Satish R Raj MD MSCI
Autonomic Dysfunction Center, Division of Clinical Pharmacology,
Departments of Medicine & Pharmacology, Vanderbilt University,
Nashville, Tennessee, USA.
Funding:
Supported in part by National Institute of Health
grants 2P01 HL56693, K23 RR020783 and M01 RR00095.
Address for
correspondence: Satish R Raj MD MSCI, AA3228 Medical Center
North, Vanderbilt University, 1161 21st Avenue South
Nashville, TN, 37232-2195, USA. Email: satish.raj@vanderbilt.edu
Abstract
Postural
tachycardia syndrome (POTS), characterized by orthostatic tachycardia
in the absence of orthostatic hypotension, has been the focus of
increasing clinical interest over the last 15 years 1. Patients
with POTS complain of symptoms of tachycardia, exercise intolerance,
lightheadedness, extreme fatigue, headache and mental clouding.
Patients with POTS demonstrate a heart rate increase of ≥30 bpm with
prolonged standing (5-30 minutes), often have high levels of upright
plasma norepinephrine (reflecting sympathetic nervous system
activation), and many patients have a low blood volume. POTS can
be associated with a high degree of functional disability.
Therapies aimed at correcting the hypovolemia and the autonomic
imbalance may help relieve the severity of the symptoms. This review
outlines the present understanding of the pathophysiology, diagnosis,
and management of POTS.
Key Words: Postural
Tachycardia Syndrome; Pathophysiology; Diagnosis; Management
Introduction
Postural tachycardia syndrome (POTS), characterized by orthostatic
tachycardia in the absence of orthostatic hypotension, has been the
focus of increasing clinical interest over the last 15 years
1. Patients with POTS complain of
symptoms of tachycardia, exercise intolerance, lightheadedness, extreme
fatigue, headache and mental clouding. This disorder is not new
2, but has gone by many different names
over the last 150 years, including mitral valve prolapse syndrome,
neurocirculatory asthenia, orthostatic tachycardia, and orthostatic
intolerance
3,4.
An advantage of the name postural tachycardia syndrome (POTS) is that
it focuses attention on the sympathetic activation which characterizes
the disorder. This review outlines the present understanding of
the pathophysiology, diagnosis, and management of POTS.
Physiology of Upright Posture
Assumption of the upright posture requires prompt physiological
adaptation to gravity. There is an instantaneous descent of ~500
ml of blood from the thorax to the lower abdomen, buttocks, and
legs. In addition, there is a 10-25% shift of plasma volume out
of the vasculature and into the interstitial tissue
5. This shift decreases venous
return to the heart, resulting in a transient decline in both arterial
pressure and cardiac filling. This has the effect of reducing the
pressure on the baroreceptors, triggering a compensatory sympathetic
activation that results in an increase in heart rate and systemic
vasoconstriction (countering the initial decline in blood
pressure). Hence, assumption of upright posture results in a
10-20 beat per minute increase in heart rate, a negligible change in
systolic blood pressure, and a ~5 mmHg increase in diastolic blood
pressure.
Pathophysiology of Orthostatic
Dysregulation
Failure of the
regulatory mechanism to respond properly may lead to either
orthostatic hypotension,
as is seen in autonomic failure, or
orthostatic tachycardia,
as is seen in POTS. Orthostatic hypotension is defined as a fall
in pressure on standing of more than 20/10 mmHg. However, it is
common in patients with autonomic failure for the decline to be much
greater than this, which may result in loss of consciousness soon after
standing. On the other hand, in POTS, blood pressure is typically
maintained on standing or may even increase. Heart rate rises more than
30 bpm and symptoms reminiscent of impaired cerebral perfusion may
develop.
Clinical Presentation of Postural
Tachycardia Syndrome (POTS)
Diagnostic
Criteria & Common Clinical Features
POTS is
defined (
Table 1) as the
presence of symptoms of orthostatic intolerance for at least 6 months
accompanied by a heart rate increase of at least 30 beats/min within
5-30 minutes of assuming an upright posture. This should occur in
the absence of orthostatic hypotension (a fall in blood pressure
>20/10 mmHg). The syndrome must occur in the absence of
prolonged bed rest, medications that impair autonomic regulation (such
as vasodilators, diuretics, antidepressants or anxiolytic agents), or
any other chronic debilitating disorders that might cause tachycardia
(such as dehydration, anemia or hyperthyroidism). It is important
to recognize that this syndrome is typically disabling. Hence,
the mere observation of orthostatic tachycardia is not, by itself,
sufficient to make the diagnosis of POTS.
