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Effects of intermittent intravenous saline infusions in patients with medication—refractory postural tachycardia syndrome

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Background The postural tachycardia syndrome (POTS) is a heterogeneous group of disorders that results in symptoms of orthostatic intolerance. Excess blood pooling has been observed to cause low effective circulating volume in the central vasculature. Consequently, acute volume loading with IV saline has emerged as a potential strategy for clinical intervention. We evaluated the impact of acute volume loading on both the signs and symptoms of patients suffering from POTS. Methods Fifty-seven subjects screened from our population of POTS patients and assenting to participation were administered the two surveys by telephone. Subjects completed each survey twice, before, and after initiating IV hydration therapy. The Orthostatic Hypotension Questionnaire (OHQ) was used to assess change in clinical symptomatology, while the short form 36 health survey (SF-36) was employed to assess the impact of IV saline infusion on quality of life. ResultsFifty-seven patients were included in the analysis. The average number of medications trialed before referral for IV hydration was 3.6 ± 1.7 medications. Saline infusions occurred with mean frequency of 11.3 ± 8.5 days and at a mean volume of 1.5 ± 0.6 l per infusion. The mean change of the OHQ was 3.1 ± 0.3 (95% CI 2.6–3.7; P < 0.001), with significant improvement in all the composite scores. The mean change in the SF-36 form was 19.1 ± 2.7 (95% CI −24.6 to −13.6; P < 0.001). Conclusions Intermittent IV infusions of saline dramatically reduce symptoms and improve quality of life in patients suffering from POTS. Further work should explore its efficacy as a bridge study for patients of high symptomatic severity.
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Effects of intermittent intravenous saline infusions
in patients with medicationrefractory postural tachycardia
syndrome
Mohammed Ruzieh
1,2
&Aaron Baugh
1
&Osama Dasa
1
&Rachel L. Parker
1
&
Joseph T. Perrault
1
&Anas Renno
1
&Beverly L. Karabin
1
&Blair Grubb
1
Received: 31 October 2016 /Accepted: 24 January 2017
#Springer Science+Business Media New York 2017
Abstract
Background The postural tachycardia syndrome (POTS) is a
heterogeneous group of disorders that results in symptoms of
orthostatic intolerance. Excess blood pooling has been ob-
served to cause low effective circulating volume in the central
vasculature. Consequently, acute volume loading with IV sa-
line has emerged as a potential strategy for clinical interven-
tion. We evaluated the impact of acute volume loading on both
the signs and symptoms of patients suffering from POTS.
Methods Fifty-seven subjects screened from our population
of POTS patients and assenting to participation were admin-
istered the two surveys by telephone. Subjects completed each
survey twice, before, and after initiating IV hydration therapy.
The Orthostatic Hypotension Questionnaire (OHQ) was used
to assess change in clinical symptomatology, while the short
form 36 health survey (SF-36) was employed to assess the
impact of IV saline infusion on quality of life.
Results Fifty-seven patients were included in the analysis.
The average number of medications trialed before referral
for IV hydration was 3.6 ± 1.7 medications. Saline infusions
occurred with mean frequency of 11.3 ± 8.5 days and at a
mean volume of 1.5 ± 0.6 l per infusion. The mean change
of the OHQ was 3.1 ± 0.3 (95% CI 2.63.7; P< 0.001), with
significant improvement in allthecompositescores.The
mean change in the SF-36 form was 19.1 ± 2.7 (95% CI
24.6 to 13.6; P<0.001).
Conclusions Intermittent IV infusions of saline dramatically
reduce symptoms and improve quality of life in patients suf-
fering from POTS. Further work should explore its efficacy as
a bridge study for patients of high symptomatic severity.
Keywords POTS .Refractory POTS .IV hydration
1 Introduction
The postural tachycardia syndrome (POTS) is a heteroge-
neous group of disorders that results in symptoms of ortho-
static intolerance. In its most common forms, excess blood
pooling has been observed to cause low effective circulating
volume in the central vasculature [1]. Consequently, acute
volume loading with IV saline has emerged as a potential
strategy for clinical intervention [2]. Despite its growing pop-
ularity, empiric evidence supporting its usage is small. Citing
this paucity of evidence, the most recent consensus guidelines
have recommended against long-term use of intravenous hy-
dration and reserve it for rescue therapy only [3]. A recent
*Mohammed Ruzieh
mohammed.ruzieh@utoledo.edu
Aaron Baugh
Aaron.Baugh@UToledo.Edu
Osama Dasa
Osama.Dasa@UToledo.Edu
Rachel L. Parker
Rachel.Parker2@rockets.utoledo.edu
Joseph T. Perrault
Joe.Perrault@rockets.utoledo.edu
Anas Renno
Anas.Renno@utoledo.edu
Beverly L. Karabin
beverly.karabin@utoledo.edu
Blair Grubb
Blair.Grubb@utoledo.edu
1
University of Toledo, Toledo, OH, USA
2
University of Toledo Medical Center, 3000 Arlington Ave,
Tol edo , OH 4 3164, U SA
J Interv Card Electrophysiol
DOI 10.1007/s10840-017-0225-y
investigation, in 2014, showed improvement in resting cardiac
output but failed to demonstrate any improvement in exercise
tolerance among POTS patients [4]. Prior investigations were
more supportive. A 1997 study in Circulation suggested that
acute volume loading with IV saline is more efficacious than
pharmacologic intervention [5]. The key to reconciling these
two results may lie in the distinction between subjective and
objective measures. While concurring with the result from
Jacob et al., a later study reported that IV salinessuperiority
in offering symptomatic improvement was distinct from its
comparatively weaker performance on observed cardiovascu-
lar parameters [6]. Similarly, a prospective study of POTS
patients found that those patients who showed symptomatic
improvement after any treatment regimen tended to do so
without improvement in the heart rate response during tilt
table testing [7].
