3rd Congress of the European Academy of Neurology

Amsterdam, The Netherlands, June 24 – 27, 2017

Teaching Course 13

How to manage a patient with autonomic dysfunction -

Level 2

How to manage a patient with orthostatic

hypotension
Anne Pavy-Le Traon
Toulouse, France

Email: pavy-letraon.a@chu-toulouse.fr
Conflict of interest: The author has no conflict of interest in relation to
this manuscript

Orthostatic Hypotension definition

OH is defined by consensus [1] as a drop in blood pressure (BP) of at least

20 mm Hg for systolic BP or 10 mm Hg for diastolic BP within 3 minutes of

standing (or during a head up tilt test to at least 60°). The clinical

features and pathophysiology of OH were reviewed in 2009 [2] and in

2011 [3] resulting in the publication of a new consensus. The authors

recommend using a drop of at least 30 mm Hg in patients with

hypertension (systolic blood pressure > 160 mm Hg) to define OH. This

consensus also identifies two other forms of OH: initial OH and delayed

OH. Initial OH is defined as an exaggerated fall in blood pressure within

the first few seconds of standing; this initial OH is considered excessive

when the transient blood pressure decrease is over 40 mm Hg (systolic

blood pressure) or 20 mm Hg (diastolic blood pressure) within 15-20

seconds of standing. This initial blood pressure fall is observed with

continuous blood pressure monitoring, generally during active orthostatic

tests and mainly in young subjects. It may be symptomatic when it occurs

within a few seconds of standing but is not due to anatomic lesions [3].

The second form is delayed OH; some patients present OH that occurs

beyond three minutes of standing (in general when orthostatic stress is

prolonged more than 5 minutes) [2]. The clinical significance of delayed

OH is less well known but may reveal an early or mild form of sympathetic

adrenergic failure [4].

1
Orthostatic intolerance may also be observed in cases of excessive

postural tachycardia (POTS for Postural Tachycardia Orthostatic

Syndrome). In this heterogeneous, multifactor syndrome, the clinical signs

of orthostatic intolerance are coupled with an excessive increase in heart

rate (>30 bpm with an HR in upright position >120 bpm) but without any

significant hypotension [5].

Pathophysiology of Orthostatic Hypotension

Under normal conditions, standing results in gravitational redistribution of

about 500 ml of blood in the splanchnic circulation and in the lower limbs.

As a consequence, venous return and cardiac filling pressure fall, resulting

in temporarily decreased cardiac output and blood pressure. In response,

the aortic and carotid baroreceptors which are sensitive to blood pressure

variations send the information to centers localized in the brainstem; as a

result the decrease in BP leads to cardiac parasympathetic inhibition and

sympathetic activation with increased heart rate and above all peripheral

vasoconstriction. Vasoconstriction in the lower members is also favored by

the veino-arterial reflex. Neuro-hormonal mechanisms rapidly take over,

triggering the renin-angiotensin system and secretion of noradrenaline (x 2

in upright position). An inadequate response from one of these

mechanisms may be responsible for OH.

Diagnosis of Orthostatic Hypotension

Blood pressure measurement

The BP must be measured in both lying and standing positions. It is

preferable to use an automatic measuring device than a manual one. The

BP and heart rate (HR) are measured after the patient has been lying

down for at least 5 min (or until BP values are stable), at a comfortable

2
temperature (20-24°C), with an empty bladder. Then the patient is asked

to stand up and BP and HR are measured every minute for three to five

minutes. The patient must be asked whether or not symptoms occur

during the test. The test may be interrupted in case of pre-syncopal

symptoms. If OH is suspected but the orthostatic test is negative, the test

must be repeated at other times. In patients with suspected neurogenic

OH, extending the orthostatic test up to 10 min is recommended in order

to check for delayed OH ([6] [7]).

Under certain conditions, a passive test on a tilt-table (+60 à +80°) may

be used to detect OH, either to sensitize the OH detection or in patients

who have physical disorders [8].

HR variations must be monitored. A limited or no increase in HR

associated with OH will indicate a neurogenic cause (Figure 1). A large

increase in heart rate will be a sign of hypovolemia or anemia. These HR

variations decrease significantly with age and should be interpreted

accordingly.

Figure 1: Changes in BP and HR during a tilt test of 5 minutes on a patient

showing neurogenic OH.
Figure from Low et al, 2013 [9]

3
In patients with autonomic failure characterized by neurogenic OH, OH is

often associated with supine hypertension [10]. In this case it may be

useful to carry out ambulatory blood pressure monitoring over 24h to

detect associated post-prandial hypotension, excessive pressure

variability, reduced or inverted circadian rhythm (non-dipping) or supine

hypertension.

