Adapted from Benarroch [1]
Cardiovascular autonomic dysfunction and disease may affect only one organ or system but may be an important feature of underlying neurological disorder [2]. Cardiovascular autonomic dysfunction is a common part of many neurological disorders and is often the most disabling part of the disorder.
This chapter outlines the diagnostic approach to the most common cardiovascular autonomic dysfunctions, hypotension, autonomically mediated (or reflex) syncope, postural tachycardia syndrome (PoTS), and autonomic failure, and how to manage these by the use of both non-pharmacological measurements and pharmacological measurements.
The clinical picture of autonomic failure is usually dominated by disabling orthostatic hypotension (OH). Severely affected patients are able to stand only for a few seconds because of dramatic blood pressure (BP) falls produced by impaired cardiovascular adaption to upright posture [3].
Patients with autonomic failure share a similar clinical presentation; they are unable to tolerate upright posture because of severe orthostatic hypotension. It is however important to distinguish the different syndromes associated with autonomic failure because they differ in their disease pathophysiology, response to pharmacological treatment, and prognosis.
Virtually any disease that affects peripheral nerve function can produce autonomic failure.
Disorders associated with autonomic failure can be classified according to the type and severity of autonomic manifestations, associated neurological symptoms, and temporal profile [1].
Orthostatic hypotension (OH) is a prominent feature of autonomic failure, and it is often the symptom that leads the patient to seek medical advice. OH, also called postural hypotension, is a temporary lowering of blood pressure (hypotension), usually due to standing up suddenly (orthostatic). The change in position causes a temporary reduction in blood flow and oxygen to the brain. Upon standing gravity promotes the pooling of blood in the lower extremities, which decreases venous return of blood circulating back to the heart. Normally, cardiac and carotid sinus baroreceptors sense the decrease in blood volume and initiate increased heart rate and peripheral vasoconstriction.
In individuals with OH, there is an impaired efferent sympathetic signal to the arterioles and a failure to release norepinephrine appropriately upon standing. The consequent vasoconstrictor insufficiency results in blood pooling in the lower extremities, with subsequent decreased venous return to the heart and brain.
OH can be confirmed by measuring blood pressures and heart rate in supine and upright positions. BP and heart rate should be measured after symptoms develop or after 3 min of standing. If the patient is unable to stand, testing for orthostatic hypotension may be done after the patient has risen to a sitting position with the feet dangling over the edge of the bed [4].
3.1.2 What Clinical Signs Hint to a Cardiovascular Autonomic Disease?
Severe orthostatic hypotension
Postprandial hypotension
Supine hypertension
High blood pressure variability
Blunted heart rate variability
Often a “non-dipping” or “reverse dipping” pattern on 24-h ambulatory blood pressure monitoring
Medications influencing the cardiovascular autonomic nervous system/polypharmacy
3.2 What Can I Differentiate Already at Bedside and How Do I Manage the Patient?
3.2.1 Hypotension
Hypotension is the most common symptom of all cardiovascular autonomic dysfunctions. It can be the only symptom, it can occur together with syncope and postural tachycardia syndrome (PoTS), or it may be the initial sign of autonomic failure in both primary and secondary disorders of the autonomic nervous system (ANS): pure autonomic failure (PAF), multiple system atrophy (MSA), Parkinson’s disease (PD), dementia with Lewy bodies, autoimmune autonomic ganglionopathy, amyloidosis, and diabetic autonomic neuropathy [5]. The prevalence of OH increases with age [6].
Common secondary causes are spinal cord injury (SCI), stroke, multiple sclerosis (MS), Guillain–Barré syndrome, motor neuron disease, adrenal insufficiency, and vitamin deficiencies (e.g. B1, B12).
Non-neurogenic causes are volume depletion, pump failure, drugs, mitral valve prolapse, electrolyte disturbance, prolonged bed rest, pregnancy, and alcohol [2].
3.2.1.1 Orthostatic Hypotension
Definition
Orthostatic hypotension (classic) (OH) is defined as a sustained drop in blood pressure (BP) of greater than 20 mmHg systolic or 10 mmHg diastolic 3 min after rising to a standing position from a supine position [4]. OH is an inability to maintain sufficient BP and adequate cerebral perfusion against gravity.
