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. Author manuscript; available in PMC: 2020 Dec 10.
Published in final edited form as: J Am Coll Cardiol. 2019 Dec 10;74(23):2939–2947. doi: 10.1016/j.jacc.2019.10.027

Blood Pressure Management in Afferent Baroreflex Failure: JACC Review Topic of the Week

Italo Biaggioni a,c,d,e, Cyndya A Shibao a,c,e, André Diedrich a,c,e, James A S Muldowney 3rd b,c,e, Cheryl L Laffer a,c, Jens Jordan f,g
PMCID: PMC6939863  NIHMSID: NIHMS1542829  PMID: 31806138

Abstract

Afferent baroreflex failure is most often due to damage of the carotid sinus nerve because of neck surgery or radiation. The clinical picture is characterized by extreme blood pressure lability with severe hypertensive crises, hypotensive episodes, and orthostatic hypotension, making it the most difficult form of hypertension to manage. There is little evidence-based data to guide treatment. Recommendations rely on understanding the underlying pathophysiology, relevant clinical pharmacology and anecdotal experience. The goal of treatment should be improving quality of life rather than normalization of blood pressure which is rarely achievable. Long-acting central sympatholytics are the mainstay of treatment, used at the lowest doses that prevent the largest hypertensive surges. Short-acting clonidine should be avoided because of rebound hypertension but can be added to control residual hypertensive episodes, often triggered by mental stress or exertion. Hypotensive episodes can be managed with countermeasures and short acting pressor agents if necessary.

Keywords: Autonomic nervous system, baroreflex, carotid sinus, hypertension, orthostatic hypotension

Condensed Abstract

The carotid sinus is crucial to the instantaneous regulation of blood pressure and this becomes apparent when it is damaged, most often by surgery or radiation fibrosis complicating neck cancer treatment. Patients with afferent baroreflex failure have extreme blood pressure lability and can suffer from severe hypertensive crises associated with tachycardia and flushing, profound hypotensive episodes, and disabling orthostatic hypotension. This constellation of symptoms makes baroreflex failure arguably the most difficult form of hypertension or autonomic dysfunction to treat. This review will focus on the management of these patients.

Acute changes in blood pressure are restrained by the autonomic baroreflex. The system accommodates appropriate and physiological increases in blood pressure during exercise and in response to stress (the fight or flight reaction), but otherwise maintains blood pressure under a relatively narrow range. The importance of the baroreflex is nowhere more evident than in patients with lesions of the afferent arc of the reflex. These afferent baroreflex failure patients have exaggerated blood pressure responses to pressor and depressor stimuli and present clinically with hypertensive crises, volatile labile hypertension alternating with episodes of hypotension, and orthostatic hypotension. This is arguably the most difficult form of hypertension or autonomic dysfunction to manage and unfortunately there is little evidence-based data to guide treatment. The purpose of this review is to outline a rational management approach based on the underlying pathophysiology, relevant clinical pharmacology, and empirical experience.

The Baroreflex

Blood pressure is modulated instantaneously by a feedback loop that constitutes the baroreflex (Central Illustration). A blood volume overload or an increase in blood pressure is sensed by low-pressure receptors located in the heart and great veins, and by high pressure receptors in the carotid sinus, respectively. The carotid sinus, a small blood vessel dilation just above the carotid bifurcation, plays a particularly important role in baroreflex function. Stretch receptors are located within the adventitia of the carotid arterial wall and aortic arch to sense changes in arterial blood pressure and initiate the afferent limb of the baroreflex (1,2). An increase in blood pressure is sensed by these afferents that translate mechanical stretch into action potentials that are transmitted via the carotid sinus (Hering’s) nerve, a branch of the glossopharyngeal nerve (IX). Afferents from the aortic arch travel via the vagus nerve (X). Both afferent signals are relayed to the nucleus tractus solitarii (NTS) of the brainstem.

Central Illustration. Diagram of the Baroreflex.