Table
1: Criteria for the Postural Tachycardia Syndrome
1. Heart rate increase ≥30
beats per minute from supine to standing (5-30 min)
2. Symptoms get worse with standing and better with recumbence.
3. Symptoms lasting ≥6 months
4. Standing plasma norepinephrine ≥600 pg/ml (≥3.5 nM)
5. Absence of other overt cause of orthostatic symptoms or tachycardia
(e.g. active bleeding, acute dehydration, medications).
Symptoms
include mental clouding (“brain fog”), blurred or tunneled vision,
shortness of breath, palpitation, tremulousness, chest discomfort,
headache, lightheadedness and nausea. While pre-syncope is common
in these patients, only a minority (~30%) actually pass out. The
chest pains are almost never due to coronary artery obstruction, but
are sometimes associated with electrocardiographic changes in the
inferior leads, particularly when upright
6.
Many patients
complain of significant exercise intolerance and extreme fatigue.
Even activities of daily living, such as bathing or housework, may
greatly exacerbate symptoms with resultant fatigue. This can pose
significant limitations on their functional capacity.
The disorder
primarily affects women of child-bearing age. The female:male
ratio is 4:1. The reason for the strong female predominance is
not known, but it should be noted that orthostatic tolerance is reduced
in normal healthy females
7.
Others disorders such as autoimmune diseases and irritable bowel
syndrome are seen commonly in patients with POTS, and also have higher
prevalence in women.
Patients
frequently report that their symptoms began following acute stressors
such as pregnancy, major surgery, or a presumed viral illness, but in
others cases, symptoms develop more insidiously. About 80% of
female patients report an exacerbation of symptoms in the pre-menstrual
phase of their ovulatory cycle (unpublished data). Gazit et al.
have also reported an association between joint hypermobility and POTS
8. Many patients have bowel irregularities
and have been co-diagnosed with irritable bowel syndrome, and some have
abnormalities of sudomotor regulation
9.
Psychological
Profile in POTS
Patients with
POTS are sometimes clinically diagnosed as having anxiety disorders
such as panic disorder. Indeed, patients demonstrate elevated
scores on the Beck Anxiety Inventory
10
(23±10 vs. 7±8; P<0.001), a commonly used instrument
that quantifies the magnitude of anxiety symptoms
11. Unfortunately, this
questionnaire includes somatic anxiety symptoms (such as palpitation)
which can result from a hyperadrenergic state such as is seen in
POTS. When a newer, cognitive-based measure of anxiety (the
Anxiety Sensitivity Index
12)
is used, there was a trend toward less anxiety in the patients with
POTS than the general population (15±10 vs. 19±9; P=0.063)
11. Thus, much of the anxiety
attributed to patients with POTS might be due to a misinterpretation of
their physical symptoms.
We did find
that patients with POTS often have diminished attention and
concentration compared to matched healthy volunteers
11. Using the Inattention score
from the Connors Adult ADHD Rating Scale
13,
the patients with POTS scored significantly higher than did the normal
control subjects.
Physical
Findings in POTS
The
most striking physical feature of POTS is the severe tachycardia that
develops on standing from a supine position. Blood pressure and
heart rate must be measured in both postures and should be taken not
only immediately after standing but also at 2, 5 and 10 minutes as
occasional patients have a delayed tachycardia
14.
Normal subjects commonly develop a transient tachycardia within the 1st
minute of standing that should not be mistaken for POTS. A sustained
heart rate increase ≥30 beats per minute is considered diagnostic of
orthostatic tachycardia (
Figure 1).
The systolic blood pressure should not fall by more than 20 mmHg, and
in many cases it will actually increase with standing. Recent
data suggests that there may be a significant circadian variability in
the orthostatic tachycardia seen in patients with POTS
15. In a cohort of 17 patients with
POTS, the orthostatic tachycardia was greater in the morning than in
the evening (38±4 bpm vs. 27±3 bpm; P<0.001), while
there was no diurnal difference in the orthostatic change in blood
pressure. These data suggest that to optimize diagnostic
sensitivity, postural vital signs should be performed in the morning.
