Orthostatic Circulatory Disorders: From Nosology to Nuts and Bolts

Abstract

When patients complain of altered consciousness or discomfort in the upright posture, either relieved by recumbency or culminating in syncope, physicians may find themselves baffled. There is a wide variety of disorders that cause abnormal regulation of blood pressure and pulse rate in the upright posture. The aim of this focused review is 3-fold. First, to offer a classification (nosology) of these disorders; second, to illuminate the mechanisms that underlie them; and third, to assist the physician in the practical aspects of diagnosis of adult orthostatic hypotension, by extending clinical skills with readily available office technology.

THE NORMAL ORTHOSTATIC RESPONSE

The act of standing up triggers a series of reactions that sustain perfusion pressure in response to downward blood displacement of approximately 500–700ml into the splanchnic vascular bed and lower extremities.¹ Displacement may occur within a few seconds. Orthostasis stresses circulatory regulation.² Optimum circulatory adjustment for orthostasis requires intact cardiac structure and function, intact blood vessel structure and function, adequate blood volume, and intact “muscle pumps.”

The muscle pumps comprise the skeletal muscle pump that compresses leg veins, and the respiratory–abdominal muscle pump, which enhances systemic venous return during respirations.³ Upright stance without movement causes dependent venous pooling, and the muscle pumps act to propel blood back to the heart when the patient is upright or exercising.³ Conscious skeletal muscle pump activity represents an important physical “countermeasure” against orthostatic intolerance (OI).⁴

Rapid orthostatic circulatory adjustments also depend on the autonomic nervous system. Comprising sympathetic and parasympathetic arms, the autonomic nervous system forms the framework for heart rate (HR) and blood pressure (BP) control.

The sympathetic arm acts through the neurotransmitter norepinephrine,⁵ cotransmitters neuropeptide Y, and ATP to

• 1.produce arterial vasoconstriction and venoconstriction,
• 2.increase cardiac contractility and HR,
• 3.facilitate epinephrine release, and
• 4.regulate neuroendocrine and vascular function of the kidney.

The parasympathetic arm, via vagal nerve efferents, contributes most to HR changes at rates less than the intrinsic rate.⁶ However, there are strong vagal influences on sympathoexcitation⁷ and important effects on nitrergic (nitric oxide–containing nerve) vasodilation of the large cerebral arteries.⁸ Autonomic control of HR and BP during orthostasis is achieved by subsystems designated “baroreflexes” (pressure reflexes), which maintain BP under changing conditions.⁹ Loosely grouped as arterial and cardiopulmonary baroreflexes, these maintain BP during orthostasis.

Endocrine and local vascular control systems (e.g., nitric oxide and local angiotensin) are slower to develop but alter the neurovascular environment, acting to modulate or set tonic activity of the autonomic nervous system.¹⁰

The integrated response to orthostasis

Within seconds following standing upright, there is usually a transient decrease in systolic BP (SBP) and diastolic BP (DBP) and an increase in HR; this is due to the downward translocation of blood before achieving mechanical equilibrium, and compensatory reflex sympathetic activation (~10 seconds) and is only appreciated when recording beat-to-beat BP. When the fall in BP is sufficiently large, it produces symptomatic “initial orthostatic hypotension (IOH)”¹¹ with transient lightheadedness.

After 30–60 seconds, BP and HR reach a quasi-steady state in which HR and both SBP and DBP are typically increased above supine values, with DBP increased more than SBP. Thus, there is a fall in pulse pressure and a small decrease in cerebral perfusion pressure secondary to the distance from the heart to the head when the patient is upright. During quiet standing, venous return to the heart remains reduced because of gravitational venous pooling within the lower extremities and splanchnic circulation, reducing central blood volume and cardiac output by approximately 20%. Cardiac output is partially sustained by reflex tachycardia.

The limits of normal ÄBP with orthostasis are defined at the lower end by a maximum fall of <20mm Hg in SBP and <10mm Hg in DBP,¹² and at the upper end by an increase in SBP not exceeding 20mm Hg.¹³ When SBP or DBP changes in an excess of these limits, their response to the upright posture may be characterized as “hypotensive” or “hypertensive.” Other corresponding terms are “orthostatic hypotension (OH)” and “orthostatic hypertension,” respectively. The limits of normal change in HR with orthostasis are an increase <30 beats per minute (bpm) in adults or an increase <40 bpm in youngsters under 19 years old. Failure to increase the HR on standing is abnormal.

ORTHOSTATIC INTOLERANCE

The inability to tolerate the upright posture because of signs and symptoms relieved by recumbency is termed OI¹⁴ (Table 1). OI generally results from either ineffective regulatory mechanisms or environmental conditions that exceed the ability of these homeostatic mechanisms to compensate appropriately for the environmental stress.

