Hypertension. 2005;45:834-839
Published online before print April 18, 2005,
doi: 10.1161/01.HYP.0000160355.93303.72
(Hypertension. 2005;45:834.)
© 2005 American Heart Association, Inc.
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Hypertension Grand Rounds |
Baroreflex Failure
Karsten Heusser;
Jens Tank;
Friedrich C. Luft;
Jens Jordan
From the Franz-Volhard Clinical Research Center, Medical Faculty of the Charité and Helios Klinikum, Berlin, Germany.
Correspondence to Jens Jordan, MD, Franz-Volhard Clinical Research Center, Haus 129 Wiltbergstr. 50 13125 Berlin, Germany. E-mail jordan{at}fvk.charite-buch.de
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Abstract
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The baroreflex receives less attention nowadays because most
students of hypertension are convinced that faulty volume regulation
by the kidneys is responsible for long-term blood pressure increases.
However, unusual patients with bilateral destruction of the
normal blood pressure–sensing mechanisms can develop profound
chronic hypertension. We present 2 patients with baroreflex
failure. Both had volatile hypertension with systolic readings
up to 300 mm Hg documented over years. Both had muscle sympathetic
nerve activity that was increased even while resting. Treating
these patients was a stochastic challenge. The therapy is frequently
based on medicines that are no longer commonly prescribed.
Key Words: baroreflex • sympathetic nervous system • autonomic nervous system • hypotension • bradycardia
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Introduction
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The arterial baroreflex buffers acute fluctuations in blood
pressure that occur during posture, stress, or other maneuvers.
When blood pressure rises, vascular distension is transduced
into nervous electrical activity, triggering reflex parasympathetic
activation and sympathetic inhibition. Heart rate is slowed
and vascular resistance is decreased, buffering the increase
in blood pressure. Conversely, baroreceptor activity decreases
when blood pressure falls, producing a reflex-mediated increase
in heart rate and peripheral resistance. Baroreceptor activity
is reset during sustained increases in blood pressure so that
in patients with essential hypertension, baroreceptor responsiveness
is maintained. However, the resetting of the baroreflex plays
at least a permissive role in perpetuation of hypertension.
Guyton argued that the baroreflex is responsible for the minute-to-minute
regulation of blood pressure, but that the long-term blood pressure
regulation is related to volume mechanisms adjusted by the kidneys.
1 However, faulty baroreflexes can occasionally influence long-term
blood pressure regulation. An example is the condition of baroreflex
failure. Such patients are a diagnostic challenge and a therapeutic
nightmare.
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Case 1
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A 65-year-old woman was referred to our center for evaluation
of possible baroreflex failure. Her chief symptom was volatile
hypertension. The patient had a family history of arterial hypertension.
Antihypertensive therapy was initiated at a young age and blood
pressure readings were stable for many years. Twenty-two years
before admission, a papillary thyroid cancer was diagnosed.
She was successfully treated with thyroidectomy and local radiation
followed by radio-iodine treatment. Six years before admission,
the patient experienced a neck trauma during a skiing accident.
A left common carotid artery stenosis secondary to radiation
injury was treated with angioplasty and stent implantation 4
years before admission. After the skiing accident, blood pressure
became highly volatile. Systolic blood pressure values as high
as 230 mm Hg had been recorded even during antihypertensive
therapy with amlodipine, ramipril, spironolactone, metoprolol,
and moxonidine. The hypertension was exacerbated by psychological
stress and minor physical activity such that the formerly active
woman was restricted to her home. She also noted symptomatic
hypotension with blood pressure readings of 60/30 mm Hg. Hypotensive
episodes were exacerbated with amlodipine treatment. On one
occasion, she ingested 2 mg Nifedipin solution during a hypertensive
episode. Within 15 minutes, systolic blood pressure decreased
>100 mm Hg. She did not report orthostatic symptoms or other
symptoms of autonomic dysfunction. Other secondary causes of
arterial hypertension had been carefully ruled out in another
hospital.