These results are not necessarily contradictory. As sug-
gested by a recent 5-year retrospective study by Moak et al.
[8], the dramatic subjective improvement seen after acute vol-
ume loading may increase patient compliance with behavioral
interventions (such as reconditioning) needed to realize long-
term objective improvements. However, these findings are of
uncertain generalizability, given the known changes in auto-
nomic function over the human lifespan [9].
Examining their validity in adult populations is a research
priority. We evaluated the impact of acute volume loading on
both the signs and symptoms of patients suffering from POTS
to properly rationalize its role in treatment. To the best of our
knowledge, this is the first study in an adult population to
evaluate the response to IV saline infusion in a clinical setting.
2 Methodology
This prospective observational study was approved the
University of Toledo Medical Center (UTMC) Institutional
Review Board.
All patients with POTS seen in the Syncope and
Autonomic Disorders clinic between January 1, 2010, and
February 1, 2016, were screened for possible inclusion.
Inclusion criteria was a diagnosis with POTS, made or con-
firmed by the UTMC Syncope and Autonomic Disorders clin-
ic, failure of at least one pharmacologic intervention to control
symptoms, and referral for IV hydration therapy. Diagnosis
was made as per the recent consensus guidelines for POTS
which states the following: symptoms of orthostatic intoler-
ance associated with a heart rate increase of 30 beat per minute
(bpm) that occurs within the first 10 min of standing or upright
tilt test in the absence of other secondary causes of orthostatic
intolerance [1,3]. Those who met all inclusion criteria were
contacted by phone and offered the opportunity to participate
in the study. Attempts to contact each potential participant
were made until they were reached or three calls were placed.
Patients declining participation or who could not be reached
after three attempts were excluded from the study.
Each subject underwent a comprehensive chart review to
extract baseline demographic data, comorbidities, and objec-
tive correlates of disease severity, as well as attempted proce-
dural, pharmacologic, and behavioral interventions to amelio-
rate the disease.
3Studyoutcomes
Subjects assenting to participation were administered the
Orthostatic Hypotension Questionnaire (OHQ) by telephone.
This tool, validated for clinical use in the longitudinal mea-
surement of the symptomatic severity of orthostatic hypoten-
sion [10], is routinely employed in our clinic. Patientsre-
sponses were compared before and after initiating IV hydra-
tion therapy. The questionnaire consists of ten composite
scores, six items evaluate symptoms and four assess the im-
pact of symptoms on daily activities. Each item is scored on a
Likert scale from zero to ten with zero indicating the absence
of the symptom in question and ten implicating the worst
expression of said symptom or impact on quality of life.
We also assessed quality of life using the short form 36
health survey (SF-36). The questionnaire contains 36 items
that yield eight category scales divided into two major com-
ponents: mental health and physical health. The scale ranges
from 0 to 100, with lower scores indicating higher disability
and lower quality of life. This questionnaire has been validat-
ed and used to assess quality of life in several medical condi-
tions [11]. In 2002, Benrud-Larson et al. showed that the di-
minished quality of life suffered by POTS patients is compa-
rable to those with chronic obstructive pulmonary disease and
congestive heart failure [12].
4 Statistical analysis
All data extracted underwent descriptive statistical analysis
using the SPSS 21.0 software (SPSS Inc.). Each patientsse-
rial response on the OHQ and SF-36 was analyzed for statis-
tical significance using a Studentsttest in a paired sample
design.
Atwo-tailedPvalue of <0.05 was considered to be statis-
tically significant.
5Results
Of the 382 patients with POTS who were screened, 72 patients
were prescribed the IV saline infusions and 57 assented to
participation in this retrospective study (Diagram 1).
J Interv Card Electrophysiol
The population of the study was prominently young fe-
males (96.5%) with a mean age of 35.0 ± 12.9 years and no
significant comorbidities. Three had diabetes mellitus, 10 had
hypertension, 4 had other cardiovascular diseases, and none
had kidney impairment. These demographics reflect those
commonly described in patients with POTS [3].
The fifty-seven patients included in our study had a follow-
up time ranging from 3 to 12 months. The average number of
medications trialed before referral to IV hydration was 3.6 ±
1.7 medications.
The baseline characteristics of these patients are summa-
rized in Table 1.
6 Therapy protocol
Patients received IV hydration with normal saline through
peripheral IV starts (42 [73.7%]), peripherally inserted central
catheter (PICC) line inserted by certified nurse or interven-
tional radiologist (12 [21.1%]), or subcutaneously implanted
ports (3 [5.3%]). The initial treatment consisted of 1 l of IV
normal saline infused over 12 h every week. Therapy was
then titrated up (2 l per week) or down (1 l every 24weeks)
depending on the patients response and desire.
1.5 ± 0.6 l were received per infusion with a mean frequen-
cy of 11.3 ± 8.5 days.
7Studyoutcomes
The average OHQ score before initiating IV hydration therapy
was 6.6 ± 1.5. Dizziness and fatigue were reported as the most
disabling symptoms, with scores of 7.3 ± 2.5 and 8.2 ± 1.6,
respectively.
The mean change of the OHQ was 3.1 ±0.3 (95% CI 2.6
3.7; P< 0.001), with significant improvement in all the com-
posite scores, Fig. 1.