Table 1.

Disorders of orthostatic intolerance

Orthostatic syndrome	Description	Defect/pathophysiology
OI	The presence of one or more symptoms, e.g., lightheadedness, dizziness, nausea, breathlessness, and vision change, linked specifically to assuming or maintaining upright posture, and symptoms abate once supine	Defects in the compensatory mechanisms for the orthostatic response
Initial OH	Lightheadedness with transient hypotension and excessive postural tachycardia immediately upon standing up. Dissipates within 30 seconds	Rapid redistribution of blood to dependent body with a lag in mechanical equilibrium and sympathetic activation
Chronic OI	Ongoing OI for at least 3 months with functional impairment
OH	Significant sustained hypotension with a fall in SBP exceeding 20mm Hg and a fall in DBP exceeding 10mm Hg, which occurs after transient equilibration but within 3 minutes of upright stance	Neurogenic OH = systemically defective or absent adrenergic vasoconstriction. Autonomic failure. Frequent parasympathetic dysfunction.Nonneurogenic OH = hypovolemia, vasodilator drugs
POTS	Chronic OI with excessive postural tachycardia (>30 in adults, >40 in adolescents) within 10 minutes during standardized orthostatic testing in the absence of hypotension	Neuropathic = reflex sinus tachycardia due to loss of regional vasoconstrictive ability with vagal withdrawalHyperadrenergic = excessive adrenergic activation, which accelerates the sinus node
Postural VVS	Transient loss of consciousness and postural tone when upright of rapid onset caused by reduced cerebral perfusion (due to hypotension) with spontaneous recovery when supine	Decreased cardiac output or systemic vasoconstriction or bothLoss of splanchnic-hepatic vasoconstrictive and sometimes venoconstrictor abilitiesAcute reversible baroreflex dysfunction
Chronic bed rest	Presentation as POTS, VVS, other OI	Deficits include loss of blood volume, trophic loss of cardiac muscle and vascular smooth muscle, osteoporosis, skeletal muscle wasting, refractory adrenergic response to sympathetic activation

Abbreviations: DBP, diastolic blood pressure; OH, orthostatic hypotension; OI, orthostatic intolerance; POTS, postural orthostatic tachycardia syndrome; SBP, systolic blood pressure; VVS, vasovagal syncope.

Signs and symptoms of OI may include upright

• 1.loss of consciousness or lesser cognitive deficits, such as deficits in memory, reasoning, information-processing speed, and concentration;
• 2.visual or hearing difficulties;
• 3.lightheadedness;
• 4.headache;
• 5.fatigue;
• 6.BP changes;
• 7.weakness;
• 8.nausea and abdominal pain;
• 9.sweating;
• 10.tremulousness; and
• 11.exercise intolerance.¹⁵

Common causes of OI in younger patients (aged 10–30 years) are IOH, postural vasovagal syncope (VVS), postural tachycardia syndrome (POTS; see below), and chronic bed rest. IOH is by far the most common cause of OI in the young.¹⁶ IOH followed by walking uncommonly results in syncope, which can, with practice by the patient, be eliminated by the application of physical countermeasures, including buttock and leg compression, sitting, squatting, or recumbency. IOH occurs in older patients and may importantly contribute to slips and falls. It is distinguished from true OH by its spontaneous resolution and characteristic associated tachycardia.

POSTURAL TACHYCARDIA SYNDROME

The normal increase in HR on standing generally does not exceed 30 bpm in adults or rise above 120 bpm. Excessive upright tachycardia is associated with symptoms during several states of excessive sympathetic activation and vagal withdrawal. These states include

• 1.central hypovolemia of any cause (e.g., dehydration and endocrine disorders);
• 2.inappropriate sinus tachycardia, which features supine HR exceeding 100 bpm;
• 3.vasovagal syncope (VVS) as a reflex response to reduced total peripheral resistance or cardiac output; and
• 4.POTS defined by excessive upright sinus tachycardia and chronic symptoms of OI¹⁷ without hypotension.¹⁸

An age-appropriate orthostatic test showing an excessively increased sinus HR and syncope due to hypotension is not POTS. POTS is one form of chronic OI: because it has daily symptoms of OI and because an observational period of several months is usually required before designating an illness as chronic.

