Orthostatic hypotension – a practical approach to investigation and management

Abstract

The maintenance of blood pressure upon the assumption of upright posture depends on rapid cardiovascular adaptations driven primarily by the autonomic nervous system. Failure of these compensatory mechanisms can result in orthostatic hypotension (OH), defined as sustained reduction in systolic blood pressure >20 mmHg or diastolic blood pressure >10 mmHg within 3 minutes of standing or >60° head-up tilt. OH is a common finding, particularly in elderly populations, associated with cardiovascular and cerebrovascular morbidity and mortality. Therefore, it is important to identify OH in the clinical setting. The detection of OH requires blood pressure measurements in the supine and standing positions. A more practical approach in clinics may be measurement of seated and standing blood pressure, but this can produce smaller depressor responses due to reduced gravitational stress. Heart rate responses to standing should be concomitantly measured to assess integrity of baroreflex function. Patients with OH can present with symptoms of cerebral hypoperfusion on standing predisposing to syncope and falls; however, many patients are asymptomatic. Once the diagnosis of OH is established, it is important to document potentially deleterious medications and comorbidities and to assess for neurogenic autonomic impairment to establish underlying causes. Treatment should be initiated in a structured and stepwise approach starting with non-pharmacological interventions (e.g. lifestyle modifications and physical counter-maneuvers), and adding pharmacological interventions as needed in patients with severe OH (e.g. midodrine, droxidopa, fludrocortisone). The treatment goal in OH should be to improve symptoms and functional status, and not to target arbitrary blood pressure values.

Introduction

The assumption of upright posture induces gravitational blood pooling in the lower extremities to reduce venous return to the heart. In healthy individuals, cardiac output and blood pressure (BP) are maintained upon standing due to activation of autonomic neural and hormonal reflex mechanisms that compensate for impaired venous return. Failure of these compensatory mechanisms can result in orthostatic hypotension (OH), or low BP upon standing (Figure 1). OH is defined as a sustained reduction of at least 20 mmHg in systolic BP or 10 mmHg in diastolic BP within 3 minutes of standing or >60° head-up tilt.¹ Patients with OH often experience symptoms of cerebral hypoperfusion including lightheadedness, dizziness, blurred vision, fatigue, and headache. The etiology of OH is multifactorial and can include non-neurogenic and neurogenic causes. OH can occur in otherwise healthy people when faced with severe hypovolemic or vasodilatory stress, although it is more common in people with some underlying neurovascular pathology. The incidence of OH increases with age affecting 5–16% of middle-aged and elderly community dwellers, and over 50% of elderly patients in nursing homes and geriatric wards.² OH contributes substantially to risk of falls, disability, and impaired quality of life.^2,3 The presence of OH is also associated with numerous comorbidities (e.g. hypertension, chronic kidney disease, cognitive impairment), and is an independent risk factor for cardiovascular, cerebrovascular, and all-cause morbidity and mortality.² Given the increasing aging population worldwide and potential impact of OH-related hospitalizations,³ it is critical to identify and treat this condition in clinical practice.

Figure 1.

Head-Up Tilt Table test in a patient with orthostatic hypotension showing instantaneous heart rate (top) and blood pressure trace (bottom). At baseline, the heart rate is about 75 bpm, and the blood pressure is about 120/65 mmHg. Immediately with the onset of head-up tilt at 70 degrees (vertical line), the systolic blood pressure and diastolic blood pressure both fall, with a narrowing of the pulse pressure (bottom). There is also a small, but blunted, increase in heart rate (top).

Clinical Assessment of Orthostatic Hypotension

Initial assessment for OH should include BP and heart rate measurements after the patient has been supine (>5 minutes), and again after 1 and 3 minutes of standing.¹ Passive head-up tilt table testing to an angle >60° can also be used to detect OH, but can produce false positives particularly in elderly patients due to vasovagal reactions. In clinic settings, BP is often only measured in the seated position. While due to practical limitations, this results in OH being undetected in a majority of patients. An alternative approach is measurement of BP changes from the seated to standing position, which does not require a bed and thus may be more easily performed in clinics.⁴ Since this sit-to-stand testing produces smaller depressor responses due to reduced gravitational stress, a decrease in systolic BP >15 mmHg or diastolic BP >7 mmHg should be used as the diagnostic threshold.⁴ OH detection may require measurement of BP over several days. In these cases, patients should maintain a BP diary with recording of orthostatic vitals at different times of the day and after stressors (e.g. medications, meals, exercise). The most sensitive and consistent measurements are usually obtained early in the morning when patients are most symptomatic due to nocturnal pressure natriuresis. Asymptomatic OH with intact cerebral autoregulation is a common occurrence; however, these patients should still be considered at risk for falls and syncope. Finally, ambulatory BP monitoring may be useful to detect OH and related comorbidities (e.g. supine hypertension, postprandial hypotension), but only in patients able to record postural changes.

