The Clinical Spectrum of Labile Hypertension: A Management Dilemma

Abstract

Although the management of the labile component of blood pressure elevation is a problem often encountered by clinicians, there is a paucity of information available to guide therapeutic decisions. This review discusses the clinical relevance of blood pressure lability, the limitations of current knowledge, and possible directions for future research and clinical management.

Most guidelines for treating hypertension focus on the average blood pressure (BP) assessed from either home or office readings. Little attention is paid, however, to BP lability. Virtually all physicians are familiar with the term labile hypertension, yet there are no quantitative criteria to define or diagnose it. Its effects on cardiovascular (CV) outcome are unclear, and there are no guidelines for its treatment. The effect of treating the labile component of hypertension on CV outcome is also unknown. Despite this, labile BP elevation is a commonplace clinical dilemma.

It is normal for BP to fluctuate from moment to moment and from day to day. BP fluctuation is related to many factors such as physical activity, emotion, position, respiratory cycle, diet, salt intake, alcohol ingestion, sleep deprivation, and others. Even in otherwise normotensive individuals, BP fluctuation can be substantial during moments of physical or emotional stress or even without overt provocation. In physicians’ offices, readings can be very stable in some patients, while varying markedly in others.

Ironically, in the 1960s through the 1980s, the term labile hypertension had an entirely different meaning. It was defined then as an intermediate category between normotension and sustained hypertension, with readings varying above and below the cutoff point of 140/90 mm Hg. Today this would be regarded as borderline or mild hypertension, with the term labile hypertension connoting the tendency to sizable excursions in BP. Despite the paucity of knowledge of the causes and effects of labile hypertension, a brief review is worthwhile in formulating an empiric approach to managing this common clinical dilemma.

BP Variability, Reactivity, and Liability

In describing the tendency of BP to fluctuate, the terms variability, reactivity, and lability have been widely used. BP variability is usually defined as the average variation of BP throughout the day, quantitated as the standard deviation of ambulatory BP readings. It is increased in hypertensive individuals and increases with aging. ¹ , ² , ³ Reduced baroreceptor sensitivity might be a contributing factor. ⁴ Antihypertensive drug therapy does not appear to affect it. ⁵

Studies differ as to whether BP variability is associated with CV risk. ³ , ⁵ , ⁶ However, even if such an association exists, it is unclear whether BP variability is a cause or merely a marker for CV risk, perhaps simply reflecting arterial stiffness. Physical activity might explain much of daytime BP variability, further diminishing prognostic meaningfulness. ⁷

BP reactivity is defined as the response to environmental stressors, usually quantitated as responses to standardized laboratory stressors. In both the laboratory and clinical realms, individuals with increased reactivity are sometimes referred to as “hot reactors.”

BP reactivity is difficult to quantitate because an individual’s reactivity differs from stressor to stressor, and even upon retesting with the same stressor. ⁸ Further obscuring its meaningfulness, reactivity in the laboratory is not strongly predictive of reactivity to real‐life stressors. ⁸ , ⁹ Although many have suspected that BP reactivity is predictive of future development of hypertension and of CV risk, studies have not found this to be true. ¹⁰ , ¹¹ , ¹²

BP lability is characteristic of human BP, and there is no clear definition that differentiates normal from abnormal lability. The term labile hypertension, although widely used, also lacks an accepted definition and is more a clinical impression than a specific diagnosis. Labile hypertension will be the main topic of this review.

Labile Component of BP as a Clinical Dilemma

Four circumstances in which the labile component of BP is a clinical issue are listed in Table I and are discussed below. As indicated in the table, the terms labile hypertension and paroxysmal hypertension are used to denote different disorders of BP lability. They appear to have different characteristics and to require different treatment.

Table I.

 Blood Pressure Lability as a Clinical Dilemma

The alerting phenomenon (white coat hypertension)

Labile hypertension (including preprocedural hypertension)

Paroxysmal hypertension

Normal lability in patients with vulnerable underlying conditions

Cerebral aneurysm

Chronic aortic dissection

Amyloid angiopathy (?)