Clinical signs

OH may be asymptomatic or symptomatic. There is not always a

correlation between the fall in BP and the symptoms severity.

Characteristic signs include lightheadedness, visual blurring, dizziness and

even loss of consciousness. These symptoms occur particularly when

standing, rapidly after standing up or as a result of continued standing.

Some symptoms are quite characteristic but less well known, such as a

lower cervical and shoulder pain known as “Coat hanger ache” induced by

reduced muscular flow. Some patients present non-specific complaints

such as fatigue, weakness, buzzing in their ears, lack of concentration,

orthostatic dyspnea, difficulty in walking and falls. The circumstances in

which the symptoms occur must be carefully analysed in order to identify

OH as a possible cause.

Questionnaires can also be used in particular during clinical trials to

quantify these OH symptoms; specific OH questionnaires [11] or more

general autonomic failure questionnaires could be used.

Favoring factors

Searching for favoring factors helps to identify OH. The symptoms may be

favored by heat, physical deconditioning such as bed rest, or meals; OH is

more common in the morning or after a meal. In patients with autonomic

4
failure, OH is often associated to postprandial hypotension which can be

defined as a systolic fall of over 20 mm Hg occurring within 90 minutes

following the meal. Elderly patients who are bed-ridden are particularly

susceptible to OH when getting up.

Orthostatic hypotension: a factor of morbidity-mortality

Several studies have shown that OH is an independent factor of morbidity-

mortality ([12]; [13, 14]). In a meta-analysis, Ricci et al [15] have re-

ported a relative risk of mortality of 1.5[1.24, 1.81] in patients with OH,

slightly higher in patients below 65 years (1.78 [1.25, 2.52]). OH may also

cause falls.

Main Causes of Orthostatic Hypotension

The prevalence of OH increases significantly with age (Figure 2), in

particular in institutionalised elderly individuals. [16].

Figure 2: Prevalence of OH by age group

From Wolters et al and Heart BrainConnection Collaborative Research
Group - PLoS Med. 2016 Performed on 6,204 community-dwelling
individuals participating in the Dutch population-based Rotterdam Study
(Cardiovascular Health Study )

5
In these patients the prevalence also increases with the amount of

medication. [17].

Indeed, drugs represent the first cause of OH. Some drugs may be

responsible for OH such as anti-hypertensive treatment, particularly

diuretics, vasodilators, some psychotropic drugs (antidepressants,

neuroleptics), anti-Parkinsonian agents or alpha-blockers (prescribed for

urinary disorders).

Other causes to be investigated include anemia, hypovolemia (dehydra-

tion, vomiting, diarrhea, adrenocortical insufficiency) or relative hypo-

volemia (severe venous insufficiency). OH may result from multiple factors

(hypovolemia, associated neuropathy) in patients suffering from renal

failure.

Neurogenic OH may be suspected when there are autonomic symptoms in

other areas: digestive symptoms (constipation, alternating constipation

and diarrhea ,..), urinary symptoms, erectile dysfunction, sweating dis-

orders, pupil disorders (photophobia, difficulty in accommodating), ptosis,

vasomotor symptoms, hypo-or-hyperhidrosis, cold/heat intolerance...

OH is common among diabetic patients; prevalence varies from 8.2

to 43% according to the criteria used and the studied population [18]. A

prevalence of 20% has been reported in the ACCORD (Action to Control

Cardiovascular Risk in Diabetes) study [19]. In diabetics, OH may be part

of the autonomic neuropathy which is common in this population.

6
Neurogenic OH may also be suspected in case of associated neurological

features, such as an extra-pyramidal syndrome or a peripheral neuro-

pathy. The diagnosis can be oriented according to the patient’s complaints

and associated neurological symptoms indicating a cerebral, spinal or

peripheral pathology [20]. Neurogenic OH is common in some neuro-

degenerative disorders such as Parkinson’s disease where on average 30%

of the patients are affected (Meta-analysis [21]) and up to 50% in some

studies [22]. OH may be dramatic in rarer neurodegenerative disorders

such as Multiple System Atrophy where autonomic failure is a key

symptom, associated with a Parkinson or cerebellar syndrome [23], Lewy

body dementia or pure autonomic failure (PAF) ([24], [25], [26]). PAF is a

rare neurodegenerative disorder of the autonomic nervous system

(sympathetic component) without motor symptoms; the disease duration

may last up to 20 years. However, these patients must be followed up

regularly to make sure no other neurological symptoms appear. In neuro-

degenerative disorders with autonomic failure, supine hypertension is

observed in at least 50% of the patients with neurogenic OH (NOH) [24] –

NOH severity is often correlated with supine hypertension severity ([7],

[26]). There are numerous other possible causes of autonomic failure

which may induce OH (metabolic, infectious, traumatic, paraneoplastic,

genetic and toxic). The table 1 (adapted from a document published by a

consensus of experts (French Society of Hypertension, French Society of

Geriatrics and Gerontology and European Federation of Autonomic

Societies) summarizes the main causes of OH [27].

