Labile hypertension

INTRODUCTION — Blood pressure normally varies in response to physical activity, experienced emotion, and many other factors such as posture, respiratory cycle, time of day, food ingestion, salt intake, caffeine intake, use of nicotine, alcohol ingestion, sleep deprivation, and other factors.

Beyond these routine, nearly constant fluctuations of blood pressure is an observed clinical phenomenon characterized by marked elevations in blood pressure that are recurrent, sudden, and transient. These episodic elevations in blood pressure create confusion among clinicians and patients as to presence or absence of hypertension, the severity of the hypertension, the cause of the acute elevations, the need for treatment, and the selection of an appropriate drug regimen.

The terms "labile hypertension" and "paroxysmal hypertension" are often used interchangeably to describe these episodic and marked elevations in blood pressure [1]. However, the clinical presentation and management of these two entities differ substantially from each other. Labile hypertension is presented in this topic. Paroxysmal hypertension is discussed separately. (See "Paroxysmal hypertension (pseudopheochromocytoma)".)

Other issues related to clinically important variations in blood pressure, including white coat hypertension, masked hypertension, and postural blood pressure alterations are presented in other topics:

●(See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".)

●(See "Mechanisms, causes, and evaluation of orthostatic hypotension".)

●(See "Treatment of orthostatic and postprandial hypotension".)

DEFINITION — The term "labile hypertension" is widely used as a clinical diagnosis in patients with considerable variation in their blood pressure readings (ie, variability in blood pressure that is considered more than normal). However, there are no specific numerical criteria.

We consider patients to have labile hypertension if they experience recurrent and substantial transient elevations in blood pressure (frequently, but not always, to readings above 160 mmHg). Patients usually associate their elevated readings with stress and emotional distress, although elevations can also occur without provocation. Blood pressure elevation is usually asymptomatic but can be associated with symptoms such as palpitations, flushing, or headache.

Although variation in blood pressure and transient blood pressure elevation in moments of pronounced stress are normal phenomena, labile hypertension connotes elevation that is more frequent, more severe, and/or longer lasting than that which is commonly seen in most patients.

PATHOGENESIS — The absence of a detailed definition for "labile hypertension" has hampered research concerning its pathogenesis. Most studies directed at the variable component of blood pressure have focused upon phenomena that bear relevance to lability of blood pressure, including "blood pressure variability" (BPV) and blood pressure reactivity, and have documented the role of the sympathetic nervous system [2,3]. Sympathetic nervous system involvement in blood pressure reactivity to environmental stressors is particularly relevant to the clinical entity of labile hypertension.

The mechanisms underlying the sympathetic nervous system activation are unclear. Both genetic and environmental factors are likely to be determinants of the magnitude and the duration of the sympathetic activation. The magnitude of the hemodynamic response to sympathetic activation, the amount of stress, the emotional responsiveness to stress, and many other factors also are involved. Reduced baroreceptor function, often seen with increasing age, can also be a factor.

EPIDEMIOLOGY — The phenomenon of labile hypertension is widespread and is a common reason for specialist referral. However, because of the absence of defined criteria for "labile hypertension" in terms of frequency, severity, or duration of blood pressure elevation, there are no data as to its prevalence. The diagnosis remains limited to clinical impression. (See 'Diagnosis' below.)

In our experience, labile hypertension is more likely to occur among anxious patients and patients under acute stress. It is also often identified among patients who frequently self-monitor their blood pressure (ie, multiple times daily) or who tend to measure their blood pressure specifically when they believe it is elevated. Labile hypertension commonly leads to adjustment and readjustment of antihypertensive medications, which can incur the risk of overmedication and possible hypotension.

The effect of labile hypertension on cardiovascular risk likely depends upon factors such as the frequency, severity, and duration of blood pressure elevations. Studies examining this have not been performed beyond assessing the measurable effect of the recurrent elevations on the average blood pressure observed on ambulatory monitoring.

CLINICAL PRESENTATION — Patients with labile hypertension experience recurrent episodes of transient blood pressure elevation. In some, blood pressure elevation can be substantial. Elevations are typically asymptomatic, although in some patients they can be accompanied by symptoms such as headache, palpitations, or flushing. They tend to occur at times of stress and usually are readily attributed to stress by both patient and clinician. However, they can also occur in the absence of overt stress.