Blood pressure in the supine position was 145/70 mm Hg, with a heart rate of 80 bpm. After 5 minutes standing, blood pressure and heart rate were 132/69 mm Hg and 88 bpm, respectively. Respiratory sinus arrhythmia was profoundly reduced, which is suggestive of impaired efferent parasympathetic activation of the heart. We conducted baroreflex testing with muscle sympathetic nerve activity (MSNA) recordings. MSNA was increased even while resting (Figure 1). Low phenylephrine and nitroprusside doses elicited an excessive blood pressure response compared with healthy subjects. Compensatory baroreflex-mediated heart rate and MSNA changes were profoundly reduced (Figures 1 and 2
). Intravenous application of 150 µg clonidine decreased blood pressure by 57/23 mm Hg. We discontinued the treatment with moxonidine and amlodipine and started the patient on 
-methyl-DOPA. The therapy attenuated the pressure surges.
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Figure 1. Original recordings of finger blood pressure (BP), heart rate (HR), and MSNA in a baroreflex failure patient (case 1). In this patient, MSNA was substantially increased. A sympathetic discharge was observed with almost every heart beat. Intravenous bolus application of 50 µg phenylephrine at 0 seconds caused a rapid pressor response, reaching a maximum of >25 mm Hg above baseline after 30 to 40 seconds. Normally, the phenylephrine pressor response is associated with a baroreflex-mediated decrease in heart rate and MSNA. The compensatory response was absent in our patient.
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Figure 2. We monitored changes in systolic blood pressure (SBP) and the RR interval during phenylephrine and nitroprusside application in our baroreflex patients and in a group of younger healthy subjects. In healthy subjects, changes in blood pressure with drug application led to compensatory baroreflex-mediated changes in the RR interval. In our patients, RR interval failed to respond to the change in blood pressure.
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Case 2
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The 64-year-old woman presented with a presumptive diagnosis
of baroreflex failure for further diagnostic work-up and treatment.
The previously normotensive patient experienced a cerebrovascular
accident 21 years before admission resulting from fibromuscular
dysplasia of the carotid arteries. Subsequently, both internal
carotid arteries were surgically dilated. Two years later, the
patient noted a painful mass close to the scar on the left side
of the neck. The mass encroached on the thyroid gland and was
surgically removed. During surgery, the left carotid artery
was damaged such that a carotid patch graft had to be inserted.
Pathological examination of the mass revealed an aggressive
fibromatosis. To prevent recurrence, the patient was treated
with radiation therapy to the neck. After the procedure, the
patient noted volatile hypertension with large blood pressure
swings. A left-sided Horner syndrome and paresis of the recurrent
laryngeal were also noted. Hypertension was exacerbated during
stress, whereas hypotension occurred at rest. Blood pressure
values as high as 250/130 mm Hg had been recorded, which resulted
in emergency room admissions on several occasions. Because minor
exertion induced a profound pressor response, the patient was
unable to lead a normal life. Secondary causes of hypertension
had been ruled out. Treatment with clonidine patches failed
to control blood pressure.
Blood pressure in the supine position was 247/132 mm Hg with a heart rate of 90 bpm. After 3 minutes standing, blood pressure was 239/136 mm Hg with a heart rate of 90 bpm. Respiratory sinus arrhythmia was profoundly reduced. MSNA was increased even at rest. Because of the increased basal blood pressure, baroreflex testing was only conducted with nitroprusside. The patient was exceedingly nitroprusside hypersensitive. Compensatory baroreflex-mediated heart rate and MSNA changes were profoundly reduced (Figure 2). Intravenous application of 120 µg clonidine decreased blood pressure by 78/45 mm Hg. The patient was started on -methyl-DOPA. On this treatment, blood pressure was still highly volatile but hypertensive episodes were attenuated.
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Discussion
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Baroreflexes have a pivotal role in blood pressure regulation.
Changes in blood pressure elicit changes in stretch of carotid
and aortic baroreceptors. The altered baroreceptor stretch is
conveyed to medullary brain stem nuclei via the glossopharyngeal
and vagus nerves. The primary afferent relay stations in the
brain stem are the nuclei tractus solitarii (NTS). In the brain
stem, information from baroreceptors is integrated with input
from other afferents and cortical input. Efferent parasympathetic
and sympathetic activity are adjusted to compensate for the
change in systemic blood pressure. Thus, the baroreflex attenuates
excessive blood pressure changes. This mechanism serves to maintain
blood flow to the organs, especially the brain. Moreover, the
vasculature is protected from large, potentially deleterious
fluctuations in blood pressure. More recent studies suggest
that baroreflex mechanisms are also involved in long-term blood
pressure control. Indeed, chronic unloading of carotid baroreceptors
induced by ligation of the common carotid artery proximal to
the sinus can produce neurogenic hypertension during a 7-day
period.