In POTS, females predominate 3:1 with an onset from menarche to menopause. School work or occupational activities are impaired, such deficits can serve as a test of POTS severity. Joint hypermobility syndromes¹⁹ are often present. An association between POTS and mast cell activation disorders has been proposed.²⁰

The threshold for excessive upright tachycardia in the young has recently been increased to >40 bpm over 10-minute tilt⁴ contrasting with adults, in whom an increase of >30 bpm is required on either tilt or standing tests. Longer upright testing markedly reduces specificity while minimally increasing sensitivity. Concurrent OI symptoms during orthostatic stress testing are necessary. A fraction (~30% by consensus²¹) of individuals with POTS may have had prior syncope. Most patients with POTS do not faint. Patients with POTS are usually exercise deconditioned,²² which cannot account for all findings. The prevalence of POTS is not known.¹⁵

Patients are often partitioned among “neuropathic POTS,” in which selective or “partial dysautonomic” adrenergic denervation occurs, and “hyperadrenergic POTS,” in which sympathetic overactivity prevails.

In the original descriptions, “neuropathic” POTS was proposed as a forme fruste of adrenergic denervation.¹⁸ Indeed, decreased adrenergic vasoconstriction was found in the lower extremities of patients with neuropathic POTS.^23,24 In one study, these individuals had increased venous catecholamine (i.e., norepinephrine and epinephrine) levels. Vasoconstriction can also be decreased in the splanchnic vasculature.²⁵

When patients with regionally decreased vasoconstriction are upright, excessive central hypovolemia is caused by aberrant distribution of blood volume to regional vascular beds. For example, excessive venous pooling can occur in the lower extremities and trigger reflex tachycardia.²⁶ Autonomic autoimmune neuropathy^27,28 can also elicit similar reflex tachycardia. Pharmacotherapy using vasoconstrictors (e.g., midodrine and droxidopa) and the acetylcholinesterase inhibitor pyridostigmine can help to manage reflex tachycardia in these settings. Ivabradine has been proposed.²⁹ Nonpharmacologic interventions include acute water ingestion, a palliative measure,³⁰ stimulating TRPV3 portal vein receptors. Approximately 20–30 minutes after drinking 16 oz. of water, the osmopressor reflex is triggered, yielding HR and BP benefits that last for hours.³¹

In hyperadrenergic POTS, the adrenergic synapse can be upregulated at presynaptic or postsynaptic levels. Increased supine sympathetic nerve activity has been reported,¹⁷ but the finding is not universal.³² Most POTS patients demonstrate an increased muscle sympathetic nerve activity compared to control when upright.³³ Increased synaptic norepinephrine is observed in the norepinephrine transporter deficiency including a more prevalent epigenetic variant.^34,35 Presynaptic and postsynaptic adrenergic activity may be enhanced by local signaling molecules, including angiotensin II and nitric oxide.³⁶

Prolonged bed rest simulates microgravity and has deleterious effects,³⁷ including OI.³⁸ There are profound reductions in blood volume (and distribution) and cardiac mass, as well as skeletal muscle pump atrophy.³⁹ In this setting, sympathetic nerve activity seems to be intact, yet vasoconstriction is impaired.⁴⁰ Prolonged bed rest can perpetuate a POTS-like state remediated by well-structured exercise protocols.⁴¹

SYNCOPE

Syncope is defined as a “total loss of consciousness due to transient global cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery.”⁴² Loss of consciousness without profoundly decreased cerebral blood flow is not syncope. Resuscitated sudden death is not syncope. Cardiac disease accounts for a large fraction of adults with syncope. However, VVS remains the most common syncope variant with ~40% of people experiencing at least 1 episode, most presenting initially during adolescence.^43,44 OH causes noncardiac syncope (see below). The most common precipitant cause of syncope is hypotension, which can be evoked in most people by either sufficiently large orthostatic stressors or hemorrhage.⁴⁵

A separate form of cerebral hypoperfusion without hypotension—termed “cerebral syncope”—has been reported.⁴⁶ Approximately two thirds of young patients (aged 10−30 years) are female, whereas the female:male ratio is closer to 1:1 after 40. Teenage boys with cerebral syncope tend to be tall, thin, and rapidly growing.⁴⁴ Reflex syncope includes situational syncope and VVS. Situational causes of syncope include carotid sinus syncope,⁴⁷ deglutition syncope,⁴⁸ defecation syncope,⁴⁹ micturition syncope,⁵⁰ and cough⁵¹ Syncope during exercise raises concerns for a cardiogenic etiology; the most common cause of syncope during exercise is VVS.⁵² Modest postexercise hypotension, in part driven by histamine receptors, can result in postexercise syncope in patients prone to VVS.⁵³ Postural syncope and emotional stress syncope (e.g., “blood phobia”) comprise VVS, which is the largest subgroup within reflex syncope.¹

Loss of adrenergic vasoconstriction is common to all patients with VVS.⁵⁴ Loss of consciousness is often preceded by a well-known prodrome and followed by a postdrome, but not in all cases. VVS is often episodic in otherwise healthy patients. The VVS of youth remits during later adult life, only to recur with aging (typically 60–70 years old).