Figure
1 – Hemodynamics with Upright Posture in POTS
The tracings for heart rate, blood pressure, and
tilt table angle are shown for a patient with the postural tachycardia
syndrome (POTS;
left) and for
a healthy control subject (
right)
during a 30 minute tilt head-up test. With head-up tilt, the
heart rte immediately increases in POTS and peaks at over 170 bpm prior
to the end of the tilt. In contrast the heart rate of the healthy
control subject rises to just over 100 bpm. The patient with POTS
does not experience a reduction in blood pressure during the tilt
test. It is largely unchanged during the test.
Cardiac
auscultation may reveal a murmur of mitral valve prolapse, but
significant mitral regurgitation is unusual. A striking physical
feature of POTS is the dependant acrocyanosis that occurs in 40-50% of
patients with POTS (
Figure 2).
These patients experience a dark red-blue discoloration of their legs,
which are cold to the touch. This can extend from the feet to
above the level of the knees. The reasons underlying this
phenomenon are not clear. The current data suggest that the
problem is not due to increased pooling in the venous capacitance
vessels, but rather due to decreased blood flow in the skin
16,17.
Figure
2 – Acrocyanosis in POTS
One of the more striking physical features in the
postural tachycardia syndrome (POTS) is the gross change in dependent
skin color that can occur with standing. The panel shows the legs
of 2 people who have been standing for 5 minutes, a healthy control
subject (
left) and a patient
with POTS (
right). The
patient with POTS (right) has significant dark red mottling of her legs
extending up to the knees while standing, while the control subject
does not have a similar discoloration.
Some authors advocate the use head-up tilt table testing as a
standardized method to assess an individual's response to a change in
posture
1. The patient
is positioned on a standard tilt table and following baseline
measurements of blood pressure and heart rate, the patient is inclined
to a 70-degree head-up angle. Blood pressure and heart rate are
then measured either continuously or at least every 12 minutes. The
orthostatic tachycardia is often measured in a similar fashion to the
standing test, with a similar threshold used to diagnose orthostatic
tachycardia (an increase of ≥30 bpm)
1.
However, the physiology in response to passive standing on a tilt table
(with the legs still) is not the same as “active standing” where the
patient must support their own weight and maintain their balance.
The latter requires use of the “skeletal muscle pump” and mimics real
life, while the tilt table does not. For this reason Streeten et
al. use similar criteria for orthostatic tachycardia (>27 bpm), but
only with active standing
18.
In a recent study, we compared the orthostatic heart rate response of
these 2 methods, and found that the tilt table test was associated with
an increased orthostatic tachycardia in both patients with POTS and
control subjects
19. While
both tests were sensitive for the diagnosis of POTS with a 30 bpm
threshold for orthostatic tachycardia, the stand test had a specificity
of 79% compared to only 23% for the tilt table test.
POTS patients
should have only sinus tachycardia. An electrocardiogram should
be done routinely to rule out the presence of an accessory bypass tract
or any abnormalities of cardiac conduction. A Holter monitor
might prove useful to exclude a re-entrant dysrhythmia, especially if
the patient gives a history of paroxysmal tachycardia with a sudden
onset and sudden offset. Other tests such as echocardiograms are
only required in individual cases when there is doubt about the
structural integrity of the heart.
We often
measure plasma norepinephrine levels in both a supine and standing
position (at least 15 minutes in each position prior to blood
sampling). The supine norepinephrine is often high normal in
patients with POTS, while the upright norepinephrine is usually
elevated (>600 pg/ml), a reflection of the exaggerated neural
sympathetic tone that is present in these patients while upright.
Tests of
autonomic nervous system function typically show intact or exaggerated
autonomic reflex responses. These patients often have preserved
vagal function as reflected by their sinus arrhythmia ratio in response
to deep breathing. They often have a vigorous pressor response to
the Valsalva maneuver, with an exaggerated blood pressure recovery and
overshoot both before and after release
20.
The blood
volume is low in many patients with POTS
5.
This can be objectively assessed with nuclear medicine tests to
directly measure either the plasma volume or the red cell volume.
This knowledge may help to focus the treatment plan.