2 Furthermore, bilateral electrical stimulation of the
carotid sinuses produces sustained hypotension in dogs for 7
days.
3
Nearly complete loss of afferent baroreflex function causes baroreflex failure (Figure 3). In this condition, "the brain does not know about systemic blood pressure and does whatever it wants." Any afferent arc structure including baroreceptors, the afferent neurons transmitting the information from baroreceptors, or afferent brain stem nuclei may be involved.4–7 In most baroreflex failure patients, the afferent lesion seems to be associated with damage to efferent neurons in the vagus nerve. The damage results in partial or complete parasympathetic denervation of the heart ("nonselective baroreflex failure"). The 2 patients in the case vignette fall into this group. In a minority of patients, efferent parasympathetic neurons to the heart are intact ("selective baroreflex failure").7 Selective and nonselective baroreflex failure can differ in the clinical presentation.
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Figure 3. Illustration of the baroreflex abnormalities in baroreflex failure. Near-complete loss of baroreflex afferents (BA) causes baroreflex failure. In this condition, parasympathetic nervous system (PNS) and sympathetic nervous system (SNS) efferents are not controlled by the baroreflex. However, changes in cortical input can lead to dramatic changes in efferent activity. Blood pressure increases dramatically during psychological and physiological excitation. These abnormalities are common to patients with selective and patients with nonselective baroreflex failure. In the majority of patients, the parasympathetic efferents to the heart are also damaged (nonselective baroreflex failure; top). The lesion to parasympathetic efferents protects the heart from excessive bradycardia. A minority of patients feature a selective afferent lesion with preserved efferent sympathetic and parasympathetic function. These patients may experience bradycardic episodes while cortical input is low (bottom).
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Causes of Baroreflex Failure
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In most patients, the mechanism that led to bilateral interruption
in afferent baroreflex input is suggested by the history.
5 A
common cause of baroreflex failure is extensive neck surgery
and radiation therapy for cancers of the neck, which may damage
baroreceptors or afferent baroreflex neurons.
5,8,9 In some patients,
the bilateral loss results from repeated trauma to the neck.
7 Baroreflex failure has also been described in patients with
the familial paraganglioma syndrome.
5 Bilateral damage to the
NTS, the most important relay station for afferent autonomic
input, is a rare cause of baroreflex failure.
6,10 In another
patient, baroreflex failure was secondary to paraneoplastic
encephalomyelitis.
11 In a number of patients with typical signs
and symptoms of baroreflex failure, no etiology could be documented.
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Epidemiology
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There is a large body of literature on baroreflex function in
different animal species and in humans. However, the number
of baroreflex failure patients reported in the literature is
relatively small. Impaired baroreflex function seems to be common
after radiation therapy for laryngeal cancer and after unilateral
carotid endarterectomy. However, overt baroreflex failure appears
to be uncommon in both conditions.
12,13 The small number of
reported cases may suggest that baroreflex failure is a rare
condition. Perhaps the probability to experience bilateral damage
to afferent baroreflex structures is low. An alternative explanation
for the small number of reported cases is that many cases of
baroreflex failure go undetected.
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Clinical Features
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Most patients who are ultimately diagnosed with baroreflex failure
are sent to tertiary care centers for evaluation of severe and
volatile arterial hypertension. However, in the majority of
patients, volatile arterial hypertension is not caused by baroreflex
failure. Alternative causes of volatile hypertension, such as
renovascular hypertension or pheochromocytoma, should be considered
first. Hypertensive episodes are usually accompanied by tachycardia,
a so-called "tracking" of blood pressure and heart rate.
5,7 Many patients experience sensations of warmth or flushing, palpitations,
headache, and diaphoresis. The hypertensive episodes are triggered
by factors such as psychological stress, physical exercise,
and pain. A minority of patients present with episodes of hypotension
and bradycardia. Hypotensive episodes can be observed when patients
are resting and cortical input is diminished. Severe orthostatic
hypotension is not a typical symptom of baroreflex failure.
Orthostatic hypotension may be observed in baroreflex failure
patients who are volume depleted or treated with sympatholytic
drugs.
Pheochromocytoma, panic attack, generalized anxiety disorder, hyperthyroidism, alcohol withdrawal, and drug abuse may cause symptoms resembling baroreflex failure. Certain drugs, such as amphetamines and cocaine, can sometimes mimic baroreflex failure.