Central Illustration

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An increase in blood pressure activates baroreceptors located in the carotid sinus. Afferent signals are sent through the glossopharyngeal nerve (IX) to activate the nucleus tractus solitarii (NTS) of the brainstem. This in turn activates neurons in the caudal ventrolateral medulla (CVLM) which provides inhibitory input to the rostral ventrolateral medulla (RVLM) where sympathetic activity originates. This results in a decrease in sympathetic tone that is carried through preganglionic efferent fibers in the intermediolateral column of the spinal cord (IML), and a decrease in postganglionic efferent fibers innervate the heart and blood vessels, to restore blood pressure to normal values.

The NTS receives input not only from baroreceptor afferents, but also from chemoreceptor afferents arising from the carotid body (3) and from several other visceral afferents (4). Activation of NTS neurons provide excitatory (glutamatergic) input to the caudal ventrolateral medulla, which in turn provides inhibitory input (GABAergic) to the rostral ventrolateral medulla (RVLM), where sympathetic tone is generated; at the same time, stimulation of the NTS activates the dorsal vagal nucleus of the vagus and nucleus ambiguus, where parasympathetic activity is generated. Thus, an increase in blood pressure activates arterial baroreceptors and the NTS, which induces parallel inhibition of sympathetic tone (through inhibition of the RVLM), and activation of parasympathetic tone (through activation of the dorsal vagal nucleus of the vagus). Thus, the initial increase in blood pressure ultimately leads to inhibition of sympathetic tone to the vasculature (resulting in vasodilation) and to the heart (resulting in a decrease in cardiac output), and activation of parasympathetic tone to the heart (leading to a decrease in heart rate). These actions restore blood pressure to baseline values.

Clinical Relevance of Baroreflex Function

The baroreflex provides continuous and instantaneous regulation of blood pressure that buffers acute changes in blood pressure. Acute bilateral anesthetic blockade of the carotid sinus nerves results in immediate and dramatic increases in blood pressure and heart rate, (5,6). Likewise, abolition of baroreflex function with acute ganglionic blockade results in a 5 to 10-fold increased sensitivity to pressor agents (7,8). Traditionally the baroreflex has not been thought to play a role in the long-term regulation of blood pressure, in part because baroreflex sensitivity is reset during sustained increases in blood pressure. However, resetting of the baroreflex plays at least a permissive role in the chronic sympathetic activation that perpetuates certain forms of hypertension, given that acute autonomic withdrawal (9,10) or chronic carotid baroreceptor stimulation (11,12) reduce blood pressure in these conditions.

Etiology of Afferent Baroreflex Failure

Almost all cases of afferent baroreflex failure are secondary to radiation therapy for head and neck cancer (13). Soon after neck radiation there is measurable impairment of baroreflex function (14,15), but overt baroreflex failure occurs in a minority of patients, usually years after the procedure, due to radiation injury and fibrosis involving the carotid sinus (16). The exact proportion of patients who will develop this complication and the predictors of disease are not known. In some cases radiation injury also produces carotid artery stenosis that contributes to the symptomatology.

Afferent baroreflex failure can also result from bilateral resection of neck tumors, most commonly carotid body paragangliomas, with damage to the carotid sinus nerve (17–19). It can also be caused by familial dysautonomia (hereditary sensory and autonomic neuropathy type 3), a rare congenital disease characterized by developmental failure of afferent neurons, affecting individuals of Ashkenazi Jewish ancestry (20). In very rare cases the syndrome can be due to brainstem lesions involving afferent baroreflex pathways (21–23).

Carotid endarterectomy can produce an acute impairment of baroreflex function leading to lability of blood pressure postoperatively (24). This effect is transient and in a subset of patients baroreflex function may actually improve after endarterectomy; these patients appear to have better cardiovascular and stroke outcomes compared to patients in whom baroreflex sensitivity does not improve after endarterectomy (25).