In neurogenic OH the heart rate response to changes in blood pressure is minimal, although there may be a mild compensatory increase, i.e. below 30 beats per minute.
Immediately after standing, there is gravitationally mediated redistribution of the blood volume and a pooling of 300–800 ml of blood in the lower extremities and splanchnic venous system [7]. This results in decreased stroke volume, as well as decreased systolic pressure and increased diastolic pressure.
“Initial OH” is characterised by a BP decrease immediately on standing of >40 mmHg systolic and/or >20 mmHg diastolic. BP then spontaneously and rapidly returns to normal, so the period of hypotension and symptoms is short (<30 s) [8, 9]. To confirm the presence of initial OH, BP must be recorded continuously (beat to beat) ideally in an autonomic laboratory. Bedside tests are not available.
“Delayed (progressive) OH” is not uncommon in elderly persons [10] and in patients with spinal cord injuries (SCI) [11]. Recent studies from Gibbons and Freeman [12] and Pavy-Le Traon [13] found a 10-year conversion rate to OH and higher prevalence of delayed OH in possible vs. probable MSA, respectively.
It is characterised by a slow progressive decrease in systolic BP on assuming erect posture. The absence of a bradycardiac reflex (vagal) differentiates delayed OH from reflex syncope. Delayed OH may be followed by reflex bradycardia [9].
In recently injured tetraplegics (2–13 days post injury), the basal supine level of blood pressure usually is lower than normal (mean arterial pressure, 57 mmHg in tetraplegics and 82 mmHg in normal subjects) [14]. Also in recently injured tetraplegics, the basal heart rate is usually <100 beats/min [15]. Frankel et al. found an inverse correlation between level of lesions and both systolic and diastolic blood pressure [16].
For physiology see Sect. 1.2.1, for history taking see Sect. 2.2.1.1
Epidemiology
In an unselected population >65 years, the prevalence of OH was reported to be 5–30% [17].
The prevalence of symptomatic OH increased from 14.8% in persons aged 65–69 years to 26% in persons >85 years, signifying the association between symptomatic OH and ageing [18]. In other populations, such as in Parkinson’s disease, the prevalence of OH may be as high as 60% [19]. The presence of OH increases risk for falls and all-cause mortality in middle-aged and elderly persons [20]. OH is an independent risk factor for cardiovascular morbidity and mortality from stroke, coronary heart disease, and chronic kidney disease [20].
Although symptoms of OH may include dizziness and syncope, asymptomatic OH is far more common and represents an independent risk factor for mortality and cardiovascular disease. In a prospective study of more than 33,000 individuals, asymptomatic OH was present in over 6% and was associated with age, female sex, hypertension, antihypertension treatment, increased heart rate, diabetes, low body mass index, and recurrent smoking [21]. Those with OH had significantly greater risk for all-cause mortality, especially those younger than 42 years, and higher risk for coronary events. OH has a prognostic role on cognitive and cardio- and cerebrovascular outcome in α-synucleinopathies.
Non-neurogenic Causes of OH
Drugs are the main non-neurogenic cause of orthostatic hypotension. Reducing or changing medications may lead to significant improvement. The α-blockers attenuate the α-adrenergic response, which increases vascular resistance and therefore should be avoided. The prevalence of orthostatic hypotension with the use of calcium antagonists ranges from 1% to 7%. The rate is low with thiazide diuretics and β-blockers, and some β-blockers with intrinsic sympathomimetic activity may even improve orthostatic hypotension. The co-administration of loop diuretics with other antihypertensives increases orthostatic hypotension [20].
Drugs that may cause or aggravate orthostatic hypotension and syncope [22]:
α-Adrenoceptor agonists (α-blockers)
Antipsychotics
β-blockers
Nitrates
Hypnotics
ACE inhibitors
Anaesthetics
Angiotensin II antagonists
Barbiturates
Calcium antagonists
Clonidine
Diuretics
Levodopa and dopamine agonists
Methyldopa
Nitrates
Phenothiazines
Sildenafil
Tricyclic and MAOI antidepressants
ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; MAOI, monoamine oxidase inhibitor
Other non-neurogenic causes are low intravascular volume (blood or plasma loss, fluid or electrolyte loss), impaired cardiac function due to structural heart disease, and vasodilatation due to drugs, alcohol, heat, and bed rest [2, 23].
