8 Autonomic Dysfunction
8 and Hypotension
Christopher J. Mathias
Classification of Autonomic Dysfunction. . . . . . . . . . . 1883
Clinical Manifestations. . . . . . . . . . . . . . . . . . . . . . . . . . 1883
Investigation of Autonomic Dysfunction . . . . . . . . . . . 1887
T
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 main-
taining 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 periph-
ery1 (Fig. 88.1). A key component is the baroreflex pathway,
an exquisitely sensitive mechanism that provides beat-by-
beat blood pressure control (Fig. 88.2). This chapter discusses
the classification of autonomic disorders that affect the car-
diovascular system, and describes the main clinical mani-
festations, 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,
Description of Key Autonomic Disorders . . . . . . . . . . . 1892
Management of Postural Hypotension . . . . . . . . . . . . . 1900
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1905
synonymous with the Shy-Drager syndrome) and secondary
disorders associated with a clearly defined 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 auto-
nomic abnormality, often associated with specific events
(Table 88.2). The postural tachycardia syndrome is a rela-
tively recently described disorder with orthostatic intoler-
ance 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.
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 first
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 pres-
sure usually is associated with symptoms of hypoperfusion
to various organs, especially to those above the heart, such
18 8 3
18 8 4 chapter 88

Sympathetic
nervous system Parasympathetic
Eye nervous system
Mesen- III
cephalon
Pons
medulla Tear and IX,VII
obl. salivary X
Superior glands Vagus n.

Cervical
cervical
ganglion Lung
Stellate
ganglion
Heart
Superior
mesenteric

Thoracic
ganglion Celiac Liver
ganglion
Stomach
Pancreas

Sacral Lumbar
Small
intestine
Inferior Large intestine
mesenteric rectum
ganglion
Bladder
Sympathetic trunk

Adrenal Reproductive FIGURE 88.1. Parasympathetic and sympa-

organs thetic 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 nec-
essarily 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 defi-
cits 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 stoop-
ing. 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

50
2s

FIGURE 88.2. Relationship between spontaneous fluctuations of blood pressure fluctuations. Asterisk indicates diastolic blood pres-
blood pressure and muscle-nerve sympathetic activity (left) recorded sure fall due to sudden atrioventricular (AV) block. Stippling indi-
in right peroneal nerve. The baroreceptor reflex accounts for the cates corresponding sequences of bursts and heartbeats.3
pulse synchrony of nerve activity and the inverse relationship to
 au tonom ic dysf u nc t ion a n d h y pot e nsion 18 8 5
TABLE 88.1. Outline classification of disorders resulting in 180 150

Blood pressure mm Hg
cardiovascular autonomic dysfunction Normal

Primary (etiology unknown)

(Portapres)

Heart rate bpm

Acute/subacute dysautonomias
Pure cholinergic dysautonomia
Pure pandysautonomia
Pandysautonomia with neurologic features
Chronic autonomic failure syndromes
Pure autonomic failure 60-degree head up tilt
Multiple system atrophy (Shy-Drager syndrome) 0 0
Autonomic failure with Parkinson’s disease 180 150
Diffuse Lewy body disease Autonomic

Blood pressure mm Hg
60-degree head up tilt failure
Secondary
Congenital

(Portapres)

Heart rate bpm

Nerve growth factor deficiency
Hereditary
Autosomal dominant trait
Familial amyloid neuropathy
Porphyria
Autosomal recessive trait
Familial dysautonomia: Riley-Day syndrome 0 0
Dopamine β-hydroxylase deficiency FIGURE 88.3. Blood pressure and heart rate measured continuously
Metabolic diseases before, during, and after 60-degree head-up tilt by the Portapres
Diabetes mellitus II in a normal subject (upper panel) and in patient with autonomic
Chronic renal failure failure due to multiple system atrophy (lower panel).4
Chronic liver disease
Vitamin B12 deficiency
Alcohol-induced
Inflammatory associated normally with minimal cardiovascular effects,
Guillain-Barré syndrome such as levodopa (for parkinsonism), may unmask or aggra-
Transverse myelitis vate postural hypotension. In diabetes mellitus with auto-
Infections
Bacterial: tetanus
nomic neuropathy, insulin may enhance postural hypotension
Viral: human immunodeficiency virus infection through it effects in causing vasodilatation or a reduction
Parasitic: Chagas’ disease in blood volume. Occasionally, symptoms may occur even
Prion: fatal familial insomnia with a small fall in postural blood pressure, when perfusion
Neoplasia is compounded by impairment of the vascular supply of
Brain tumors, especially of third ventricle or posterior fossa
Paraneoplastic, to include adenocarcinomas: lung, pancreas, the organ. An example is carotid artery stenosis in which
and Lambert-Eaton syndrome symptoms of cerebral hypoperfusion may be difficult to
Surgery distinguish from a transient ischemic attack caused by
Organ transplantation: heart thromboembolism.
Vagotomy and drainage procedures: dumping syndrome
Trauma
Hypoperfusion of organs other than the brain may result
Spinal cord injury in a variety of symptoms. Suboccipital and paracervical pain
Drugs in a “coat hanger” distribution is probably due to reduced
Neuropathy
Direct effects (see also Table 88.12)

