Assessment and Management of Neurogenic Orthostatic Hypotension (nOH) and Postural Orthostatic Tachycardia Syndrome (POTS)

The central theme of neurogenic orthostatic hypotension (nOH) and postural orthostatic tachycardia syndrome (POTS) is that orthostatic changes in heart rate (HR) and blood pressure (BP) are fundamental elements of the conditions, their evaluation, and their treatment. As such, clinical assessments must involve hemodynamic measurements in response to a change in position, from supine to standing.

Upon standing, ~.5-1 L of venous fluid shifts from the thorax to the lower abdomen and lower extremities. Resulting venous return to the heart is reduced, and stroke volume and cardiac output decrease by 40% and 20%, respectively.^1,2 BP is usually maintained by compensatory increases in HR and systemic vascular resistance mediated by the sympathetic branch of the autonomic nervous system. Failure of the regulatory mechanisms that respond to these hemodynamic changes can lead to either nOH, as is seen in autonomic nervous system failure (“autonomic failure”), or excessive orthostatic tachycardia, as is seen in POTS.

Clinical Definitions

Orthostatic hypotension is defined as a BP drop ≥20/10 mmHg within 3 minutes of standing or head-up tilt (HUT)³ (Figure 1A). It is common, however, for BP to drop significantly more in patients with nOH. Patients with nOH will have a ∆HR/∆SBP ratio <.50 bpm/mmHg, indicative of an inadequate compensatory tachycardia relative to the BP drop.⁴ These criteria can help distinguish patients with nOH vs non-nOH in the clinic (sensitivity 91%; specificity 88% AUC = .96).⁴ Symptoms of OH may include lightheadedness, blurred vision, triangular “coat-hanger” neck pain, generalized weakness, lethargy, and syncope. Notably, some patients may experience minimal or no orthostatic symptoms despite profound BP changes.⁵

A POTS diagnosis requires a HR increase ≥30 bpm within 10 minutes of standing or HUT in the absence of OH (Figure 1B).⁶ Excessive orthostatic tachycardia must also be accompanied by chronic (≥3 months) orthostatic symptoms, many of which get better with recumbence. Symptoms may include palpitations, chest discomfort, lightheadedness, blurred vision, shortness of breath, and nausea. Despite symptoms of cerebral hypoperfusion, syncope occurs in only a minority of patients.⁷

All patients suspected of either nOH or POTS should have a careful review of their medication list for medications and supplements that can exacerbate OH or postural tachycardia. Confounding medications may prevent an accurate diagnosis of nOH or POTS, or conversely, lead to a false positive diagnosis. More details regarding medications and supplements are provided in the management sections below.

Orthostatic Vital Sign Assessment

Patient Setup

BP and HR are the minimum hemodynamic measurements required to diagnose nOH and POTS. Orthostatic vital signs should be performed on all patients with suspected autonomic impairment.

Traditional hemodynamic assessment: Automated oscillometric brachial cuff devices or a sphygmomanometer can be used to obtain hemodynamic measurements. To enhance accuracy, be sure to select the appropriate cuff size and instruct patients to wear loose-fitted clothing or a short-sleeve shirt. Apply cuff to either arm, roughly 1-2 cm above the elbow.

Beat-to-beat hemodynamic assessment: If available, beat-to-beat BP and HR monitoring should be employed to capture continuous hemodynamic changes. This can provide information about rapid and dynamic changes that can be missed with brachial cuffs alone. Place the finger cuff around the middle phalanx with the photosensors adjacent to the digital arteries (Figure 2). For optimal signals, ensure the patient’s hand is warm. A Finometer (Finapres Medical Systems), Task Force Monitor (CNS Systems), or Nexfin (Edwards Lifesciences) also provide non-invasive estimates of stroke volume, cardiac output, and systemic vascular resistance (Video 1).

Heart Rate and Blood Pressure Challenges

Supine measurements: Patients should remain supine for a minimum of 5 minutes for adequate cardiovascular stabilization and stable baseline measures. During stable baseline, measure and record ≥2 supine BP and HR measurements, approximately 1-2 minutes apart. These values can also identify supine hypertension in nOH patients (see section on Common Clinical Features of nOH).