Marfan syndrome

Angina

The Alerting Phenomenon

The alerting phenomenon is the tendency of BP to rise at the time of measurement, usually, but not always, due to consciously perceived anxiety over the measurement. Although typically described as occurring during measurement by a physician, it can also occur during measurement at home. When limited to physician’s offices, it is regarded as white coat hypertension. Surprisingly, studies show that patients with white coat hypertension do not have abnormal lability outside of physicians’ offices. ¹³

White coat hypertension is associated with a lower risk of CV events than is sustained hypertension, but the risk of events and of target organ damage is greater than that in normotensive individuals. ¹⁴ , ¹⁵ , ¹⁶ The risk of ultimately developing sustained hypertension is also greater. ¹⁷ Therefore, it is essential that ambulatory or home BP be monitored for future development of sustained hypertension.

Many patients who are anxious about their BP enter a vicious cycle in which elevated readings trigger anxiety, which results in yet higher readings, possibly including home readings, and more anxiety. Some patients end up incessantly checking their BP, further aggravating this problem. Ultimately, in some patients, it can become difficult to obtain a meaningful measure of BP, whether in the office or at home, that is not contaminated by this alerting phenomenon.

In addition to the alerting phenomenon, measurement technique can also misleadingly contribute to the impression of excessive lability. Home readings taken without resting prior to the measurement, recording of single readings rather than 3 consecutive readings, use of too narrow a cuff or a wrist cuff can all yield misleadingly high readings. In addition, readings taken specifically at times of suspected BP elevation, eg, during perceived agitation, can be misconstrued as excessive lability rather than appropriate physiologic reactivity. Similarly, office readings taken with the wrong cuff size, or without waiting, or while the patient is talking will also overstate the lability of the patient’s BP.

Labile Hypertension

Patients with labile hypertension experience transient but substantial increases in BP. The increases often, but not always, occur in the setting of emotional distress, particularly anxiety, and are likely mediated by sympathetic activation. Labile hypertension can be asymptomatic or can be accompanied by symptoms such as headache, palpitations, or flushing. The BP usually falls spontaneously without intervention. BP elevation is usually readily attributed to emotional stress, by both physician and patient.

A particular problem arises in patients who experience marked elevations prior to medical or surgical procedures, sometimes leading to postponement of necessary procedures. In some patients, prophylactic management becomes a necessity.

Paroxysmal Hypertension (Pseudopheochromocytoma)

In contrast to patients with labile hypertension, in patients with “paroxysmal hypertension” (pseudopheochromocytoma), BP elevation generally occurs in the absence of overt emotional distress, with most patients describing the paroxysms as having occurred “out of the blue” (Table II). ¹⁸ , ¹⁹ Paroxysms characteristically begin very abruptly and can last minutes, hours, or even days. ¹⁹ Abrupt BP elevation is accompanied by prominent and very distressing physical symptoms, such as headache, palpitations, flushing, weakness, or dyspnea. ¹⁹ The paroxysms often provoke a marked fear of imminent death or stroke; the fear follows rather than precedes the onset of physical symptoms. Fear of recurrent symptomatic paroxysms can lead to restriction of lifestyle and functioning. ¹⁹

Table II.

 Differing Manifestations of Labile vs Paroxysmal Hypertension

Labile Hypertension	Paroxysmal Hypertension (Pseudopheochromocytoma)
Can be asymptomatic or symptomatic	Markedly symptomatic
Usually triggered by a stressor and accompanied by emotional distress experienced by the patient	Usually appears out of the blue without antecedent emotional distress
Patient usually links the blood pressure elevation to emotional distress	Patient usually insists that the blood pressure elevation is not related to emotional distress

Biochemical screening for a pheochromocytoma is mandatory, although such a tumor is found in <2% of patients with paroxysmal hypertension. ²⁰ Catecholamine studies are usually normal but can be mildly abnormal either during or even between paroxysms, reflecting activation of the sympathetic nervous system. ¹⁹ , ²¹

Paroxysms typically present with 1 of 2 hemodynamic/hormonal patterns. One is characterized by an increase in heart rate and epinephrine level and the other by an increase instead in norepinephrine level without an increase in heart rate. ¹⁸ This suggests that stimulation of the adrenergic limb of the sympathoadrenal system is dominant in some and of the neural limb in others.