Distinction Between Afferent Baroreflex Failure, and Central and Efferent Autonomic Failure

Neurological disease can affect the integrity of the baroreflex arc at sites other than the afferent limb. In particular, primary neurodegenerative autonomic disorders can affect either central autonomic pathways (multiple system atrophy) or efferent pathways (pure autonomic failure, Parkinson’s disease) (Figure 1) involving the baroreflex (28). These patients, therefore, also have “baroreflex failure”, which makes them hypersensitive to pressor agents (26). Their clinical picture, however, is characterized by posture-related blood pressure abnormalities, with supine hypertension and profound disabling orthostatic hypotension (27); the labile hypertension triggered by mental stress, characteristic of afferent baroreflex failure, is absent.

Figure 1. Pathophysiological and Clinical Differences Between Afferent Baroreflex Failure and Autonomic Failure.

Figure 1.

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Normal baroreflex function, shown in the Central Illustration, maintains blood pressure under relatively narrow range. Afferent baroreflex failure (Panel A) is due to loss of inhibitory input from the carotid sinus, the nucleus tractus solitarii (NTS) and the caudal ventrolateral medulla (CVLM), leaving cortical input (mental stress) to the rostral ventrolateral medulla (RVLM) unopposed, resulting in paroxysmal surges in muscle sympathetic nerve traffic (MSNA) and parallel increases in blood pressure and heart rate. In primary Autonomic Failure (Panel B) autonomic regulation is impaired because of neurodegeneration of central autonomic pathways (multiple system atrophy, MSA) or efferent autonomic fibers (pure autonomic failure, PAF,). In either case the clinical picture is characterized by supine hypertension and orthostatic hypotension; patients also have impaired baroreflex function leading to hypersensitivity to pressor agents or depressor stimuli, but do not have the paroxysmal hypertensive surges seen in afferent baroreflex failure.

Traditionally, the clinical term “Baroreflex Failure” has been used to describe disorders affecting the afferent limb, and “Autonomic Failure” has been used to describe central and efferent disorders. We prefer, therefore, to use the term “Afferent Baroreflex Failure” to describe disorders of deafferentation and avoid confusion. The clinical distinction between efferent and afferent forms of baroreflex failure is reviewed elsewhere in more detail (13).

Clinical Picture of Afferent Baroreflex Failure

The main clinical features of afferent baroreflex failure are: 1) hypertensive crises, 2) hypotensive episodes, and 3) orthostatic hypotension The hallmark of the disease is extreme lability of blood pressure, with dramatic surges of blood pressure and parallel increases in heart rate (Figure 1). Hypertensive crises are often triggered by mental stress or exertion (28), and are driven by sympathetic activation as evidenced by concurrent increases in plasma norepinephrine and by direct measurements of sympathetic nerve traffic. Facial flushing is common during these episodes (17) and is also seen in other disorders characterized by episodic central sympathetic activation (29), but is rarely seen in pheochromocytoma, where hypertensive crises are instead associated with pallor. The difference could be explained by the fact that in pheochromocytoma, tumor-derived epinephrine and norepinephrine act as a circulating hormones, whereas in baroreflex failure norepinephrine is released “physiologically’ from adrenergic fibers.

Whereas hypertensive episodes are universally present in patients with afferent baroreflex failure, alternating episodes of hypotension is seen in many but not all patients (30,31). The pathophysiology of the hypotensive episodes is not readily apparent. It is unlikely to be simply due to a reduction in sympathetic tone because supine blood pressure does not fall to hypotensive levels in hypertensive patients even during complete autonomic withdrawal with ganglionic blockade (32). On the other hand, patients may develop hypovolemia as seen in pheochromocytoma, or post-prandial hypotension as seen in autonomic failure (33). Short acting sympatholytics commonly used to treat these patients can also induce hypotensive episodes (see below under Management). It is possible, therefore, that hypotensive episodes result from a combination of these factors. Regardless, hypotension can be severe and disabling, and its presence complicates the management of these patients.

Considering the role of the baroreflex to maintain upright blood pressure, it is not surprising that orthostatic hypotension can be a prominent feature in baroreflex failure patients. However, orthostatic hypotension is not a universal finding. It is possible that in some patients, aortic baroreceptors and vestibular afferents can increase sympathetic activity on standing and provide effective compensatory mechanisms. Some patients can develop vascular damage of the carotid artery secondary to radiation injury and present with localized neurological deficits triggered by standing. In such patients, revascularization procedures can be considered but may be limited by extensive vascular and tissue damage.