TABLE 88.3. Some of the symptoms resulting from postural

hypotension and impaired perfusion of various organs
Cerebral hypoperfusion
Dizziness
Visual disturbances
TABLE 88.2. Disorders resulting in intermittent autonomic Blurred—tunnel
dysfunction that affect the circulation Scotoma
Graying out—blacking out
Neurally mediated syncope Color defects
Vasovagal syncope Loss of consciousness
Carotid sinus syncope Cognitive deficits
Miscellaneous (situational) syncope* Muscle hypoperfusion
Micturition syncope Paracervical and suboccipital (“coat-hanger”) ache
Defecation syncope Lower back/buttock ache
Cough syncope
Laughter-induced syncope Subclavian steal-like syndrome
Swallow syncope Renal hypoperfusion
With glossopharyngeal neuralgia Oliguria
With tracheal stimulation in tetraplegics Spinal cord hypoperfusion
Transient postural hypotension Nonspecific
Postural tachycardia syndrome Weakness, lethargy, fatigue
* Some examples of miscellaneous syncope.
Falls
18 8 6
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 coro-
nary 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 hypoten-
sion caused by autonomic failure, hypotension often is asso-
ciated with, but may be independent of, being upright. The
fall in blood pressure often is accompanied by clinical fea-
tures indicative of autonomic activation that include palpita-
tions 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 mech-
anisms 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 dis-
section, 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 head-
ache 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 pal-
pitations. Increased sympathetic nervous activity may initi-
ate or maintain hypertension in organ transplantees receiving
cyclosporine as immunosuppressant therapy.11 Sympathetic
chapter 88
overactivity may be a factor in hypertension associated with
renal artery stenosis,12,13 and in pregnancy-induced hypoten-
sion,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 β-
adrenoceptor stimulation. In PoTS, the tachycardia usually is
associated with head-up postural change and exertion. Tachy-
cardia may result from cardiac parasympathetic (vagal) dener-
vation, 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 parasympa-
thetic activity may be a key feature in carotid sinus hyper-
sensitivity and other forms of neurally mediated syncope.
The rapid rise in blood pressure in pheochromocytoma may
result in bradycardia with escape rhythms and atrioventricu-
lar 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 medi-
ated syncope. Facial pallor due to vasoconstriction may
accompany other features of excessive sympathoadrenal acti-
vation in pheochromocytoma. Facial vasodilatation accom-
panied 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 accompa-
nied by flushing and sweating over the face and neck; the
mechanisms are unclear. In Horner’s syndrome, facial vaso-
dilatation and anhidrosis with pupillary constriction may
result from lesions to sympathetic neural pathways within
the brain, spinal cord, or periphery. In the harlequin syn-
drome there also is facial vasodilatation and anhidrosis, but
without the ocular features of Horner’s syndrome; this sug-
gests a preganglionic lesion below the first 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 gene-
related peptide. In erythromelalgia, hands and feet are hot,
painful, and red; there are abnormalities in sympathetic
 au tonom ic dysf u nc t ion a n d h y pot e nsion 18 8 7
function and neuropeptides released from sensitized nocicep- in intravascular and extravascular fluid volume, thus contrib-
tors may be responsible.18 uting to worsening postural hypotension, especially in the
morning.22 Sexual dysfunction is common in the male, with
SKELETAL MUSCLE AND SPLANCHNIC VASCULATURE both erectile and ejaculatory failure. Drugs such as sildenafil
The regional vascular control of skeletal muscle and various (Viagra) are beneficial; their vasodilator properties, however,
organs may be affected in autonomic failure and account for can worsen postural hypotension.23 In multiple system
various manifestations. Thus, abnormal splanchnic control atrophy, unlike pure autonomic failure, there often is involve-
may contribute to postprandial hypotension,19 and renal oli- ment of the respiratory system, with nocturnal stridor that
gemia while the patient is upright may contribute to oligu- may be associated with abductor cord paresis, involuntary
ria. Exercise induces hypotension in autonomic failure, with inspiratory, gasps and periodic apnea.24 The latter may cause
abnormal changes in many vascular regions.20 Hypoperfu- oxygen desaturation; whether hypoxia contributes to sudden
sion of specific areas within the brain, or their increased death in such subjects remains a possibility.
sensitivity to ischemia, may cause or contribute to the symp-
toms of postural hypotension: in the brainstem to dizziness,
the occipital lobes to visual disturbances, and areas con- Investigation of Autonomic Dysfunction
cerned with cognition to attention and allied deficits.21 These
usually are transient and reversible once blood pressure is The key aims of investigation of autonomic dysfunction are
restored. as follows:
1. To determine whether autonomic function is normal
Noncardiovascular Features or abnormal; screening investigations to evaluate cardiovas-
The function of virtually every organ is influenced by the cular autonomic function are highlighted in Table 88.6.
autonomic nervous system with a wide variety of features, 2. If an abnormality has been observed, to assess the
especially in the generalized autonomic disorders (Table degree of autonomic dysfunction with an emphasis on the
88.5). Some of these also have an influence on cardiovascular site of lesion and functional deficit.
dysfunction. Sudomotor dysfunction, with overheating, can 3. To determine whether the abnormality is of the
result in cutaneous vasodilatation, which may contribute to primary or secondary variety, as the need for further inves-
postural hypotension. Nocturnal polyuria is frequent and is tigation, along with prognosis and management, is depen-
probably due to the raised supine level of blood pressure, fluid dent on the diagnosis; in some patients, investigations of
shifts into the central compartment, and therefore better various systems is required.
perfusion of the renal vasculature. Nocturia can result in a
considerable reduction in body weight, with a presumed fall
Cardiovascular System
Postural hypotension often is a cardinal and disabling feature
TABLE 88.5. Some noncardiovascular manifestations of of autonomic dysfunction, and investigations are designed to
autonomic dysfunction confirm its presence in evaluating exacerbating factors in
daily life, so as to guide treatment strategies. In our labora-
Sudomotor
Anhidrosis tories, screening investigations include head-up tilt and
Hyperhidrosis standing, with further tests to determine if postural hypo-
Gustatory sweating tension is the result of neurogenic or nonneurogenic mecha-
Hyperpyrexia nisms.25 Consideration of the latter (Table 88.7) is of particular
Heat intolerance
importance even in neurogenic postural hypotension, as
Alimentary
minor changes, such as a reduction in intravascular volume
Xerostomia
Dysphagia due to vomiting or diarrhea, can considerably worsen hypo-
Gastric stasis tension in such subjects.
Dumping syndromes The measurement of blood pressure and heart rate ideally
Constipation should be continuous and with the use of automated, nonin-
Diarrhea
vasive techniques. Investigation on a tilt table is advanta-
Urinary
geous in patients with severe postural hypotension or with
Nocturia
Frequency neurologic deficits, as they can be returned rapidly to the
Urgency horizontal, especially if they are near syncope or have lost
Incontinence consciousness. In some, prolonged head-up tilt is of value,
Retention especially with suspected neurally mediated syncope. The
Sexual use of a tilt table is of particular importance when carotid
Erectile failure
hypersensitivity is being considered, as carotid sinus massage
Ejaculatory failure
Retrograde ejaculation also should be performed during head-up tilt, especially in
Eye the vasodepressor forms, when blood pressure is dependent
Pupillary abnormalities to a greater extent on sympathetic neural activity, and its
Ptosis withdrawal can have substantial effects.26
Alacrima The cardiovascular responses to the Valsalva maneuver,
Abnormal lacrimation with food ingestion
during which intrathoracic pressure is raised, also tests the
18 8 8 chapter 88

