J Appl Physiol 125: 1396 –1403, 2018.
First published August 23, 2018; doi:10.1152/japplphysiol.00377.2018.
RESEARCH ARTICLE
Hemodynamic characteristics of postural hyperventilation: POTS with
hyperventilation versus panic versus voluntary hyperventilation
Julian M. Stewart,1,2 Paul Pianosi,3 Mohamed A. Shaban,1 Courtney Terilli,1 Maria Svistunova,1
Paul Visintainer,4 and Marvin S. Medow1,2
1
Department of Pediatrics, New York Medical College, Valhalla, New York; 2Department of Physiology, New York Medical
College, Valhalla, New York; 3Paediatric Respiratory Medicine, King’s College Hospital National Health Surface Foundation
Trust, London, United Kingdom; and 4Epidemiology and Biostatistics, Baystate Medical Center, University of Massachusetts
School of Medicine, Worcester, Massachusetts
Submitted 1 May 2018; accepted in final form 23 August 2018
Stewart JM, Pianosi P, Shaban MA, Terilli C, Svistunova M,
Visintainer P, Medow MS. Hemodynamic characteristics of postural
hyperventilation: POTS with hyperventilation versus panic versus
voluntary hyperventilation. J Appl Physiol 125: 1396 –1403, 2018. First
published August 23, 2018; doi:10.1152/japplphysiol.00377.2018.—Up-
right hyperventilation occurs in ~25% of our patients with postural
tachycardia syndrome (POTS). Poikilocapnic hyperventilation alone
causes tachycardia. Here, we examined changes in respiration and
hemodynamics comprising cardiac output (CO), systemic vascular
resistance (SVR), and blood pressure (BP) measured during head-up
tilt (HUT) in three groups: patients with POTS and hyperventilation
(POTS-HV), patients with panic disorder who hyperventilate (Panic),
and healthy controls performing voluntary upright hyperpnea (Volun-
tary-HV). Though all were comparably tachycardic during hyperven-
tilation, POTS-HV manifested hyperpnea, decreased CO, increased
SVR, and increased BP during HUT; Panic patients showed both
hyperpnea and tachypnea, increased CO, and increased SVR as BP
increased during HUT; and Voluntary-HV were hyperpneic by design
and had increased CO, decreased SVR, and decreased BP during
upright hyperventilation. Mechanisms of hyperventilation and hemo-
dynamic changes differed among POTS-HV, Panic, and Volun-
tary-HV subjects. We hypothesize that the hyperventilation in POTS
is caused by a mechanism involving peripheral chemoreflex sensiti-
zation by intermittent ischemic hypoxia.
NEW & NOTEWORTHY Hyperventilation is common in postural
tachycardia syndrome (POTS) and has distinctive cardiovascular
characteristics when compared with hyperventilation in panic disorder
or with voluntary hyperventilation. Hyperventilation in POTS is
hyperpnea only, distinct from panic in which tachypnea also occurs.
Cardiac output is decreased in POTS, whereas peripheral resistance
and blood pressure (BP) are increased. This is distinct from voluntary
hyperventilation where cardiac output is increased and resistance and
BP are decreased and from panic where they are all increased.
hyperventilation; postural tachycardia; systemic vascular resistance
INTRODUCTION
Standing upright can evoke symptoms, such as lightheaded-
ness, headache, nausea, fatigue, cognitive deficits, and exercise
intolerance, relieved by recumbency (39, 42). This defines
orthostatic intolerance (OI). Signs such as marked changes in
Address for reprint requests and other correspondence: J. M. Stewart, New
York Medical College, Center for Hypotension, 19 Bradhurst Ave., Suite
1600S, Hawthorne, NY 10532 (e-mail: julian_stewart@nymc.edu).
1396 8750-7587/18 Copyright © 2018 the American Physiological Society
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heart rate (HR), blood pressure (BP), or respiration may also be
present. Postural tachycardia syndrome (POTS) is a common
form of chronic OI in which excess upright tachycardia is
associated with OI symptoms in the absence of hypotension
(20, 26, 40). Postural hyperventilation has been reported in the
“hyperventilation syndrome” (28), which has been regarded as
a psychologically induced event (14). For example, hyperven-
tilation is present in many but not all patients with panic
disorder, and postural stress may trigger onset of panic, dys-
pnea, and hyperventilation (17). Hyperventilation is excessive
ventilation, or ventilation out of proportion to metabolic de-
mand, such that PaCO2 falls and a respiratory alkalosis ensues.