Once the diagnosis of OH has been established, a detailed history and physical examination should be performed to document medications, comorbidities, and symptoms. Idiopathic OH is common with advanced age due to arterial stiffness and reductions in baroreceptor reflex sensitivity, muscle pump activity, and α1-adrenergic vasoconstriction.^1,2 Additional causes of OH include side effects of medications, anemia, volume loss (e.g. dehydration, severe vomiting or diarrhea), physical deconditioning, benign infections (e.g. urinary tract infection), and systemic diseases involving autonomic nerves (e.g. amyloidosis, diabetes mellitus, Parkinson’s disease).^1,2 Exaggerated orthostatic tachycardia may suggest volume depletion or these other secondary causes. Patients with acute or subacute onset of OH and severe presyncopal symptoms should be evaluated for autoimmune or paraneoplastic syndromes. In rare cases, patients with OH have a primary neurodegenerative disorder (e.g. Multiple System Atrophy, Pure Autonomic Failure, Lewy Body Dementia). These patients often present with severe OH and lack of compensatory heart rate increase with standing (<15 bpm). Standardized autonomic function testing is recommended to confirm diagnosis of primary neurodegenerative disorders associated with OH.⁵

Treatment of Orthostatic Hypotension

Treatment of OH should involve a structured stepwise approach, which may include both non-pharmacological and pharmacological interventions (Table 1).² The treatment goal for OH patients is to improve symptoms and functional status, and not to achieve target BP values. The need for treatment should be determined on an individual basis with consideration given for OH severity and presence of comorbidities. Patients should maintain a diary of symptoms and orthostatic vitals to help assess treatment efficacy. There is limited evidence to guide OH treatment, and recommendations are often based on small cross-sectional trials with acute interventions in neurogenic OH.⁵ Potential limitations are that these previous studies may not reflect the more common idiopathic OH, have not been validated in large controlled clinical trials, and have not evaluated long-term treatment efficacy.

Table 1.

Treatment Approaches in Orthostatic Hypotension

Non-Pharmacological Interventions:Reduce Venous Pooling Physical Counter-Maneuvers (e.g. standing with legs crossed, squatting, active tensing of leg muscles, breathing-related maneuvers to increase inspiratory resistance, and avoiding getting up too quickly or standing motionless,) Compression stockings or abdominal binders (30–40 mmHg) Increase Central Volume Increase sodium intake (6–9 grams/day) Increase water intake (2–3 liters/day) Raise head of bed during night to prevent pressure natriuresis (6–9 inches) Other Lifestyle Modifications Eat small frequent meals Physical activity such as water exercise, recumbent bicycling, or rowing Avoid alcohol consumption Avoid situations that increase core body temperature such as prolonged hot showers

Pharmacological Interventions:Increase Intravascular Volume Fludrocortisone (0.1–0.2 mg/day, PO) Increase Vascular Resistance Midodrine (2.5–10 mg, PO) Droxidopa (100–600 mg, PO) Atomoxetine (18 mg, PO) Yohimbine (5.4 mg, PO) Pyridostigmine (60 mg, PO) Octreotide (12.5–25 μg, subcutaneous) Pseudoephedrine (30 mg, PO) Combination Therapy Fludrocortisone (0.1–0.2 mg/day, PO) and midodrine (5–10 mg, PO) Ergotamine (1 mg, PO) and caffeine (100 mg, PO) Midodrine (5–10 mg, PO) or pseudoephedrine (30 mg, PO) and water (500 ml)

Non-Pharmacological

Medications known to aggravate OH should be discontinued when appropriate. Since OH patients are preload dependent, nitrates and diuretics should be stopped. Other medications that may worsen or contribute to OH can include dopaminergic drugs, anticholinergics, tricyclic antidepressants, α1-blockers (e.g. tamsulosin), and antihypertensives.² Discontinuation of antihypertensive medications, however, should be approached with caution for several reasons. First, while a relationship has been established with use of sympatholytics (e.g. α and β-adrenergic antagonists), the association of other antihypertensive medications with OH is uncertain. Second, studies have shown an increased fall risk in elderly patients with uncontrolled hypertension. Finally, withholding antihypertensives can worsen OH by promoting pressure diuresis. Therefore, judicious use of short-acting antihypertensives is recommended in patients with OH with close monitoring of orthostatic vital signs and symptoms.