Figure 2shows the mean SF-36 for each category at base-
line and after the intervention. As illustrated, IV saline infu-
sion leads to significant improvement in quality of life with
mean difference of 19.1 ± 2.7 (95% CI 24.6 to 13.6;
P< 0.001). This significant improvement was valued across
all the domains appraised by the SF-36.
Most patients reported an immediate improvement in
symptoms that lasted for 3.3 ± 2.2 days.
Four patients reported no improvement in symptoms or
quality of life to our intervention. This subgroup was entirely
Caucasian with a mean age of 19. Three of them had POTS
secondary tohypermobility syndrome. Mean OHQ and SR-36
before intervention were 6.6 and 47.3, respectively.
Hypermobility and young age were the only factors found to
predict poor response to IV hydration, P= 0.015 and P=
0.009, respectively. However, given our small total sample,
it is unclear that this finding is generalizable.
During the study period, the overwhelming majority of
subjects saw sufficient symptomatic improvement to discon-
tinue IV saline infusion altogether. Of the 50 patients who
successfully weaned from saline infusion during the study
period, all had done so in less than 6 months, and 44% did
so in less than 3 months. There was no clear demographic,
behavioral, or treatment characteristic common to this group
Table 1 Characteristics of patients in our study (N=57)
Females, N(%) 55 (96.5%)
Age in years (mean ± SD) 35.0 ± 12.9
Ethnicity
White 55 (96.5%)
Other, N(%) 2 (3.5%)
Cause of orthostatic intolerance, N(%)
Idiopathic 41 (71.9%)
Hypermobility 14 (24.6%)
Hyperadrenergic 2 (3.5%)
Previous medication failed, N(%)
Beta-blockers 35 (61.4%)
Midodrine 28 (49.1%)
SSRIs and SNRIs 25 (43.9%)
Desmopressin 24 (42.1%)
Fludrocortisone 17 (29.8%)
Bupropion 14 (24.6%)
Pyridostigmine 14 (24.6%)
Octreotide 10 (17.5%)
Dextroamphetamine/amphetamine 9 (15.8%)
Other 9 (15.8%)
Northera 8 (14.0%)
Epoetin alfa 4 (7.4%)
Ivabradine 2 (3.5%)
Nnumber, SD standard deviation, SSRI selective serotonin reuptake in-
hibitor, SNRI serotoninnorepinephrine reuptake inhibitor
72 patients with
POTS prescribed IV
noraml saline
infusions
53 Patients responded
significantly with
improvement in
symptoms and quality of
life
4 Patients with no
improvement in
symptoms or quality of
life and subsequenty
stopped the therapy
15 Patients lost to follow
up or declined participation
in the study
Diagram 1 Outline of t he study
J Interv Card Electrophysiol
of high-responders. Eventually, four would suffer relapse, re-
quiring transition back to saline infusion therapy. However,
even in these cases, relapsed subjects showed dramatically
reduced need for intervention, with average frequency of in-
fusion lowering from 9.25 ± 4.65 to 20.13 ± 7.88 days.
Among subjects that successfully weaned from saline infusion
for any length of time, some return to therapy during episodes
of acute exacerbation or for limited periods of annual peak
symptomology. There was no clear demographic, behavioral,
or treatment characteristic that allowed discrimination be-
tween those who would could be weaned from therapy and
those who remained on therapy for at least one years time.
There were no hospitalizations attributable to IV saline in-
fusion during the period studied. One patient discontinued the
therapy due to development of hypertension. There were no
reported cases of deep vein thrombosis or soft tissue infection.
Despite the apparent gulf in complication rate, these results are
in line with the major trends seen in comparable studies. As
compared with our own study population, where 73.7% of
subjects received therapy via peripheral IV starts, this same
modality of represented only 25.6% of the subjects studied
by Moak [8]. Significantly, the entirety of their reported
complications was among subjects employing peripherally
inserted central catheter (PICC) lines or infusion ports. Risks
associated with IV saline infusion may be more particular to
the modality of administration than intrinsic to the therapeutic
intervention.
8Discussion
In line with other recent publications, this study offers support
for the safety and efficacy of medium-term IV saline infusion
in the treatment of POTS. The principle distinction between
the recently published work of Moak et al. [8] and this work is
the population under study. There are a number of behavioral
and physiologic changes with age which might predispose to
worsening of the disease.
Unambiguously, a recent systematic review on sedentary
behavior found a positive correlation between age and total
sedentary time in 70% of all studies reviewed [13].
Deconditioning after prolonged bed rest is associated with a
decline in stroke volume [14]. Exercise is a first-line interven-
tion in POTS, with even short-term regimens demonstrating
6.6
8.2
7.4
6.6
7.5
4.5
6.3
5.9
4.2
8.2
7.2
3.5
4.5
3.9
3.1
4.2
3
3.4
3.6
2
4.3
2.8
0123456789
Over all score
Walking long time
Walking short time
Standing long time
Standing short time
Daily activity scale
Head/ Neck discomfor
Weakness
Cognitive impairtment
Vision changes
Fatigue
Dizziness
Symptoms scale
Composite score from zero to ten, lower scores indicating less severe symptoms
After intervention Before intervention
Fig. 1 Difference in OHQ before
and after IV hydration therapy
0
10
20
30
40
50
60
70
80
90
100
Total SF-
36 score
PF RP BP GH Physical
health
VT SF RE MH Mental
health
PF: Physical function, RP: Role-physical, BP: Bodily pain, GH: General health, VT: Vitality,
SF: Social function, RE: Roleemotional, MH: Mental health
Before intervention After intervention
Fig. 2 SF-36 point score before and after the intervention, lower score indicating lower quality of life
J Interv Card Electrophysiol
up to 8% augmentation of stroke volume [15]. This combina-
tion of physiological and behavioral changes over the life
cycle would be expected to render persistent adult cases of
POTS more refractory to treatment than their juvenile coun-
terparts. Our results were supportive of such a finding; our
subjects having failed a mean of [3.6 ± 1.7] medications as
opposed to the 3.1 trials reported by Moak [8].