Dyspnea (shortness of breath), hyperventilation, and hypo-
capnia [reduced carbon dioxide (CO2) in the blood] in the
absence of cardiopulmonary disease have been reported in
association with POTS and typically take the form of postural
hypocapnic hyperpnea (hyperpnea is excessive depth of breath-
ing) (9, 34, 43, 47). We observed hypocapnic hyperpnea in
POTS in response to a rapid initial orthostatic decrease in
cardiac output (CO) and cerebral blood flow (CBF) (9) during
poikilocapnic (uncontrolled CO2) experiments. Poikilocapnic
hyperventilation produces sinus tachycardia (29), and hypo-
capnia reduces CBF, resulting in symptoms and maladaptive
effects, including impaired neuronal activation (22). We re-
cently demonstrated that postural hypocapnic hyperpnea can
cause POTS, rather than resulting from POTS (9). Data sug-
gests that ischemia of the carotid body (“stagnant hypoxia”) (9)
is the candidate mechanism for hyperventilation and results
primarily from low CO and secondarily from sympathetic
vasoconstriction of the artery to the carotid body (9, 11).
We hypothesize that postural hyperventilation causing
POTS is identifiably different from voluntary hyperpneic hy-
perventilation and from hyperventilation in panic disorder.
Differences comprise distinctive changes in BP, CO, and
systemic vascular resistanc, whereas excessive tachycardia is
present in all.
METHODS
Subjects. The POTS group was comprised of 16 subjects aged
13–26 yr old (mean age 18.1 ⫾ 1.2 yr; 14 women, 2 men) with POTS
as defined by standard criteria (40) and who additionally complained
of shortness of breath when upright. All had normal pulmonary
function tests and no discernible cardiopulmonary or systemic illness.
We have regarded these dyspneic patients as a distinct subgroup of
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 CHARACTERISTICS OF POSTURAL HYPERVENTILATION
POTS denoted “postural hyperpnea” because tidal volume (TV)
increases with orthostatic stress but respiratory rate (RR) does not (9).
We recently described a distinct subset of patients with POTS who
exhibit hyperventilation elicited by the imposition of an orthostatic
challenge. All of these had normal pulmonary function tests and no
discernible cardiopulmonary or systemic illness. They exhibited pos-
tural hyperventilation in the form of hypocapnic hyperpnea causing
reduced CBF velocity (CBFv), consequent lightheadedness, and in-
creased BP. This POTS-HV comprised ~25% of our enrolled patients.
All patients were recruited from our Center for Hypotension, which
is an outpatient referral center for patients with POTS, OI, and other
disorders related to autonomic nervous system dysfunction. All pa-
tients with POTS had day-to-day symptoms of OI for 6 mo or more,
and symptom relief was provided by recumbency and exhibited
characteristic features such as lightheadedness, diaphoresis, warmth,
nausea, hyperventilation, pallor, and a postdrome of fatigue and
headache following imposition of an orthostatic challenge, along with
age-dependent changes in upright HR. Signs and symptoms of OI and
an excessive increase in HR without hypotension were evident within
10 min of head-up tilt (HUT) (26, 31, 37). If age was ⬍19 yr,
excessive tachycardia was defined as an increase in HR of at least 40
beats/min or a HR ⬎120 beats/min in the absence of postural hypo-
tension (41) during the 10 min upright tilt table test. If age was ⬎19
yr, excessive tachycardia was defined by an orthostatic HR increment
exceeding 30 beats/min (40). Other medical problems that could
explain these signs or symptoms had been ruled out. We excluded
potential enrollees with a history of respiratory disease, sleep apnea,
obesity, or anxiety disorders. Patients with diagnosed panic disorder
were specifically excluded from this group.