OH IN THE ADULT

OH is a heterogeneous entity and may be found as a result of systemic autonomic disorders, volume depletion, medications that impair the function of the autonomic nervous system or meals. It needs to be evaluated in the clinical setting of the individual patient.

The 3 watchwords for the clinician are detection, repetition, and suspicion.

The most sensitive method for detection of OH is to compare supine with erect BP readings or employ a tilt table¹⁴ and observe for a fall in SBP or DBP of 20/10mm Hg after 2–3 minutes standing. When the supine BP is in excess of 160mm Hg, the fall in SBP should be more than 30mm Hg.¹⁴ Casual comparison of BP seated and after 30 seconds of standing has a sensitivity of only 15%.⁵⁵

Repetition is important because adult OH is poorly reproducible and often found in the asymptomatic patient.⁵⁶ A wide variety of remediable conditions,⁵⁷ meals, and seasonal change⁵⁸ can cause transient OH. The patient’s BP should be remeasured after they are corrected. They are assessed by history and physical exam, using 3 excellent reviews as a guide.^57,59,60

OH is more likely to be reproducible as a function of age. When found initially, it could be identified subsequently in only 1% of adults in the 5th⁶¹ and 3% in the 8th decades.⁶² In the 9th decade, even postprandial, intraday sampling yielded only 35% reproducibility.⁶³ This procession is in tune with declining baroreceptor function in the old.⁶⁴ But an even greater consistency is found when there is an associated systemic autonomic disorder.

Thus, the index of suspicion should be highest when there are signs of systemic disorders or symptoms of OI.^14,15 Causes, signs, symptoms, and lab values in most neurodegenerative disorders, which are marked by deposits of α-synuclein in neural tissue, are detailed in Table 2, along with a mention of OI and hyperadrenergic OH. Immune, paraneoplastic, infiltrative, and vascular syndromes are detailed in Table 3.

Table 2.

Adult orthostatic syndromes that involve the central nervous system, and hyperadrenergic OH

Disease State	Symptoms	Signs	Laboratory or physiologic findings
Synucleopathies (α-synuclein inclusions in Lewy bodies)
MSA65–67	Erectile dysfunctionUrinary incontinenceOHImpaired gaitParkinsonian features appear later, but pill-rolling tremor is absentOnset age 30–75	OHAtaxia of gait and speechCerebellar oculomotor dysfunctionPoor response to l-dopa	α-Synuclein as cytoplasmic inclusions in glia, with neurodegenerative changes in olivopontocerebellar or striatal structuresIncreased post void residual urineUniform (adrenergic and parasympathetic failure on Valsalva analysis)Plasma NE: supine = 203 pg/ml; erect = 283 pg/ml
PD68–72	Asymmetric onset of tremor or rigidityAnosmia an early sign when only OIOH often precedes motor findingsOI partly related to gait disturbance	4–6 Hz resting tremorLimb and truncal rigidityBradykinesiaPostural instabilityExcellent response to l-dopa in >70%; choreiform movements a marker of effectivenessOH 50% may precede motor symptoms by 5 years	VM may be normal or abnormal even before OH Plasma NE: supine = 141 pg/ml; on 5 minutes’ tilt, 286 pg/ml when no OHSupine = 118 pg/ml; erect = 206 pg/ml when OH
LBDD73–75	Early dementiaFluctuating cognitionVisual hallucinationsREM sleep disorder with motor featuresOversensitivity to neuroleptics	Parkinsonian syndrome at onset of or within 1 year<50% respond to l-dopaOH	α-Synuclein in cortical cells and synapsesAdrenergic and parasympathetic function are severely deranged, in contrast to Alzheimer type dementiaPlasma NE: supine = 172 pg/ml; erect = 274 pg/ml after 5 minutes’ tiltSupine = 91 pg/ml; erect = 142 pg/ml
PAF67,76,77	OI with genitourinary dysfunction is prominent abnormalityAutonomic abnormalities may be absentObserve for emergence of other autonomic symptomsFormerly termed idiopathic OH	Initially, OH may be sole feature	α-Synuclein and Lewy bodies in sympathetic ganglia, distal sympathetic axons and skin; locus coeruleus, spinal cord, and parasympathetic nerves of the bladder and in cortical cells and synapsesPlasma NE: supine 91 pg/ml, erect = 142 pg/ml (after 5 minutes’ tilt)
Neurogenic hyperadrenergic OH,78  delayed OH79–81	Similar to other OH causes	OH with elevated plasma NE In delayed OH, vasovagal syncope may occur	Plasma NE: supine = 475 pg/ml; after standing × 16 minutes, 1,035 pg/mlLess depression of nadir during phase 2 of VM, and shorter pressure recovery time, vs. patients with lower NE levelsNadir is not as steep in hyperadrenergic form and in delayed OHPlasma NE levels are uncertain in delayed OHSynuclein deposition has not been reported

Abbreviations: LBDD, Lewy body disease with dementia; MSA, multiple system atrophy; NE, norepinephrine; OH, orthostatic hypotension; OI, orthostatic intolerance; PAF, primary autonomic failure; PD, Parkinson’s disease; REM, rapid eye movement; VM, Valsalva maneuver.