There also seems to be a difference in the clinical presentation of acute forms of baroreflex failure (e.g., bilateral carotid sinus denervation for paragangliomas) and the more insidious sequelae of radiation injury. In the former, hypertensive episodes are severe and often accompanied by nausea, vomiting, headache, diaphoresis, anxiety and emotional lability; orthostatic hypotension also appears to be less of a problem. In the latter, episodes of nausea and emotional lability are less common but hypotensive episodes and orthostatic hypotension appear to be more prominent.

Differential Diagnosis and Autonomic Testing

Essential hypertension is by far a more common cause of labile hypertension than actual baroreflex failure. This is particularly true in patients with essential hypertension treated with short acting central sympatholytics such as clonidine, which can induce hypotensive episodes followed by rebound hypertension, resulting in a clinical picture resembling baroreflex failure (34). Tizanidine, a commonly used “central muscle relaxant”, is chemically related to clonidine, has similar central sympatholytic effect and can also produce rebound hypertension mimicking baroreflex failure (35). Pheochromocytoma is a rare cause of hypertension but has to be considered in the differential diagnosis and can be ruled out by measuring plasma fractionated metanephrines, derived from extra-neuronal catecholamine metabolism (36). Pseudopheochromocytoma (37) is also characterized by paroxysmal hypertension often associated with mental stress but with intact baroreflex function. The treatment of the hypertensive surges may be similar that outlined below for afferent baroreflex failure. Other conditions characterized by hyperadrenergic surges, such as use of sympathomimetics (amphetamine and cocaine), panic attacks, postural tachycardia syndrome and mast cell activation (29) also need to be considered.

A carefully conducted history is key to the diagnosis. The absence of neck radiation or surgery should make us doubt the diagnosis of baroreflex failure. Ambulatory blood pressure monitoring can be useful in documenting parallel changes in blood pressure and heart rate, and the normalization of blood pressure during sleep when central nervous system influences are reduced. Autonomic testing with continuous blood pressure monitoring, now available with non-invasive devices, is the only way to document absence of baroreflex function. Traditionally, blood pressure is increased with intravenous bolus injections of phenylephrine and decreased with sodium nitroprusside; patients with baroreflex failure have exaggerated blood pressure responses to these agents, but lack the appropriate reciprocal changes in heart rate and sympathetic nerve activity (obtained by a recording electrode place in the peroneal nerve) normally mediated by the baroreflex. If pharmacologic testing is not available, the response to the Valsalva maneuver may provide supportive evidence of the diagnosis, by documenting absence of reciprocal changes in heart rate; i.e., no increase in heart rate during the drop in blood pressure induced during strain (phase 2), and no decrease in heart rate during the blood pressure overshoot triggered during release (phase 4). These findings confirm the presence of baroreflex failure, but not whether the lesion is in the afferent, central or efferent limb of the baroreflex (Figure 1). Adding a cold pressor test (immersion of hand in ice water for 60–90 seconds) can be useful to document an exaggerated pressor response which is only seen in afferent baroreflex failure.

Preventing Baroreflex Failure and the Bionic Baroreflex

In patients needing neck surgery, it would stand to reason that techniques that spare the carotid snus nerve will prevent cases of baroreflex failure. In the case of carotid endarterectomy there are conflicting opinions about the preferred surgical approach (standard longitudinal arteriotomy vs. oblique circumferential transection) (38). In the case of paragangliomas, unilateral resection is usually well tolerated, but often patients develop bilateral lesions. If surgical excision of the contralateral tumor is essential, conservative surgery to preserve the remaining carotid sinus nerve is preferable. In regard to neck radiation, only a small proportion of patients appear to develop baroreflex failure but there are no studies with enough patients followed over a long enough period to determine predictors of disease that can be used to prevent subsequent development of baroreflex failure.

