The autonomic nervous system has a sympathetic and parasympathetic outflow, which supplies the heart, blood vessels,
and a variety of organs that contribute to cardiovascular
control. This normally works seamlessly, in a variety of situations, ensuring that there is adequate blood flow to vital
organs, commensurate with their particular needs. The intricate complexity of the autonomic nervous system, with
central, spinal, peripheral, and even intra-organ connections,
enables considerable flexibility in a variety of situations.
However, it may result in autonomic dysfunction, when
disease affects single or multiple sites; malfunction also may
Exercise
75 W100 W
50 W
25 W
75 W
140
120
100
80
60
40
20
0
0
5
10
15
20
25
Time (min)
FIGURE 88.27. Systolic and diastolic blood pressure (left) and heart
rate (right) in two patients with autonomic failure before, during,
and after bicycle exercise performed with the patients in the supine
position at different workloads, ranging from 25 to 100 watts. In the
patient on the left there is a marked fall in blood pressure on initiating exercise; she had to crawl upstairs because of severe exerciseinduced hypotension. In the patient on the right, there are minor
CAR088.indd 1905
0
5
10
15
20
25
Time (min)
changes in blood pressure during exercise, but a marked decrease
soon after stopping exercise. This patient was usually asymptomatic
while walking, but developed postural symptoms when he stopped
walking and stood still. It is likely that the decrease in blood pressure postexercise was due to vasodilatation in exercising skeletal
muscle, not opposed by the calf muscle pump.
12/1/2006 3:41:38 PM
19 0 6
chapter
result from intermittent short-lived failure. Autonomic disorders affect the cardiovascular system, and the diseases
causing them were described.
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