Table 3.

Immune, infiltrative, and vascular origins of adult orthostatic syndromes

Disease state	Symptoms	Signs	Laboratory/physiologic findings
Immune neuropathies
Sjögren’s syndrome, primary or secondary to other autoimmune disorders (e.g., RA, SLE, scleroderma)27,82	XerostomiaXerophthalmiaSensory symptoms of limb neuropathy	↓ Salivary poolSensory/cranial neuropathyAdie’s tonic pupil (Holmes-Adie syndrome, tonic pupils with ↓ light reflex/constriction on near-distance reading	cAnti-Ro-La Ab (salivary gland biopsy may be necessary to establish diagnosisAb vs. ganglionic α-3 AchRAb vs. muscarinic 3 receptor, which impairs bladder/bowel functionParasympathetic sympathetic impairment VM
AAG (when chronic, resembles PAF)82–85	Diffuse autonomic dysfunction after viral infection, with xerostomia and GI dysmotilityMonophasic or slow onsetMay improve over time/respond to IV immunoglobulin plasmapheresis/ chemotherapy	Adie’s tonic pupil (Holmes-Adie syndrome)Anhidrosis/hypohidrosis	Abnormal Valsalva analysisGanglionic nicotinic α3 AchR Ab (titer correlates with disease severity)
Paraneoplastic autonomic neuropathy82	WeaknessPainful sensory impairment/ hyperalgesiaSicca syndrome	Areflexia + proprioceptive lossAdie’s tonic pupil (Holmes-Adie syndrome)	Autoimmune channelopathies with Ab vs. ion channels/ associated proteinsSearch for visceral cancer if not immediately apparent
Systemic amyloidosis82	Neuropathic symptomsPanautonomic dysfunction	HepatosplenomegalyGlossomegalyCardiomegaly with signs of CHFNephrotic renal insufficiencySitting hypotensionEnlarged fibular peroneal nerveSigns of carpal-tunnel syndromePeriorbital petechiae	Monoclonal gammopathyTTR gene mutation on gingival, fat, or rectal biopsy
Diabetic autonomic neuropathy86	NumbnessNeuropathic painUrinary retentionGastroparesisSexual dysfunction (male/female)↓ Hallux monofilament sensation↓ Position and vibration sense	Accentuated hypoglycemiaMicrovascular disease (proteinuria, retinopathy)OH/syncope after diureticsAnkle areflexiaTransient oculomotor neuropathies	↓ HR variability, with parasympathetic sympathetic involvementNocturnal parasympathetic function most impairedAbnormal Valsalva analysis (most data refer to parasympathetic limb)↓ NE response to standingFasting hyperglycemia, ↑ HbA1c

Abbreviations: AAG, autoimmune autonomic ganglionopathy; CHF, congestive heart failure; GI, gastrointestinal; HR, heart rate; NE, norepinephrine; OH, orthostatic hypotension; OI, orthostatic intolerance; PAF, primary autonomic failure; RA, rheumatois arthritis; SLE, systemic lupus erythematosus; TTR, transthyretin; VM, Valsalva maneuver.

Given that “orthostatic reaction may vary over time… more accurate diagnostic methods are recommended to identify high-risk patients with persistent OH.”⁶¹ What measures are readily available to the clinician and what are their errors?

STEPS IN THE WORK-UP OF ADULT OH

To the extent that the finding of OH is not constant, it is difficult to follow the progress of the syndrome by BP change alone. Available office procedures, ranging from simple to more sophisticated, can expand the diagnostic dimension.

Auscultation is the most convenient and, in fact, important measurement of BP. Unfortunately, this widely applied method is subject to large potential errors. First, the consensus definition¹⁴ of a fall in BP of 20−30mm Hg systolic and 10mm Hg diastolic after 2 or 3 minutes is a narrow window. An error of only ±5mm Hg to the systolic and the diastolic can miss some patients with true OH and misclassify others to this category. A true orthostatic fall is likely to be masked when untrained individuals do the measurement.^87,88

The HR is recorded in the supine and erect posture. A postural increase of less than 10 bpm is more consistent with baroreceptor dysfunction, and over 20 bpm, volume depletion.⁵⁷ One should also consider evaluating “standing time”: the interval between the patient’s standing up and the onset of OH symptoms.⁸⁹ This assessment takes into account both the extent of the fall in BP and the competence of cerebral autoregulation.

