Baroreflex Function after Spinal Cord Injury
Aaron A. Phillips,1–3Andrei V. Krassioukov,2–4Philip N. Ainslie,5and Darren E.R. Warburton1–3
Significant cardiovascular and autonomic dysfunction occurs after spinal cord injury (SCI). It is now recognized that
cardiovascular disease is a leading cause of morbidity and mortality in SCI. Patients with SCI may also suffer severe
orthostatic hypotension and autonomic dysreflexia. Baroreflex sensitivity (i.e., the capability of the autonomic nervous
system to detect and respond effectively to acute changes in blood pressure) has been recognized as having predictive
value for cardiovascular events, as well as playing a role in effective short-term regulation of blood pressure. The purpose
of this article is to review the mechanisms underlying effective baroreflex function, describe the techniques available to
measure baroreflex function, and summarize the literature examining baroreflex function after SCI. Finally, we describe
the potential mechanisms responsible for baroreflex dysfunction after SCI and propose future avenues for research.
Briefly, although cardiovagal baroreflex function is reduced markedly in those with high-level lesions (above the T6
level), the reduction appears to be partially mitigated in those with low-level lesions. Although no studies have examined
the sympathetic arm of the baroreflex in those with SCI, despite this being arguably more important to blood pressure
regulation than the cardiovagal baroreflex, nine articles have examined sympathetic responses to orthostatic challenges;
these findings are reviewed. Future studies are needed to describe whether dysfunctional baroreflex sensitivity after SCI is
due to arterial stiffening or a neural component. Further, measurement of forearm vascular conductance and/or muscle
sympathetic nerve activity is required to directly evaluate the sensitivity of the sympathetic arm of the baroreflex in those
Key words: blood pressure regulation; parasympathetic; spinal trauma, sympathetic
58 per million persons in nations where data are available, and
tends to be highest in regions with more elderly individuals and
greater access to motor vehicles.1As such, developing nations are
expected to have marked increases in SCI prevalence in the near
future.2Although SCI is widely considered a condition primarily
associated with a loss of motor ability, SCI also results in other
important limitations such as severe cardiovascular dysfunction.3
After SCI, supraspinal regulation of autonomic function is dis-
rupted. Owing to the dissociation between autonomic function and
supraspinal control, many of those living withSCI have low resting
blood pressure, hypotensive bouts during an orthostatic challenge
(such as changing postures quickly), and suffer uncontrolled bouts
of hypertension, a condition known as autonomic dysreflexia.4
Related to both of these conditions, cardiovascular diseases are
among the most common causes of death in those with SCI.5–7
he incidence of spinal cord injury (SCI) ranges from 14–
and parasympathetic divisions. Parasympathetic nervous outflow
inferiorly. As the cranial nerves do not transmit through the spinal
cord, vagal (cranial nerve X) control of the heart rate is preserved
after SCI.4Sympathetic nervous outflow occurs from the T1–L2
level into the sympathetic paravertebral ganglia (sympathetic
chain).8After SCI, sympathetic control in regions below the lesion
level are severely disrupted.4Drastic changes in cardiovascular
regulation occur in those with lesion levels above the T6 spinal
control over the heart and splanchnic blood vessels,9both of which
are required for effective long- and short-term blood pressure
The baroreflex is a complex and multi-factorial negative feed-
back system that is integrated in concert with respiration and cir-
culating blood gases. Arterial stretch receptors provide surrogate
information on current blood pressure to the nucleus tractus
1Cardiovascular Physiology and Rehabilitation Laboratory, Physical Activity Promotion and Chronic Disease Prevention Unit,
Medicine Program, Faculty of Medicine,3International Collaboration of Repair Discoveries, and4Division of Physical Medicine and Rehabilitation,
Department of Medicine, University of British Columbia, British Columbia, Canada.