The onset of baroreflex failure can be very abrupt or more gradual. An abrupt onset of symptoms typically occurs in patients with baroreflex failure attributable to neck surgery. Arriving at the correct diagnosis may be straightforward in this group. Baroreflex failure with a more gradual onset as a consequence of radiation therapy or neuronal degeneration may be difficult to diagnose.
The degree of hypertension seems to be different during the acute and the chronic phase of the disease. After acute interruption of afferent baroreflex input, blood pressure is particularly high ("Entzügelungshochdruck," ie, unleashed hypertension).14,15 Apneic spells can be seen during the first 24 hours, when carotid body input to the central nervous system (CNS) is lost. In the more chronic phase, the average blood pressure tends to decrease. Yet blood pressure remains highly variable. A similar time effect has been observed in animal models of baroreflex failure.
Because of the loss of baroreflex buffering, patients with impaired baroreflex function are extremely hypersensitive to vasoactive medications. Standard doses of antihypertensives may cause a profound depressor response. Pressor agents, which may be contained in over-the-counter medications or dietary supplements, can raise blood pressure to dangerously high levels. Baroreflex failure patients are extremely volume sensitive. Volume loss worsens hypotensive episodes. Volume expansion has the opposite effect.
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Diagnostic Testing
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Most of the important clinical features of baroreflex failure
can be elucidated with a careful history and physical examination.
In patients with baroreflex failure, orthostatic hypotension
is not a typical finding. Some baroreflex failure patients feature
an increase in blood pressure with standing.
7 In contrast, patients
with dysfunction of the efferent arc of the baroreflex (ie,
autonomic failure) experience profound orthostatic hypotension
in the absence of an adequate heart rate increase.
16,17 The
hypotension is immediately reversible in the supine position.
The distinctive features of baroreflex failure and autonomic
failure are given in the
Table. Simple cardiovascular autonomic
tests, such as determination of respiratory sinus arrhythmia,
a Valsalva maneuver, and cold-pressor and handgrip testing,
can be helpful to further elucidate the pathophysiology. Sympathetic
efferents to the vasculature and to the heart are intact in
baroreflex failure patients. Therefore, these patients exhibit
a normal or even an increased pressor response to cold-pressor
and handgrip testing. In contrast, these responses are attenuated
in patients with autonomic failure. Respiratory sinus arrhythmia
is reduced in nonselective baroreflex failure because parasympathetic
efferents to the heart are damaged. In contrast, respiratory
sinus arrhythmia may be retained in selective baroreflex failure.
7 Twenty-four–hour blood pressure monitor can be useful
to demonstrate the large blood pressure fluctuations and the
tracking of blood pressure and heart rate.
Baroreflex testing should be considered in patients with typical signs and symptoms of baroreflex failure after more common entities have been ruled out. Baroreflex heart rate control can be assessed noninvasively using cross-spectral analysis18 or the sequence method.19,20 These methods have not been evaluated in baroreflex failure patients and cannot be recommended as a diagnostic test in this setting. Instead, baroreflex function should be evaluated with pharmacological methods. During baroreflex testing, beat-by-beat blood pressure and heart rate must be monitored continuously. The diagnostic abnormality is the absence or a substantial reduction of a bradycardic response to pressor agents or a tachycardic response to a vasodilator.5 Normal subjects will decrease the heart rate 7 to 21 bpm in response to a phenylephrine dose that raises systolic blood pressure 20 mm Hg and will increase the heart rate 9 to 28 bpm in response to a nitroprusside dose that lowers blood pressure by 20 mm Hg. In contrast, baroreflex failure patients did not alter their heart rate by >4 bpm with either maneuver. The loss of baroreflex blood pressure buffering in these patients is associated with an 
10- to 20-fold hypersensitivity to vasoactive medications. Therefore, baroreflex testing should be conducted starting with low doses of phenylephrine (12.5 µg) and nitroprusside (0.1 µg/kg). The doses should be increased to obtain a change in systolic blood pressure of at least 20 to 25 mm Hg. Theoretically, one would like to assess baroreflex regulation of heart rate and sympathetic nerve traffic, which are both impaired in baroreflex failure.4,7 However, recording of sympathetic activity is only available in a few specialized institutions. Abnormal baroreflex tests alone are not sufficient to diagnose baroreflex failure. Absence of heart rate changes during baroreflex testing can also be observed in autonomic failure patients. Determination of the norepinephrine response to clonidine can be useful to differentiate baroreflex failure from pheochromocytoma. Determination of sensitivity to the clonidine-induced depressor response may be useful to confirm sympathetically mediated hypertension and to guide therapy.