The panic disorder group was comprised of 7 subjects aged 15–22
yr old (mean age 16.4 ⫾ 2.5 yr; 5 women, 2 men). Patients were
diagnosed with recurrent panic attacks by a psychiatrist, fulfilling
criteria contained in DSM-V-TR Axis I Disorders (1). These patients
with panic disorder were referred for complaints of upright tachycar-
dia, shortness of breath, or symptoms of hyperventilation, such as
lightheadedness, numbness, and tingling of the arms and around the
mouth, during panic attacks triggered by orthostasis.
There were two groups of healthy volunteers: one that performed
voluntary hyperpnea during HUT (designated Voluntary-HV) and a
second group of true controls that breathed normally, against which all
other groups (POTS-HV, Panic, and Voluntary HV) were compared.
Healthy control subjects were nonsmokers with no known medical
conditions, taking no medications, with a normal physical exam and
electrocardiogram. Healthy control subjects were included only if free
of systemic illness and of OI of any type. We studied 7 Voluntary-HV
subjects, aged 17–25 yr (mean age 19.1 ⫾ 2.6 yr; 5 women, 2 men)
and 10 true control subjects, aged 18 –25 yr (mean age 18.8 ⫾ 2.2 yr;
8 women, 2 men).
Patients and control subjects were required to refrain from all
medications, including anxiolytic medications, for at least 2 wk before
the study, with the exception of contraceptive or thyroid medications.
Since all enrollees with POTS were either on no medication or able to
tolerate being off of medication for at least 2 wk before testing, and
all were able to complete the entire day of testing, they could be
described as being “moderately” affected by their condition. Enrollees
were required to stop ingestion of xanthine-, caffeine-, or alcohol-
containing substances 72 h before study. A light breakfast was
permitted on testing day if eaten 2 or more hours before testing.
The Institutional Review Board of New York Medical College
reviewed and approved this protocol. Each subject received a detailed
description of all protocols and was given an opportunity to have their
questions answered. Signed informed consent was obtained from all
participants or their parents.
Instrumentation. All subjects were instrumented in a similar fash-
ion by the same operator. Height and weight were measured, and body
mass index was calculated. During instrumentation, all subjects lay
supine on an electronic motorized tilt table (Colin Medical Instru-
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1397
ments Corp., San Antonio, TX) with a footboard. An electrocardio-
graph measured HR from the beat-to-beat cardiac electrical interval.
Beat-to-beat BP was monitored by a volume clamp method using
finger arterial plethysmography (Finometer; FMS, Amsterdam, the
Netherlands) on the right middle or index finger and corrected for tilt
angle using ModelFlow software. Finometer data were calibrated to
brachial artery pressure and intermittently checked against oscillomet-
ric BP measurements.
The Finometer uses the Modelflow algorithm to estimate beat-to-
beat CO by pulse-wave analysis (15). Before experiments began,
Modelflow CO was calibrated against an Innocor inert gas rebreathing
CO measurement (Innovision, Denmark) while supine. We computed
systemic vascular resistance (SVR) by dividing the time average
arterial pressure [mean arterial pressure (MAP)] by the Modelflow CO
averaged over each cardiac cycle. The first value of SVR was also
calculated by measuring a manual BP, calculating the estimated MAP
from the formula MAP ⫽ (systolic BP ⫹ 2diastolic BP)/3, and divid-
ing that result by the measured (supine) CO. Thereafter, continuous
SVR was calculated from Modelflow data. To estimate TV, respira-
tory plethysmography (Respitrace, NIMS Scientific, Miami Beach,
FL) calibrated by measurements made using a pneumotachogram
(Hans Rudolph, Shawnee KS) and nasal cannula capnography com-
bined with a pulse oximeter (Smith Medical PM, Waukesha, WI)
measured respiration, end tidal CO2 (ETCO2), and oxygen saturation.
Transcranial Doppler (TCD) (Neurovision; Multigon, Yonkers, NY)
measured CBFv of the left middle cerebral artery (MCA) using a
2-MHz probe fixed to the subject’s head by a custom-made headband.
Signals were acquired at 200 samples/s, multiplexed, and A/D-
converted using custom software. These measurements are routine
during our tilt table studies.