5School of Health and Exercise Sciences, Faculty of Health and Social Development, University of British Columbia Okanagan, Kelowna, British
JOURNAL OF NEUROTRAUMA 29:2431–2445 (October 10, 2012)
ª Mary Ann Liebert, Inc.
solitarius, which then influences efferent autonomic nerve traffic.11
This system employs both the sympathetic and parasympathetic
autonomic divisions to regulate blood pressure within a narrow
range over a wide variety of environmental conditions and body
positions.12The importance of the baroreflex system to cardio-
vascular regulation has been supported by studies showing that
when sino-aortic autonomic control is interrupted, there is an in-
crease in blood pressure variability, as well as frequent bouts of
orthostatic hypotension.13Cerebral oxygen delivery, which is the
pressure maintenance through the baroreflex (as well as cerebral
autoregulation) in order to maintain sufficient cerebral blood
flow.14,15Another case for the necessity of a functional baroreflex
system can be made through evidence from evolutionary biology
showing that the system (although in a more rudimentary form) is
even present among the simplest vertebrates, and has a complexity
similar to our own in reptiles.16
The purpose of this review is to summarize and evaluate the
current literature examining baroreflex function in those with SCI.
Further, we evaluate SCI-related changes in baroreflex function in
relationtolesionlevel,withspecific emphasis onthosewithlesions
above and below the T6 spinal segment.
Physiology of the Baroreflex
It is pertinent to first understand the normal functioning of the
baroreflex in order to appreciate alterations occurring after SCI.
Currently, it is well established that the baroreflex is comprised of
two interdependent systems,17,18that work in concert as one reflex
a low-pressure system, is made up of cardiopulmonary stretch re-
ceptors located in the heart and lungs, which augments sympathetic
nervous system activity in response to reductions in central venous
pressure and volume.19The second, a high-pressure baroreflex
system, consists of stretch receptors located in the tunica adventitia
of the aortic arch and carotid bulbs.20These spray-like nerve
endings generate a more rapid rate of depolarization, and hence
increase the frequency of actionpotentials inafferent nerves during
periods of increased wall distension.21The signal is transmitted
from the carotid bulb via the glossopharyngeal nerve (cranial nerve
IX), and the aortic arch via the vagal nerve (cranial nerve X), to the
nucleus of the solitary tract in the medulla oblongata.11This
transmission, which provides surrogate information on systemic
blood pressure, is integrated with other afferent information in
order to modulate efferent nervous activity transmitted through the
vagal nerve and sympathetic chain to target organs, with the aim of
rapidly maintaining blood pressure at a set point.21Specifically,
increases in blood pressure lead to increased vagal tone and sym-
pathetic inhibition, which consequently results in decreased vas-
the reverse actions occur in response to reductions in blood pres-
sure).22Baroreflex sensitivity (BRS), describes the rate and mag-
nitude by which the system outputs (e.g., heart rate and vasomotor
tone) respond to changes in system input (e.g., blood pressure and
stretch-receptor loading/unloading).23Thus a more sensitive bar-
oreflex system will have more rapid and greater responses to the
same change in blood pressure, and will more effectively maintain
blood pressure within the desired range.
In addition to the integration of the low- and high-pressure bar-
oreflex systems, it is important to understand that the baroreflex is
integrated with chemoreflex and pulmonary afferent information in
order toproduce a suitable efferentresponse. Assuch, the baroreflex
is influenced by both respiration and arterial blood gases. For ex-
ample, inspiration decreases the cardiovagal baroreflex response,
is related to inspiratory time, suggesting a fundamental gating rela-
tionship between baroreflex adjustment and respiration.25Further-
more, hypoxic peripheral chemoreflex activation leads to a resetting
of both the sympathetic and parasympathetic baroreflex to a higher
blood pressure, but this may or may not affect the sensitivity of the
baroreflex per se.25,26These examples highlight that chemoreceptor,
baroreceptor, and pulmonary afferent information are tightly regu-
lated, leading to a complex interdependent relationship in which
baroreceptor (and pulmonary) afferents modulate the chemoreflex
influence on autonomic function.27
The recent proliferation of studies examining baroreflex func-
tion is in large part due to clinical interest stemming from evidence
showing that cardiovagal BRS holds prognostic value for cardio-
vascular events in a number of clinical populations.28,29Further-
more, long-term disruption of the cardiovagal baroreflex function
has led to increases in blood pressure variability, with little or no
influence on mean arterial blood pressure.30Resting measures of
cardiovagal BRS are also relatively simple to carry out, requiring
concurrent recordings of beat-to-beat blood pressure and R-R in-
tervals. As such, the literature is disproportionally represented by
studies examining the cardiovagal branch of the baroreflex. How-
ever, there is limited value of the cardiovagal branch of the bar-
oreflex in preventing syncope or orthostatic hypotension. Although
those individuals with complete autonomic failure show severe and
marked reductions in blood pressure during orthostatic challenges,
identical, before and after complete vagal efferent blockade.30,31
Considering Poiseuille’s law, blood pressure is affected to the
fourth power by arterial diameter, and only linearly by increases in
flow (heart rate-derived changes in cardiac output). As such, it is
not surprising that the vasomotor branch of the baroreflex is much
more important than the vagal branch for the maintenance of mean
arterial blood pressure.