OH and tachycardia may occur after prolonged bed rest or following exposure to microgravity, such as in spaceflights [24].
Examination
The history is of particular importance and has a high diagnostic value (including pre-existing conditions, a detailed description of the order of symptoms, and exhaustive drug history including over-the-counter drugs) [5].
The European Federation of Neurological Societies (EFNS) guidelines on the diagnosis and management of OH [23] recommend the following actions:
Structured history taking see Sect. 2.2.1.1
Detailed physical examination
12-lead ECG recording
Laboratory testing [25]:
Blood tests (HbA1C), oral glucose tolerance test, urea and electrolytes, thyroid-stimulating hormone, HIV serology, hepatitis C serology/viral load, ACE level, ANA, anti-Ro/La antibodies, rheumatoid factor/anti-cyclic citrullinated peptide antibodies, anti-tissue transglutaminase antibody, serum electrophoresis, vitamin B12 levels, leucocyte α-galactosidase A activity (Fabry’s disease), lipid profile, erythrocyte sedimentation rate, and SAP (serum amyloid P component)
Eventually additional tests are needed:
Genetic testing: SCN9A/SCN10A mutations and transthyretin mutations (familial amyloid)
Imaging: if malignancy or sarcoidosis suspected, chest X-ray/CT with contrast and SAP (Serum Amyloid P component) scan (amyloid)
Tissue biopsy: abdominal fat biopsy (amyloid), small bowel biopsy (coeliac disease), biopsy of suspicious lesion to confirm malignancy, lip biopsy (Sjögren’s syndrome), and nerve biopsy (generally not performed unless there is large fibre involvement)
BP measurements while supine and upright
Cardiologic referral, if heart disease or abnormal ECG is present or suspected
Active standing or head-up tilt (HUT), ideally with continuous assessment of BP and HR for 3 min
Further ANS screening tests, with other appropriate investigations, depending on the possible aetiology of the underlying disorder
Non-neurogenic causes of OH must be considered, as they can exacerbate neurogenic OH [5].
Treatment of OH
General Management [5, 26]
Longitudinal studies have suggested that OH can increase the risk for stroke, myocardial ischaemia, and mortality. The therapeutic goal is to attenuate or eliminate symptoms rather than restore normotension.
Non-pharmacological Treatment
Non-pharmacological measurements are the basis for all interventions. Commonly before starting on any medication, the patient should have boosted the blood pressure by non-pharmacologic measurements first for a couple of months, i.e. venous compression, use of physical counter manoeuvres, and intermittent water bolus treatment. Treatment can be difficult, and the development of supine hypertension should be minimised, especially in patients with diabetes, heart failure, or cardiac ischaemia [20].
Standing upright results in translocation of between 500 and 700 mL of blood from central compartments to the lower limbs; this causes marked pressure differentials, with a substantial rise in pressure below and a fall in pressure above heart level [27]. It is essential to use adaptive mechanisms to ensure the maintenance of arterial blood pressure and in providing an adequate perfusion pressure to organs, to avoid malfunction especially while standing upright.
Avoidance of factors that may induce OH, like elevated environmental temperatures (hot bath, hot shower, and sauna) which may cause venous pooling.
Avoid prolonged recumbence during daytime.
Avoid sudden head-up postural change (especially on waking when BP may be lowered by nocturnal polyuria) [28]. In the morning, move to head-up position slowly, sit on the edge of the bed for some minutes after recumbence, and activate calf muscles while supine.
Two glasses of water on the bed table, slowly getting out of bed [29].
Elevation of the bed head (20–30 cm) to avoid supine hypertension.
High salt diet (6–10 g/day).
High fluid intake (six to eight cups of water each day) [29].
A small amount of coffee or tea is beneficial, coffee (one or two cups) after meals.
Avoid alcohol.