It is now technically feasible to mathematically model the complex dynamic input-response features of the baroreflex to construct a bionic baroreflex with identical response characteristics to the native baroreflex (39,40). Proof of concept studies have been performed in animals (41,42) and in spinal cord injury patients to reverse orthostatic hypotension (43). While encouraging, it is uncertain when this technology can be applied to baroreflex failure patients.

Management

Afferent baroreflex failure is characterized by unpredictable hypertensive crises, extremely labile hypertension, symptomatic hypotensive episodes, and orthostatic hypotension. This constellation of abnormalities makes baroreflex failure arguably the most challenging hypertensive or autonomic disorder to manage. It is virtually impossible to normalize blood pressure, and this should be discussed with patients and care providers, so they have realistic expectations about treatment. Nonetheless, in most cases it is possible to manage the blood pressure abnormalities well enough to improve the patient’s quality of life. The overall strategy is presented in the Table. It is important to emphasize that there is no evidence based for these recommendations. Instead, we rely on our understanding of the underlying pathophysiology, relevant clinical pharmacology, and empirical experience.

Table.

General Guidelines for the Management of Baroreflex Failure

  1. Accept the fact that we will not normalize blood pressure

  2. For labile hypertension:
    • Do not “chase” blood pressure (i.e., wait for blood pressure to increase to treat individual hypertensive surges); do not use short acting clonidine
    • Use longer-acting central sympatholytics (methyldopa, guanfacine, clonidine patch) at the lowest dose that prevents the biggest blood pressure surges; do not try to normalize blood pressure
    • For breakthrough hypertension episodes, add clonidine, alpha blockers
    • For hypertensive crises triggered by stress: consider biofeedback, benzodiazepines, cannabinoids
    • For “background” essential hypertension: ARB, ACEI
    • For cardioprotection: beta blockers (added to above, not as initial treatment)
  3. For hypotensive episodes or orthostatic hypotension:
    • Oral water bolus, physical stimulation, abdominal binder
    • Midodrine PRN
    • Fludrocortisone in otherwise treatment resistant cases (but may promote cardiovascular damage)

  4. In severe cases: “clamp” blood pressure with high-dose central sympatholytics and “rescue” midodrine
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ARB, angiotensin receptor blockers; ACEI, angiotensin converting enzyme inhibitors

Given that the hypertension in baroreflex failure is driven by sympathetic surges, central sympatholytics should be the mainstay of the treatment of labile hypertension and paroxysmal hypertensive crises. We recommend against “chasing the blood pressure”; i.e., waiting until blood pressure is increased to treat with short acting antihypertensives; most medications take about one hour to have an effect, and by that time the blood pressure may be on its way down. We particularly argue against short acting oral clonidine as single agent; in our experience its use leads to an acute lowering blood pressure, often to hypotensive levels, followed by rebound hypertension because of the short half-life of this drug.

We recommend instead the use of long-acting central sympatholytics initiated at low doses and titrated carefully to avoid hypotensive episodes. The goal should be to use the lowest does that prevents the larger blood pressure surges, rather than to attempt to normalize blood pressure. Methyldopa and guanfacine are our drugs of choice; transdermal clonidine may be tried, but in our experience it is less effective (13). If blood pressure surges are not completely controlled, clonidine can be added, particularly in patients in whom blood pressure predictably increases at certain time of day or by physical or mental stress. The alpha 2 agonist dexmedetomidine has been used as an intranasal preparation in the acute treatment of adrenergic crisis in patients with familial dysautonomia (44) but its effects are brief. Alpha blockers, or combined alpha-beta blockers can also be tried judiciously, alerting patients to be careful when standing to prevent orthostatic hypotension.

In patients with afferent baroreflex failure blood pressure is “at the mercy” of cortical input which is no longer restrained. Mental stress is the most common trigger of hypertensive crises. Even trivial stimuli can trigger paroxysmal hypertension, and these patients often have an extreme case of “white-coat” hypertension. This is the one form of hypertension that may respond to biofeedback techniques, benzodiazepines and cannabinoids. This is particularly true in the acute forms of baroreflex failure following bilateral neck surgery. The use of high carbohydrate drink can also help to control the hypertensive episodes by inducing post-prandial hypotension.