Non-pharmacological approaches should then be initiated as first line treatment and include physical counter-maneuvers and lifestyle modifications (Table 1). Patients should be educated on use of physical counter-maneuvers to reduce venous pooling such as changing positions gradually, leg crossing, squatting, and active tensing of leg muscles. Breathing-related counter-maneuvers may also benefit cardiovascular stability in OH patients through actions on the respiratory pump to facilitate venous return to the heart from the abdomen and upper extremities. These respiratory maneuvers include slow deep breathing and creation of inspiratory resistance through use of an impedance threshold device, inspiratory sniffing, or inspiration through pursed lips. Custom-fitted thigh or waist high compression stockings and abdominal binders also reduce venous pooling to improve orthostatic tolerance, when graded pressures of at least 30–40 mmHg are applied. To improve central volume, increased ingestion of sodium (6–10 grams/day) and water (2–3 liters/day) is recommended. Rapid ingestion of plain water also serves as a rescue measure in OH (500 ml ingested within 2–3 minutes), by eliciting a sympathetic-nervous-system-mediated BP elevation for 60–90 minutes. In patients with supine hypertension, elevating the head of the bed (6–9 inches) reduces nocturnal pressure natriuresis to attenuate morning volume depletion. In terms of lifestyle modifications (Table 1), patients should engage in physical activity as tolerated to avoid deconditioning, avoid alcohol, eat small frequent meals to prevent postprandial hypotension, and avoid situations that increase core body temperature to elicit peripheral vasodilation. These non-pharmacological approaches are cost-effective and can be safely combined with pharmacological interventions; however, there is often poor compliance.

Pharmacological

The addition of pharmacological interventions may be necessitated in patients with severe OH, when non-pharmacological approaches are insufficient to prevent presyncopal symptoms (Table 1).^2,5 Pharmacological treatment is unlikely to improve outcomes in asymptomatic patients. The presence of hypertension and underlying cardiovascular disease must also be considered.

In patients with hypertension or cardiovascular disease, short-acting pressor agents to increase vascular resistance are preferred. Midodrine is FDA-approved for symptomatic OH and improves orthostatic tolerance in controlled clinical trials.⁵ Midodrine is a prodrug whose metabolite desglymidodrine stimulates α1-adrenoreceptors in blood vessels to increase vascular resistance. Since midodrine has a short half-life, it can be given as needed 30–45 minutes prior to upright activities (2.5–10.0 mg PO Q4H x3). Caution is recommended in patients with congestive heart failure and renal failure. Side effects include piloerection, scalp pruritus, and urinary retention. Patients should avoid the supine position within 5 hours of taking midodrine due to the risk of supine hypertension (so it should not be dosed within 4–5 hours of bedtime). Nominal dosing times are 8am, 12pm, and 4pm.

More recently, the FDA approved droxidopa for neurogenic OH treatment in the United States (not available in Canada). Droxidopa is a synthetic prodrug that is converted to norepinephrine in the brain and peripheral tissues. Circulating norepinephrine levels are maximally increased at 6 hours post droxidopa, with persistent elevation for 46 hours. Droxidopa is well tolerated and improves orthostatic tolerance in controlled trials in neurogenic OH (100–600 mg PO, TID). Similar to midodrine, droxidopa should not be taken within 5 hours of bedtime. Caution is recommended in patients with congestive heart failure and chronic renal failure and side effects include headache, dizziness, nausea, and fatigue.

In patients without hypertension or heart failure, fludrocortisone (0.1–0.2 mg/day) is considered first line pharmacotherapy. Fludrocortisone acts at renal mineralocorticoid receptors to promote sodium and water retention and thus increase intravascular volume. Long-term BP effects of fludrocortisone, however, are attributed to enhanced blood vessel sensitivity to pressor hormones such as norepinephrine and angiotensin II. Patients should be monitored for headaches, volume overload, and hypokalemia. Chronic fludrocortisone can also exacerbate supine hypertension and contribute to end-organ damage.

Other medications have shown treatment efficacy in neurogenic OH including pseudoephedrine, atomoxetine (norepinephrine reuptake inhibitor), yohimbine (α2-adrenergic receptor antagonist), pyridostigmine (cholinesterase inhibitor), and octreotide (somatostatin analog) [Table 1]. Patients refractory to individual treatments may benefit from combination therapy including fludrocortisone plus midodrine, ergotamine plus caffeine, midodrine or pseudoephedrine plus water bolus, and yohimbine plus atomoxetine (Table 1). If patients are unresponsive to these treatment options, referral to a specialized autonomic center may be necessary.