TABLE 88.6. Outline of investigations in autonomic disease TABLE 88.7. Nonneurogenic causes of postural hypotension
Cardiovascular Low intravascular volume
Physiologic Head-up tilt (60 degrees)*; standing*; Blood/plasma loss Hemorrhage, burns, hemodialysis
Valsalva’s maneuver* Fluid/electrolyte deficiency
Pressor stimuli* (isometric exercise, cold Diminished intake Anorexia nervosa
pressor, mental arithmetic) Loss from gut Vomiting, ileostomy losses,
Heart rate responses: deep breathing*, diarrhea
hyperventilation*, standing*, head-up Loss from kidney Salt losing nephropathy, diuretics
tilt*, 30 : 15 R-R interval ratio Endocrine deficiency Adrenal insufficiency (Addison’s
Liquid meal challenge disease)
Exercise testing Cardiac insufficiency
Carotid sinus massage Myocardial Myocarditis
Biochemical Plasma noradrenaline: supine and head-up Impaired ventricular filling Atrial myxoma, constrictive
tilt or standing; urinary catecholamines; pericarditis
plasma renin activity and aldosterone Impaired output Aortic stenosis
Pharmacologic Noradrenaline: α-adrenoceptors, vascular
Isoprenaline: β-adrenoceptors, vascular and Vasodilatation
cardiac Endogenous Hyperpyrexia
Tyramine: pressor and noradrenaline Hyperbradykininism
response Systemic mastocytosis
Edrophonium: noradrenaline response Varicose veins
Atropine: parasympathetic cardiac blockade Exogenous Drugs such as glyceryl trinitrate
(GTN)
Endocrine Clonidine: α2-adrenoceptor agonist: Alcohol
noradrenaline suppression; growth Excessive heat
hormone stimulation
Sudomotor Central regulation thermoregulatory sweat
test
Sweat gland response to intradermal
acetylcholine, quantitative sudomotor sympathetic efferent outflow. Cardiac parasympathetic effer-
axon reflex test (Q-SART), localized sweat ent pathways are assessed by measuring the heart rate
test responses to a variety of stimuli that include postural change,
Sympathetic skin response the Valsalva maneuver, breathing (sinus arrhythmia) (Fig.
Gastrointestinal Video-cine-fluoroscopy, barium studies, 88.5), and hyperventilation.
endoscopy, gastric emptying studies,
lower gut studies
A variety of other tests should be considered in individual
cases. These include evaluation of the response to food inges-
Renal function and Day and night urine volumes and sodium/
urinary tract potassium excretion
Urodynamic studies, intravenous urography,
ultrasound examination, sphincter 160 80
Blood pressure mm Hg

Normal
electromyography
Sexual function Penile plethysmography
(Portapres)

Heart rate bpm

Intracavernosal papaverine
Respiratory Laryngoscopy
Sleep studies to assess apnea and oxygen
desaturation
Eye and lacrimal Pupil function, pharmacologic and
function physiologic 15 seconds
0 0
Schirmer’s test 160 100
Blood pressure mm Hg

* Indicates screening autonomic tests used in our London Unit. Multiple system atrophy

Heart rate bpm

(Portapres)

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 arith-
metic (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
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 expi-
ratory 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.
 au tonom ic dysf u nc t ion a n d h y pot e nsion 18 8 9
Blood pressure mm Hg 180 80 patient is upright. They are used in patients with autonomic
Normal failure, and also some with neurally mediated syncope, espe-
cially when the history favors a relationship to these stimuli.
(portapres)

Heart rate bpm

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
10 seconds of deep breathing blood pressure and heart rate enable 24-hour recordings in a
0 0
natural setting such as at home (Fig. 88.8). It is imperative
180 100 that a suitable diary is maintained to record the responses
Blood pressure mm Hg

Pure autonomic
to key stimuli such as posture, food, and exercise. This
failure
enables evaluation of the presence and severity of supine
(portapres)

Heart rate bpm

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.
10 seconds of deep breathing
In neurally mediated syncope a variety of investigations,
0 0
in addition to standard head-up tilt, have been introduced.31
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 These include the effect of prolonged tilt and in some labo-
autonomic failure (lower panel). There is a marked reduction in ratories the administration of drugs, such as isoprenaline and
sinus arrhythmia in the patient with autonomic failure. 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 pres-
tion, as postprandial hypotension can be a problem in some sure.34 These maneuvers induce presyncope or syncope even
patients27 (Fig. 88.6). This can be tested by recording the car- in normal subjects who have never fainted. In suspected
diovascular responses before and after a standard meal, carotid hypersensitivity, it is important to ensure that carotid
ideally liquid, and by assessing the responses to head-up artery stenosis is excluded to reduce the risk from thrombo-
postural change both before and after food ingestion.28 Other embolism and stroke, although this risk is small.35 Carotid
approaches are used in relation to exercise, another stimulus sinus massage should be performed while the patient is hori-
that can lower blood pressure substantially29,30 (Fig. 88.7). zontal and during head-up tilt.26
These protocols enable evaluation of responses to the stimu- The measurement of plasma catecholamine levels pro-
lus while gravitationally neutral and additionally when the vides further information on the neurogenic component to

Exercise 75 W
50 W
140 25 W
Systolic and diastolic blood pressure (mm Hg)

130 40 Controls
Change in systolic blood pressure (mm Hg)

MSA
120 Control subjects 30 PAF
110
20
100
90 10

80 0
70 –10
60
–20
50
Autonomic failure –30
40
Meal
–40
9 0 3
post 2 post 5 post 10 6
Time (min)
–30 –15 0 15 30 45 60 90 120 180
FIGURE 88.7. Changes in systolic blood pressure during supine
Time (min) bicycle exercise at three incremental levels (25, 50, and 75 watts) in
FIGURE 88.6. Supine systolic and diastolic blood pressure before normal subjects (controls) and patients with multiple system atrophy
and after a standard meal in a group of normal subjects (shaded area) (MSA) and pure autonomic failure (PAF). The bars indicate standard
and in a patient with autonomic failure. Blood pressure does not error of the mean. Unlike controls where there is a rise, there is a
change in the normal subjects after a meal taken while lying flat. fall in blood pressure in both MSA and PAF. Blood pressure returns
In the patient there is a rapid fall in blood pressure to levels around rapidly to the baseline in controls, unlike in the two patient groups
80/50 mm Hg, which remains low while in the supine position over in whom it takes almost 10 minutes. All remained horizontal
the 3–hour observational period. during and for 10 minutes postexercise.
 18 9 0
Heart rate (beats/min) Blood pressure (mm Hg) chapter 88

200 Systolic Diastolic FIGURE 88.8. Twenty-four hour noninvasive ambulatory blood pres-
In bed
sure profile, showing systolic (solid line) and diastolic (dashed line)
150 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
100 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 pres-
sure usually the result of postural changes, either sitting or standing.
50
Supine blood pressure, particularly at night, is elevated. Getting up
to micturate causes a marked fall in blood pressure (at “03” hours).
0 There is a reversal of the diurnal changes in blood pressure. There are
09 11 13 15 17 19 21 23 01 03 05 07
Sample time/24 h relatively small changes in heart rate, considering the marked changes
150 in blood pressure. (C) 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
75 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.
0
09 11 13 15 17 19 21 23 01 03 05 07
A Sample time/24 h
In bed
Systolic Diastolic
Heart rate (beats/min) Blood pressure (mm Hg)

200

150

100 600 Supine Tilt

Noradrenaline (pg/mL)
50 500

400
0
09 11 13 15 17 19 21 23 01 03 05 07 300
150 Sample time/24 h
200

100
75
* *
0
Controls MSA PAF DBH DBH
0 defn-1 defn-2
600
09 11 13 15 17 19 21 23 01 03 05 07
B
Adrenaline (pg/mL)

Sample time/24 h 500

200 In bed 400

Heart rate (beats/min) Blood pressure (mm Hg)