Patients may also require treatment for any underlying cardiovascular disease they may have, unrelated to baroreflex failure. In patients with pre-existing essential hypertension blood pressure may remain elevated between hypertensive surges, and this can be treated with antihypertensives less likely to worsen orthostatic hypertension (45) including angiotensin converting enzyme inhibitors and angiotensin receptor antagonists. Diuretics should be avoided because these patients are sensitive to volume changes. Vasodilators, such as nitrates and calcium channel blockers can elicit profound hypotension in some patients and, therefore, should be used with caution. In patients with coronary artery disease, beta-blockers can be added for cardioprotection, particularly given that these patients are exposed to significant sympathetic surges. Beta-blockers should be started carefully because of the theoretical possibility that, by leaving alpha vasoconstriction unopposed, they may elicit a paradoxical increase in blood pressure as seen in pheochromocytoma.

There is little information about the best approach to reverse hypotensive episodes. These patients are very sensitive to volume changes and ensuring adequate hydration and liberalizing dietary sodium may be required. Hypertension itself can beget hypotension through pressure diuresis; thus, controlling the hypertensive crises can paradoxically reduce hypotensive episodes. Hypotensive episodes may worsen with initiation of sympatholytic treatment, but they tend to improve with continued therapy. This problem can be lessened by initiating treatment at low doses. In some patients with short hypotensive episodes, simply lying down with elevation of lower limbs may be all that is needed. Interventions that are effective in treating hypotension in other forms of low sympathetic tone can be tried (46), but none have been rigorously tested in baroreflex failure. These include 16 oz oral water bolus, abdominal binder compression and midodrine. We can also take advantage of the fact that these patients have exaggerated pressor response to cold, painful stimuli and handgrip, and all of these can be tried as a way to reverse hypotension. Some patients, however, may require the addition of fludrocortisone but this approach has not been rigorously tested, carries the risk of exacerbating underlying hypertension, and could augment long-term cardiovascular damage.

In extreme cases where the above measures are not effective to control labile hypertension, we have had to resort to using higher doses of central sympatholytics to control hypertension, combined with midodrine to rescue blood pressure, as a way to replace the baroreflex by “clamping” blood pressure.

Conclusions

In summary, afferent baroreflex failure is a challenging condition to treat. Effective management requires an understanding of the underlying pathophysiology and of the clinical pharmacology of antihypertensives. The goal of treatment should not be to normalize blood pressure as we do in other forms of hypertension, because it is rarely achievable. Rather the goal should be to reduce the extreme ranges seen in blood pressure to improve the patients’ quality of life. This often requires continuous adjustments in their treatment. Further research is needed to validate treatment recommendations, as well as strategies to prevent the development of baroreflex failure.

Bullet Points:

  • Afferent baroreflex failure can cause severe supine hypertension, episodes of profound hypotension and orthostatic hypotension, making it one of the most challenging forms of hypertension to manage.

  • Long-acting central sympatholytics are the mainstay of treatment; short-acting agents should be avoided because of rebound hypertension.

  • More research is needed to validate treatment recommendations and develop preventive measures.

Funding:

The study was supported by NIH R01 HL122847, HL149386, DK111175-01, FD04778-04, and Vanderbilt CTSA grant 1UL1 RR000445

Disclosures: C.A.S. has received a research grant from Doris Duke Foundation. I.B. and C.A.S. received grant support from Office of Orphan Products Development. Food and Drug Administration, Grant #FD-R-04778-01-A3. C.A.S. has received speaker honorarium from Lundbeck Pharmaceuticals. I.B., C.A.S., and J.A.S.M.III received consulting honoraria from Lundbeck. I.B., C.A.S., and J.J, received consulting honoraria from Theravance Biopharma. C.A.S is member of the Board for the American Autonomic Society. J.J. is Cofounder of Eternygen GmbH. None of these disclosures are directly related to the current manuscript. The remaining authors have nothing to disclose.

Abbreviations:

MSNA

muscle sympathetic nerve activity

NTS

nucleus tractus solitarii

RVLM

rostral ventrolateral medulla

Footnotes

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