Published online before print April 18, 2005, doi: 10.1161/01.HYP.0000160355.93303.72
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(Hypertension. 2005;45:834.)
© 2005 American Heart Association, Inc.
Hypertension Grand Rounds |
Baroreflex Failure
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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 Top Abstract IntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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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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TopAbstractIntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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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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TopAbstractIntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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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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Case 2 |
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TopAbstractIntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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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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TopAbstractIntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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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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Causes of Baroreflex Failure |
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TopAbstractIntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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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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TopAbstractIntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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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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TopAbstractIntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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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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TopAbstractIntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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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.
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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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TopAbstractIntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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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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TopAbstractIntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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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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References |
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TopAbstractIntroductionCase 1Case 2DiscussionCauses of Baroreflex FailureEpidemiologyClinical FeaturesDiagnostic TestingTreatmentSummaryReferences |
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19. Bertinieri G, Di Rienzo M, Cavallazzi A, Ferrari AU, Pedotti A, Mancia G. A new approach to analysis of the arterial baroreflex. J Hypertens Suppl. 1985; 3 (suppl): 79–81.
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