Frequent blood pressure self-measurement may capture normal physiologic variations in blood pressure and produce a clinical impression of labile hypertension. Many patients tend to measure their blood pressure when they feel anxious or stressed, identifying these moments of normal physiologic blood pressure elevation. In others, elevated readings are provoked by anxiety about the blood pressure self-measurement (ie, alerting phenomenon). In these instances, increasing antihypertensive drug therapy is unnecessary and incurs the risk of hypotension.

DIAGNOSIS — Labile hypertension is a clinical diagnosis made in patients who display, in the judgment of the clinician, excessive variability in blood pressure, with episodes of substantially increased blood pressure. (See 'Clinical presentation' above.)

There are no widely accepted criteria for the diagnosis. Blood pressure fluctuation occurs in all individuals, and some degree of elevation at the time of considerable stress clearly can be considered normal. In addition, thresholds distinguishing "normal" from "abnormal" variability do not exist. However, the frequent occurrence of marked blood pressure elevation to levels that differ substantially from an individual's usual baseline readings is consistent with a clinical diagnosis of labile hypertension.

Differential diagnosis — In addition to labile hypertension, the following diagnoses should be considered among patients presenting with prominent episodic blood pressure elevations.

Pheochromocytoma — A screening test to exclude the diagnosis of pheochromocytoma should be performed in all patients who experience episodes of severe blood pressure elevations, particularly if unprovoked. Assays of plasma or urine catecholamines or their metabolites are diagnostic in 95 percent of patients with symptoms, and the high sensitivity of the plasma metanephrine assay is also documented [4-6]. False-positive tests, characterized by mild elevations of catecholamines or metanephrines, are relatively common [7]. Although there is still uncertainty as to the "best" test [4,5,8], patients with a pheochromocytoma have results that are usually profoundly, rather than mildly, abnormal. (See "Clinical presentation and diagnosis of pheochromocytoma".)

Paroxysmal hypertension (pseudopheochromocytoma) — Patients with pseudopheochromocytoma typically present with abrupt, often severe elevation of blood pressure accompanied by an equally abrupt onset of distressing physical symptoms, such as headache, chest pain, dizziness, nausea, palpitations, flushing, and diaphoresis. Unlike labile hypertension, attacks typically are unprovoked and "out of the blue," and most patients insist that the episodes are not related to stress. They are not triggered by anxiety, although fear does occur as a consequence of the frightening physical symptoms. Between episodes, the blood pressure is often normal but can be elevated in patients who also have underlying sustained hypertension. Patients who present with paroxysmal hypertension should always be tested for pheochromocytoma. (See "Paroxysmal hypertension (pseudopheochromocytoma)".)

Panic disorder — Panic disorder is characterized by episodes of fear or panic that are commonly associated with physical symptoms such as chest pain, headache, palpitations, flushing, and dizziness, along with some degree of blood pressure elevation [9-13]. Panic disorder differs from labile hypertension with regard to the greater severity of emotional distress and the prominence of physical symptoms. Blood pressure elevation tends to be milder. Patients primarily complain about anxiety or panic rather than about the accompanying, more incidental, blood pressure elevation. Treatment should be directed primarily at the panic disorder. (See "Panic disorder in adults: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical Manifestations'.)

Other causes of episodic blood pressure elevations — Many additional disorders, listed below, may present with pronounced, episodic elevations in blood pressure. Although such disorders must be considered, they usually present with clinical features that are typical of those disorders [14]:

●Hyperthyroidism. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)

●Cluster or migraine headaches. (See "Cluster headache: Epidemiology, clinical features, and diagnosis" and "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)

●Hypertensive encephalopathy. (See "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults".)

●Acute coronary syndrome.

●Renovascular hypertension. (See "Evaluation of secondary hypertension".)

●Central nervous system lesions, such as stroke, tumor, hemorrhage, compression of lateral medulla, and trauma. (See "Clinical diagnosis of stroke subtypes".)

●Seizure disorder.

●Carcinoid. (See "Clinical features of carcinoid syndrome".)

●Drugs – Cocaine, lysergic acid diethylamide, amphetamine, and clozapine [15].

●Tyrosine ingestion in patients who are taking a monoamine oxidase inhibitor.

●Baroreflex failure, which is characterized by marked and frequent fluctuations in blood pressure [16]. In contrast to labile hypertension, baroreflex failure is characterized by both hypertensive and hypotensive readings, as well as symptomatic orthostatic hypotension. It is caused by hypofunctioning of the baroreflexes that normally buffer blood pressure fluctuations. The disorder is usually a result of injury to carotid baroreceptors, with most patients reporting a history of neck irradiation or surgery.