Some patients
with POTS have co-existent complaints of episodic flushing. In
about half of these cases there is an associated mast cell activation
disorder
20. This can
be diagnosed by collecting urine from individual 2-4 hour voids
following a severe flushing spell for determination of
methylhistamines.
Differential Diagnosis
The
clinical picture of POTS can be confused with pheochromocytoma because
of the paroxysms of hyperadrenergic symptoms. Patients with
pheochromocytoma are more likely to have symptoms while lying down than
POTS patients, and often have much higher plasma norepinephrine
levels. The diagnosis of pheochromocytoma is made by assessment
of plasma or urinary metanephrines
21.
There is
commonly some confusion between neurally mediated syncope and
POTS. There is a clinical overlap between the 2 disorders, such
that about 30% of patients with POTS also have neurally mediated
syncope. Nonetheless, most patients with POTS do not faint.
Almost all
patients with POTS also have associated fatigue. The reasons are
not entirely clear. In some patients, but not all, the fatigue
improves with pharmacological control of the orthostatic
tachycardia. Some patients with POTS have symptomatic overlap
with chronic fatigue syndrome.
Pathophysiology of POTS
Tachycardia
and asthenia on standing is a final common pathway of many
pathophysiological processes. POTS is therefore best viewed as a
syndrome rather than a disease. Many disorders with a common key
clinical presentation (the orthostatic tachycardia) have been
described. Over the last decade, much has been learned about
specific forms or sub-types within POTS, although a simple test to
categorize the individual patient remains elusive. We discuss
here the common POTS phenotypes including neuropathic POTS and central
hyperadrenergic POTS (
Figure 3).
Figure 3 –
Pathophysiological Schema in POTS
There are multiple distinct pathophysiological subtypes within the
postural tachycardia syndrome (POTS). The top panel (3a) shows a basal situation with a
normal amount of sympathetic nervous system outflow from the brain that
activates receptors in the blood vessels (vascular tone & venous
return), heart (heart rate & contractility) and kidney (blood
volume regulation through renin). Panel 3b shows a schematic of
Neuropathic POTS. There is patchy denervation of the sympathetic
innervation of the blood vessels in the extremities (especially the
legs) and the kidney with subsequent hypovolemia and increased
orthostatic venous pooling. This feeds back to the brain to
increase sympathetic nervous system outflow in a compensatory
effort. This increased sympathoneural flow is sensed most in the
heart where there is no denervation. Panel 3c shows a schematic of
Central Hyperadrenergic POTS. In this case, the underlying
problem is excessive sympathetic nervous outflow from the brain that
affects the blood vessels, kidneys and the heart. In addition to
tachycardia, this form of POTS is often associated with orthostatic
hypertension.
Considering
that POTS patients have high plasma NE levels, it would seem
paradoxical that a neuropathy is proposed as an underlying
process. Yet some of them have a form of dysautonomia, with
preferential denervation of sympathetic nerves innvervating the lower
limbs
22-24.
There have been several findings consistent with this hypothesis.
The results of sudomotor axon reflex testing
22
and galvanic skin stimulation
23
support this as well as skin biopsy results
25.
Further, these patients have been found to be hypersensitive to
infusions of norepinephrine and phenylephrine into veins of the foot,
despite high circulating plasma norepinephrine concentrations
24. This suggests that there is a
denervation hypersensitivity of the leg veins. Using a segmental
norepinephrine spillover approach, Jacob et al.
26
demonstrated that patients with POTS had normal sympathetic neuronal
norepinephrine release in their arms, but less norepinephrine release
(and thus less sympathetic activation) in their lower body.
Hypovolemia
& Blood Volume Regulation
Many patients
with POTS have low plasma volumes
27,28, but not all
29.
To determine if hypovolemia existed in an unselected group of POTS
patients, we studied 15 patients with POTS (not selected for blood
volume) and 14 control subjects
5.
Plasma volume was measured using
131-I
labeled human serum albumin using a dye dilution technique, and
compared to the predicted blood volume for each individual, based upon
their height, weight, and gender. As can be seen in
Figure 4, the control subjects did
not have a significant plasma volume deficit (0.8±2.5%).
In contrast, the patients with POTS had a plasma volume deficit of
12.8±2.0% (P<0.001).