Protocol. Subjects arrived at 9:30 AM. Following instrumentation,
subjects remained awake and supine for 30 min to acclimate. Baseline
data was comprised of continuously measured HR, BP, RR, TV,
expiratory minute volume (V̇E), ETCO2, CO, SVR, and CBFv. For
purposes of comparison, we used averaged data for the 10 min
immediately preceding tilt to determine baseline supine values. Mean
ETCO2 over the last 10 min of the rest period was defined as baseline
CO2 for each subject throughout the protocol.
After supine data collections were complete, all subjects were tilted
upright over 8 s to 70° for 10 min or as tolerated. Voluntary
hyperventilation in healthy volunteers began 2 min after initiation of
upright tilt by having them take maximum breaths at their supine RR
for two minutes. This emulates the hyperpneic breathing typically
seen in most patients with POTS. Healthy volunteers had ETCO2
values that ranged between 38 and 43 Torr supine, which decreased
with upright tilt but was never less than 33 Torr. We, therefore,
defined hyperventilation by an ETCO2 consistently ⬍30 Torr during
upright tilt. Continuously measured HR, BP, ETCO2, respiratory data,
CO, SVR, and CBFv data were recorded for offline analysis.
Normalized respiratory impedance data was used to calculate RR
and estimate TV and V̇E. Data were detrended to remove artifact, and
TV was obtained as peak-to-trough volume per breath. V̇E was
determined by averaging TV over 1 min and multiplying by the RR.
Data analysis. All data were continuously sampled at 200 Hz,
converted with an analog-to-digital converter (DI-720 DataQ Ind,
Milwaukee, WI) connected to a personal computer, and analyzed
offline.
Baseline data was recorded for 10 min before upright tilt. The first
minute of tilt following a prolonged supine rest often includes a period
of hemodynamic instability known as “initial orthostatic hypotension”
(IOH) (52). IOH is caused by the rapid translocation of blood from the
upper body to the lower body and the normal lag in the onset of
compensatory adrenergic vasoconstriction. For these reasons, the first
minute of tilt is often avoided for purposes of analysis. However, our
prior data showed that this time period may be critical to initiating
hypocapnic hyperpnea (9). Therefore, we retained early physiological
measurements following the initiation of upright tilt and graphically
1398 CHARACTERISTICS OF POSTURAL HYPERVENTILATION

Table 1. Supine baseline hemodynamic and Voluntary HV, respirations became stable by 2–3 min and became
cardiopulmonary data stable in the panic group by 1–2 min. Measurements were made in
healthy volunteer hyperventilators (Voluntary HV) during the last 20 s
Healthy POTS Panic of voluntary hyperventilation when respirations were stable. Data was
Volunteer Hyperventilation Disorder time-averaged during these time periods.
Heart rate, beats/min 66 ⫾ 3 82 ⫾ 5* 74 ⫾ 5 Data presentation and statistics. There were four groups in all:
Systolic BP, mmHg 115 ⫾ 3 118 ⫾ 2 114 ⫾ 3 hyperventilating POTS (POTS-HV), panic disorder (Panic), voluntary
Diastolic BP, mmHg 60 ⫾ 2 62 ⫾ 2 68 ⫾ 3 hyperventilators (Voluntary HV), and healthy control volunteers who
MAP, mmHg 79 ⫾ 4 77 ⫾ 4 81 ⫾ 4 underwent tilt table testing without voluntary hyperventilation. The
Pulse pressure, mmHg 54 ⫾ 3 55 ⫾ 4 47 ⫾ 3 data from healthy, nonhyperventilating volunteers were used to eval-
Respiratory rate, breaths/min 14 ⫾ 1 15 ⫾ 1 14 ⫾ 1 uate differences in supine baseline hemodynamic and cardiopulmo-
V̇E, l/min 6.8 ⫾ 0.7 7.4 ⫾ 0.7 6.7 ⫾ 0.7
nary data compared with POTS-HV and Panic subjects. It was
Tidal volume, liters 0.49 ⫾ 0.03 0.50 ⫾ 0.08 0.51 ⫾ 0.05
ETCO2, Torr 41.4 ⫾ 0.6 38.2 ⫾ 0.8 41.9 ⫾ 0.5 additionally used as a visual, but not a statistical, comparison of the
Cardiac output, l/min 5.7 ⫾ 0.4 5.4 ⫾ 0.2 5.8 ⫾ 0.4 response to orthostasis. All tabular results are reported as mean ⫾ SE,
TPR, mmHg·l⫺1·min⫺1 16.3 ⫾ 1.5 15.6 ⫾ 1.5 15.1 ⫾ 1.0 and statistical differences between values shown in the tables were
Mean CBFv, cm/s 72 ⫾ 3 73 ⫾ 6 75 ⫾ 3 calculated using t-test with significance set at P ⱕ 0.05, comparing
Healthy with POTS-HV and with Panic subjects.