●Factitious hypertension.

●Anxiety-induced hyperventilation [17].

MANAGEMENT

Treatment of labile hypertension — Research concerning the treatment of labile hypertension is largely lacking, and there are no randomized trials to help guide therapeutic decisions.

Two considerations in its management are:

●Choice of therapy for the underlying chronic hypertension (see 'Chronic therapy' below)

●Treatment of acute episodes of blood pressure elevation (see 'Acute therapy of episodic blood pressure elevation' below)

Chronic therapy — In patients with labile hypertension, clinicians must decide whether to treat chronically with antihypertensive therapy and, if so, whether to use drugs that are preferred as first-step agents (ie, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], diuretics, and calcium channel blockers) or drugs that target sympathetically mediated mechanisms (ie, beta- and alpha-adrenergic inhibitors). (See "Choice of drug therapy in primary (essential) hypertension".)

Our approach to patients with labile hypertension is as follows:

●Patients with uncontrolled hypertension and labile hypertension – In patients with labile hypertension who also have sustained blood pressure elevation (ie, uncontrolled hypertension) despite treatment with recommended first-step antihypertensive agents (ACE inhibitor or ARB, calcium channel blocker, diuretic), we suggest adding a combination of a beta blocker and alpha blocker. We typically prescribe this combination as two separate pills in order to permit separate titration of alpha and beta blocking effects. We typically prefer a nonlipophilic beta blocker (eg, bisoprolol, betaxolol), since they achieve reliable blood levels and do not penetrate the blood-brain barrier, rather than a lipophilic beta blocker (eg, metoprolol) [18]. We usually prescribe a 1 mg tablet of the alpha blocker doxazosin daily; in some patients, one-half of a tablet is sufficient. Drugs that combine beta and alpha blocking effects (eg, carvedilol, labetalol) are an alternative, although there is considerably more interindividual variability in plasma levels achieved. If blood pressure comes under control, reduction or elimination of other antihypertensive medications is then an option.

●Patients with controlled hypertension and labile episodes – In patients with labile blood pressure elevations whose usual, average blood pressure is well controlled by preferred, first-step antihypertensive therapy (eg, an ACE inhibitor and a calcium channel blocker) and if blood pressure elevations are not severe or frequent, we usually do not add beta and alpha blockers to their existing regimen or substitute beta and alpha blockers for their current drugs. Rather, we treat at the time of acute episodes, if necessary. However, if episodes are frequent or severe, an alternative approach is to substitute a beta blocker, or the combination of an alpha and beta blocker, for one or more current drugs to maintain blood pressure control and mitigate episodic elevation. (See 'Acute therapy of episodic blood pressure elevation' below.)

●In untreated patients with labile blood pressure elevations who are otherwise normotensive, we do not treat with chronic antihypertensive therapy unless elevations are experienced with considerable frequency. Rather, we treat at the time of acute episodes, if necessary. (See 'Acute therapy of episodic blood pressure elevation' below.)

The approach outlined above is based upon our clinical experience and our understanding of the pathophysiology of labile hypertension. There are no published treatment trials. (See 'Pathogenesis' above.)

Because of the central pathogenetic role of the kidneys in most patients with sustained essential hypertension, drugs such as diuretics, ACE inhibitors, and ARBs that target nephrogenic mechanisms of hypertension are typically employed and are effective in most patients. However, blood pressure variability (BPV) and reactivity, and rapid changes in heart rate and blood pressure, are largely sympathetically mediated. Thus, a regimen that antagonizes sympathetically mediated blood pressure elevation would be expected to be more effective in patients with labile hypertension than one directed at renal mechanisms. Consistent with this understanding, studies show that ACE inhibitors and diuretics do not reduce sympathetically mediated blood pressure reactivity to stressors [19-21].

In addition, neither beta blocker monotherapy nor alpha blocker monotherapy reduces blood pressure reactivity to stressors [22]. However, the combination of the two, which opposes sympathetically mediated increases in both peripheral resistance and cardiac output, does reduce blood pressure reactivity, suggesting that such a regimen could be superior to other regimens in treating hypertension characterized by an important labile component [23-25].

Central sympathetic agonists, such as clonidine, also mitigate sympathetically mediated blood pressure elevation, but their use on a chronic basis is discouraged due to prominent side effects.