Orthostatic measurements: After baseline, use a head-up tilt or an active stand test (described below) to obtain orthostatic vital signs. Instruct patients to maintain normal breathing and quiet standing for the duration of the orthostatic test.⁸ An upright duration of 10 minutes is required for the diagnosis of POTS, while 3-5 minutes might be enough for nOH. In the absence of continuous monitoring, systolic and diastolic pressures and HR should be obtained and recorded at minutes 1, 3, 5, and 10 post-stand. During continuous monitoring, changes in orthostatic BP and excessive orthostatic tachycardia meeting the diagnostic criteria for nOH or POTS must be sustained and persistent. To rule out transient hemodynamic changes using non-continuous brachial cuff measures, at least 2 consecutive measurements separated by 1 minute must meet the clinical diagnostic criteria (unless the patient is unable to stand any longer).

Head-up tilt: Following adequate supine rest, tilt patients upright to a 60^º-80^º angle from the horizontal (Video 1). For beat-to-beat BP monitoring, the hand should be maintained at heart level, or a height correction tool should be enabled.

Active stand test: After supine rest, instruct patients to stand up as quickly as possible. During this maneuver, patients should maintain normal breathing and avoid holding their breath. Older and/or frail patients may require assistance standing.

Ancillary Autonomic Testing

Valsalva maneuver: The Valsalva maneuver is one of the most informative ancillary autonomic tests if beat-to-beat hemodynamic monitoring is available. The Valsalva is a simple, 15-second, non-invasive maneuver that provides a comprehensive autonomic diagnostic assessment. A normal Valsalva response indicates intact afferent baroreceptor function, proper brainstem integration, and intact efferent sympathetic and parasympathetic outflow. This test also provides immediate insight into adrenergic and cardiovagal health. An intact adrenergic response is evident by the presence of late phase II and phase IV of the BP response (Figure 3B), whereas absence of these phases indicates adrenergic failure (Figure 3C). The Valsalva ratio, calculated from the HR response, provides a measure of cardiovagal activity.⁸

Application: Patients blow into a mouthpiece (Figure 3A) for 15 seconds, maintained at an expiratory pressure of 40 mmHg. The stress of this maneuver reliably drops BP, forcing the autonomic nervous system to respond. In effect, the Valsalva maneuver can be considered a cardiovascular autonomic stress test.

Orthostatic catecholamine measures: In patients with nOH, plasma norepinephrine (NE) levels fail to increase upon standing. In patients with central autonomic impairments, resting supine NE levels can be normal, whereas patients with peripheral lesions will tend to have reduced resting supine and upright NE levels.

POTS: Many POTS patients will have elevated orthostatic plasma NE levels >600 pg/ml while upright, and a minority might also have NE>1000 pg/ml while upright. This might become a treatment target. Yet some patients also show evidence of selective lower limb sympathetic denervation resulting in less NE release in the lower extremities.⁹ This is not recommended routinely, but it might be helpful in selected patients with POTS.⁶

Neurogenic Orthostatic Hypotension

Causes

nOH occurs due to impaired sympathetically-mediated vasoconstriction of skeletal muscle vasculature while in the upright position.³ The most common cause of nOH is a peripheral sensory and autonomic neuropathy secondary to long-standing and/or poorly controlled diabetes mellitus. nOH is also a cardinal feature of autonomic failure, a common feature of several neurodegenerative α-synucleinopathies including Parkinson’s disease, multiple system atrophy, Lewy body dementia, and pure autonomic failure. Other secondary causes of autonomic failure include autoimmune autonomic ganglionopathies, paraneoplastic syndrome, amyloidosis, and dopamine-β-hydroxylase deficiency.¹⁰

Common Clinical Features

Patients may complain of large BP swings that can abruptly change from abnormally high to normal or low (labile blood pressure). These BP changes are associated with a change in position, and as such, orthostatic vitals should be obtained. Complaints of abnormally high BP may be indicative of nOH complicated by supine hypertension (Figure 1A). Approximately 50% of patients with nOH have concomitant supine hypertension (140/90 mmHg),^11,12 which can be misdiagnosed as “plain hypertension” if original BPs were obtained in the supine position. Supine hypertension can worsen nocturia, and this can worsen OH and symptoms in the morning. Other clinical features of nOH may include bowel dysfunction (often severe constipation), bladder dysfunction (frequency, urgency, incomplete emptying), erectile dysfunction, impaired ability to sweat in the hands and feet, and rapid eye movement (REM) sleep behavior disorder.