Values are means ⫾ SE. BP, blood pressure; CBFv, cerebral blood flow Graphic data are depicted as mean ⫾ SE. Data were obtained from
velocity; ETCO2, end tidal carbon dioxide; MAP, mean arterial pressure;
POTS, postural tachycardia syndrome; TPR, total peripheral resistance. *P ⬍
original time series averaged over 15-s intervals centered at the time
0.05 difference from healthy volunteer control subject. markers. Data were collected and analyzed by the same investigator
throughout.
We used repeated-measures ANOVA (rmANOVA) to compare
displayed BP, CO, CBV, HR, and SVR during this early “initial” tilt study groups on outcomes over time intervals. To address our hypoth-
epoch. Thereafter, data were tabulated at 1 min after tilt and again eses, we were interested in how the study groups differed in outcome
when respirations had become stable in patients with POTS and in measures over time during the tilt. As such, we focused on the “gr-
patients with panic disorder. In patients with POTS-HV, respirations oup ⫻ time interaction” in the rmANOVA. We assumed a covariance
became stable upon tilt and remained stable up to ~4 min. In structure of compound symmetry. Reported P values reflect the

Fig. 1. Respiratory data and cerebral blood

flow velocity (CBFv) are shown for all sub-
jects before [baseline (Base)] and following
head-up tilt measured at the time epochs
shown. The increase in expiratory minute
volume (V̇E) resulted from an increase in
tidal volume (TV) in all groups compared
with control (P ⬍ 0.001). Respiratory rate
(RR) only increased significantly (P ⬍
0.001) in the Panic group. End tidal CO2
(ETCO2) decreased similarly and signifi-
cantly for all groups (P ⬍ 0.001), whereas
CBFv decreased in parallel, as expected.
HV, hyperventilation; Panic, panic disorder;
POTS, postural tachycardia syndrome.

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 CHARACTERISTICS OF POSTURAL HYPERVENTILATION 1399
interaction term using the Greenhouse-Geisser correction. To control
for multiple comparisons, pairwise comparisons among groups, fol-
lowing a significant omnibus rmANOVA test, were conducted using
Scheffe’s test. Statistical significance was set at P ⱕ 0.05. Results
were calculated by using GraphPad Prism version 4.0.
Sample size estimation. For sample size estimation, we assumed a
repeated measures design with measurements at baseline and four
subsequent time points within each study participant. Basing our
calculations on HR and assuming a within-subject correlation of HR
measures of 0.50 on repeated assessment, a sample size of 7 individ-
uals per group with 5 assessments would provide 80% power to detect
a standardized effect size of 0.85 for the between-group comparison
and more than 80% power to detect a group-by-time interaction effect
size of 1.0 or larger. This sample size incorporates a Greenhouse-
Geisser correction to the F-test.

RESULTS

Height was 162 ⫾ 4 cm in POTS-HV, 168 ⫾ 4 cm in

Voluntary HV, and 166 ⫾ 3 cm in the Panic group, whereas
weights were 58 ⫾ 2 kg, 63 ⫾ 2 km, and 61 ⫾ 4 kg, respec-
tively. Height was 169 ⫾ 3 cm, whereas weight was 67 ⫾ 2 kg
for control subjects. There were no differences in these param-
eters either within or between groups.
Supine baseline data. Baseline supine data for BP, HR, CO,
SVR, CBFv, V̇E, and ETCO2 are shown in Table 1. There was
no significant difference in CO, SVR, V̇E, MAP, systolic BP,
diastolic BP, pulse pressure, ETCO2, or mean CBFv between
POTS-HV, Panic, and Voluntary HV. HR was significantly
increased in POTS-HV but not in Panic.