There is additional technical difficulty since the SBP at 2–3 minutes of standing is a moving target. The time it takes for patients to fully stand also varies, which further influences the “standing” pressure.⁹⁰ Repeated determinations during the 2- and 3-minute intervals can help reduce the error. For the determination of the supine value, Mader⁹⁰ found that an interval of at least 5 minutes’ supine rest, taking a mean of the second and third subsequent BPs, offered the best comparison.

One recommendation to optimize the reliability of auscultation in patients who have a minimal orthostatic fall in BP is to measure supine BP with the antecubital fossa at the level of the right atrium. Measuring BP at this locus (approximately the anterior axillary line) minimizes spurious (mean = 4.6mm Hg) elevations in supine BP,⁹¹ which occur when the arm is flat on the table.

Once the diagnosis of OH is established by auscultation, there is a role for electronic oscillometric BP monitors (EOMs) sanctioned by the US Association for the Advancement of Medical Instrumentation.⁹² These devices provide important hour-by-hour BP data in a setting of high levels of BP variability. The patient should be properly trained to use the monitor,⁸⁷ in both the supine and erect positions and report the timing of activity and meals.

Information from EOMs yield an assessment of progress beyond just clocking the frequency of falls. For example, when the EOM indicates a deficient or excessive pressor response to a pressor agent (e.g., midodrine), fludrocortisone can be added, or the dose reduced in advance of a hypertensive catastrophe. EOMs also provide convenient reports about the depressor effects of meals, or the pressor effects of injected octreotide or the ingestion of water, at mealtime.^20,93

A sensor in the EOM detects expansions in the brachial cuff and generates an electrical signal in response to distending pulses in the underlying artery. A computer algorithm processes the signal into a number representing SBP and DBP. The distensibility of the brachial artery translates intraarterial BP into the oscillometric expansion.

Many studies have been done to determine how well the pressures generated by an EOM represent the equivalent auscultatory reading. They generally employ a “same arm simultaneous” method, using a 3-way connector to a mercury manometer, or a same arm sequential method.⁹² From one large epidemiologic survey,⁹⁴ one could expect a particular EOM to produce SBPs of +9 to −15mm Hg more or less than auscultation, with 95% confidence interval.

However, disease alters arterial distensibility and distorts the coupling of the 2 impulses. In OH, for instance, there is suggestive evidence that the distensibility of muscular arteries is different in OH than in a control population.⁹⁵ In addition, there are significant differences between manufactured devices.⁹⁶ These factors have the potential to increase error even further and even render the diagnosis of OH inaccurate. For the most precise estimation of absolute BP from a given EOM, it should be standardized on the arm of the individual patient.

An advantage of ambulatory BP monitoring (ABPM) over home BP is that day and night readings are taken at fixed intervals. The BP can be assessed with regular sampling, and not just when the patient might choose to activate the device on account of symptoms. Nocturnal hypertension is present in 50% of OH patients.^70,97 Office supine BP measured by auscultation predicted the presence of overnight supine hypertension.⁹⁸ But in that study, erect BP on a tilt table could not predict daytime hypotensive episodes. The authors concluded by recommending ABPM as the better means of correlating daytime readings with symptoms of OI or postprandial hypotension.

Elevating the head of the bed to 5–12degrees at night may lower nocturnal BP and relieve the nocturnal sodium diuresis, which occurs when the BP is high. When these elevations have not improved daytime hypotension,⁹⁹ it is helpful to know if the nocturnal hypertension has actually been corrected.

In our experience, office and home EOM BPs are often skewed upwards, due to the emotional experience of physician or self-measurement. Others have alluded to this phenomenon.⁹⁷ Such amplified BPs are common in baroreceptor failure.¹⁰⁰ We have generally not found them to be present on ABPM.

ABPM should be performed in concert with timed daytime/erect and nighttime/supine urinary sodium and creatinine excretion (see “Timed Urinary Collection” below). Each of these measures should be repeated to assess the effects of physical or pharmacologic corrective measures.⁶⁷

OH is associated with high BP^56,67 and all of its major cardiovascular consequences. How does the practitioner assess cardiovascular risk in the OH patient? Trying to estimate the BP load in a patient with daytime hypotension and nocturnal hypertension is a conundrum.