Figure 4 – Blood Volume
Deviation in POTS
The 3 panels
show the blood volumes of control subjects and patients with POTS
compared to hat expected based on their individual height, weight and
gender. Data are shown for plasma volume (PV; Panel A), red cell volume (RC; Panel B) and total blood volume (TBV; Panel C). The plasma
volume and total blood volume of the control subjects was similar to
their expected values. The patients with POT had a deficit of their
plasma volume (Panel A), red
cell volume (Panel B) and total
blood volume (Panel C) compared
to the control group. Figures adapted with data from Raj SR,
Biaggioni I, Yamhure PC, Black BK, Paranjape SY, Byrne D, Robertson
D. The Renin-Aldosterone Paradox and Perturbed Blood Volume
Regulation Underlying the Postural Tachycardia Syndrome.
Circulation 2005; 111:1574-1582.
The
renin-angiotensin-aldosterone system plays a key role in the
neurohormonal regulation of plasma volume in humans. Plasma renin
activity and angiotensin II would be expected to increase in response
to hypovolemia in order to promote blood volume expansion.
Angiotensin II promotes sodium and water retention directly by
stimulating sodium resorption in the proximal tubules, and indirectly
by stimulating aldosterone secretion.
Patients with
orthostatic tachycardia who were also hypovolemic have low levels of
standing plasma renin activity and aldosterone compared to normovolemic
patients
21,2.
This is true in both supine (190±140 pM vs. 380±230 pM;
P=0.017) and upright posture (480±290 pM vs. 810±370 pM;
P=0.019). One would have expected a compensatory increase in both
plasma renin activity and aldosterone given the hypovolemia in these
patients. This low level of plasma renin activity and aldosterone is a
paradox that remains unexplained. These data suggest that
abnormalities in the renin-angiotensin-aldosterone axis might have a
role in the pathophysiology of POTS by contributing to hypovolemia and
impaired sodium retention. Such hypovolemia could be accounted for by a
neuropathic process involving the kidney. A significant modulator
of renin release is the sympathetic nervous system. Thus perturbations
in the renin-aldosterone system might result from partial sympathetic
denervation involving the kidney.
Central
Hyperadrenergic POTS
As a part of
the definition, POTS is associated with a hyperadrenergic state (
Table 1). In many such cases,
the hyperadrenergic state is secondary to a partial dysautonomia or
hypovolemia. There are some cases, however, in which the primary
underlying problem seems to be excessive sympathetic discharge.
These patients often have extremely high levels of upright
norepinephrine. While we require the upright norepinephrine level
to be >600 pg/ml for the diagnosis of POTS, the hyperadrenergic
subgroup often has upright norepinephrine level >1000 pg/ml and it
is occasionally >2000 pg/ml. These patients sometimes have
large increases in blood pressure on standing, indicating that
baroreflex buffering is somehow impaired.
Central
hyperadrenergic POTS in its most florid form is much less common than
neuropathic POTS, comprising only ~10% of patients. Thus therapy
in these cases usually targets a decrease in sympathetic tone both
centrally and peripherally.
Central
sympatholytics such as methyldopa or clonidine can be used.
Peripheral beta-adrenergic blockade may be better tolerated by these
patients than by those with neuropathic POTS.
Norepinephrine
Transporter Deficiency
A specific
genetic abnormality has been identified in a kindred with
hyperadrenergic POTS
30.
These individuals have a single point mutation in the norepinephrine
transporter (NET). The resultant inability to adequately clear
norepinephrine produces a state of excessive sympathetic activation in
response to a variety of sympathetic stimuli. While rare, this mutation
has taught us much about the importance of a functional NET.
Although
functional NET mutations might be infrequent, pharmacological NET
inhibition is very common. Many antidepressant and attention
deficit medications work at least in part through inhibition of
NET. This includes traditional drugs such as tricyclic
antidepressants, and newer medications which are pure NET inhibitors
(e.g. atomoxetine or reboxetine). Both we
31 and others
32
have found that pharmacological NET inhibition can recreate an
orthostatic tachycardia phenotype in susceptible healthy volunteer
subjects. Yohimbine, a central alpha-2 antagonist that will also
increase synaptic norepinephrine, can also cause orthostatic tachycardia
33.