Techniques To Measure Baroreflex Sensitivity
Although it is likely impossible to study so called low-pressure
or high-pressure systems in isolation,17,18several techniques are
available to measure baroreflex function, some with considerable
limitations for use in SCI. Spontaneous techniques such as 3- to 5-
min recordings ofresting values tendtobe themost commondue to
inexpensive software and their non-invasive nature. Two options
exist for evaluating spontaneously-occurring baroreflex function.
First, cross-spectral analysis of an input and output (for example
systolic blood pressure and R-R interval for cardiovagal BRS) can
be evaluated in the low frequency range (0.04–0.15Hz), with the
gain and phase used to determine the sensitivity and timing of the
relationship between the measures32(Fig. 1). The second, com-
monly referred to as the sequence technique, involves calculating
linear regressions between spontaneously occurring changes in
input and the resulting output33(Fig. 2). With no external pertur-
bation of blood pressure, however, it is debatable whether resting
detecting baroreflex function, or are the result of oscillatory influ-
ences from other factors independently influencing blood pressure
and heart rate.5
Convincing evidence against spontaneous transfer analysis was
demonstrated in a recent article by Kamiya and associates.34These
2432PHILLIPS ET AL.
authors used an animal model to characterize and compare the
open-loop and closed-loop baroreflexes. To simulate the open-loop
characteristics carotid sinus pressure (CSP) was perturbed using
random white noise, thereby isolating the carotid pressure from the
arterial pressure. To simulate the closed-loop characteristics the
CSP was matched to the aortic pressure (AP). In both situations
they simultaneously measured renal sympathetic nerve activity
(SNA) and AP. This enabled them to independently examine the
neural (CSP to SNA) and peripheral (CSP to AP) arcs of the bar-
oreflex, which reflect the feedback and feedforward components of
the baroreflex, respectively, as well as the total arc (neural and
peripheral). In brief, their results indicated that the spontaneous
baroreflex as assessed under closed-loop conditions predicted the
peripheral but not the neural arc, whereas the open-loop condition
could predict both. Given that the baroreflex is a feedback mech-
anism, they subsequently argued that the spontaneous baroreflex
bore no resemblance to baroreflex function. Moreover, the lack of
reliability of the spontaneous baroreflex led them to advocate the
use of open-loop methods for assessing baroreflex function. In this
context the open-loop methods, which involve large and dynamic
perturbations of blood pressure sufficient to overcome internal
of assessing baroreflex function. To overcome this limitation, other
more invasive techniques also exist. The modified Oxford
system activity are evaluated using cross-spectral analysis. Cross-spectral power in the low frequency range (i.e., around 0.1Hz), where
coherence is greater than 0.5, provides an estimate of closed-loop baroreflex sensitivity. Spectral power of the R-R interval (C), and of
the systolic blood pressure (D) are also shown.
A minimum of 5-min-long recordings of resting (A) R-R interval, and (B) blood pressure or muscle sympathetic nervous
two measures, with each solid line in C representing a sequence relating changes in R-R interval and systolic blood pressure over a
number of cardiac cycles. The dotted line in C represents the average regression and provides an estimate of closed-loop baroreflex
sensitivity. Typically, in order to have a sequence included in the average regression, R-R interval variation should be greater than
5 msec, and changes in blood pressure should be greater than 0.5mm Hg over a duration of four heartbeats.