Acute therapy of episodic blood pressure elevation — There are no published studies concerning the acute treatment of episodes of blood pressure elevation in patients with labile hypertension. The following treatment approach is based upon our understanding of the pathophysiology, drug mechanisms and pharmacokinetics, and clinical experience.

Although pharmacologic treatment is sometimes provided, all patients with labile hypertension should be counseled in the following way:

●Reassure patients that, in the absence of a high-risk comorbidity, transient, non-extreme blood pressure elevation is extremely unlikely to cause a stroke or other sudden cardiovascular event.

●Instruct patients that it is normal for blood pressure to increase in moments of anxiety.

●Discourage patients from repeatedly checking their blood pressure at moments of anxiety.

●Instruct patients to sit quietly for five minutes after putting on the cuff before self-measuring their blood pressure, in accord with standard guidelines pertaining to blood pressure measurement. A lower reading will often be obtained, which will reduce the patient's anxiety as well as the need for acute intervention.

Episodic blood pressure elevation in labile hypertension generally is not considered a "hypertensive urgency." However, we often advise treatment if blood pressure elevation is symptomatic, produces substantial psychologic distress, is severe (eg, systolic blood pressure ≥180 or 200 mmHg and/or diastolic blood pressure ≥110 or 120 mmHg), or confers increased risk due to comorbidities (eg, preexisting coronary heart disease, history of hemorrhagic stroke). We generally provide patients with a small supply of medication for use as needed, individualizing the decision to treat episodes based upon factors such as the blood pressure level, age, cardiovascular risk factors, and risk of complications due to comorbidities.

Conversely, we do not treat episodic blood pressure elevations that are not severe, are asymptomatic, and do not result in substantial psychologic distress.

When we do treat, we prefer agents with a relatively rapid onset and short duration of action, such as short-acting antihypertensive agents and/or benzodiazepines. Treatment with antihypertensive agents incurs a risk of symptomatic hypotension. Treatment with benzodiazepines incurs the risk of sedation, and frequent use may result in dependency.

The antihypertensive agent that we usually prescribe is the alpha and beta blocker labetalol (typically 100 or 200 mg orally) because of its rapid onset of action (1 to 1.5 hours); clonidine (0.1 mg orally) is an alternative (see "Management of severe asymptomatic hypertension (hypertensive urgencies) in adults", section on 'Treatment'). Among the benzodiazepines, we prefer alprazolam (usual dose, 0.25 mg orally), which has the advantages of rapid onset (30 to 45 minutes) and short duration of action (4 to 6 hours).

No studies have been performed to compare the efficacy of an antihypertensive agent versus a benzodiazepine. A benzodiazepine seems preferable in patients who are anxious during episodes or have milder blood pressure elevations. In other patients, either agent can be employed (or both), depending upon clinician and patient preference.

In selected patients with infrequent episodes of blood pressure elevation and no history of substance use disorder, consumption of an alcoholic beverage can provide an alternative to pharmacologic treatment with an antihypertensive agent or benzodiazepine. In the author's clinical experience, it usually relaxes patients and lowers blood pressure, consistent with studies that demonstrate the short-term, blood pressure-lowering effect of alcohol ingestion, an effect that stands in contrast to the long-term blood pressure elevation associated with heavy, chronic alcohol consumption [26,27]. Like benzodiazepines, alcohol ingestion can produce sedation and may result in alcohol use disorder.

Preprocedural blood pressure elevation — Many patients experience a marked increase in blood pressure in anticipation of a medical or surgical procedure, sometimes necessitating its postponement. Treatment or prevention of this increase in blood pressure may be needed to permit a planned procedure to be performed; in most cases postponement of the procedure can be avoided. Management of intraoperative blood pressure elevation is presented separately. (See "Anesthesia for patients with hypertension", section on 'Management in the immediate preoperative period'.)

We typically manage patients with severe blood pressure elevation arising prior to a medical procedure with an oral anxiolytic agent (eg, 0.25 or 0.5 mg of alprazolam or 0.5 or 1 mg of lorazepam).

Alternatively, we prescribe the combination of an alpha and beta blocker (labetalol 100 to 200 mg orally) or clonidine (0.1 or 0.2 mg orally) one to two hours prior to preparation for the procedure. Although data are scarce, these agents often mitigate adrenergically driven transient blood pressure elevation. Another option is intravenous treatment with labetalol or an anxiolytic agent immediately prior to the procedure.