There is no clear consensus in medical literature as to the
role and efficacy of intermittent intravenous fluid loading in
POTS patients. While contemporary treatment protocols for
intravenous hydration space interventions in days to weeks,
responsiveness to crystalloid bolus is usually understood over
a much shorter time frame. Studying healthy volunteers,
Grothwohl reported a complete reversal of the peak expansion
in plasma volume in only 8 h [16]. In critically ill postopera-
tive patients, hemodynamic benefits were reversed in 2 h [17].
While a comprehensive mechanism for this disparity in time
course is as yet unarticulated, suggestive evidence has begun to
emerge in understanding factors controlling blood pressure
[18]. In normal human physiology, responsiveness to sympa-
thetic neural activity seems to vary inversely with CVP [19,
20]. This relationship serves as a compensatory homeostatic
mechanism during hypovolemia. The particular defects of
POTS may compromise this function. An experimental model
using nitroprusside-induced hypotension found that in compar-
ison to controls, these patients could increase the frequency but
not amplitude of sympathetic neural activity [21]. This has
been interpreted in light of extant evidence as attributable to
sympathetic denervation. Though even these results are incon-
sistent [22], and other defects seem responsible for some symp-
tomatic complaints in this patient population [23], saline infu-
sion may be effective insofar as it decreases reliance on path-
ologically influenced system. Further complicating this pic-
ture, our study joins a sizable preceding body of work that
failed to identify clinically significant hemodynamic changes
to correlate with the subjectsself-reported improvements.
The present results nonetheless present a powerful role for
saline infusion as a bridge therapy in the treatment of POTS.
Deconditioning creates a vicious cycle of symptomatic worsen-
ing in this patient population and represents a major challenge in
treatment. For instance, one exercise-based regimen reported
both an excellent response rate of 71% disease remission and
that a full 23.6% of all enrollees withdrew from therapy as they
found the required exercise too difficult [24]. It stands to reason
that bridge therapies which alleviate acute symptomatic com-
plaints might facilitate increased compliance. This effect has
already been observed in a major study of adolescent POTS
patients [8]. Researchers found no instrument ideal for tracking
compliance during the present study. However, the sustained
independence from saline infusion in the majority of our sub-
jects, all of whom were treatment refractory upon enrollment,
suggests a similar dynamic wherein short-term symptom relief
facilitates long-term disease control. In the context of both acute
exacerbations and medication-refractory initial presentations, IV
saline infusion seems an effective method for breaking the pos-
itive feedback between deconditioning and symptom severity.
The first major study of this kind was published in 2015
[8]. Both that study and this one are single center using self-
reported scales as a primary outcome. Results were of a con-
sistent magnitude and statistical robustness. Their findings
might also be considered complimentary. While the former
employed a non-specific quality of life questionnaire, with
implicitly presumed attribution to improvement in disease
state, our study added a validated instrument for tracking dis-
ease severity and consequent improvement in quality of life.
Anumberoflimitationswereinherentinthenatureofthis
study. The relatively young age of the subjects [mean age of
35.0 ± 12.9] without significant comorbidities may have led to
a more favorable outcome and reduced complications.
Moreover, compliance to other medical therapy and exercise
programs was not accounted for, which could have altered the
course of the disease. This may also have allowed the develop-
ment of psychological dependence to saline infusion to go
undetected.
As a non-blinded non-controlled observational study, pla-
cebo effect cannot be excluded. A blinded study protocol
comparing sham and actual saline infusions is justified clarify
this point. Nonetheless, these results provided a preliminary
evidence for the efficacy of IV hydration therapy and thereby
provide justification for larger better controlled studies. As a
whole, our sample was highly responsive to IV fluid loading,
with improvement reported in 93.0% of subjects. It is worth
examining whether this represents a particular subset of the
disease by etiology or presentation, and which medications
might be synergistic with IV fluid loading. The present study,
like other existing literature, suggests a wide variability in the
duration of intravenous hydration therapy. With increasing
clinical experience, the contours of a regimen for timing and
method of discontinuation IV therapy should emerge. While
increased compliance with behavioral interventions such as
reconditioning has been informally observed, it is unclear
whether these or some alternative mechanism are the driver
of the long-term improvements observed.
This study examined the validity of IV infusion as a
second-line therapy without regard to defining the efficacy
of any first-line treatment program. For the first-line therapy,
patients should be treated in accordance with our previously
published recommendations [1,3].
In, conclusion, intermittent IV infusions of saline dra-
matically reduce symptoms in patients suffering from
postural tachycardia syndrome. Paired with its relative
safety and low cost, this quality makes it an ideal can-
didate for bridge therapy to allow the implementation of
long-term interventions in highly symptomatic patients.
Further studies will be necessary to better refine this
application.
J Interv Card Electrophysiol
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Disclosures None.
Source of funding None.
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J Interv Card Electrophysiol
... This intervention has already shown to improve resting hemodynamics in patients with postural orthostatic tachycardia syndrome (POTS), which is a disease characterized by decreased stroke volume and abnormally elevated heart rate in response to positional changes. This observation seems notable because POTS is also a common comorbidity with ME/CFS [12]. ...