From continuous recordings of (A) R-R interval and (B) systolic blood pressure, linear regressions are generated between the
BAROREFLEX FUNCTION IN SPINAL CORD INJURY2433
nitroprusside (NP) and phenylephrine (PE). The relationship between increasing or decreasing blood pressure and changes in R-R
interval or muscle sympathetic nervous system activity provide an estimate of open-loop baroreflex sensitivity. Note the reduced R-R
interval response to changes in systolic blood pressure shown in (D) compared to (E).
Arterial pressure (A), systolic blood pressure (SBP, B), and R-R interval (C) responses after bolus injections of sodium
information on short-term blood pressure changes. The relationship between carotid distending pressure and R-R interval, vascular
resistance, or muscle sympathetic nervous activity changes provide information on carotid baroreceptor sensitivity. The addition of
vascular resistance or recordings of muscle sympathetic nervous activity allows the calculation of the vascular arm of the baroreflex as
well as the cardiac arm (via the changes in R-R interval; MAP, mean arterial pressure).
Positive (A) or negative (B) pressure serve to compress or distend carotid stretch receptors, which provide surrogate afferent
2434 PHILLIPS ET AL.
technique, for example, likely the most accurate method, involves
bolus injections of phenylephrine and sodium nitroprusside to in-
crease and then decrease blood pressure over a 2-min trial35(Fig.
3). Alternatively, manipulation of the carotid baroreceptors using
positive and negative pressures using a modified neck collar is a
non-pharmacological approach.20,36Both these techniques involve
potential risk for the participant, including carotid stenosis rupture,
and transient hypo- and hypertension. The neck cuff technique also
does not allow for measurement of the aortic baroreceptors20(Fig.
4), although differentiation between the carotid and aortic stretch
receptor afferent signals cannot be made with the Oxford technique
either. Another technique to evaluate baroreflex function in an
open-loop model involves using cross-spectral analysis during
relatively large oscillatory blood pressure changes at 0.05 and
0.1Hz (eitherby repeated squat stands or by repeated short boutsof
lower body negative pressure; Fig. 5).37These large oscillatory
perturbations of blood pressure provide similar or greater coher-
ence between blood pressure and heart rate, but appear to show
different information compared to spontaneous indicators. Speci-
fically, reduced gain (i.e., baroreflex sensitivity) during the squat-
stand maneuver suggests that feedforward mechanisms may play a
role in spontaneously derived baroreflex gain. Also, enhanced gain
Hz frequency provides evidence that the cardiovagal baroreflex
maybe moreactive inmitigatingbloodpressure changes atspecific
frequencies.37Collectively, the lack of reliability of the spontane-
ous baroreflex15,38supports the use of open-loop methods for as-
sessing baroreflex function. In this context the open-loop methods,
which involve large and dynamic perturbations of blood pressure
sufficient to overcome internal noise and engage the baroreflex, are
deemed a more reliable method of assessing baroreflex function. A
final way in which baroreflex sensitivity can be evaluated involves
pressure recovery in phase II and cardiopressor response in phase IV are indices of vasoconstrictor and contractile integrity. Baroreceptor-
generally reported as the ratio of the R-R interval changes divided by systolic blood pressure changes over phase II and transitioning from
phase III to IV.
The quantitative Valsalva maneuver is performed by blowing with an open glottis into a mouthpiece connected to the mercury
and during active squat-stand maneuvers at 0.1Hz (B) and 0.05Hz (C). Note the large and coherent oscillations in blood pressure and
heart rate during these maneuvers relative to resting conditions.