Upright tilt data. It was uncommon for a patient with panic
disorder to endure upright positioning for more than a few
minutes of tilt, although one patient was able to endure 11 min.
Postural hyperventilation in POTS was characterized by hy-
perpnea without tachypnea, as previously reported (9, 45).
Respiratory responses and CBFv. Figure 1 shows that TV
immediately increased in POTS-HV with tilt and accounted for
much of the V̇E increase (P ⬍ .001) because there was no Fig. 2. Representative tracings of mean arterial pressure (MAP), cardiac output
increase in RR in this group. Rather, there was a small, albeit (CO), and systemic vascular resistance (SVR) from a Voluntary HV, POTS-
nonsignificant, decrease in RR with time following the initial HV, and Panic subject. MAP increased in POTS-HV and Panic, decreased in
tilt-induced increase. This contrasted with Panic in which TV Voluntary HV with the onset of upright hyperventilation. CO decreased in
POTS-HV but increased in Panic and Voluntary HV. SVR increased similarly
increased only after the initial period and was associated with in POTS-HV and Panic but decreased markedly in Voluntary HV. HV,
a significant increase in RR. By design, RR was fixed for the hyperventilation; Panic, panic disorder.
Voluntary HV group. Their TV increased during the period of
voluntary hyperpnea to levels similar to those observed in
POTS-HV. ETCO2 decreased similarly for patients with DISCUSSION
POTS-HV, Panic, and Voluntary HV enrollees, whereas CBFv
decreased in parallel for all of these groups, as expected. Patterns of hyperventilation in POTS compared with panic.
Hemodynamic responses to tilt. Figure 2 shows representa- Poikilocapnic hyperventilation is defined by an increase in V̇E,
tive tracings of MAP, CO, and SVR for Voluntary HV, causing decreased blood CO2 and ETCO2. V̇E may be in-
POTS-HV, and Panic. MAP increased in POTS-HV and Panic, creased by an increase in RR alone (tachypnea), an increase in
whereas it decreased in Voluntary HV with the onset of TV alone (hyperpnea), or a combination of both, depending on
upright hyperventilation. CO significantly decreased in the nature of the stressor (50). In the absence of administered
POTS-HV but increased in Panic and Voluntary HV. SVR CO2, the respiratory response to pain or panic is a combination
increased similarly in POTS-HV and Panic but decreased of hyperpnea and tachypnea, as observed here and described in
markedly in Voluntary HV. the literature (6, 30, 53). In contrast, V̇E increased in POTS-HV
Representative findings were confirmed by data in Fig. 3, by an increase in TV with either no change or a small decrease
which shows the groups and normative control data. HR in RR, as shown previously (9). TV alone was increased during
increased during periods of hyperventilation for all groups. voluntary hyperventilation in healthy volunteers by design so
MAP increased in POTS-HV and Panic, CO decreased in as to mimic the isolated hyperpnea in POTS.
POTS-HV but increased in Panic and Voluntary HV, and SVR Three factors contribute to tachycardia during hyperventila-
increased in POTS-HV and Panic but significantly decreased in tion (29). In order of increasing potency, they are: 1) lung
Voluntary HV. inflation reflexes, 2) effects because of ischemia of central

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1400 CHARACTERISTICS OF POSTURAL HYPERVENTILATION
Fig. 3. Heart rate (HR), mean arterial pres-
sure (MAP), cardiac output (CO), and sys-
temic vascular resistance (SVR) from Vol-
untary HV, POTS-HV, Panic, and Control
subjects. HR increased significantly (P ⬍
0.001) during periods of hyperventilation for
all groups. MAP increased in POTS-HV and
Panic, whereas Voluntary HV was signifi-
cantly reduced compared with all other
groups (P ⬍ 0.025). CO decreased signifi-
cantly (P ⬍ 0.005) in POTS-HV, in Panic
(P ⬍ 0.025), and in Panic and Voluntary HV.