7
Secondary OH Neurogenic OH

Medications Neurodegenerative Diseases (mainly Neoplasia :

Antihypertensive
Psychotropics (neuroleptics,
antidepressants)
Vasodilatators (nitrates,
alpha-blockers, sildénafil…)
Antiparkinsonian
Anticholinergics
Opiates,
..
Hypovolemia
Dehydration
Salt-free diet
Denutrition
Anemia
Adrenal insufficiency
Venous insufficiency
(relative hypovolemia)
synucleinopathies) - Paraneoplastic
- Parkinson’s Disease - Brain tumors (posterior
- Lewy Body Disease fossa, medullary)
- Multiple System Atrophy * - Cervical radiotheray
- Pure Autonomic Failure *
Spinal cord injuries
Familial Dysautonomia ** - Traumatic
- Multiple sclerosis
Dopamine beta-hydroxylase deficiency**
- Myelitis
Autoimmune Autonomic neuropathy
Other traumatic injuries :
- Autoimmune ganglionopathy
- Sympathectomy
- Guillain-Barre syndrome
- Cervical surgery
Amyloidosis
Infections :
Diabetes mellitus - Botulism
- HIV
Chronic Renal Failure
- Chagas disease, …
Other metabolic causes :
Toxic substances :
- Vitamin B deficiency
- Heavy metals
- Alcoholism - Medications (ex :
- Porphyria
vincristine , ..)
- Fabry disease
- Ciguatera
- …

Table 1: Main causes of Orthostatic Hypotension adapted from Pathak et

al, Expert Consensus, 2014, [27]. *In these diseases, OH is a main symptom
** These genetic diseases are very rare.

In some cases it may be useful to get the opinion of a specialist, to search

and quantify more precisely the autonomic failure through specific

investigations of the autonomic nervous system (ANS) available in some

centres. These tests are based on continuous monitoring of BP and HR and

assess the response of the sympathetic, parasympathetic and baroreflex

systems during physiological stimulations [9] Sweating may also be

studied, to detect associated sympathetic sudoro-motor impairment [28].

8
Treatment of Orthostatic Hypotension

Identification of the mechanism of OH (disease, drug or other causes) is

the first step in the treatment, followed by non-pharmacological

measures. OH must be treated whilst it is symptomatic and/or severe.

First of all, and when possible, treatments likely to induce OH should be

stopped or limited. The factors favoring OH should be investigated and

explained to the patient. Hot baths, large meals, especially meals high in

carbohydrate and alcohol which are vasodilators, should be avoided [29].

The patient must also avoid changing positions too quickly.

Non-pharmocological measures

Non-pharmacological measures can be used to limit OH and its symptoms:

• Wearing force 2 to 3 compression tights or stockings (to be put

on in the morning before getting up). Compression stockings

which prevent blood from being stored under the waist are

more efficient than stockings [25].

• Sufficient hydration, by drinking one to two large glasses of

water before each meal to limit post-prandial hypotension,

often associated with NOH. The increase in BP observed after

drinking water is induced by a reflex mechanism [30].

• Eating meals more often, in small quantities and poor in rapidly

absorbed carbohydrate, to limit post-prandial hypotension.

• Salty diet (to be adapted in case of edema/heart failure).

• Elevating the head and neck during the night (30° tilt) to

activate the carotid and aortic baroreceptors and the renin-

angiotensin-aldosterone system, in order to limit supine hyper-

tension and reduce early morning hypotension.

9
Pharmacological measures

The drugs generally used and recommended to treat neurogenic OH are

midodrine and fludrocortisone, either alone or together. Since 2014,

Droxi-Dopa (L-Threo DOPS) can be used in US to treat NOH (FDA

agreement); currently this drug does not have drug marketing approval for

NOH in Europe. Other drugs such as dihydroergotamine and etilefrine have

been prescribed for treating NOH but none of them proved to be effective

for NOH. Some drugs listed hereafter are more rarely used and should be

administered by a specialist.