Orthostatic symptoms: Due to the non-specific nature of symptoms (ie, lightheadedness, fatigue, pain, weakness, syncope), the diagnosis of nOH is often missed or delayed. Patients frequently seek medical attention due to syncopal/non-mechanical falls prior to proper diagnosis. A detailed symptom inquiry can help unmask nOH. nOH symptoms often occur in the upright position and resolve with recumbence, often occur first thing in the morning, and are often exacerbated by higher ambient temperatures, hot showers/bath, and following large meals.^13,14

Management

The initial approach to treatment is to withdraw drugs that may be exacerbating OH (Figure 4). Drugs that decrease cardiac pre-load such as diuretics and daytime nitrates are most problematic. Other medications that can worsen OH include  α-1-blockers (often prescribed for benign prostate hypertrophy (eg, tamsulosin) and tricyclic antidepressants.

Identifying supine hypertension is important, as this clinical feature can limit the degree of pharmacological intervention. In patients with supine hypertension, shorter acting pressor agents are preferred over longer acting medications. OH symptoms are the most debilitating symptoms of nOH, and are associated with increased fall risk, morbidity, and mortality. Non-pharmacological and pharmacological interventions are geared toward symptom improvement. All patients should be made aware of the non-pharmacological interventions (Table 1) aimed to increase intravascular volume and increase venous return to the heart.

Pharmacological treatment for nOH: To improve BP management and symptom mitigation, non-pharmacological and pharmacological interventions are frequently required (Table 2). Pharmacological therapies primarily act to: (1) improve vasoconstriction, or (2) increase intravascular volume.¹⁵ Midodrine, a peripheral α1-agonist pro-drug approved for symptomatic OH, promotes vasoconstriction and venoconstriction to facilitate an increase in stroke volume and subsequent increase in BP. Midodrine may be taken up to 3 times/day (ie, 8 am, noon, and 4 pm), but ideally not within 4h of the patient lying down. Due to its relatively short half-life (each dose works for about 4 hours) and duration of onset (30-45 minutes), midodrine can be titrated based on day-to-day activities and symptoms. Droxidopa, a prodrug of norepinephrine (NE), can be taken up to 3 times/day to increase circulating NE. Droxidopa is approved by the U.S. Food and Drug Administration (FDA) for treatment of nOH, but it is currently routinely unavailable in Canada and Europe for treatment of autonomic failure. Fludrocortisone, a mineralocorticoid receptor agonist, increases intravascular volume by promoting sodium and water reabsorption by the kidneys. Fludrocortisone also increases α-adrenoreceptor sensitivity to circulating catecholamines, and therefore can be used in combination with droxidopa or midodrine. Unlike droxidopa and midodrine, fludrocortisone has a much longer functional half-life. It should be taken routinely as scheduled, and not on an “as needed” basis. Fludrocortisone should be used with caution (or not at all) in patients with congestive heart failure and severe hypertension. Other pharmacological therapies may include pseudoephedrine, atomoxetine, pyridostigmine, caffeine, and octreotide.

Nearly all anti-hypotensive agents can cause or exacerbate supine hypertension. This could, in turn, worsen renal and cardiovascular outcomes, and exacerbate morning OH. Short-acting pressor agents should not be taken within 5 hours of bedtime or prior to being supine for any significant period of time. Ongoing assessment of supine hypertension is recommended, and adjustments to the daytime medication or the use of short-acting antihypertensives at night are sometimes required. Tight BP control (as suggested by various hypertension guidelines) may not be possible for patients with concomitant OH and supine hypertension. Under such circumstances, clinicians should be flexible with their treatment of hypertension. Slightly elevated BPs are better than aggressive treatment of hypertension as this will worsen orthostatic hypotension, orthostatic symptoms, and increase fall risk.