Changes in arterial blood pressure (ABP), heart rate (HR), and end-tidal CO2in a young subject under resting conditions (A),
BAROREFLEX FUNCTION IN SPINAL CORD INJURY2435
Table 1. Summary of Studies Examining Cardiovagal Baroreflex Function in Humans with Spinal Cord Injury
Convertino et al.50
Supine carotid-vagal (neck cuff)
Krum et al.74
Gupof modified Oxford technique
Trend toward reduced
Koh et al.51
Supine carotid-vagal (neck cuff)
Vagal response to modified Oxford technique
Grimm et al.84
Seated heart rate response to phase IV Valsalva
Houtman et al.85
n=11 high lesion
Seated heart rate response to phase IV Valsalva
Trend for the high-lesion
group to be reduced
compared to AB; high
spontaneous BRS than
Supine spontaneous cardiovagal
Iellamo et al.91
Supine spontaneous cardiovagal
Seated spontaneous cardiovagal
Munakata et al.70
n=14 high lesion
n=12 low lesion
Supine spontaneous cardiovagal
High-level group included
injuries from C3–T3,
while low injury levelwas T4–L1
Spontaneous cardiovagal during 60? HUT
Legramante et al.89
n=8 high lesion
n=7 low lesion
Supine spontaneous cardio-vagal
Similar reduction in BRS
after HUT in all groups;
in the head-up position,the low-lesion group
had reduced ratio ofbaroreflex to non- baroreflex sequences,
and in the high-lesion
group was further
reduced; the high-lesion
group had reduced non- baroreflex sequences
when supine, but theywere increased duringHUT compared to the
low-lesion group and
Spontaneous cardiovagal during 70? HUT
Table 1. (Continued)
Gao et al.92
Aslan et al.93
n=5 high lesion
n=5 low lesion
Supine spontaneous cardiovagal
All acute injury patients;
low-lesion group had
reduced BRS in supinerecovery from
orthostatic challenge,but not during
challenge; the high-
lesion group had
response to AB during
Castiglioni et al.94
Supine spontaneous cardiovagal
effectiveness index was
reduced in SCI; heartrate response to blood
pressure (phase) wasdelayed in SCI at low
Claydon and Krassioukov73
n=9 high lesion level
n=8 paraplegic (T2–T11)
Supine spontaneous cardiovagal
Seated spontaneous cardiovagal
aEffect size values were calculated from graphical estimates and not numerical data.
[=Significant increase compared to able-bodied controls;Y= significant decrease compared to able-bodied controls;& = no difference compared to able-bodied controls.
High lesion denotes those with injuries at or above the T6 spinal segment; low lesion level denotes those with injures below the T6 level unless otherwise stated.
SCI, spinal cord injury; BRS, baroreflex sensitivity; SCI, spinal cord injury; HUT, head-up tilt; AB, able-bodied; ES, effect size; d, Cohen’s d value; Gup, increasing blood pressure; Gdown, decreasing blood pressure.
using the Valsalva maneuver. Briefly, this technique involves
evaluating the blood pressure and heart rate response during phase
of BRS involve calculating the slope between the blood pressure
and heart rate changes during phase IV;41however, blood pressure
responses during phases II and IV can help indicate vasoconstrictor
effectiveness39,40(Fig. 6). Changes in both the sympathetic and
parasympathetic wings of the autonomic nervous system can be
measured using any of these techniques with simultaneous re-
cordings of vascular resistance, or muscle sympathetic nervous
system activity (MSNA) with blood pressure and heart rate.42
These techniques can evaluate the baroreflex-mediated output re-
sponse to either or both increasing (Gup) and decreasing (Gdown)
the region of dysfunction cannot be differentiated by the techniques used to examine cardiovagal baroreflex function.
baroreflex dysfunction may occur after spinal cord injury. Numbers indicate references examining dysfunction in this pathway.
Summary of evidence from studies examining baroreflex function in those with high-level spinal cord injury. *Indicates that
and peripheral chemoreceptors, and low-pressure pulmonary centers converge in the cardiovascular control center. The complex
interplay of these factors regulates the blood pressure set point, and influences the rate and amplitude of the autonomic response to acute
blood pressure changes (baroreflex sensitivity). This is achieved through rapid alterations of HR (heart rate), SV (stroke volume), and
most importantly TVC (total vascular conductance), by adjusting autonomic outflow to cardiac and vascular tissue.
baroreflex dysfunction may occur after spinal cord injury (1, arterial stiffening; 2, integration in the nucleus tractus soleus; 3, sym-
pathetic descending pathway disruption; 4, sino-atrial node transmission). *Note that when a complete injury occurs, sympathetic
vasomotor control is disrupted below the lesion level.
Neural signals from the brain (central command), as well as afferent input from the aortic and carotid stretch receptors, central
2438PHILLIPS ET AL.