Avoid large meals (especially with refined carbohydrate).
Maintain postural stimuli.
Move slowly when sitting up or standing after lying down.
Avoid standing for long periods of time.
Physical counter manoeuvres (e.g. leg crossing on standing, gentle marching on the spot instead of standing still) (Fig. 3.1).
Elastic stockings and abdominal compression bands reduce venous pooling [32].
Avoid straining during micturition and defaecation. For males: moving to a sitting position for micturition. The use of prokinetic drugs to avoid constipation.
Resting in morning and postprandial.
Staged standing.
Physical activity: carefully controlled and individualised exercise training (swimming, aerobics, cycling, and walking if possible) often improves OH.
Correction of anaemia.
Education of patients and carers on the mechanisms of OH.
Black liquorice (3 g/day) (should not be used for a longer period due to potential hormonal side effects) [33].
Fig. 3.1
Counter manoeuvre showing recommended poses: the trace shows beat to beat blood pressure recordings and consecutive changes after initiation of the counter manoeuvre: (a) leg crossing, (b) squatting, (c) bending, (d) foot on the chair
Pharmacologic Treatment
Non-pharmacological treatment should always be optimised before starting on drugs. Strategies in pharmacological treatment are volume expansion, vasoconstriction, or combination of the two [20].
Volume expansion
Vasoconstriction
Combination therapy
Fludrocortisone (0.1–0.3 mg/day) and Midodrine (5–10 mg tds)
Midodrine (5–10 mg) or Pseudoephedrine (30 mg) and water bolus
3.2.1.2 Postprandial Hypotension (PPH)
Definition
Postprandial hypotension (PPH) was first described by Seyer-Hansen in a patient with severe Parkinson’s disease in 1977 [46]. PPH is by definition a decrease in systolic blood pressure of ≥20 mm Hg or a decrease below 90 mm Hg from a pressure of ≥100 mm Hg within 2 h after a meal [39]. PPH can be detected by either a 24-h blood pressure profile or testing in the autonomic laboratory.
Risk Factors for Postprandial Hypotension [47]
Medications
Polypharmacy (>3 medications)
Diuretics
Meals
Carbohydrate-rich meals
Breakfast
Hot meals
Alcohol
Comorbid conditions
Diabetes mellitus
Autonomic dysfunction
Parkinson’s disease
Hypertension
End-stage renal disease on haemodialysis
Fragile X mutation
Treatment of PPH
Non-pharmacological Management [48]
Drink water before meals.
Eat frequently, smaller meals.
Assume a recumbent or sitting position after a meal.
Avoid large meals.
Avoid alcohol before and after meal.
Dietary modification, reduce refined carbohydrates.
Water with the meal.
Wear abdominal binders.
3.2.1.3 Exercise-Induced Hypotension (EIH) and Post-exercise Hypotension (PEH)
Definition
Exercise-induced hypotension was first reported in autonomic failure patients cycling in supine position in 1961 by Shepherd and colleagues in a group of patients who performed supine cycling exercise [51].
Exercise-induced hypotension (EIH) is defined as a ≥10 mmHg fall in systolic blood pressure during exercise due to fall in total peripheral resistance [52]. Impairment of sympathetic vasoconstriction in autonomic failure has been documented as systemic vascular resistance falls substantially in the patients during exercise [53]. EIH can be a significant symptom in patients with PAF, MSA, and SCI. The severity of EIH seems to be higher during dynamic relative to static exercise [52].
Post-exercise hypotension (PEH) is defined as a reduction in systolic and/or diastolic arterial blood pressure (i.e. reduction in mean arterial pressure) below control levels after a single bout of exercise for approximately 1–3 h [54]. PEH has been well documented in humans with both borderline hypertension and hypertension [55], with diabetes [56], in healthy endurance training athletes [57], and in SCI [58]. Data suggest that PEH may also occur after resistance exercise [55]. Studies have suggested that a reflex similar to the Bezold–Jarisch reflex is the final pathway triggering the vasovagal reaction in exercise-induced neurally mediated syncope [53]. The Bezold–Jarisch reflex is a triad of responses (apnoea, bradycardia, and hypotension) and depends on intact vagal nerves and is mediated through cranial part of medullary centres controlling respiration, heart rate, and vasomotor tone [59].