The sudden and severe elevation of BP during paroxysms would seemingly put patients at risk for an acute cerebrovascular or CV event, although there are no reports confirming such an occurrence. The risk, over years, of ischemic lesions on magnetic resonance imaging even without clinical events has not been assessed.

Case series have linked paroxysmal hypertension to emotional repression, either repression of emotions related to previous severe emotional trauma or a lifelong tendency to repress rather than experience distressful emotion. ¹⁹ The presence of 1 or the other of these 2 patterns of repression is characteristic of the disorder and is helpful in supporting the diagnosis of pseudopheochromocytoma.

Normal Lability in Patients With Vulnerable Underlying Conditions

Although fluctuation of BP is a normal phenomenon, even normal lability would seem potentially harmful in patients with certain medical conditions. For example, in patients with chronic aortic dissection, Marfan syndrome, angina, or cerebral aneurysm, and possibly in patients with recurrent nonhypertensive cerebral hemorrhage from amyloid angiopathy, transient BP elevation might be deleterious and reduction of even normal lability could be proposed to be beneficial.

Treatment

To date, the treatment of hypertension has focused on measurement of resting BP. Virtually no attention has been given to the indications for, and benefit of, treatment of the labile component of BP elevation or to the drug treatment strategies that might best reduce BP lability. In the absence of guidelines, treatment is largely a seat‐of‐the‐pants clinical decision, often guided by the level of concern of the physician or the patient. Nevertheless, a logical framework can be suggested as a starting point.

Treatment of BP Variability and BP Reactivity

Little attention has been paid to the effect of drug treatment on BP variability or reactivity or to the effect of such treatment on CV outcome. Antihypertensive drug therapy does not appear to reduce BP variability. ⁵ Monotherapy with either a diuretic, angiotensin‐converting enzyme (ACE) inhibitor, α‐blocker, or β‐blocker does not reduce BP reactivity to stressors, although lowering of resting BP will predictably lower peak pressure as well. ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷

Contrary to widespread belief, studies consistently show that β‐blocker monotherapy does not reduce BP reactivity to stressors. ²² It mitigates the increase in heart rate and cardiac output but does not reduce BP reactivity, which is maintained instead by an increase in peripheral resistance. ²⁸ , ²⁹ Similarly, α‐blocker monotherapy blocks the increase in peripheral resistance, but BP reactivity is unaltered due to an increase instead in cardiac output. ²⁹ , ³⁰ In contrast, studies suggest that the combination of an α‐ and β‐blocker, which blocks increases in both cardiac output and peripheral resistance, does reduce BP reactivity. ²³ , ³¹ , ³² , ³³

Approach to Drug Therapy for BP Lability

Eliminating BP lability is not possible but reducing it is often achievable. A regimen that antagonizes sympathetically mediated BP elevation would seem more logical than treatment with agents directed at other mechanisms, such as ACE inhibitors, angiotensin receptor blockers, or diuretics, the mainstays of treatment of sustained hypertension. However, little has been published concerning treatment of the labile component of BP or concerning the effect of such treatment on long‐term outcomes.

The clear relationship between sympathetic activation and BP reactivity to emotional distress and the documented effect of combined α‐/β‐blockade on sympathetically mediated BP reactivity to laboratory stressors suggest a role for combined α‐/β‐blockade in treating patients with labile hypertension. Clinical studies in this area are needed.

Carvedilol and labetalol each provides both α‐ and β‐blocking effects but might not be ideal because of unpredictable bioavailability resulting from first‐pass hepatic metabolism. ³⁴ , ³⁵ Alternatively, two separate agents, a β‐blocker, preferably one whose β‐blocking effect is not greatly affected by hepatic metabolism (eg, atenolol, nadolol, bisoprolol, betaxolol, or nebivolol), combined with an α‐blocker, such as doxazosin, can be prescribed.