Mast Cell
Activation
Some patients
with POTS have co-existent mast cell activation. These patients have
episodic flushing and abnormal increases in urine methylhistamine (the
primary urinary metabolite of histamine)
20.
Methylhistamine should ideally be measured in 2 hour aliquots at the
time of a flushing episode and not just in a random 24 hour
period. Other associated symptoms include shortness of breath,
headache, lightheadedness, excessive diuresis, and gastrointestinal
symptoms such as diarrhea, nausea, and vomiting. Flushing can be
triggered by long-term standing, exercise, premenstrual cycle, meals,
and sexual intercourse. These patients often have a
hyperadrenergic response to posture, with both orthostatic tachycardia
and hypertension. They demonstrate a vigorous sympathetic
vasopressor response during the Valsalva maneuver with a blood pressure
overshoot in late phase II and an exaggerated phase IV blood pressure
overshoot. It is not clear if mast cell activation, releasing
vasoactive mediators, represents the primary event in these patients or
if sympathetic activation, through release of norepinephrine,
neuropeptide Y and ATP, is the cause of mast cell activation
34.
In these
patients, beta-adrenergic antagonists can actually trigger an episode
and worsen symptoms. Centrally acting agents to decrease the
sympathetic nervous system discharge (e.g. methyldopa or clonidine) may
prove effective. Alternatively, treatment could target mast cell
mediators with a combination of antihistamines (H1- and H2-antagonists)
and with the cautious use of non-steroidal agents (high dose aspirin)
in refractory cases.
Non-Pharmacological Treatment of
POTS
No therapy is
successful for all patients with POTS. Initial efforts should focus on
identifying and treating any reversible causes. Potentially
contributory medications (especially vasodilators, diuretics, and drugs
that inhibit NET) should be withdrawn. If a patient has been
through prolonged bedrest, their symptoms will gradually improve as
they recondition themselves to upright posture. Treatment should
be optimized for any chronic disease that is present. If there is
clear evidence of a re-entrant supraventricular arrhythmia, then this
should be treated, including with radiofrequency ablation as
appropriate. However, radiofrequency sinus node modification for
the sinus tachycardia of POTS is not recommended. This often
makes the patient’s symptoms worse (and occasionally the patient
becomes pacemaker dependent). Specific therapies are summarized in
Table 2.
Table
2: Treatments for the Postural Tachycardia Syndrome
NaCl – Table
salt; PO – by mouth; OD – once daily; BID – twice daily; TID – three
times daily; QID – four times daily; IV – intravenous;
It is
important to educate the patient about the nature of the
disorder. The patient should avoid aggravating factors such as
dehydration, and extreme heat. In order to ensure adequate
hydration, we ask our patients to consume 8-10 cups of water daily and
to rapidly drink 16 fl oz of water to lower their heart rates
35. In addition, they are asked to
aggressively increase their sodium intake up to 200 mEq/day. This
is often hard to achieve without NaCl tablets 1 gm/tablet TID with
meals. Elastic support hose can help to minimize the degree of
peripheral venous pooling and enhance venous return. We recommend
30-40 mmHg of counter-pressure and they should come up to the
waist. If the stockings are only knee-high, a line of edema can
form just above the stockings. Their use can be limited by their
tolerability as the stockings can be hot, itchy and
uncomfortable. Exercise (both aerobic and resistance training) is
also encouraged and has been shown to be beneficial
36. In addition to reversing any
“deconditioning”, this intervention can also increase blood
volume. Vigorous exercise may acutely worsen symptoms and may
even result in prolonged fatigue. It is important that patients
start slowly and remain within range of their “target heart rate” in
the early stages to avoid symptoms that might discourage further
exercise.
Acute blood
volume expansion is effective at controlling the heart rate and acutely
improving symptoms. Jacob et al.
37
found that 1 liter of physiological saline infused intravenously over 1
hour decreased the orthostatic tachycardia from 33±5 bpm before
the infusion to 15±3 bpm immediately following the
infusion. The physiological saline was more effective at heart
rate control than were treatments with either an alpha-1 agonist or an
alpha-2 agonist. This treatment is not practical on a day to day
basis as a medical setting is required to insert the intravenous
catheter and infuse the saline. Recently, there have been reports
of patients having regular saline infusions, typically 1 liter of
normal saline every other day or every day. Many report an
improvement in symptoms. However, there are not yet objective
data to substantiate such benefit. Further, there is a risk of
vascular access complications or infection. At this time, such
therapy for patients with POTS should be considered cautiously.