Baroreflex Function after Spinal Cord Injury
After SCI, a significant disruption of the autonomic nervous
system occurs. Similarly to motor deficits after SCI, the level of the
spinal lesion greatly influences the amount of cardiovascular reg-
ulation possible after injury. Although vagal influence on chrono-
tropy is maintained after SCI,43several reports have shown that the
sensitivity of the cardiovagal baroreflex is impacted (Table 1). As
cardiovagal BRS has shown predictive value for future cardio-
vascular events in able-bodied individuals, these findings support
epidemiological studies indicating that cardiovascular risk is in-
creased in those with SCI.29,44,45As mentioned previously, the
cardiovagal baroreflex is unlikely to influence the overall absolute
mean arterial blood pressure response to orthostatic challenge.
However, evidence indicates that in able-bodied individuals, the
vagal influence on heart rate (and therefore cardiac output) plays an
important role in the short-term regulation of blood pressure (100%
in the first 2–3sec after a stimulus), but only a minor role after that
(23%).46Further, the cardiovagal baroreflex is intimately related to
the brain’s ability to maintain effective perfusion (cerebral auto-
regulation).47,48As such, it is reasonable to suggest that abnormal
cardiovagal baroreflex function after SCI is associated with the
reduced orthostatic tolerance seen after injury.30
The loss of the sympathetic branch of the baroreflex is far more
detrimental to blood pressure regulation after SCI, as the des-
cending sympathetic pathway becomes disrupted and results in
significant reductions in the control of vasomotor tone below the
lesion level (Fig. 7).4,8,49Those with lesions above the T6 spinal
level have more severe autonomic dysfunction compared to those
with lesions below this level.43This is partially due to decreased
sympathetic activity within the sympathetic post-ganglionic fibers,
which innervate the splanchnic vascular bed, and originate from
below the sixth thoracic segment, and therefore do not have supra-
spinal descending communication.43Additionally, autonomic
dysfunction (e.g., autonomic dysreflexia) results from a lack of
descending supra-spinal inhibition during periods of noxious or
non-noxious stimuli reaching the spinal cord below the level of
injury, such as catheterization, bladder distension, bowel evacua-
tion, and even a tight shoelace.8,9,43As with motor impairment,
there is a high level of variability in the level of autonomic dys-
function, even for individuals with the same lesion level, which is
likely due to variability in the number of preserved descending
autonomic pathways synapsing on sympathetic pre-ganglionic
neurons below the level of injury.4,9,43
High lesion level
Our literature search revealed 12 studies that examined vagally-
mediated baroreflex function in those with high-level SCI (above
T6; Table 1). Five of these 12 articles reported a decrease in car-
diovagal BRS, one showed an increase, and the remaining seven
demonstrated no difference between individualswithSCI and able-
bodied controls. As SCI is an uncommon condition, typically
studies of reduced statistical power are published. The average
Cohen’s d value for effect size (i.e., the difference between the two
means divided by the pooled standard deviation) is 0.29–0.7 in
studies investigating cardiovagal baroreflex function in humans
with high-level SCI. These values show that the SCI and able-
bodied groups differed on average by approximately 0.3–0.7
standard deviations. Considering that a Cohen’s d value of 0.29 is
considered a small effect, and the variability between articles was
more than twice the mean, these values do not compellingly il-
lustrate that BRS is reduced in those with a high lesion. This is not
surprising, considering not only the small sample sizes, but also the
extreme heterogeneity of SCI.3Interestingly, the two studies using
the neck-cuff technique reported very high Cohen’s d values, at
1.8 and 0.99, suggesting greater sensitivity when using this
If cardiovagal BRS is indeed reduced in high-level SCI, some
consideration of this condition is deserved. Cardiovagal BRS is
influenced by any of the following mechanisms: (1) arterial stiff-
ening, reducing the input from stretch receptors; (2) a reduction in
or (3) changes in the efferent signal transmission at the sino-atrial
(SA) node41(Fig. 8). As neither the vagal or glossopharyngeal
nerves are damaged during high-level SCI, we speculate that re-
ductions in cardiovagal BRS are associated primarily with arterial