Postural Orthostatic Tachycardia Syndrome

Causes

POTS is a chronic condition of orthostatic intolerance, estimated to affect between 500 000 and 3 000 000 people in the U.S. alone. POTS is associated with reduced quality of life, sleep disturbances, and significant morbidity. Patients with POTS frequently report significant delays between symptom onset and proper diagnosis,¹⁶ and are frequently misdiagnosed with an anxiety disorder.⁷ POTS represents the final common clinical presentation of several pathophysiological processes, which may include sympathetic denervation, hypovolemia with impaired blood pressure regulation, and excessive adrenergic activity. POTS is also associated with several comorbidities including irritable bowel syndrome, Ehlers-Danlos syndrome, and migraine headaches.¹⁶

Common Clinical Features

POTS has a strong female predominance (5:1; female:male), largely affecting women of child-bearing age.¹⁶ Patients will often report reduced exercise tolerance, “brain fog”, and extreme fatigue. Symptoms are also frequently exacerbated by activities of daily living. In the history, it is important to inquire about major events preceding symptom onset as symptoms can frequently appear following viral illness, infection, pregnancy, or major surgery. Formal autonomic reflex testing typically shows exaggerated late phase II and phase IV BP responses to Valsalva (Figure 3D).

Management

Overt causes for orthostatic symptoms and tachycardia should be ruled out (eg, acute dehydration, medications that can worsen tachycardia, prolonged bedrest),¹⁷ as should diseases that could cause the orthostatic tachycardia. Initial efforts should focus on removing medications, supplements, caffeine in excess, and caffeinated energy drinks that can cause or exacerbate tachycardia (Figure 4). These include medications for attention deficit disorder, calcium channel blockers, tricyclic antidepressants, and medications that inhibit NE transporters (including serotonin and norepinephrine reuptake inhibitors [SNRI]).^6,17 Patients should be counselled on non-pharmacological interventions (Table 1), and instructed to avoid circumstances that exacerbate symptoms including high ambient temperatures and dehydration.

Pharmacological treatment for POTS: Pharmacological intervention should be considered for patients who remain symptomatic despite non-pharmacologic treatment (Table 2). The goal of treatment is to reduce sinus tachycardia and mitigate symptoms through intravascular volume expansion or vasoconstriction.⁶ Propranolol and other non-selective beta-blockers reduce orthostatic tachycardia. The key to using propranolol is that POTS patients tend to benefit from (and tolerate) low doses, but do not tolerate higher doses.¹⁸ Patients unable to tolerate beta-blockers may benefit from ivabradine (a novel funny channel blocker),¹⁹ though this should be avoided during pregnancy due to potential teratogenic effects. Midodrine can cause vasoconstriction and venoconstriction, and decrease the secondary (or reflex) tachycardia. Dosage, frequency, side effects, and precautions are the same as those mentioned for OH. Methyldopa, a centrally-acting sympatholytic, can be prescribed for patients with hyper-adrenergic symptoms or hypertension to reduce palpitations, tremors, and BP. Fludrocortisone increases renal sodium and water reabsorption and improves intravascular volume. Encourage patients to maintain adequate salt and fluid consumption to increase effectiveness. Fludrocortisone can worsen migraine headaches, lead to some weight gain, edema/ “puffiness”, and rarely hirsutism.

Conclusions

Cardiovascular autonomic physiology is uniquely positioned between cardiology and neurology. Despite this, or perhaps because of this, patients with autonomic disorders represent a largely under-recognized patient population. One contributing issue is that office vital signs are frequently taken in the seated or supine position, when HR and BP are most likely to be normal or high. This common practice leads to significant diagnostic delays and often improper and inadequate treatment. Recognizing the common clinical features of nOH and POTS, and having a low threshold for assessing orthostatic vital signs, has the potential to significantly improve the quality of life of hundreds of thousands of patients. 

Disclosures: The authors have no conflicts of interest to report regarding the content herein. Outside the submitted work, Dr. Raj reports payments to the institution from the Canadian Institutes of Health Research, Dysautonomia International, Medtronic, and Abbott Laboratories. He reports consulting fees from Lundbeck LLC, Theravance Biopharma, Medscape LLC, Academy for Continued Healthcare Learning, and Spire Learning. He also reports payment for participation on a Data Safety Monitoring Board or Advisory Board from Arena Pharmaceuticals. He is on the Board of Directors with the American Autonomic Society, and on the Medical Advisory Board for Dysautonomia International and PoTS-UK. Outside the submitted work, Dr. Baker reports payment/honoraria from the Cardiac and Circulatory Physiology Rounds, Mount Sinai, Toronto. She reports support for travel from the Hotchkiss Brain Institution Brain Create Travel Award. She is on the Meeting Committee for the American Autonomic Society and on the Trainee Committee for the American Autonomic Society.   

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Video 1:

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