Pharmacological Treatment of POTS
No
medicines are approved by the United States Food and Drug
Administration for the treatment of POTS. Thus all agents are
used for this disorder are “off label”. Furthermore, there are no
pharmacological agents that have been tested in a long-term properly
powered randomized clinical trial.
In patients in
whom the presence of hypovolemia is either known or strongly suspected,
fludrocortisone (an aldosterone analogue) is often used. Through
enhanced sodium retention, it should expand the plasma volume, although
there is a paucity of data regarding the exact mechanisms of
action. Although fairly well tolerated, side effects can include
hypokalemia, hypomagnesemia, worsening headaches, acne, and fluid
retention with edema. Another volume expanding agent that may be
helpful for short-term use is oral vasopressin (DDAVP). This
agent causes the kidney to retain free water, but not sodium.
Potential side effects include hyponatremia, edema and headache.
Erythropoietin has occasionally proven useful in patients with POTS who
are refractory to other forms of therapy. While the primary mode
of action is likely an increase in intravascular volume via its
increase in red cell mass, erythropoietin also appears to have a direct
vasoconstrictive effect, possibly through enhanced red cell mediated
nitric oxide scavenging
38.
Treatment with erythropoietin has many drawbacks including the
significant expense and the need for subcutaneous administration.
Central
sympatholytic medications are often useful and well tolerated in
patients with the central hyperadrenergic form of POTS, but may not be
as well tolerated in neuropathic POTS. Clonidine is an alpha 2
agonist that acts centrally to decrease sympathetic nervous system
tone. Clonidine, at doses of 0.05 mg to 0.2 mg PO BID, can
stabilize heart rate and blood pressure in patients with a large amount
of postganglionic sympathetic involvement. Unfortunately, it can
also cause drowsiness, fatigue and worsen the mental clouding of some
patients. Methyldopa, a false neurotransmitter, is sometimes more
successful in controlling symptoms in these patients at doses of 125 mg
to 250 mg PO TID
39.
When used in
low doses, beta-adrenergic antagonists can be useful. We typical
use propranolol 10-20 mg PO BID-QID. While this dose range is
small, such doses can often have a significant impact on heart rate
control, and higher doses are often not tolerated due to hypotension
and fatigue.
Since a
failure of vascular resistance may be an integral part of neuropathic
POTS, vasoconstrictors such as midodrine (an alpha-1 agonist) can be
employed
40. Some
patients cannot tolerate this agent due to the unpleasant sensation of
scalp tingling or goosebumps. Midodrine can also cause
hypertension.
We recently
reported that an unselected group of patients seen in our inpatient
research unit were given a trial of the acetylcholinesterase inhibitor
pyridostigmine. By increasing the levels of synaptic
acetylcholine at both the autonomic ganglia and the peripheral
muscarinic parasympathetic receptors, pyridostigmine significantly
restrained the heart rate in response to standing in our patients with
POTS. We prescribe pyridostigmine 30mg to 60 mg PO TID alone or
in combination with low dose propranolol. Pyridostigmine can
enhance bowel motility, so it is not always well tolerated in patients
with diarrhea-predominant irritable bowel syndrome symptoms.
While most of
the treatments discussed above have focused on the control of heart
rate, many patients are also greatly troubled by mental clouding.
Modafinil, a stimulant whose mechanism is not yet clear, has been used
in some patients with resulting improvement in alertness.
However, caution is advised as it may aggravate the orthostatic
tachycardia
41.
Conclusions
POTS is a
disorder of the autonomic nervous system in which many symptoms can be
treated. The cardinal manifestation is symptomatic orthostatic
tachycardia. The disorder can produce substantial disability among
otherwise healthy people. Patients with POTS demonstrate a heart
rate increase of ≥30 bpm with prolonged standing (5-30 minutes), often
have high levels of upright plasma norepinephrine, and many patients
have a low blood volume. Therapies aimed at correcting the
hypovolemia and the autonomic imbalance may help relieve the severity
of the symptoms. Continued research is vital to better understand
this disorder and to differentiate its various subtypes.
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