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Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) causes significant impairment in daily activities, including the ability to pursue daily activities. Chronotropic intolerance is becoming better characterized in ME/CFS and may be the target of supportive treatment. Objective: To document the effect of repeated intravenous (IV) saline administration on cardiovascular functioning and symptoms in a 38-year old female with ME/CFS. Methods: The patient received 1 L of 0.9% IV saline through a central line for a total of 675 days. Single CPETs were completed periodically to assess the effect of treatment on cardiopulmonary function at peak exertion and ventilatory anaerobic threshold (VAT). An open-ended symptom questionnaire was used to assess subjective responses to CPET and self-reported recovery time. Results: Improvements were noted in volume of oxygen consumed (VO2), heart rate (HR), and systolic blood pressure (SBP) at peak and VAT. Self-reported recovery time from CPET reduced from 5 days to 1-2 days by the end of treatment. The patient reported improved quality of life related, improved capacity for activities of daily living, and reduced symptoms. Conclusions: IV saline may promote beneficial effects for cardiopulmonary function and symptoms in people with ME/CFS, which should be the focus of formal study.
... The importance of hypovolemia in POTS pathophysiology is illustrated by the finding that some patients have reduced orthostatic tachycardia and improved symptoms after acute plasma volume expansion (e.g. intravenous saline, the vasopressin analog desmopressin, exercise training) (Coffin et al., 2012;Fu et al., 2010;Jacob et al., 1997;Ruzieh et al., 2017b). Ongoing studies are examining the impact of increasing plasma volume with dietary sodium, chronic intravenous saline, or albumin infusions in POTS. ...
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Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust.
... Most common medications used in the management of POTS include midodrine, [20][21][22] propranolol, 17,23,24 pyridostigmine, 25,26 fludrocortisone, 27,28 ivabradine, 29-31 clonidine, 32 and intermittent intravenous (I.V.) normal saline infusions. 33,34 These data are from acute randomized, controlled trials, or retrospective noncontrolled series. There are no medium-term or long-term randomized controlled trials of pharmacological therapy for POTS. ...
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The current definition of postural orthostatic tachycardia syndrome (POTS) dates back to a small case series of patients with a subacute illness who presented with excessive orthostatic tachycardia and orthostatic intolerance, in the absence of another recognized disease. Conventional POTS criteria require an excessive orthostatic tachycardia in the absence of substantial orthostatic hypotension, and predominant symptoms of orthostatic intolerance, worse with upright posture and better with recumbence. POTS is a heterogeneous syndrome with likely several underlying pathophysiological processes, and not a specific disease. The primary panel for this Canadian Cardiovascular Society position statement sought to provide a contemporary update of the best evidence for the evaluation and treatment of POTS. We performed a systemic review of evidence for the evaluation of treatment of POTS using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, and developed recommendations on the basis of the Canadian Cardiovascular Society approach to position statements. One identified problem was that numerous patients who did not meet criteria for POTS would still be given that diagnoses by providers to validate the illness even though this diagnosis is incorrect. This includes patients with postural symptoms without tachycardia, orthostatic tachycardia without symptoms, and those with orthostatic tachycardia but another overt cause for excessive tachycardia. We developed a novel nomenclature ecosystem for orthostatic intolerance syndromes to increase clarity. We also provide more clarity on how to interpret the orthostatic vital signs. These concepts will need to be prospectively assessed.
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Postural Orthostatic Tachycardia Syndrome (POTS) is a variant of autonomic cardiovascular disorder characterized by an excessive increase in heart rate upon standing associated with light-headedness, headaches, chest pain, shortness of breath, and brain fog. The etiology of POTS is largely unknown and often debilitating. The three major hypotheses about the pathophysiology of POTS are autoimmunity, abnormally increased sympathetic activity, and sympathetic denervation leading to central hypovolemia and reflex tachycardia. Given its heterogeneous nature, it is crucial to understand each component of POTS with more emphasis on incorporating a multidisciplinary approach to control the symptoms. Future works should focus on better understanding the POTS pathophysiology and designing randomized controlled trials for implementing effective therapy. In this review, we outline the extent of the problem, studies and resources needed to address the issue, and the diagnostic and therapeutic updates on POTS.
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Hydration with water and salt is the mainstay of treatment for autonomic nervous system disorders that impair orthostatic tolerance. The goal is to expand intravascular volume to compensate for the downward displacement of blood volume that occurs when standing and thereby sustain cerebral perfusion and restore quality of life. Despite strong consensus recommendations for salt supplementation as standard treatment of these disorders, published evidence of benefit is relatively weak, and no randomized clinical trials have occurred. This review summarizes the physiological rationale for hydration and evaluates the literature on oral and intravenous hydration in the treatment of neurogenic orthostatic hypotension, postural tachycardia syndrome, and recurrent vasovagal syncope. We conclude that oral salt replacement is indicated for treatment of neurogenic orthostatic hypotension because these patients have excessive renal sodium excretion, and for treatment of chronic orthostatic intolerance because these patients are often hypovolemic. As not all patients are able to tolerate sufficient oral hydration, there is also a role for intravenous volume-loading in severe cases of postural tachycardia syndrome. We offer guidance, based on review of the literature and the clinical judgment of a cardiologist and neurologist with experience treating autonomic disorders, regarding the option of ongoing intravenous hydration for treatment of severe, refractory cases of postural tachycardia syndrome.