Increased left ventricular mass (LVM) on the echocardiogram is a surrogate marker for cardiovascular events in hypertensives,¹⁰¹ and it regresses when the BP is lowered.¹⁰² LVM is increased in OH patients as in others with hypertension.¹⁰³ The observation of increased LVM in an OH patient should alert the practitioner that the algebraic sum of hypotension and hypertension is putting the patient at risk. There is no evidence base to show how hypertensive OH patients benefit from antihypertensive therapy. The decision to prescribe, or to augment, antihypertensive therapy, is often intuitive. Brain imaging may be added to help make a decision. However, the treating physician has the means to observe whether LVM is improving or worsening. When the echocardiogram is repeated at short intervals, there is a >95% likelihood that a change of ±35g in LVM is significant.¹⁰⁴

During the first 3 minutes of standing, the baroreceptor arc provides the most consequential reflexive response to the orthostatic decrease in BP.¹⁰⁵ Baroreceptor failure is marked not only by an inability to counter the decline in BP, but also, equally importantly, to offset the abnormal rise in BP in the supine posture.¹⁰⁶

Baroreceptor testing involves the analysis of data from the Valsalva maneuver (Figure 1) and is not difficult to apply in the office setting.

Figure 1.

The 4 phases of the Valsalva maneuver. The start of phase 3 is denoted by the black arrows. Phase 2 occupies the rectangles underneath Roman numeral II. In the control, the nadir is at a systolic blood pressure (BP) of about 20mm Hg below baseline. The time it takes for the BP to recover to baseline (the “pressure recovery time”) is short. In the subject with orthostatic hypotension (OH), the nadir is 60mm Hg below baseline, and the pressure recovery time is markedly prolonged. If this were a patient with the hyperadrenergic form of OH,⁷⁸ or with orthostatic intolerance,⁸¹ the nadir would be intermediate between the normal and the neurogenic OH pattern. Close inspection shows that the longest beat-to-beat interval in phase 4 (overshoot) is greater than the shortest beat-to-beat interval in phase 2. The relationship between them describes the “valsalva ratio,” an index of parasympathetic activity. Reprinted by permission from Goldstein, DS, Sharabi, Y. Neurogenic orthostatic hypotension: a pathophysiologic approach. Circulation 2009;119:139-146, copyright American Heart Association.

With every pulse, a finger plethysmograph¹⁰⁷ provides data about BP and HR. As compression of the airway against a measured resistance is applied, an initial rise in BP (phase 1) is followed by a rise in HR and a nadir of BP (phase 2). The depth of this lower limit is determined by a sympathetic counter response.¹⁰⁸ This response continues into phase 3, when compression is ended, and BP ascends sharply. The BP rises above, and the pulse rate falls below, baseline (phase 4). The magnitude of the nadir of BP in phase 2 and the time needed for SBP to return to baseline in phase 3 (i.e., pressure recovery time) are indices of sympathetic activity (adrenergic baroreceptor sensitivity) and vasoconstrictive adequacy.

In the case of neurogenic OH, and in the asymptomatic elderly,¹⁰⁹ both the depth of the BP nadir in phase 2 and the pressure recovery time correlate inversely with muscle nerve sympathetic activity.⁶⁴ In hyperadrenergic OH,⁷⁸ the decrease in BP at the nadir is less than in hypoadrenergic comparators. In the hyperadrenergic form, a larger rise in plasma norepinephrine at the nadir denotes a robust sympathetic response.⁷⁸ In OI, the mean decrease in BP at the nadir is generally more modest than in neurogenic OH, and a large percent of the subjects present with VVS.

Indications of vagal responses (parasympathetic baroreceptor sensitivity) include the ratio of:

• 1.highest HR in phase 2 to lowest HR in phase 4 (“Valsalva ratio”) and
• 2.longest-to-shortest electrocardiographic RR interval measured during deep breathing.

Baroreceptor testing can help to determine progression or regression of autonomic insufficiency. Certain autonomic syndromes improve^27,82 or worsen⁸⁶ over time, and the changes are detectable by repeated Valsalva maneuver. Valsalva maneuver analysis is also used as a marker for a more generalized disorder of autonomic regulation in that large proportion⁷¹ of patients with Parkinson’s disease who have OH but who have not yet developed movement disorders. Even when there is no OH, such generalized autonomic dysregulation may also be present in patients with primary autonomic failure, Parkinson’s disease, multiple system atrophy, and Lewy body disease with dementia.⁷² In OI^79,80 where hypotension is not apparent, Valsalva maneuver can identify a diagnosis of latent autonomic failure (Table 2 and Figure 1).