The Alerting Phenomenon and White Coat Hypertension

The treatment of white coat hypertension has engendered considerable controversy. It would seem unnecessary, and perhaps harmful, to prescribe antihypertensive drugs if home readings are truly normal, as treatment could confer the risk of iatrogenic hypotension. However, given the increased likelihood of developing sustained hypertension, patients need to be observed for progressive elevation of home readings over time. Treatment should be aimed at reducing home BP, if it is elevated, using the usual pharmacologic agents.

Labile Hypertension (Including Preprocedural BP Elevation)

There are no recognized criteria for treating labile hypertension, other than the mean 24‐hour BP observed on ambulatory monitoring. Frequent home monitoring, which can foster anxiety and elevated readings, should be discouraged. In patients whose hypertension is characterized by frequent severe elevations, eg, systolic readings >180 mm Hg, or who have runaway anxiety about their BP, treatment to achieve more normal readings can be helpful both in lowering BP and in reducing the vicious cycle of anxiety. Here, institution of a standing regimen combining an α‐ and β‐blocker, at their usual dosages, would seem preferable to an as‐needed regimen that perpetuates the constant rechecking of BP. Such a regimen would also seem preferable to standard ACE inhibitor/diuretic combinations that are not directed at sympathetically driven hypertension. However, no studies have explored this question.

In patients who repeatedly experience marked and problematic BP elevation when presenting for medical or surgical procedures, intravenous administration of an anxiolytic agent and/or the α/β‐blocker labetalol can acutely lower BP. A prophylactic regimen consisting of an α‐ and a β‐blocker (any standard β‐blocker given in combination with an α‐blocker, such as doxazosin (0.5–1 mg daily or twice a day), given for 2 or 3 days, can often mitigate the preprocedural elevation in BP. If necessary, an anxiolytic agent, such as lorazepam (0.5–2 mg), or alprazolam (0.25–1 mg), can also be administered shortly before the procedure. Temporary treatment with a central α‐agonist, such as clonidine, is another possible alternative, usually given at a dose of 0.1 to 0.2 mg every 8 hours.

Paroxysmal Hypertension

The difficult problem of treating paroxysmal hypertension, which can be disabling, has recently been reviewed. ³⁶ Pharmacologic, psychopharmacologic, and psychologically based interventions alone or in combination can eliminate paroxysms in most patients and enable resumption of a normal life. Treatment may involve acute management to lower BP and reduce symptoms during paroxysms or chronic management to prevent recurrent paroxysms, or both (Table III).

Table III.

 Suggested Indications and Regimens for Pharmacologic Treatment of Labile Forms of Hypertension^a

Preprocedural blood pressure (BP) elevation

Prophylactic management

Oral α‐blocker + β‐blocker for 2–3 days and/or anxiolytic agent

Acute management

Intravenous (IV) labetalol and/or anxiolytic agent (oral or IV)

Severe labile hypertension

Acute management

Indications for acute management not established

Consider intravenous labetalol if severe or symptomatic elevation

Chronic management

Oral α‐blocker + β‐blocker + other agents if resting BP is elevated

Runaway anxiety about BP readings

Acute management

Not indicated

Chronic management

Oral α‐blocker + β‐blocker

Paroxysmal hypertension

Acute management of paroxysms

Severe paroxysm (eg, systolic BP >220 mm Hg or diastolic BP >130 mm Hg, or lower readings depending on clinical circumstances) or severe symptoms

IV labetalol or IV nitroprusside

Milder paroxysms

Central α‐agonist (eg, oral clonidine ) and/or  anxiolytic

Or oral α‐blocker + β‐blocker with fairly rapid onset  (eg, labetalol or metoprolol + prazosin)

Chronic preventive management

Less intensive regimen: for mild to moderate recurring paroxysms

α‐Blocker + β‐blocker

More intensive regimen (if frequent, severe paroxysms despite α‐/β‐blockade and/or reduced functioning resulting from recurring paroxysms):

Antidepressant agent (selective serotonin reuptake  inhibitor or tricyclic or other antidepressant agent),  probably with α‐blocker + β‐blocker

Normal lability in patients with vulnerable underlying conditions

Chronic management

Oral α‐blocker + β‐blocker combined with other agents to achieve lowest acceptable resting BP

^aSee text for details.