SUMMARY AND RECOMMENDATIONS

●The term "labile hypertension" is widely used as a clinical diagnosis in patients with considerable variation in their blood pressure readings (ie, variability in blood pressure that is considered more than normal). However, there are no specific numerical criteria. We consider patients to have labile hypertension if they experience recurrent and substantial transient elevations in blood pressure (frequently, but not always, to systolic readings above 160 mmHg). (See 'Definition' above.)

●Sympathetic nervous system involvement in blood pressure reactivity to environmental stressors is thought to be particularly relevant to the clinical entity of labile hypertension. (See 'Pathogenesis' above.)

●The phenomenon of labile hypertension is widespread and is a common reason for specialist referral. However, because of the absence of defined criteria for "labile hypertension," there are no data as to its prevalence. In our experience, labile hypertension is more likely to occur among anxious patients and patients under acute stress. It is also often identified among patients who frequently self-monitor their blood pressure (ie, multiple times daily) or who tend to measure their blood pressure specifically when they believe it is elevated. (See 'Epidemiology' above.)

●Patients with labile hypertension experience recurrent episodes of transient blood pressure elevation. In some, blood pressure elevation can be substantial. Elevations are typically asymptomatic, although in some patients they can be accompanied by symptoms such as headache, palpitations, or flushing. They tend to occur at times of stress and usually are readily attributed to stress by both patient and clinician. (See 'Clinical presentation' above.)

●Labile hypertension is a clinical diagnosis made in patients who display, in the judgment of the clinician, excessive variability in blood pressure, with episodes of substantially increased blood pressure. There are no widely accepted criteria for the diagnosis. (See 'Diagnosis' above.)

●In addition to labile hypertension, diagnoses that should be considered among patients presenting with prominent episodic blood pressure elevations include pheochromocytoma, paroxysmal hypertension (pseudopheochromocytoma), and panic disorder, among others. (See 'Differential diagnosis' above.)

●Two considerations in the management of labile hypertension are the choice of therapy for the underlying chronic hypertension and treatment of acute episodes of blood pressure elevation (see 'Treatment of labile hypertension' above):

•Our approach to chronic therapy in patients with labile hypertension depends upon the patient's usual, average blood pressure, as follows (see 'Chronic therapy' above):

-In patients with labile hypertension who also have sustained blood pressure elevation (ie, uncontrolled hypertension) despite treatment with recommended first-step antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs], calcium channel blockers, diuretics), we suggest adding a combination of a beta blocker and alpha blocker (Grade 2C). We typically prescribe this combination as two separate pills in order to permit separate titration of alpha and beta blocking effects.

-In patients with labile blood pressure elevations whose usual, average blood pressure is well controlled by preferred, first-step antihypertensive therapy, we usually do not add beta and alpha blockers to their existing regimen or substitute beta and alpha blockers for their current drugs. Rather, we treat at the time of acute episodes, if necessary. Similarly, in untreated patients with labile blood pressure elevations who are otherwise normotensive, we do not treat with chronic antihypertensive therapy unless elevations are experienced with considerable frequency, severity, or symptoms. Rather, we treat at the time of acute episodes, if necessary.

•Our approach to acute therapy of episodic blood pressure elevation in patients with labile hypertension is as follows (see 'Acute therapy of episodic blood pressure elevation' above):

-Provide counseling and reassurance, including the following measures: reassure patients that, in the absence of a high-risk comorbidity, transient, non-extreme blood pressure elevation is extremely unlikely to cause a stroke or other sudden cardiovascular event; instruct patients that it is normal for blood pressure to increase in moments of anxiety; and discourage patients from repeatedly checking their blood pressure at moments of anxiety.

-We generally avoid treating acute episodes with pharmacologic therapy. However, in patients whose acute, episodic blood pressure elevations are associated with prominent symptoms, produce substantial psychologic distress, or are severe (eg, systolic blood pressure ≥180 or 200 mmHg and/or diastolic blood pressure ≥110 or 120 mmHg), and in patients who are at risk for complications from pronounced blood pressure elevation (eg, known aneurysm, prior aortic dissection, symptomatic coronary disease), we suggest acute treatment to lower the blood pressure (Grade 2C). Treatment often consists of a short-acting benzodiazepine (eg, alprazolam) and/or a short-acting antihypertensive agent (eg, oral labetalol or clonidine). Typically, we provide such patients with a small supply of medication to use at home and instructions for their use.