SVR increased significantly in POTS-HV
(P ⬍ 0.005) and Panic (P ⬍ 0.025) but de-
creased significantly (P ⬍ 0.01) in Volun-
tary HV. HV, hyperventilation; Panic, panic
disorder; POTS, postural tachycardia syn-
drome.
medullary chemoreflexes and inspiratory neurons (7), and 3)
direct actions of hypocapnia on the sinoatrial node (29). In
healthy volunteers, with normal autonomic function, tachycar-
dia is accompanied by a rise in CO and fall in SVR.
Our major findings contrast changes in CO, SVR, and BP
during hyperventilation in patients with POTS-HV, panic dis-
order with hyperventilation, and in voluntary hyperpneic hy-
perventilation in healthy control subjects.
An outline of characteristic directional changes in BP, CO,
and SVR is summarized in Table 2.
Hyperventilation in POTS. All patients with POTS, regard-
less of hyperventilation, have thoracic hypovolemia and in-
creased SVR, sufficient to prevent postural hypotension when
upright, despite reduced preload and CO (13, 25, 44). Stroke
volume and cardiac preload are reduced (27), whereas sympa-
thoexcitation is increased (2). POTS-HV comprises ~25% of
our POTS population. The relationship of hyperventilation
causing upright tachycardia has been revived by reports from
our laboratory (9, 43) and has been previously reported by
others (34), following the definition of POTS (40). Hyperven-
tilation during orthostasis in POTS appears to be driven by
rapid and excessively decreased initial CO, BP, and CBF. Our
Table 2. Characteristic directional hemodynamic changes
during orthostatic hyperventilation
Voluntary POTS
Hyperventilation Hyperventilation
MAP, SBP, DBP 2 1
Cardiac output 1 2
SVR 2 1
DBP, diastolic blood pressure; MAP, mean arterial pressure; POTS, postural
tachycardia syndrome; SBP, systolic blood pressure; SVR, systemic vascular
resistance.
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data show that reduced CBF is immediately followed by
hyperpnea and hypocapnia (9). A reduction in CBF implies a
reduction in carotid artery and carotid body blood flows.
Hypocapnia perpetuates the reduction in CBF (48). This or-
thostatic epoch of IOH (52) results in “stagnant hypoxia” of the
carotid body (9, 19). The carotid body cannot distinguish
stagnant hypoxia [also known as “ischemic hypoxia” (10)]
from hypoxic hypoxia. Upright patients with POTS-HV have
an atypical presentation of chronic intermittent hypoxia.
Chronic intermittent hypoxia increases the sensitivity of the
peripheral chemoreflex sensitivity to hypoxia (11), increases
sympathetic activity, increases vasoconstriction, and increases
BP (24, 36). Our past findings support peripheral chemoreflex
sensitization by showing enhanced hypoxic ventilatory re-
sponse in patients with POTS studied without regard for
complaints of hyperventilation or dyspnea (46). The hyperp-
neic response in patients with POTS consisting of raised TV
during HUT may be explained by a unique pattern of respira-
tory muscle recruitment.
In vivo and in situ studies of young animals exposed to
chronic intermittent hypoxia demonstrate a breathing pattern of
active expiration at rest (55), suggesting that the neural mech-
anisms responsible for active expiration (normally a passive
phenomenon) are hyperactive. The significance of this active
expiration (typically employed during exercise) is a reduction
in end-expiratory lung volume which lengthens the diaphragm,
Panic augmenting subsequent TV beyond that obtained simply by
Disorder increased inspiratory diaphragmatic excursion. Such increased
1 intraabdominal pressure would further compromise venous
1 return from below the diaphragm that impairs such individuals’
1 ability to maintain CO during HUT.
It may be useful to classify patients with POTS-HV as
having a dysfunctional breathing phenotype (3), as there are a
growing number of reviews on the use of breathing exercises to
 CHARACTERISTICS OF POSTURAL HYPERVENTILATION
mitigate dysfunctional breathing or reduce dyspnea in pulmo-
nary diseases, such as asthma (49) or chronic obstructive
pulmonary disease (18). A relevant example of breathing
modifications that may be applicable to our patients with
POTS-HV is a study that showed improvement in autonomic
function in patients with essential hypertension (33). BP fell
over a 3-mo period with both slow and fast breathing training,
but Valsalva ratio, HR variation with respiration, and BP
response in the hand grip and cold-pressor test showed signif-
icant improvement only in patients using slow breathing.