Acute Management of Hypertensive Paroxysms: Pharmacologic and Psychopharmacologic Agents

For patients with severe BP elevation, a rapid‐acting intravenous agent, such as labetalol can be administered. An intravenous bolus of 10 mg to 20 mg can be given, followed by repeat boluses of 20 mg to 80 mg at 10‐ to 15‐minute intervals until a response is seen. In the absence of a response or in the presence of extreme BP elevation nitroprusside can be administered.

In patients with less severe BP elevation, oral therapy with clonidine or the combination of an α‐ and a β‐blocker can be given as an alternative to intravenous treatment. Clonidine can be given at a dose of 0.1 mg or 0.2 mg repeated after 90 minutes in nonresponders. α‐/β‐Blockade can be given as labetalol 100 mg to 300 mg every 6 to 8 hours, with response expected within 1.5 to 2.5 hours or alternatively as a β‐blocker with fairly rapid onset of action, such as metoprolol (25–50 mg orally every 6 hours), combined with prazosin (1 mg orally every 8–12 hours). ³⁵ Milder paroxysms can be managed in some patients with a rapid‐acting anxiolytic agent, such as alprazolam, given alone or in combination with an antihypertensive agent. Under a physician’s supervision, reliable patients who have responded well to clonidine and/or an anxiolytic agent can self‐administer either or both drugs at home during subsequent paroxysms rather than seek emergency department care for each attack. Clonidine can be taken at a dosage of 0.1 mg or 0.2 mg and repeated at 6‐ to 8‐hour intervals.

Chronic Preventive Management: Pharmacologic and Psychopharmacologic Agents

Chronic therapy with an α‐blocker combined with a β‐blocker given orally has been reported to reduce severity of BP elevation during paroxysms. ¹⁹ Extended use of a central α‐agonist such as clonidine has not been reported and in many cases its use would be limited by side effects, particularly fatigue.

The use of antidepressant and anxiolytic agents to prevent attacks was suggested by the similarity of the syndrome to panic disorder. Antidepressant agents, including selective serotonin reuptake inhibitors and tricyclic antidepressants, have been reported to prevent recurrent paroxysms in most patients at dosages recommended for treating panic disorder. ¹⁸ , ¹⁹

For patients with mild or infrequent paroxysms, acute management with alprazolam or clonidine and/or maintenance therapy with combined α‐ and β‐blockade is usually sufficient. An antidepressant should be considered mainly in patients with severe and recurrent hypertensive paroxysms or in those in whom the disorder has resulted in impaired functioning.

Psychological Interventions

Reassurance.  Symptomatic hypertensive paroxysms are terrifying to most patients, and the fear of dying during an attack can come to dominate their life. A physician’s confident reassurance that the disorder can be treated and that a catastrophic event or death during a paroxysm is very unlikely can help reduce the terror and possibly the number and severity of attacks.

Awareness.  In some cases, gaining awareness of the origin of the disorder in repressed emotions can reduce or eliminate recurrence of paroxysms. ¹⁹ , ³⁶ In patients open to such awareness, subsequent psychotherapy can be helpful. However, most patients who are survivors of severe trauma will continue to defend against awareness of potentially overwhelming emotion. They are unlikely to be interested in or benefit from psychotherapy and should not be coerced into it. Among patients who do not have a history of trauma but who have a lifelong tendency to repress emotions, psychotherapy is an option, although a repressive coping style is difficult to alter.

Normal Lability in Patients With Vulnerable Underlying Conditions

Treatment of the labile component of BP in patients with underlying comorbidities (Table I) is also an area that has been inadequately studied. In the example of patients with chronic aortic dissection, most physicians focus on achieving the lowest possible resting BP. Treatment with combined α‐ and β‐blockade, given its observed effects on BP reactivity, in addition to its ability to lower resting BP, would seem logical and merits consideration for both further study as well as empiric use.

Conclusions

Although the management of labile forms of hypertension is a frequently encountered clinical dilemma, specific criteria for diagnosing labile hypertension and clinical trials to guide management do not exist. The clinical spectrum of this problem and a treatment approach based on published reports and physiologic principles has been presented. Studies to assess the effects of labile hypertension and outcome of treatment are needed.