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Dysautonomia (autonomic dysfunction) occurs in the Ehlers–Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD). Symptoms include palpitations, dizziness, presyncope, and syncope, especially when standing upright. Symptoms of orthostatic intolerance are usually relieved by sitting or lying and may be exacerbated by stimuli in daily life that cause vasodilatation, such as food ingestion, exertion, and heat. Neurocardiovascular dysautonomia may result in postural tachycardia syndrome (PoTS), a major cause of orthostatic intolerance. It is defined by a rise in heart rate of >30 beats per minute (bpm) in adults and >40 bpm in teenagers while upright, without a fall in blood pressure (BP; orthostatic hypotension). In some, it can be compounded by the presence of low BP. For many, there is delay in clinicians recognizing the nature of the symptoms, and recognizing EDS or HSD, leading to delays in treatment. The onset of PoTS may be linked to an event such as infection, trauma, surgery, or stress. Gastrointestinal and urinary bladder involvement may occur, along with thermoregulatory dysfunction. In some, the mast cell activation syndrome may be contributary, especially if it causes vasodilatation. This paper reviews neurocardiovascular dysautonomia with an emphasis on PoTS, its characteristics, associations, pathophysiology, investigation, and treatment.
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Postural orthostatic tachycardia syndrome (POTS) is a common and therapeutically challenging, condition affecting numerous people worldwide. Recent studies have begun to shed light on the pathophysiology of this disorder. At the same time, both non-pharmacologic and pharmacologic therapies have emerged that offer additional treatment options for those afflicted with this condition. This paper reviews new concepts in both the pathophysiology and management of POTS.
Chapter
Postural tachycardia syndrome (PoTS)Postural tachycardia syndrome is a heterogeneous clinical syndrome of orthostatic intoleranceOrthostatic intolerance. Distinct subtypes (neuropathicNeuropathic, hypovolemic, and hyperadrenergicHyperadrenergic PoTS) have been developed in an effort to better understand the physiological underpinnings of the disorder. These subtypes are problematic, due to lack of standard definitions, implied exclusivity, and poor explanatory power regarding the underlying pathophysiologyPathophysiology. Our continued investigation of PoTS has recently revealed a number of novel mechanisms, such as the involvement of the immuneImmune system (including mast cellMast cell activationActivation syndrome), physical deconditioning, norepinephrineNorepinephrine transporter deficiency, and impaired cerebral autoregulationCerebral autoregulation. A more comprehensive paradigm is needed, including a precise description of how these diverse processes might overlap, and how each contributes to the clinical presentation of a given PoTS patient. This understanding is critical to the diagnosisDiagnosis and treatment of patients with PoTS.
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Purpose of review Postural tachycardia syndrome is a common condition characterized by the presence of orthostatic intolerance in conjunction with excessive postural tachycardia. This review will focus on treatment updates in postural tachycardia syndrome and will include a discussion of rehabilitative, vasopressor, heart rate modulation, volume expansion, and immunomodulatory treatment strategies. Recent findings A recent study added to existing literature the benefits of exercise retraining in postural tachycardia syndrome (POTS) patients who were able to successfully complete a 3-month exercise regimen. Another recent, novel study reported the benefits of respiratory retraining in POTS patients reporting breathlessness. The benefits of volume expansion in the treatment of POTS were strengthened by 2 recent studies, including a study demonstrating the value of oral rehydration salts in improving hemodynamic parameters in POTS patients and another prospective study demonstrating the value of IV saline infusions in POTS patients. A recent meta-analysis reviewed the efficacy of ivabradine in the treatment of POTS, while another systematic review and meta-analysis reviewed the benefits of metoprolol in the treatment of childhood and adolescent POTS. Also included in this review is that of a large clinical trial comparing propranolol and bisoprolol alone and with pyridostigmine, demonstrating efficacy of beta blockers and an absence of any clear additive benefit with pyridostigmine. A retrospective review of droxidopa in a large POTS cohort reported improvement in only 27% of POTS patients. Recent approaches to the pharmacologic and non-pharmacologic treatment of cognitive dysfunction and fatigue in POTS patients were reviewed. Finally, a retrospective series of the benefits of intravenous immunoglobulin in POTS suspected of being autoimmune is reviewed. Summary The treatment of postural tachycardia syndrome is complex and nuanced, requiring a combination of lifestyle and pharmacologic treatments in most patients. This review provides treatment updates for this enigmatic condition.
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Background Recent research shows that sedentary behaviour is associated with adverse cardio-metabolic consequences even among those considered sufficiently physically active. In order to successfully develop interventions to address this unhealthy behaviour, factors that influence sedentariness need to be identified and fully understood. The aim of this review is to identify individual, social, environmental, and policy-related determinants or correlates of sedentary behaviours among adults aged 18–65 years. Methods PubMed, Embase, CINAHL, PsycINFO and Web of Science were searched for articles published between January 2000 and September 2015. The search strategy was based on four key elements and their synonyms: (a) sedentary behaviour (b) correlates (c) types of sedentary behaviours (d) types of correlates. Articles were included if information relating to sedentary behaviour in adults (18–65 years) was reported. Studies on samples selected by disease were excluded. The full protocol is available from PROSPERO (PROSPERO 2014:CRD42014009823). Results 74 original studies were identified out of 4041: 71 observational, two qualitative and one experimental study. Sedentary behaviour was primarily measured as self-reported screen leisure time and total sitting time. In 15 studies, objectively measured total sedentary time was reported: accelerometry (n = 14) and heart rate (n = 1). Individual level factors such as age, physical activity levels, body mass index, socio-economic status and mood were all significantly correlated with sedentariness. A trend towards increased amounts of leisure screen time was identified in those married or cohabiting while having children resulted in less total sitting time. Several environmental correlates were identified including proximity of green space, neighbourhood walkability and safety and weather. Conclusions Results provide further evidence relating to several already recognised individual level factors and preliminary evidence relating to social and environmental factors that should be further investigated. Most studies relied upon cross-sectional design limiting causal inference and the heterogeneity of the sedentary measures prevented direct comparison of findings. Future research necessitates longitudinal study designs, exploration of policy-related factors, further exploration of environmental factors, analysis of inter-relationships between identified factors and better classification of sedentary behaviour domains.