Cortical influences can override reflex breathing patterns, and
it is conceivable that such learned breathing patterns may at
least counteract expiration described above, with consequent
improvement in venous return to the heart among other puta-
tive benefits.
Hyperventilation in panic disorder. Epinephrine spillover
from the heart is present in patients with panic disorder, even
at rest. During panic attacks, there are large increases in
circulating epinephrine as well as sympathetic activity in skel-
etal muscle (5, 12, 23, 54). Beta adrenergic receptors are
therefore activated in panic disorder and mediate hyperventi-
lation (16). In addition, epinephrine is known to induce panic
attacks with hyperventilation (51). The observed hemodynamic
effects of increased epinephrine shown here are as expected.
Voluntary hyperpneic hyperventilation in healthy volun-
teers. Voluntary poikilocapnic hyperventilation in normal man
produces a small decrease in MAP, a decrease in SVR because
of vasodilation, and an increase in HR and CO (4, 38). Under
healthy conditions, hypocapnia vasodilates the systemic vas-
culature because of central and peripheral effects of alkalosis
on sympathetic vasoconstriction (4, 21, 29, 38). Venous return
is also augmented by actions of the respiratory muscle pump
(32). These mechanisms may also occur in hyperventilation
during panic disorder, although overshadowed by sympathetic
activation. In contrast, voluntary hyperpnea produces direc-
tionally opposite changes in CO and SVR in POTS-HV, shown
in Table 2, because of increased vasoconstriction and often
reduced blood volume or its redistribution in upright patients
with POTS, effectively reducing preload (44), as described
above.
Upright hyperventilation causes tachycardia, but is it really
POTS? All subjects who hyperventilated experienced excess
upright tachycardia and symptoms attributable to hypocapnia
(e.g., lightheadedness because of decreased CBF). It would be
specious reasoning to include voluntary hyperventilation or
panic disorder as forms of POTS. Similarly, perhaps upright
spontaneous POTS-HV is best regarded as postural hyperpnea
rather than POTS.
Limitations. TCD only measures blood flow through specific
cerebral blood vessels. The MCA is the main vessel supplying
the area of the brain activated during executive memory test-
ing. Perfusion during orthostatic stress may vary with brain
location, but such variations are often small (8). We did not
measure TCD in both hemispheres; previous work showed that
MCA CBF was not different between the hemispheres during
orthostatic stress (35).
The Modelflow algorithm used by the Finometer yields
relative measures of CO. While we standardized supine CO
against inert gas rebreathing CO, the inert gas technique
requires breathing alterations that greatly affected results.
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1401
We did not measure absolute total blood volume or central
blood volume. However, we have shown in previous experi-
ments that these quantities are absolutely reduced for patients
with POTS with reduced resting CO (44).
Respitrace inductance respiratory plethysmography was
used to estimate changes in TV and V̇E. These were calibrated
against inductance plethysmography.
In addition, the use of nasal probes can underestimate
ETCO2 if the probe moves from the nose or if the subject
breaths through mouth.
Conclusion. Hyperventilation is common in postural tachy-
cardia syndrome and has distinctive cardiovascular character-
istics when compared with hyperventilation in panic disorder
or to voluntary hyperventilation. Hyperventilation in POTS is
hyperpnea only, distinct from panic in which tachypnea also
occurs. CO is decreased in POTS, whereas peripheral resis-
tance and BP are increased. This is distinct from voluntary
hyperventilation where CO is increased and resistance and BP
are decreased and from panic where they are all increased.
GRANTS
Funding for this project was provided by Grants RO1-HL-134674 and
RO1-HL-112736 from the National Heart, Lung, and Blood Institute.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
J.M.S. and M.S.M. conceived and designed research; M.A.S., C.T., and
M.S. performed experiments; J.M.S., P.P., P.V., and M.S.M. analyzed data;
J.M.S., P.P., M.A.S., P.V., and M.S.M. interpreted results of experiments;
J.M.S. and M.S.M. prepared figures; J.M.S., P.P., and P.V. drafted manuscript;
P.P. and M.S.M. edited and revised manuscript; J.M.S., P.P., M.A.S., C.T.,
M.S., P.V., and M.S.M. approved final version of manuscript.
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