300
150
200
100
100

50 0 * *
Controls MSA PAF DBH DBH
defn-1 defn-2
0 600
Dopamine (pg/mL)

500
200
150 400
100 300
50
200
0
10 12 14 16 18 20 22 0 2 4 6 8 100
C Sample time/24 h
0
Controls MSA PAF
DBH DBH
defn-1 defn-2
postural hypotension and in some on the underlying dis-
FIGURE 88.9. Plasma noradrenaline, adrenaline and dopamine
order.36 Supine norepinephrine levels often are normal in levels (measured by high-pressure liquid chromatography) in normal
multiple system atrophy (where the lesion is predominantly subjects (controls), patients with multiple system atrophy (MSA),
central) and are below normal in pure autonomic failure pure autonomic failure (PAF) and two individual patients with dopa-
(where the lesion is peripheral). With head-up tilt or standing, mine β-hydroxylase (DBH defn) while supine and after head-up tilt
to 45 degrees for 10 minutes. The asterisk indicates levels below the
plasma norepinephrine levels rise in normal subjects but not detection limits for the assay, which are less than 5 pg/mL for nor-
in autonomic failure (Fig. 88.9). Supine levels may provide adrenaline and adrenaline and less than 20 pg/mL for dopamine.
information on the underlying lesion, as in dopamine Bars indicate ± standard error of the mean (SEM).
 au tonom ic dysf u nc t ion a n d h y pot e nsion 18 91
β-hydroxylase deficiency where plasma norepinephrine levels 22 Controls (n = 27)
are extremely low or undetectable, whereas levels of the 20 PAF (n = 19)
precursor substance, dopamine, are elevated.37 In high spinal
18 MSA (n = 31)
cord lesions, paroxysmal hypertension during autonomic

Growth hormone (mU/l)

dysreflexia may be mistaken for a pheochromocytoma; in the 16
former supine plasma norepinephrine levels are low, and 14
although they rise during autonomic dysreflexia, these levels 12
often are no higher than the basal levels in normal humans,
10
in contrast to the grossly elevated plasma catecholamine
levels often observed in pheochromocytoma.38 8
Measurement of plasma catecholamine levels in response 6
to various interventions are of diagnostic value in certain 4
conditions. Thus, in pheochromocytoma, where there is
autonomous catecholamine secretion, plasma norepineph- 2
rine and epinephrine levels are not suppressed, as they would 0
be after administration of the centrally acting sympatholytic –10 0 15 30 45 60
agent clonidine and the ganglionic blocker pentolinium.
A Time (min)
This differs from the responses observed in normal subjects 12 IPD
and those with essential hypertension (Fig. 88.10). The α2- 11
(n = 14)
adrenoceptor agonist clonidine has additional central effects Parkinsonian
10 MSA (n = 15)
on central sympathetic pathways and the hypothalamus,
9

Growth hormone (mU/l)

resulting in elevation of serum growth hormone 39; this has MSA-C
been utilized to determine if the autonomic lesion is central 8 (n = 16)
or peripheral.40 In multiple system atrophy with central auto- 7
nomic failure, after clonidine there is no rise in levels of 6
serum growth hormone, unlike patients with pure auto- 5
nomic failure and a peripheral lesion, where the rise in
4
growth hormone levels is similar to that observed in normal
subjects41 (Fig. 88.11). 3
2
1
9000 0
15 –10 0
30 45 60
7000
B Time (min)
FIGURE 88.11. (A) Serum growth hormone (GH) concentrations
before (0) and at 15-minute intervals for 60 minutes after clonidine
5000
(2 μg/kg/min) in normal subjects (controls) and in patients with pure
Plasma noradrenaline (pg/mL)

autonomic failure (PAF) and multiple system atrophy (MSA). The

3000 GH concentrations rise in controls and in patients with PAF with a
peripheral lesion; there is no rise in patients with MSA with a
1000 central lesion. (B) Lack of serum GH response to clonidine in MSA
(the cerebellar form; MSA-C and the parkinsonian forms) in con-
Clonidine
trast to patients with idiopathic Parkinson’s disease (IPD) with no
500
autonomic deficit, in whom there is a significant rise in GH
levels.
400

300 The measurement of other hormones such as renin (by

measuring plasma renin activity or angiotensin II levels) and
200 plasma aldosterone may be helpful. In diabetes mellitus,
hyporeninemia and hypoaldosteronism may contribute to
100 hyperkalemia. In Addison’s disease, measurement of plasma
cortisol levels before and after administration of synthetic
30
0
–30
60 0 90 120
adrenocorticotrophic hormone determine if there is an endo-
crine contribution to postural hypotension.
Time (min)
An increasing number of investigative approaches, using
FIGURE 88.10. Plasma noradrenaline levels in a patient with a
phaeochromocytoma (closed triangles) and in a group of patients a variety of techniques, some of which are noninvasive,
with essential hypertension (open triangles) before and after intra- address various aspects of autonomic function. A direct
venous clonidine, indicated by an arrow (2 μg/kg over 10 minutes). technique to measure muscle and skin sympathetic nerve
Plasma noradrenaline levels fall rapidly in the essential hyperten- activity utilizes percutaneous insertion of a tungsten micro-
sives after clonidine and remain low over the period of observation.
The stippled area indicates the ± SEM. Plasma noradrenaline levels
electrode into the peroneal or median nerve42 (Fig. 88.2).
are considerably higher in the pheochromocytoma patient and are Sympathetic microneurography has enabled further under-
not affected by clonidine. standing of normal sympathetic function, and of mecha-
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 sym-
pathetic contributions to both blood pressure and heart rate
control.44 Sympathetic innervation of the heart can be evalu-
ated 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 cho-
linomimetic, such as pilocarpine. The cardiovascular auto-
nomic deficits include postural hypotension and, in some,
exaggerated responses to pressor stimuli, which can cause
transient but marked hypertension. The lesion appears pre-
dominantly 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
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 hyperventila-
tion. Upregulation of cardiac adrenoreceptors may result in
enhanced responses to adrenoceptor agonists such as iso-
prenaline.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 dis-
section of responses.51 Mild exercise results in a similar rise
in heart rate in both denervated donor and innervated recipi-
ent atria; in the former, the rise is slower because of depen-
dence 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 dener-
vated 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, result-
ing in an elevated heart rate with alacrima, xerostomia, dys-
phagia, large bowel atony, detrusor muscle dysfunction, and,
in men, erectile failure; anhidrosis also occurs. Postural
hypotension does not occur, as sympathetic adrenergic func-
tion is not affected. There is a response to cholinomimetic
agents, such as bethanechol, indicating preservation of post-
synaptic cholinergic receptor function and suggesting a pre-
synaptic 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 pos-
tural 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. Hyperther-
mia should be prevented, especially when there is widespread
anhidrosis. Adequate fluid intake and nutrition is of impor-
tance, particularly if there is a paralytic ileus. The investiga-
tion of dysphagia, especially inacute 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-
 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. Cholinomi-
metics 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 Guillain-
Barré syndrome.58 Autonomic disturbances affecting the cir-
culation contribute to both morbidity and mortality.
Chronic Autonomic Failure Syndromes
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 involve-
ment 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 defined cause or association, the term Shy-
Drager syndrome was used after the first neuropathologic
description; multiple system atrophy (MSA) now is used.62 It
is a sporadic, progressive disorder characterized by auto-
nomic dysfunction, parkinsonism, and ataxia in any combi-
nation.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. Distin-
guishing the two disorders is important because the progno-
MSA
P C M PAF PD PD+AF PSP LBD
Autonomic
Parkinsonian
Cerebellar/
pyramidal
Dementia
FIGURE 88.12. The major clinical features in parkinsonian syn-
dromes 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 fea-
tures 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).
18 9 3
TABLE 88.9. Some clinical manifestations in patients with
primary autonomic failure
Cardiovascular system Postural hypotension
Sudomotor system Anhidrosis, heat intolerance
Alimentary tract Xerostomia, oropharyngeal dysphagia,
constipation, occasionally diarrhea
Urinary system Nocturia, frequency, urgency,
incontinence, retention
Reproductive system Erectile and ejaculatory failure (in the
male)
Respiratory system Stridor, involuntary inspiratory gasps,
apneic periods
Ocular Alacrima, anisocoria, Horner’s
syndrome
Other neurologic deficits 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 condi-
tions differ.64–66 Differentiation of the two groups is impor-
tant 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, ortho-
static hypotension and autonomic failure may be severe and
an early manifestation, even before the onset of parkinso-
nian 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 dis-
orders is described, along with some other conditions.
18 9 4 chapter 88