Treatment of EIH and PEH
Non-pharmacological Measurements
Adequate hydration prior to exercise.
Avoiding food intake for several hours before exercise to prevent postprandial hypotension.
Increased daily salt intake [60].
Prevention of dehydration after exercise by oral water intake during exercise [61].
Muscle tensing [60].
Use of abdominal compression/binders and lower limb elastic stockings [60].
Mild physical exercise/activity [60].
Pharmacological Measurements
Unfortunately there are limitations to pharmacological treatment in exercise-induced hypotension [52]. Both octreotide and midodrine did not show any effect on exercise-induced hypotension in studies; however, the increase in blood pressure overall may be beneficial in reducing fatigue [62].
In a small study with four patients with SCI (C6–C8), treatment with 10 mg Midodrine was associated with elevated systolic blood pressure during peak exercise in three participants. Two participants showed a concurrent decrease in perceived exertion and increase in oxygen consumption, suggestive of some benefit from Midodrine on EIH in SCI [63].
3.2.1.4 Supine Hypertension
Supine hypertension is a common finding in autonomic failure and complicates the treatment of the OH [64]. Supine hypertension can worsen OH and predispose to end-organ damage [65], resulting from medication and/or being part of the disease, especially in PAF.
Supine hypertension, defined as a systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, is present in one half of patients with severe autonomic failure, despite normal seated and low upright blood pressures [64, 66].
Nocturnal hypertension is defined as night-time BP means ≥120/70 mm Hg (fixed cut-off limits) [67]. A 24-h ambulatory BP monitor is needed to screen for nocturnal hypertension and missing dipping and may be very useful before and if needed after starting a new therapy [68].
Ways to Counteract Supine Hypertension [65]
Avoid supine position during daytime.
Patients can sit in a reclining chair with feet on the floor when rest is needed.
Avoid pressor medications after 16.00 h.
Elevate the bed head (20–30 cm).
Have a snack just before going to bed (inducing postprandial hypotension).
If Fludrocortisone is used, this may worsen the supine hypertension. Changing to a short-acting pressor agent (e.g. Midodrine, Droxidopa, etc.) may sometimes be of help.
Avoid over-the-counter medications that increase blood pressure such as nasal decongestants or eye drops containing sympathomimetics and non-steroidal anti-inflammatory agents (indomethacin and ibuprofen).
Pharmacological Interventions (Single Dose Given at Bedtime)
Losartan (angiotensin I receptor blocker), 50 mg at bedtime [70].
Transdermal nitroglycerin, 0.05–0.2 mg/h only during night [3].
Hydralazine, 50 mg [3].
Short-acting nifedipine, 30 mg [3].
Clonidine 0.1 mg early in the evening – Clonidine has a long half-life which may exacerbate morning OH [3].
Sildenafil, 25 mg [3].
Minoxidil, 2.5 mg [3].
3.2.2 Syncope
Syncope is defined as transient loss of consciousness due to global cerebral hypoperfusion. It is characterised by rapid onset, brief duration of loss of consciousness with spontaneous, and full recovery [9].
Syncope is a common medical problem, with a frequency between 15% and 39% [70]. In the general population, the annual number episodes are 18.1–39.7 per 1000 patients, with similar incidence between genders. The first report of the incidence of syncope is 6.2 per 1000 person-years [9], with a significant increased incidence after 70 years of age [70]. Syncope is responsible for 3–5% of emergency department visits [70].
The prognosis depends on the diagnosis [71]. If the patient has a structural heart disease or primary cardiac disease, there is an increased incidence of sudden death and overall mortality. If the syncope is caused by orthostatic hypotension, it is associated with a twofold increase in mortality, while young patients with neurally mediated syncope have a very good prognosis [71].
