NR Rau, Gurukanth Rao,
ManipalAffecting 1 billion people worldwide, hypertension remains the most common, readily identifiable, and reversible risk factor for myocardial infarction, stroke, heart failure, atrial fibrillation, aortic dissection, and peripheral arterial disease. Because of escalating obesity and population aging, the global burden of hypertension is rising and projected to affect 1.5 billion persons—one third of the world’s population—by the year 2025. Currently, high blood pressure (BP) causes about 54% of stroke and 47% of ischemic heart disease worldwide.1
BP varies considerably in individual subjects and may vary significantly throughout the day. This variation causes considerable difficulties in identifying individuals who have hypertension. The differing BP values are due to both biologic variation (variations of pressures within a given individual) and variation in the measurement itself. Errors in measurement can be minimized by attention to the proper technique for recording Blood Pressure. Biologic variation is addressed by repeated BP measurement at a given visit (at least two pressures taken at least 5 minutes apart or additional BP measurements if there is a 5-mm Hg difference between repeated measures). In addition, in most patients with milder forms of hypertension, repeated measurements during different clinic visits over time are recommended to approach the true Blood pressure.
Definition
Hypertension currently is defined as a usual BP of 140/90 mm Hg or higher, for which the benefits of drug treatment have been definitively established. This conservative definition has been called into question by epidemiologic data showing continuous positive relationships between the risk of coronary artery disease (CAD) and stroke deaths with systolic or diastolic BP down to values as low as 115/75 mm Hg. This artificial dichotomy between “hypertension” and “normotension” can delay medical treatment until vascular health has been irreversibly compromised by elevated BP values previously considered to be normal. Thus, for certain high-risk patients, especially those with CAD, the recommended medical treatment threshold recently has been lowered to 130/80 mm Hg
LabiLe Hypertension
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 momentsof 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.
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bp VariabiLity reaCtiVity anD LabiLity 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.
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.2 Further obscuring its
meaningfulness, reactivity in the laboratory is not strongly predictive of reactivity to real-life stressors. 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.3
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 CoMponent of bp as a CLiniCaL DiLeMMa
Four circumstances in which the labile component of BP is a clinical issue are listed in Table 1 and are discussed below. As indicated in the Table 1, the terms labile hypertension and paroxysmal hypertension are used to denote different disorders of BP lability. They appear to have different characteristics and require different treatment.
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.4
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.
Paroxysmal Hypertension (Pseudopheochromocytoma)
In contrast to patients with labile hypertension, inpatients 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’’.5 Paroxysms characteristically
begin very abruptly and can last minutes, hours, or even days5. Abrupt BP elevation is accompanied by prominent
and very distressing physical symptoms, such as headache, palpitations, flushing, weakness, or dyspnea5. 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.
Biochemical screening for a pheochromocytoma is mandatory, although such a tumor is found in<2% of patients with paroxysmal hypertension. Catecholamine studies are usually normal but can be mildly abnormal either during or even between paroxysms, reflecting activation of the sympathetic nervous system.6
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 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.
table 1 : 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
to reduce BP variability. 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.
Contrary to widespread belief, studies consistently show
that β-blocker monotherapy does not reduce BP reactivity to
stressors.7 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.
Similarly, α-blocker monotherapy blocks the increase in
peripheral resistance, but BP reactivity is unaltered due to an increase instead in cardiac output. 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.8
approaCH to DrUG tHerapy for bpLabiLity
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, ARBS or diuretics, the mainstays of treatment of sustained hypertension
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. 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.9,10 Alternatively, two separate agents, a β-blocker, preferably one whose β-blocking effect is not greatly affected by hepatic
metabolism (e.g., atenolol, nadolol, bisoprolol, betaxolol, or
nebivolol), combined with an α-blocker, such as prazosin,
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.
table 2 : suggested indications and regimens for pharmacologic treatment of Labile forms of Hypertension 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 (e.g., 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 (e.g., oral clonidine ) and ⁄or anxiolytic Or oral α-blocker + β-blocker with fairly rapid onset (e.g., 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 (SSRI 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
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
LabiLe Hypertension (inCLUDinG preproC-eDUraL 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, e.g., systolic readings >180mm 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 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.
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 aβ-blocker (any standard β-blocker given in combination with an α-blocker,
such as prazosin (2.5-5mg once or twice daily), 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. 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 2).
aCUte ManaGeMent of HypertensiVe par-oxysMs: pHarMaCoLoGiC anD psyCHopHar-MaCoLoGiC 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 to80 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 aβ-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). 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 of0.1 mg or 0.2 mg and repeated at 6- to 8-hourintervals.
CHroniC preVentiVe ManaGeMent: pHar-MaCoLoGiC anD psyCHopHarpHar-MaCoLoGiC aGents
Chronic therapy with an α-blocker combined with
aβ-blocker given orally has been reported to reduce severity of BP elevation during paroxysms. 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 panicdisorder.11
For patients with mild or infrequent paroxysms, acute
management with alprazolam or clonidine and⁄ or maintenance
therapy with combined a- and b-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. 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 VULner-abLe UnDerLyinG ConDitions
Treatment of the labile component of BP inpatients with underlying comorbidities (Table 1) 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 b-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 hypertensions 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.
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