- Midodrine is a prodrug which when hydrolysed becomes desmo-

glymidodrine, an α1 adrenoceptor agonist. This molecule has proved to

be effective on NOH by increasing peripheral vascular resistance ([31];

[32]; [33]). This α1-adrenoceptor agonist (2.5 mg/tablet) can be

administered up to maximum 30 mg/d, taken in three or four doses due

to its short half-life (3-4 h). The last dose should be taken at least 4-5

h before sleeping to prevent supine hypertension.

Midodrine may favor the occurrence of urinary retention. Other side-

effects are mainly piloerection (dose-dependent) and to a lesser degree

irritability and insomnia. Midodrine is eliminated through the kidneys so

renal function should also be monitored. Further studies are still

needed to assess the benefit/risk ratio of midodrine in the long term in

patients suffering from NOH.

- Fludrocortisone increases renal sodium re-absorption and expands

plasma volume, thus leading to increased blood pressure. Effects last

longer than those of midodrine, thus making it more difficult to avoid

nocturnal supine hypertension. Fludrocortisone's efficacy remains

10
 insufficiently documented. The dosage of around 50 to 150µg per day

can be gradually incremented (up to a maximum of 300µg/day). Side-

effects, resulting from its mineralocorticoid activity, are salt and water

retention and hypokalemia. This drug may cause edema and may be

contra-indicated with patients with heart failure.

- L-threo DOPS or Droxidopa, is a noradrenergic precursor, initially

commercialised in Japan for Parkinson’s disease; it has been shown to

improve NOH in clinical trials carried out against placebo, in patients

suffering from neurodegenerative diseases (Parkinson’s Disease, Pure

Autonomic Failure, Multiple System Atrophy) and familial amyloid

neuro-pathy ([34]; [35]; [36]). This drug is also used in dopamine –

beta-hydroxylase deficiency (very rare genetic disease). The drug

received FDA approval for NOH treatment in US in February 2014 but is

not routinely available in Europe. A clinical trial in MSA patients is still

ongoing in France.

- Pyridostigmine is a cholinesterase inhibitor that may improve OH by

facilitating ganglionic transmission; it has been shown to improve OH in

comparison with placebo [37]. The same authors have suggested using

it alone to treat moderate OH, starting with a dose of 30 mg 2 to 3

times a day (maximum dose 180 mg/d). –

- Desmopressin, similar to vasopressin, reduces nocturnal polyuria and

might improve morning OH ([38]; [39]). This treatment requires blood

electrolyte monitoring.

- Erythropoietin which increases blood volume can also be used, when

autonomic failure is associated with a reduced red cell mass.

11
Treatment of associated supine hypertension

Patients with autonomic failure are often experiencing both NOH and

supine hypertension which may be severe. In these cases fludrocortisone

should be limited and using evening short-acting antihypertensive agents

may be proposed. However, long-term CV risks of supine hypertension in

this population are not well known and the decision to treat or not the

patient should be individualized [25].

Conclusion

OH is often under-estimated. Identification of OH mechanisms (disease,

drug or other causes) is the first step in the management of these

patients. Non-pharmacological measures are recommended first alone or

associated with pharmacological treatment. An expert advice may be

needed in some cases of NOH. There is no consensus regarding the

treatment of associated supine hypertension.

12
 Orthostatic Hypotension

Avoid and treat any potential factor which may favor OH ((hypovolemia, anemia, medications (in
particular diuretics and alpha-blockers))

Non-pharmacological measures:

ü Educate the patient : avoid precipitating factors such as rapid postural change, hot baths,
alcohol, prolonged bed rest )

ü Increase water intake (up to 1.5 to 2 L) and add salt to the diet (6 à 10 g Na Cl/day – to be
adapted in case of edema/cardiac failure) –Intake of two glasses of water before meals
ü Compression tights or stockings
ü Elevating the head of the bed of about 30° during the sleep

Sufficient No or insufficient improvment-

improvment symptomatic OH

Pharmacological treatment: Midodrine (or

DroxiDopa*)

or Fludrocortisone (si contra-indication)

Maintain non-
pharmacological Maintain treatment
(under regular Yes Improvment
measures
medical and
biological follow-up)

No

Midodrine (or DroxiDopa*)

+ Fludrocortisone (under medical

and biological follow-up)

* available in US and Japan – no marketing approval in Europe. **Other medications could be used in some
cases such as pyridostigmin or erythropoietin (see corresponding text)

Figure 3 : Management of Orthostatic Hypotension

13
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