Cerebral Disorders 180 150

Blood pressure mm Hg
Normal
Autonomic failure may result from specific lesions, espe-

(portapres)
cially in the brainstem. Posterior fossa tumors and syringo-

Heart rate bpm

bulbia may cause postural hypotension by ischemia or
destruction of brainstem cardiovascular centers. Demyelin-
ation or plaque formation in multiple sclerosis may cause a
variety of autonomic defects of cerebral origin, although it is
10 min of 60-degree head up tilt
difficult to exclude a spinal contribution.77,78 Autonomic 0 0
failure in the elderly may be largely central, due to wide- 180 150

Blood pressure mm Hg
spread neuronal degeneration, although peripheral neural Spinal
and target organ deficits may contribute.79 injury

(portapres)
Certain cerebral disorders cause a pathologic increase in

Heart rate bpm

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 increas-
ing 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 sensitiv-
ity of brainstem centers through retrograde spread of tetanus
toxin along the nerve fibers. In fatal familial insomnia, a
prion disease predominantly involving the thalamus, abnor-
malities 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
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 effer-
ents to the heart remain intact and functional. Thus, hypo-
tension occurs during postural change because of the inability
of the brain to activate peripheral sympathetic efferent83
3 min of 60-degree head up tilt
0 0
FIGURE 88.13. Blood pressure and heart rate measured continu-
ously 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 diaphrag-
matic innervation at the fourth and fifth cervical segments),
require artificial respiration. They are prone to severe bra-
dycardia 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 dysre-
flexia does not occur. Disconnection of the respirator and
tracheal suction, as for intermittent tracheal toilette, acti-
vates vagal afferents that then increase vagal efferent activ-
ity (Table 88.11). This is not opposed by sympathetic activity,
as normally would occur. Furthermore, the cardiac effects
(ng/mL) (mm Hg) (beats/min) (mm Hg)

200
pathways, and the heart rate rises because of baroreceptor
BP

activation and withdrawal of cardiac vagal tone (Fig. 88.13).

With time, compensatory mechanisms, which include acti- 0
vation of the renin-angiotensin-aldosterone system and an 100
HR

improvement in cerebrovascular autoregulation, help reduce

postural hypotension and its symptoms. The reverse, hyper- 0 Bladder stimulation
tension followed by bradycardia, may occur during auto- 100
nomic dysreflexia when isolated spinal cord sympathetic
IVP

pathways are activated by stimulation of skin, skeletal 0

muscle, or viscera below the level of the lesion82 (Fig. 88.14). 0.20
NA and A
Plasma

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).
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 stimu-
lation 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 indepen-
dently of adrenomedullary activation.
 au tonom ic dysf u nc t ion a n d h y pot e nsion 18 9 5
TABLE 88.10. Drugs used in the management of autonomic Atropine
dysreflexia with their major site of action 0.6 mg i.v.
Afferent Topical lignocaine 200

Spinal cord
Sympathetic efferent
BP (mm Hg)
Clonidine
Reserpine
Spinal anesthetics
Ganglia: hexamethonium
Nerve terminals: guanethidine 0 Off respirator
α-Adrenoceptors: phenoxybenzamine
100

HR (beats/min)
Target organ
Blood vessels Glyceryl trinitrate, nifedipine
Sweat glands Anticholinergics: probanthine
Anal sphincter Botulinumtoxin
Skeletal muscle Dantroleine sodium
0
6 h post atropine Time (min)
A (0.6 mg i.v.)
of vagal nerves cannot be reversed by the inflation “reflex”
because of respiratory paralysis. Hypoxia secondary to a
200
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, intra-
venous 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, espe-
cially when there is inadequate cardiac vagal blockade. Such
patients should be administered atropine, ideally intrave-
nously, before intubation.
The Riley-Day Syndrome (Familial Dysautonomia)
The Riley-Day syndrome is an autosomal recessive disorder
predominantly affecting autonomic and sensory neurons.87
BP (mm Hg)
Off respirator
0 for suction
100
HR (beats/min)
0
20 min post atropine Time (min)
B (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 electro-
cardiograph) 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 tra-
cheal suction did not lower either heart rate or blood pressure.86
It occurs mainly in Ashkenazi Jews with a history of con-
sanguinity. 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 Hypoxia