The clinician can improve confidence in baroreceptor measurements by referring to matrices that establish 95% age-adjusted confidence intervals for

• 1.baroreceptor adrenergic sensitivity,
• 2.values of the Valsalva ratio, and
• 3.variation in the electrocardiographic RR interval with measured deep breathing.¹¹⁰

Timed urinary collection

Deficient sodium balance reduces the efficiency of adrenergic vasoconstrictive impulses. Patients with autonomic insufficiency are often sodium depleted because natriuresis tends to increase with rise in BP (especially overnight) in the denervated kidney.⁹⁷ As a consequence, hypotensive symptoms tend to be worst in the morning. Administered at bedtime, nitroglycerin and amlodipine reduce nocturnal supine hypertension.⁹⁷ Surprisingly, these agents do not relieve overnight sodium losses, even as they lower BP,¹¹¹ on account of a direct natriuretic effect. But elevation of the patient’s head during sleep does improve overnight sodium loss modestly.¹¹²

Normally, daytime sodium excretion should exceed nighttime values. But nocturnal sodium excretion is twice that of daytime values in patients with neurodegenerative syndromes.⁹⁷ Timed urinary sodium and creatinine values allow one to compute the relationship between day (erect) and night (supine.) They also reflect total daily sodium intake. 24-hour urinary sodium should be at a minimum of 150¹¹³ to 170¹¹⁴ mEq. This level of sodium excretion can be accomplished by administering a combination of 1.0g sodium chloride tablets and foods high in sodium (www.ndb.nal.usda.gov/ndb/search/list). As with other assessments in the work-up of OH, timed urinary sodium collection tests should be repeated. Doing so assists in estimating the effects of elevation of the head of the bed or a recliner. Ideally, the collections should be performed with simultaneous ABPM, in order to evaluate the relationship between reduction of overnight sodium loss and control of nocturnal hypertension.

Tilt-table testing is generally done in the hospital setting. It can reduce uncertainty about a postural fall in BP upon standing for 2–3 minutes. In one study, head-up 70degree tilt-table testing had a sensitivity of 100% for OH within 3 minutes.¹¹⁵ However, in a subset of patients with delayed OH,^80–,82 up to 30 minutes of head-up tilt may be necessary to detect a decline in BP.

The approach to the patient that incorporates the measures we have outlined is summarized in Figure 2.

Figure 2.

A suggested approach to the patient with orthostatic circulatory disorders. Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure; ECHO, echocardiography; EOM, electronic oscillometric monitors; OI, orthostatic intolerance; OH, orthostatic hypotension; POTS, postural orthostatic tachycardia syndrome; VM, Valsalva maneuver analysis.

FUTURE DIRECTIONS

The final common path for symptoms in orthostatic circulatory disorders is a critical reduction in cerebral perfusion. Symptoms may vary from one patient or another, at equivalent BP or pCO₂ levels. Drugs that elevate BP may not offer parallel benefit to cerebral blood flow.¹¹⁶

Transcranial doppler can detect decreases in cerebral blood flow velocity. These falls may be dissociated from cerebral perfusion pressure, as in POTS, and the “postural hyperpnea” variant of OI¹¹⁷ or from pCO₂, as in cerebral syncope.¹¹⁸ More commonly, they occur as a function of a falling BP. In that setting, patients show considerable variations in the responses of their cerebral blood flow to hypotension, which are in turn dependent on the integrity of cerebral autoregulation. Those with the greatest impairment are the most likely to faint and to require more aggressive drug support for their standing BP.^119,120

The most sophisticated methods for assessing autoregulation of cerebrovascular flow utilize the comparison of doppler waveforms recorded at the middle cerebral artery and the corresponding beat-to-beat BP signals from finger photoplethysmography, during tilt. The comparisons are then made in the time or frequency domain,^117,121 with end tidal pCO₂ maintained constant.¹²²

In the future, physicians’ offices should have the ability to define what is adequate autoregulation of cerebral blood flow. More normative data, convenient hardware, and computational aids will be needed to adapt this technique to office management.

Thoracic bioimpedance measurements are a means of assessing cardiopulmonary blood volume, with 99% reproducibility.¹²³ While absolute values are subject to the distorting influence of cardiac diastolic dysfunction, they are sufficiently sensitive to quantify a fall in thoracic fluid content on standing. More information on how these changes correspond to the displacement of blood volume into the splanchnic circulation, and how these measurements can help determine the proper dose of octreotide, will be useful adjuncts to office evaluation.

CONCLUSIONS

We have attempted to extend and enrich the understanding of orthostatic circulatory disorders by physicians. It is our hope that this effort will advance needed clinical and technological skills among a broad spectrum of office-based specialists and hence redound to the benefits of their patients with these conditions.

DISCLOSURE

The authors declared no conflict of interest.