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Treatment
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The first step in the treatment of patients with impaired baroreflex
function is the education of the patient, family members, and
the referring physicians. Patients and family members must be
trained how to measure blood pressure. It is particularly important
to convey the information that many medications that do not
elicit changes in blood pressure in healthy subjects may have
a dramatic effect in baroreflex failure patients. For example,
we encountered a patient who experienced life-threatening hypotension
after application of a standard dose of sublingual nitroglycerin.
7 Therefore, vasodilating drugs such as calcium channel blockers
should be avoided in baroreflex failure patients. Medications
that may change sympathetic activity or vascular tone, including
a variety of over-the-counter drugs, must be used with great
caution in susceptible individuals. Changes in sodium balance
may shift the average blood pressure to higher or lower values
in patients with baroreflex failure. Therefore, antihypertensive
therapy with diuretics cannot be recommended for the majority
of patients.
One of the main goals in treating baroreflex failure patients is to prevent episodes of extreme hypertension. Clonidine and -methyl-DOPA decrease sympathetic activity in the CNS and in the periphery. Moreover, they cause mild sedation. These effects attenuate pressure surges.5,7 Our experience in patient 2 suggests that clonidine patches may not be suitable for all patients. We speculate that clonidine absorption through the skin may be impaired during sympathetic activation that is associated with skin vasoconstriction. In some baroreflex failure patients, clonidine or -methyl-DOPA can cause intolerable side effects, such as exacerbation of depression. In these patients, peripherally acting sympatholytic agents, such as guanethidine and guanadrel, have been used successfully.7 Unfortunately, these drugs are no longer available in many countries. Perhaps, -adrenoreceptor and ß-adrenoreceptor blockers could be used in patients who do not tolerate central sympatholytic agents. Our second patient experienced substantial volume retention after initiation of -methyl-DOPA treatment. In such patients, low doses of diuretics may be added cautiously. Because the hypertension in baroreflex failure patients is often driven by cortical input, which is unopposed by the baroreflex, benzodiazepines elicit a reduction in blood pressure and can be used in selected patients. Benzodiazepines are particularly useful in the acute phase of baroreflex failure.
In particular, patients with selective baroreflex failure experience hypotensive episodes.7 Sometimes, the hypotension is acutely exacerbated by the antihypertensive treatment. However, in the long term, prevention of hypertension may attenuate pressure-induced volume loss through the kidney. Thus, effective control of the hypertension may improve hypotension. We encourage patients who experience hypotension on chronic antihypertensive treatment to increase their dietary salt intake. In selected patients, pharmacological treatment of the hypotension is required. Because of its long duration of action, fludrocortisone is a good choice for the treatment of hypotension in these patients. Other pressor agents should be used with great caution.
In a few patients with malignant vagotonia, hypotensive episodes may be accompanied by life-threatening bradycardia and asystole. Implantation of a cardiac pacemaker may be required in these rare patients.7,21
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Summary
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Baroreflex failure results from bilateral damage to baroreflex
afferents. In the majority of patients, the afferent lesion
is accompanied by efferent parasympathetic dysfunction (nonselective
baroreflex failure). In rare patients, with selective baroreflex
failure, parasympathetic efferents are spared. Most baroreflex
failure patients present with volatile arterial hypertension.
The hypertension is exacerbated by sympathetic stimuli. Hypotension
and bradycardia are particularly common in selective baroreflex
failure patients and occur while patients are relaxed and resting.
Because of the loss of baroreflex blood pressure buffering,
patients may experience potentially life-threatening hypotension
with vasodilating drugs. Sympatholytic drugs are quite useful
to attenuate pressure surges. The paradoxical combination of
sympatholytic drugs with pressor agents may be required in occasional
patients with particularly severe hypotensive episodes. Symptomatic
bradycardia in selective baroreflex failure is an indication
for pacemaker implantation.
Received January 19, 2005;
first decision February 3, 2005;
accepted February 10, 2005.
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Abstract
Introduction