Normal 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
Tetraplegics 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 “fixed” respiratory rate
Increased vagal cardiac tone
Bradycardia and cardiac arrest
18 9 6 chapter
extraction should point to the diagnosis. An abnormal intra-
dermal 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, constipa-
tion, and diarrhea), and urinary bladder disturbances. Neu-
rologic abnormalities, psychometric abnormalities, associated
skeletal problems (scoliosis), and renal failure may occur.
The prognosis is dependent on anticipating complica-
tions 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 tem-
perature and requires appropriate therapy. Reduced food
intake because of periodic vomiting and impaired gastro-
esophageal motility may impair growth and result in anemia;
a gastrostomy is often helpful.
Diabetes Mellitus
Peripheral and autonomic neuropathy often complicates dia-
betes mellitus, especially in patients who are poorly con-
trolled 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, sympa-
thetic 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 main-
tained 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 vaso-
constrictor 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 attrib-
uted to impaired vagal function in diabetes, therefore, may
have an alternative cause, and be associated with intermit-
88
160
300
Blood glucose (mg%)
120
BP (mm Hg)
200
80
100
40 56 u 48 u
S–C S–C
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 pres-
sure 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, some-
times secondary to renal impairment, may contribute.
In the later stages of diabetes, impairment of barorecep-
tors 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 pres-
sure is further compromised by damage to innervation of the
renal juxtaglomerular apparatus, leading to hyporeninemic
hyperaldosteronism.
Awareness of hypoglycemia is dependent in part on sym-
pathetic activation, and may be diminished with autonomic
nerve damage. There also may be involvement of the gastro-
intestinal 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 gusta-
tory 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 amyloi-
dosis from mutations in the genes for transthyretin, apolipo-
protein 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 infec-
tions and inflammatory disorders, there is deposition of the
protein AP, derived from a serum protein, SAP.
In the familial disorder, abnormalities result from depo-
sition in peripheral nerves of mutated amyloid protein,
mainly produced in the liver. Classification of FAP is now
 au tonom ic dysf u nc t ion a n d h y pot e nsion
based on the chemical and molecular nature of the constitu-
ent 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 neu-
ropathy often begins in the lower limbs. The disease relent-
lessly 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 cur-
rently to reduce levels of variant transthyretin and its deposi-
tion in nerves. This prevents progression and may reverse
some neuropathic features. It may be of greater value if per-
formed before substantial nerve damage, or cardiac deposi-
tion, occurs.
Neurally Mediated Syncope
In neurally mediated syncope, there is an intermittent abnor-
mality 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. Faint-
ing 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
18 9 7
140 160
Start of presyncopal symptoms
Blood pressure mm Hg (portapres)
Heart rate bpm
0 0
60-degree head up tilt
A
140 160
Start of presyncopal symptoms
Blood pressure mm Hg (portapres)
Heart rate bpm
0 0
60-degree head up tilt
B
FIGURE 88.17. (A) Blood pressure and heart rate with continuous
recordings from the Portapres II in a patient with the mixed (cardio-
inhibitory 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 pseudovene-
puncture.95 In the mixed form, where the role of bradycardia
is not clear and a cardiac demand pacemaker is being con-
sidered, an atropine test often is useful. Atropine for a short
period maintains an elevated heart rate; a reduction in symp-
toms 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 unpredict-
ability in inducing an episode with head-up tilt tests. This
has led to combining additional physiologic and pharmaco-
logic stimuli to induce an attack, such as by lower body
negative pressure, or drugs such as isoprenaline and glycer-
yltrinitrate. 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,
18 9 8 chapter 88

cognitive behavioral psychotherapy is helpful. A combina- 200 Food

HR (bpm)
tion of nonpharmacologic approaches should include a high
salt diet, fluid repletion, exercise especially to strengthen 100
lower limb muscles, measures that activate the sympathetic
nervous system such as sustained handgrip, the use of the 0
calf muscle pump to prevent pooling, and various maneuvers 250

BP (mm Hg)
that include leg crossing.101–104 The ideal approach, when
there are symptoms suggestive of an oncoming attack, is to 125
sit or lie down, if needed, with the legs up. Drugs are used
especially when there is a low supine blood pressure and 0
nonpharmacologic measures alone are not successful. They 100

SV (mL)
include low-dose fludrocortisone, and sympathomimetics
50
such as ephedrine and midodrine. The 5-hydroxytryptamine
uptake release inhibitors have been used with varying
0
success. There is a limited role for beta-blockers. In the car-
10
dioinhibitory form, a cardiac demand pacemaker initially

CO (L/min)
was found to be of value,105 although this was not clearly so
5
in a later study.106 The long-term prognosis is favorable.
0
Carotid Sinus Hypersensitivity 10

TPR (MU)
The incidence of carotid sinus hypersensitivity increases
with advancing age and is more common than previously 5
thought, especially in older patients with unexplained falls.107
0
Some give a history of attacks induced by neck movements
or fastening of the collar. The provocative stimulus of carotid 500
LVET (ms)

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 brady-
cardia 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.
Miscellaneous Causes
There are a variety of situations, often referred to as situa-
tional syncope, which can cause intermittent bradycardia
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 periph-
eral 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 pres-
sure remained low. A cardiac pacemaker was avoided.

160 120 and hypotension. Syncope has been reported with swallow-
ing (Fig. 88.19); in some this is associated with glossopharyn-
Blood pressure mm Hg (portapres)

geal neuralgia. In some, instrumentation, even during

anesthesia, may result in cardiac arrest. It may occur during
pelvic and rectal examination, during micturition and defe-
Heart rate bpm

cation, and in trumpet blowers and weight lifters. Changes

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 findings indicate the mixed (cardioin-
hibitory and vasodepressor) form of carotid sinus hypersensitivity.
in intrathoracic pressure may contribute in cough and laugh-
ter-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 vasocon-
striction. 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
 au tonom ic dysf u nc t ion a n d h y pot e nsion
250
Blood pressure
200
(mm Hg)
150
100
50
Squatting Standing
0 hyperventilation straining
Middle cerebral artery ETCO2 (%)
10
5 lower limb autonomic denervation, affecting vascular and
0
200
blood flow velocity
150
(cm·s–1)
100
50
0 volemia and contributory factors (such as hyperventilation)
Time (s)
10 sec
FIGURE 88.20. Finger arterial blood pressure at heart level, end-
tidal 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 con-
sciousness. This is the basis of the “fainting lark” as used by
children.
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 hypo-
tensive effect of certain drugs may be neurally mediated, via
the Bezold-Jarisch reflex.
Transient Orthostatic Hypotension
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 exaggera-
tion 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 hypo-
perfusion), 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 chal-
lenge heart rate increases by over 30 beats per minute, or
rises above 120 bpm (Fig. 88.21). It has been observed pre-
dominantly 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 neuro-
circulatory aesthenia). There is an association with mitral
valve prolapse, chronic fatigue syndrome, and decondition-
ing following prolonged bed rest and microgravity during
18 9 9
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 nor-
adrenaline levels; mutation of the gene encoding the nor-
adrenaline transporter was thought to be responsible.119 The
possibility of immunologically mediated autonomic neurop-
Lying athy 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
sudomotor function, occurs.121–123 Venous pooling may be a
problem.124 There is a strong association with the joint hyper-
mobility syndrome (Ehlers-Danlos type III)125 (Fig. 88.22).
Psychogenic components also need to be evaluated, espe-
cially 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 hypo-
is important. Beta-blockers, especially those that are cardi-
oselective, may reduce tachycardia. As in neurally mediated
syncope, use of nonpharmacologic measures should be intro-
duced. With time some recover spontaneously. The compli-
cations of associated disorders, such as the joint hypermobility
syndrome, need to be addressed.
Drugs, Poisons, and Toxins
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, moxoni-
dine), or peripherally (β-adrenoceptor blockers). They may
cause marked bradycardia and hypotension even when used
locally; examples are xylometazoline hypochloride used
200 140
60-degree head up tilt
Blood pressure mm Hg (portapres)
0 Normal 0
200 140
60-degree head up tilt
Heart rate bpm
AF
0 0
200 140
60-degree head up tilt
0 0
FIGURE 88.21. Blood pressure and heart rate measured continu-
ously before, during, and after 60-degree head-up tilt by the Porta-
pres 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).
19 0 0 chapter 88