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Orthostatic intolerance (OI) is common in teenagers (T) and young adults (A). Despite treatment with oral fluids, medication, and exercise, a significant number have symptoms from multiple organ systems and suffer low quality of life (QOL). Previous studies showed that acute intravenous (IV) hydration (IH) could help restore orthostatic tolerance; however, no data are available about the intermediate-term effects of IH. We therefore studied the efficacy of IH to improve QOL and manage medication-refractory OI patients. Our study population consisted of 39 patients (mean age = 16.1 ± 3.3) years; thirty-two were female. Average number of medications failed = 3.1. Average QOL score on self-reported OI questionnaire was 4.2 (normal QOL = 10). IV hydration consisted of normal saline (1-2 l/day, 3-7 days/week). 1) Orthostatic testing revealed Postural Orthostatic Tachycardia (24), Neurally Mediated Hypotension (14) or OI (1). 2) Average orthostatic change in heart rate was 48 ± 18 bpm. 3) IH was performed via intermittent IV access (10), PICC line (22), and Port (7). 4) Duration of IH varied from 1 week to 3.8 years (mean = 29 ± 47 weeks). 5) Overall, 79 % (n = 31) demonstrated clinically improved self-reported QOL. 6) Six patients who discontinued IH requested to restart treatment. (7) Complications consisted of upper extremity deep vein thrombosis (n = 3) and infection (n = 4). IH is an effective therapy to improve QOL in T&A with medication-resistant OI. Most patients continued to report improved QOL once IH was discontinued. IH should be considered a therapeutic option in medication-resistant OI patients with low QOL.
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2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope. Available from: https://www.researchgate.net/publication/276467926_2015_Heart_Rhythm_Society_Expert_Consensus_Statement_on_the_Diagnosis_and_Treatment_of_Postural_Tachycardia_Syndrome_Inappropriate_Sinus_Tachycardia_and_Vasovagal_Syncope [accessed Aug 18 2022]. This document is intended to help front-line cardiologists, arrhythmia specialists, and otherhealth care professionals interested in the care of patients who present with presumedpostural tachycardia syndrome (POTS), inappropriate sinus tachycardia (IST), and vasovagalsyncope (VVS). It is not intended to be a comprehensive narrative review, as excellent reviews, chapters, and entire volumes have appeared recently.1–3 This document has 3objectives: (1) establish working criteria for the diagnosis of POTS, IST, and VVS; (2)provide guidance and recommendations on their assessment and management; and (3)identify key areas in which knowledge is lacking, to highlight opportunities for future collaborative research efforts.To maintain this pragmatic focus, we excluded several related topics, including a detailed approach to syncope and other syndromes of transient loss of consciousness, the impact of syncope on other disorders, most orthostatic hypotension syndromes, the effects of the autonomic system on arrhythmias, the use of syncope scores or syncope units, and recommendations on training programs and staffing criteria. A number of sections contain very brief reviews, given that the material has recently been covered elsewhere.
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Patients with the postural orthostatic tachycardia syndrome (POTS) are primarily premenopausal women, which may be attributed to female sex hormones. We tested the hypothesis that hormonal fluctuations of the menstrual cycle alter sympathetic neural activity and orthostatic tolerance in POTS women. Ten POTS women were studied during the early follicular (EF) and mid-luteal (ML) phases of the menstrual cycle. Haemodynamics and muscle sympathetic nerve activity (MSNA) were measured while supine, and during 60° upright tilt for 45 min or until presyncope, cold pressor test (CPT), and Valsalva manoeuvres. Blood pressure and total peripheral resistance were higher during rest and tilting in the ML than EF phase; however heart rate, stroke volume, and cardiac output were similar between phases. There were no differences in MSNA burst frequency (8 ± 8 [SD] EF phase vs. 10 ± 10 bursts/min ML phase at rest; 34 ± 15 EF phase vs. 36 ± 16 bursts/min ML phase at 5 min tilt), burst incidence, or total activity, or in the cardiovagal and sympathetic baroreflex sensitivities between phases in any condition. The incidence of presyncope was also the same between phases. There were no differences in haemodynamic or sympathetic responses to CPT or Valsalva. These results suggest that the menstrual cycle does not affect sympathetic neural activity, but modulates blood pressure and vasoconstriction in POTS women during tilting. Thus, factors other than sympathetic neural activity are likely responsible for symptoms of orthostatic intolerance across the menstrual cycle in women with POTS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Introduction: Postural tachycardia syndrome (POTS) is associated with exercise intolerance, hypovolemia and cardiac atrophy, which may contribute to reduced stroke volume and compensatory exaggerated heart rate (HR) increases. Acute volume loading with intravenous saline reduces HR and improves orthostatic tolerance and symptoms in POTS, but its effect on exercise capacity is unknown. In this study, we determined the effect of intravenous saline infusion on peak exercise capacity (VO2peak) in POTS. Methods: Nineteen POTS patients participated in a sequential study. VO2peak was measured on two separate study days, following placebo or 1 L intravenous saline (NaCl 0.9%). Patients exercised on a semi-recumbent bicycle with resistance increased by 25 watts every 2 minutes until maximal effort was achieved. Results: Patients exhibited blood volume deficits (-13.4±1.4% ideal volume), consistent with mild to moderate hypovolemia. At baseline, saline significantly increased stroke volume (saline: 80±8 mL vs. placebo: 64±4 ml; p=0.010), increased cardiac output (saline: 6.9±0.5 l/min vs. placebo: 5.7±0.2 l/min; p=0.021), and reduced systemic vascular resistance (saline: 992.6±70.0 dyn-s/cm(5) vs. placebo: 1184.0±50.8 dyn-s/cm(5); p=0.011), with no effect on VO2peak, heart rate (HR) or blood pressure. During exercise, saline did not produce differences in VO2peak (saline: 26.3±1.2 mg/kg/min vs. placebo: 27.7±1.8 mg/kg/min; p=0.615), peak HR (saline: 174±4 bpm vs. placebo: 175±3 bpm; p=0.672) or other cardiovascular parameters. Conclusions: These findings suggest that acute volume loading with saline does not improve VO2peak or cardiovascular responses to exercise in POTS, despite improvements in resting hemodynamic function.