3.2.2.1 Classification
Causes of Syncope [72, 73]
Neurally mediated (vasovagal/reflex) syncope
- (a)
Vasodepressive
- (b)
Cardioinhibitory
- (c)
Mixed
Situational syncope (vasovagal in nature)
Cough and sneeze
Micturition (post-micturition)
Post-exercise
Postprandial
Gastrointestinal stimulation (swallow, defaecation, visceral pain)
Other (laughter, brass instrument playing, weightlifting)
Post-ejaculation
Carotid sinus syncope
Orthostatic/postural syncope
- (a)
Autonomic failure
Primary autonomic failure syndromes (i.e. pure autonomic failure, multiple system atrophy, Parkinson’s disease with autonomic failure, dementia with Lewy bodies)
Secondary autonomic failure syndromes (i.e. diabetic neuropathy, amyloid neuropathy)
Post-exercise
Postprandial
- (b)
Volume depletion
Haemorrhage, diarrhoea, and Addison’s disease
Cardiac arrhythmias as primary cause
Sinus node dysfunction (including bradycardia/tachycardia syndrome)
Atrioventricular conduction system disease
Paroxysmal supraventricular and ventricular tachycardias
Inherited syndromes (i.e. long QT syndrome, Brugada syndrome)
Implanted device (pacemaker, implantable cardioverter defibrillator) malfunction
Drug-induced arrhythmias
Structural cardiac or cardiopulmonary disease
Obstructive cardiac valvular disease
Acute myocardial infarction/ischaemia
Obstructive cardiomyopathy
Atrial myxoma
Acute aortic dissection
Pericardial disease/tamponade
Pulmonary embolus/pulmonary hypertension
Cerebrovascular
Vascular steal syndromes
Epilepsy with bradyarrhythmias/asystole (ictal asystole)
Non-cardiovascular/nonsyncopal causes of transient loss of consciousness
Epileptic
Non-epileptic (“sleep attacks”)
Metabolic disorders (hypoglycaemia)
Neuroendocrine disorders (pheochromocytoma, carcinoid)
Drugs
Psychogenic pseudo-syncope and psychogenic non-epileptic seizure
Traumatic
3.2.2.2 Neurally Mediated Syncope (Vasovagal/Reflex)
Vasovagal syncope was first used by William Gowers in 1907, and Thomas Lewin described the mechanism in 1932 [70]. The neurally mediated syncope, known as neurocardiogenic or vasovagal syncope, is the most frequent, accounting for one third of the causes and reaching 66% of cases of syncope in emergency units [70].
Neurally mediated syncope is characterised by periodic syncopal episodes with normal autonomic function between episodes. Symptoms that trigger syncope include orthostatic stress, prolonged standing, hot temperature, emotional stress, pain, or sight of blood. During neurally mediated syncope, vasodilatation and bradycardia occur simultaneously. The bradycardia is due to increased parasympathetic (vagal) outflow to the sinus node of the heart. The decrease in blood pressure is due to vasodilatation most likely by brainstem shut down of vascular sympathetic outflow, but the mechanism is not clear.
These reflex bradycardia and hypotension are similar to the response evoked by the Bezold–Jarisch reflex. The characteristic pre-syncopal symptoms are weakness, light-headedness, feelings of warmth or cold, and eventual brief loss of consciousness. Potential cardiac causes of syncope must be considered before making the diagnosis. Spontaneous syncope is common, and in the absence of any underlying cardiovascular, neurologic, or other disease, an isolated vasovagal syncope may represent a variation of normal. The persons are usually normotensive with normal blood pressure regulation.
The diagnosis may sometimes be difficult to make. Situational syncope must be excluded, as well as phobia syndromes or other organic causes. Tilt table testing has good specificity but uncertain sensitivity in diagnosis and is not always reproducible. Implantable loop recorders, which store 45 min of retrospective electrocardiographic data, may also be used and can be activated by patients after each syncopal event.
Related posts:
Autonomic History Taking and Key Symptoms: Where Is the Autonomic Disease?
Sleep: Cardiovascular and Ventilatory Disorders
Gastrointestinal Dysfunction
Sweating Disorders
General Approach to Patients with Autonomic Disorders: “What Is the Autonomic Disease?” – A Basic Tutorial to Autonomic Physiology and Pathophysiology
Bladder and Sexual Dysfunction
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