A B
FIGURE 88.22. (A,B) Joint hyperextensibility as demonstrated by a patient with the joint hypermobility syndrome and postural tachycardia
syndrome (PoTS).

intranasally as a decongestant, and timoptolol used intraocu-

larly for glaucoma. Drugs may raise heart rate either through
TABLE 88.12. Drugs, chemicals, poisons, and toxins causing increasing sympathetic activity (e.g., amphetamines), or by
autonomic dysfunction affecting the cardiovascular system reducing cardiac parasympathetic activity. Drugs that
Decreasing sympathetic activity increase cholinergic activity can lower heart rate. Reef fish
Centrally acting containing ciguera toxin may cause bradycardia through
Clonidine increased vagal tone. Alcohol and perhexiline maleate may
Methyldopa
Moxonidine
affect cardiovascular function by causing an autonomic
Reserpine neuropathy.
Barbiturates Certain antihypertensive agents such as the angiotensin-
Anesthetics converting enzyme inhibitors (captopril and enalapril), and
Peripherally acting α-adrenoceptor blockers (prazosin) may cause syncope, espe-
Sympathetic nerve ending (guanethidine, bethanidine)
α-Adrenoceptor blockade (phenoxybenzamine) cially after the first dose. The postulated mechanisms include
β-Adrenoceptor blockade (propranolol) activation of cardiac C-fiber afferents, an increase in cholin-
Increasing sympathetic activity ergic activity, and a withdrawal of sympathetic activity
Amphetamines similar to the Bezold-Jarisch reflex, resulting in bradycardia
Releasing noradrenaline (tyramine) and vasodilatation.
Uptake blockers (imipramine)
Monoamine oxidase inhibitors (tranylcypromine)
β-Adrenoceptor stimulants (isoprenaline)
Decreasing parasympathetic activity
Management of Postural Hypotension
Antidepressants (imipramine)
Tranquilizers (phenothiazines) Postural hypotension may cause considerable disability and
Antidysrhythmics (disopyramide) there is the potential risk of serious injury. The key aims in
Anticholinergics (atropine, probanthine, benztropine) management, therefore, are to provide low-risk therapy,
Increasing parasympathetic activity ensure appropriate mobility and function, prevent falls and
Cholinomimetics (carbachol, bethanechol, pilocarpine,
mushroom poisoning)
associated trauma and maintain a suitable quality of life,
Anticholinesterases depending on the underlying disorder and individual priori-
Reversible carbamate inhibitors (pyridostigmine, neostigmine) ties. In nonneurogenic postural hypotension, the underlying
Organophosphorous inhibitors (parathion, sarin) problem often needs to be rapidly resolved. It may be an
Miscellaneous indicator of substantial blood and fluid loss, or a serious
Alcohol, thiamine (vitamin B1. deficiency underlying disorder such as adrenal insufficiency. This may
Vincristine, perhexiline maleate
Ciguatera toxicity
include reducing fluid loss, replacing blood and fluids, cor-
Jellyfish and marine animal venoms recting the endocrine deficiency, improving cardiac function,
First dose of certain drugs (prazosin, captopril) and preventing vasodilatation. In neurogenic orthostatic
Withdrawal of chronically used drugs (clonidine, opiates, hypotension, cure is less likely, and long-term management
alcohol) usually needs to be considered. This in part is dependent on
 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 refined 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 consider-
ably exacerbate neurogenic postural hypotension.
This section focuses on the management of neurogenic
postural hypotension. The main therapeutic strategies
include both nonpharmacologic and pharmacologic mea-
sures126 (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 non-
pharmacologic approaches, in particular, is especially depen-
dent 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 symp-
toms 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 hypoten-
sion, 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 non-
neural mechanisms such as the renin-angiotensin-aldoste-
rone system, which then reduce recumbency-induced diuresis
and help maintain blood pressure; it is particularly effective
in combination with low-dose fludrocortisone.128 When head-
up tilt is impractical, or the degree of tilt achieved inade-
quate, nocturnal polyuria and nocturia can be reduced with
19 01
the antidiuretic agent desmopressin.129 Straining during mic-
turition and bowel movements should be avoided. In hot
weather the elevation of body temperature, because of impair-
ment 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 hypoten-
sion.130,131 Determining the appropriate degree and type of
exercise is important and the advice requires individual tai-
loring. 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 light-
weight 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 amy-
loidosis 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 manage-
ment 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 sympa-
thetic nerve activity only while drinking.141 It seems unlikely
that this is the predominant mechanism in primary auto-
nomic 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 acti-
vation 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 dehy-
drated because of nocturnal polyuria.22
19 0 2 chapter 88

150
Finap (mm Hg)

75

0
0 30 60 0 30 60 0 30 60
Time (s)
62 yrs PAF
FIGURE 88.23. Physical countermaneuvers using isometric con- man with pure autonomic failure and incapacitating postural hypo-
tractions of the lower limbs and abdominal compression. The effects tension. The patient was standing prior to the maneuvers during
of leg crossing in standing and sitting position, placing a foot on a which there is an increase in blood pressure and the pulse
chair, and squatting on finger arterial blood pressure in a 54-year-old pressure.

PAF subject Pharmacologic Measures

160
Drugs are needed when nonpharmacologic approaches are
Continuous finger blood pressure (mm Hg)

140 not completely successful. They raise blood pressure in

Water various ways (Table 88.14). The starter drug is the mineralo-
120 corticoid fludrocortisone, which acts by reducing salt and
water loss and may increase α-adrenoceptor sensitivity. Pre-
100 vious reports include its use in diabetes and levo-dopa–
induced hypotension.144,145 A low dose of 100 to 200 μg may
80
be used at night, when there is the greatest natriuresis and
60 diuresis. Side effects are minimal with these doses. With
higher doses, hyperkalemia and excessive fluid retention
40 may occur. Its benefits may not be realized until it is
stopped.
20 Drugs that mimic the deficient neurotransmitter norepi-
nephrine should be considered next. Ephedrine has both
0
–5 0 5 10 15 20 25 30 35 42 45 50 55 direct and indirect actions and is of value in central auto-
nomic disorders such as multiple system atrophy, at dosages
Time (minutes)
of 15 to 45 mg thrice daily. It ideally is taken on waking, with
FIGURE 88.24. Changes in blood pressure before and after 500 mL
distilled water ingested at time 0 in a patient with pure autonomic
further doses before lunch and dinner. It is not recommended
failure. Blood pressure is measured continuously using the Porta- at night when its pressor effects are not needed and when it
pres II. may cause insomnia. Other side effects, especially in higher
 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-adreno-
ceptors.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 mech-
anisms. 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 post-
synaptic 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 sup-
press 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
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 sympatho-
mimetic 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 sympathomi-
metic does not produce the desired effect, selective targeting,
depending on the underlying pathophysiologic abnormali-
ties, is needed. In postprandial hypotension, the somatosta-
tin analogue octreotide is effective presumably because it
inhibits the release of vasodilatory gastrointestinal pep-
tides.153,154 Importantly, it does not enhance nocturnal hyper-
tension.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 combi-
nation 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 noc-
turnal 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 oxygen-
ation. 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 vasodila-
tory prostaglandins, by causing salt and water retention
through their renal effects, or both.162,163 They have poten-
tially serious side effects, however, such as gastrointestinal
ulceration and hemorrhage. The dopamine antagonists meto-
clopramide 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 pyridostig-
mine 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 occa-
sionally 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 hypoten-
sion, and even nocturnal use of short-acting vasodilatators
have been suggested.
19 0 4 chapter 88