Article
Background: The postural orthostatic tachycardia syndrome (POTS) affects primarily young women and impairs quality of life. We found that in a research setting, exercise training along with lifestyle intervention is effective as a non-drug therapy for POTS. Objective: To evaluate the efficacy of our exercise training/lifestyle intervention in POTS patients in a community environment. Methods: We established a POTS registry and enrolled 251 patients (86% women, 26±11 [SD] years) through their physicians. A 3-month program involving mild-to-moderate intensity endurance training (progressing from semi-recumbent to upright, 3-5 times/wk, 30-45 min/session) plus strength training was implemented along with increasing salt/water intake. The program was delivered to the physicians, who oversaw training in their patients. A 10-min stand test was performed at the physician's office and patient quality of life was assessed using the 36-item Short-Form Health Survey. Results: 103 patients completed the program. Of those that completed, 71% no longer qualified for POTS and were thus in remission. The increase in heart rate from supine to 10-min stand was markedly lower (23±14 versus 46±17 beats/min before intervention; P<0.001), while patient quality of life was improved dramatically after intervention (P<0.001). Of those who were followed for 6-12 months (n=31), the effect was persistent. Conclusions: A training/lifestyle intervention program can be implemented in a community setting with physician supervision and is effective in the treatment of POTS. It remains to be determined whether exercise can be an effective long-term treatment strategy for this condition, though patients are encouraged to maintain an active lifestyle indefinitely.
Article
To validate a new patient-reported outcome measure for routine clinical use. A total of 50 older individuals with orthostatic hypotension who attended a falls and syncope clinic completed three questionnaires, the recently developed Orthostatic Hypotension Questionnaire, the existing Orthostatic Grading Scale and the quality of life measure EQ-5D-5L. Validity of the Orthostatic Hypotension Questionnaire was tested against the aforementioned questionnaires for symptoms and for quality of life. Comorbidity was quantified using the Charlson Comorbidity Index. The cohort of 50 individuals had a median age of 67 years (interquartile range 26-89 years) with a median Charlson Comorbidity Index of 3 (interquartile range 2-5). The total Orthostatic Hypotension Questionnaire Symptom Assessment score correlated strongly with the Orthostatic Grading Scale (0.616, P < 0.001) and the Orthostatic Hypotension Questionnaire Daily Activity Scale correlated strongly with daily activity on the EQ-5D-5L (0.61, P < 0.001). Using the Orthostatic Grading Scale, individuals' symptoms were categorized as mild, moderate or severe, the Orthostatic Hypotension Questionnaire scores were significantly different between these groups (P < 0.001). Internal consistency was high (Cronbach's apha 0.882), and ceiling or floor effects did not limit the total scores. The Orthostatic Hypotension Questionnaire is a valid patient report tool to quantify the symptom burden of people with orthostatic hypotension. Because the symptoms associated with orthostatic hypotension are frequently non-specific, it will be a clinically useful tool to measure and quantify symptom load in people with orthostatic hypotension. Geriatr Gerontol Int 2015; ●●: ●●-●●. © 2015 Japan Geriatrics Society.
Article
To prospectively evaluate patients who met standard criteria for postural tachycardia syndrome (POTS), at baseline and 1-year follow-up, using standard clinical and laboratory methods to assess autonomic function. Fifty-eight patients met the study criteria (orthostatic symptoms and a heart rate increment of ≥ 30 beats/min on head-up tilt) and completed 12 months of follow-up. All patients were enrolled and completed the study from January 16, 2006, through April 15, 2009. Patients underwent standardized autonomic testing, including head-up tilt, clinical assessment, and validated questionnaires designed to determine the severity of autonomic symptoms. Patients were predominantly young females (n=49, 84%), with 20 patients (34%) reporting an antecedent viral infection before onset of symptoms. More than one-third (37%) no longer fulfilled tilt criteria for POTS on follow-up, although heart rate increment on head-up tilt did not differ significantly at 1 year (33.8 ± 15.1 beats/min) compared with baseline (37.8 ± 14.6 beats/min) for the entire cohort. Orthostatic symptoms improved in most patients. Autonomic dysfunction was mild as defined by a Composite Autonomic Severity Score of 3 or less in 55 patients (95%) at baseline and 48 patients (92%) at 1 year. To our knowledge, this is the first prospective study of the clinical outcomes of patients with POTS. Orthostatic symptoms improved in our patients, with more than one-third of patients no longer fulfilling tilt criteria for POTS, although the overall group change in heart rate increment was modest. Our data are in keeping with a relatively favorable prognosis in most patients with POTS.