CH2 CH NH2 there are undetectable plasma norepinephrine and epineph-

Tyrosine
COOH rine concentrations, the ideal therapy is the prodrug l-threo-
HO
dihydroxyphenylserine, which is similar in structure to
Tyrosine hydroxylase
norepinephrine except for a carboxyl group; the enzyme
dopa-decarboxylase coverts it into norepinephrine 36,169 (Fig.
HO CH CH NH2
HO CH2 CH NH2 88.25). In addition to its particular value in DBH deficiencies
Dopa
COOH HO
OH COOH (Fig. 88.26), l-DOPS has been of value in neurogenic postural
HO
hypotension due to primary autonomic failure,170,171 familial
Dopa decarboxylase DL–DOPS
amyloid polyneuropathy,172,173 and hemodialysis-induced
hypotension.174,175
HO CH2 CH2 NH2 In Parkinson’s disease, postural hypotension occurs in a
Dopamine substantial number of patients.176,177 There are many causes
HO of postural hypotension in patients with parkinsonian fea-
Dopamine β-hydroxylase
tures (Table 88.15), including the effect of antiparkinsonian
and coincidental drugs, and an erroneous diagnosis, as par-
kinsonism may be the presenting feature of the primary
HO CH CH2 NH2 autonomic failure syndrome multiple system atrophy. Effec-
Noradrenaline
OH tive treatment, therefore, is dependent on the causative and
HO
Phenylethanolamine contributory factors. Management of postural hypotension
N-methyltransferase in elderly patients may be a problem as multiple factors con-
tribute, including dementia.178,179 Lack of adherence to advice
HO CH CH2 NH and poor drug compliance are additional factors that compli-
Adrenaline OH CH3
cate their management. In a recent study of elderly patients,
HO 55% had postural hypotension and antihypertensive drug
FIGURE 88.25. Biosynthetic pathway in the formation of adrena- treatment was considered to be causative.180
line and noradrenaline. The structure of dihydroxyphenylserine In some disorders, the prevention of progression, or
(DL-DOPS) is indicated on the right. It is converted directly to nor-
adrenaline by dopa decarboxylase, thus bypassing dopamine reversal, of the underlying pathophysiologic mechanisms
β-hydroxylase.

To overcome the problems with lability of blood pressure, DBH deficient (1)
150
a subcutaneous infusion pump, as in the control of hypergly-
cemia with insulin in diabetes mellitus, has been used,
Blood pressure (mm Hg)

infusing the short-acting vasoconstrictor noradrenaline. Pre-

vious studies with a pilot device had been successful,167 but 110
with a number of practical problems, including accurate
monitoring of blood pressure without an intraarterial cathe-
ter. Some of these have been overcome successfully.168 This
may benefit the severely hypotensive patient who is refrac- 70
tory to the combination of nonpharmacologic and conven-
tionally administered drug therapy.

30
Therapy in Specific Disorders and Situations L T L T L T

In secondary autonomic failure, modifications to therapy

Noradrenaline/dopamine (pg/mL)

often are needed to encompass the different pathophysiologic 800 No drugs DL-Dops L-Dops
processes, the effects of the underlying disease, and the inter-
actions of drugs used to treat this disorder. In diabetes
600
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, 400
and enhancing supine hypertension, as the latter may impair
renal function and accelerate renal failure. In high spinal 200
cord injuries, the balance between paroxysmal hypertension
induced during autonomic dysreflexia and hypotension when * *
0
upright must be considered. In systemic amyloidosis, exces- L T L T L T
sive proteinuria and hypoalbuminuria result in a low intra- FIGURE 88.26. Blood pressure (systolic and diastolic) while the
vascular volume and peripheral edema; this often is worsened patient is lying down (L) and during head-up tilt (T) in one of two
by fludrocortisone and compounded by refractoriness to siblings with dopamine β-hydroxylase (DBH) deficiency (1) before,
during, and after treatment with DL-DOPS (racemic mixture;
sympathomimetic agents because of amyloid deposits in DOPS, dihydroxyphenylserine) and L-DOPS (levo form). The levo
blood vessels. In disorders with specific enzymatic defects, form causes a greater rise in blood pressure and a greater reduction
such as dopamine β-hydroxylase (DBH) deficiency, where in postural hypotension than the racemic mixture.
 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 dysauto-
nomia, 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 pos-
tural hypotension in these conditions. After pancreatic-
renal 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 depos-
its when assessed by serum amyloid scintigraphy, distur-
bances affecting the gastrointestinal tract are unchanged,
but cardiomyopathy is more common and cardiac dysrhyth-
mias still occur.183,184
Various therapeutic approaches have been used when
stimuli in daily life, such as food and exercise, induce hypo-
Exercise
75 W
160 50 W
25 W
Blood pressure (mm Hg)
140
120
100
80
60
40
20
0
0 5 10
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 initiat-
ing exercise; she had to crawl upstairs because of severe exercise-
induced hypotension. In the patient on the right, there are minor
19 0 5
tension or exacerbate postural hypotension, especially in
patients with autonomic failure. In postprandial hypoten-
sion, 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-dihydroxyphenylser-
ine (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 gastrointes-
tinal tract peptides, including those with vasodilatory prop-
erties, 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 auto-
nomic failure is difficult to treat. In some, activation of the
calf muscle pump is successful, especially in the postexer-
cise phase (Fig. 88.27). Water drinking reduces exercise-
induced 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 para-
sympathetic 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 situ-
ations, ensuring that there is adequate blood flow to vital
organs, commensurate with their particular needs. The intri-
cate 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
15 20 25 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 pres-
sure postexercise was due to vasodilatation in exercising skeletal
muscle, not opposed by the calf muscle pump.
19 0 6 chapter
result from intermittent short-lived failure. Autonomic dis-
orders affect the cardiovascular system, and the diseases
causing them were described.
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