stiffening in this population. Increased arterial stiffening leads to
decreased activation of arterial stretch receptors for a given change
in intra-arterial pressure, thus directly reducing the sensitivity of
the system.43,52,53Arterial stiffening is enhanced by physical in-
activity, which is highly prevalent in SCI.54These pathways are
well known and have recently been reviewed.55However, studies
have reported that arterial stiffness is increased in those with SCI,
even when matched for physical activity patterns.56–58The mech-
anisms responsible for increased stiffness specific to the SCI pop-
ulation include: reduced shear stress leading to reduced arterial
caliber and increased wall thickness; endothelial cell glucose in-
sensitivity; and sympathetic dysfunction.59–61As further evidence,
upon movement from supine to 45? of head-up tilt, high-level le-
sion SCI patients have greater reductions in carotid arterial diam-
eter and blood flow velocity compared to both low-level lesion SCI
and AB controls.62
SCI. Those with high-level SCI have chronically elevated renin
concentrations, and this may impact sino-atrial vagal sensitivi-
ty.63,64Further, autonomic regulatory centers in the brain require
sufficient perfusion to maintain effective blood pressure regula-
tion.65Also, considering that individuals with chronic hypotension
also have reduced cerebral perfusion, it is plausible that the neural
BRS pathway is also disrupted in those with high-level SCI.66In-
deed, a marked inability to maintain cerebral blood flow during
orthostatic challenge has been shown in high-level SCI.67–69
The one study to show a paradoxically significant increase in
cardiovagal BRS used a similar technique (power spectral transfer
and above).70The authors speculated that cardiovagal sympathetic
afferent activity may be reduced during head-up tilt in the high-
level injury group due to reductions in venous return and cardiac
dimensions, thus decreasing sympathetic afferent and the subse-
quent efferent activity. However, it is well established that resting
sympathetic nervous system (SNS) activity in a complete lesion
above T6 is severely disrupted, and that outside of autonomic
dysreflexia, sympathetic tone is essentially null.71As such, it is
unlikely that the above theory explains this paradoxical finding, as
sympathetic outflow to the heart typically occurs at the T4–T5
level, and all participants had complete injury levels at T3 or
above.70Alternatively, these contrary spontaneous cardiovagal
BRS results may be due to the uncommon technique of examining
mid-frequency ranges (i.e., 0.02–0.4 ). Also, Munakata and asso-
generated in the high-frequency range, due to low coherence over
the low and mid-range frequencies; they have been shown to have
increased coherence due to respiration.15On the other hand,
BAROREFLEX FUNCTION IN SPINAL CORD INJURY2439
group has demonstrated increases in supine cardiac vagal tone in
those with high-level SCI.73These studies provide an explanation
for the number of articles that reported preserved cardiovagal BRS
in those with SCI, if we assume arterial stiffness was increased.
The T6 level has been shown to be an important lesion level due
to the loss of descending supra-spinal sympathetic signals in the
crucial splanchnic region. Accordingly, SCI above the T6 spinal
segment leads to serious disturbances in autonomic cardiovascular
regulation. After high-level SCI, sympathetic outflow is differen-
tially influenced, depending on both the lesion level and the com-
pleteness of injury. It is important to note that sympathetic
vasomotor innervation persists after high-level SCI. A combination
a1and a2agonists and angiotensin II after high-level SCI leads to
inappropriate adrenergic responses.43,74To our knowledge, only
those with high-level SCI, and none used established blood pres-
sure-perturbing techniques known to provide the most accurate and
reliable results (Table 2).5Sympathetic dysfunction below the le-
sion level has made measuring the sensitivity of the sympathetic
baroreflex difficult.Several studiesusingindirect estimates derived
from frequency analysis of heart rate and systolic blood pressure
suggested a reduced sympathetic response to an orthostatic chal-
lenge in those with high-level SCI. These measures cannot be in-
terpreted to directly relate to sympathetic activity, and the use of
frequency analysis-derived measures to quantify sympathetic
Table 2. Summary of Studies Potentially Highlighting Sympathetic Baroreflex Function
in Humans with Spinal Cord Injury
ReferencesVariable High lesion Low lesionNotes
Guzetti et al.95
RRILF/RRIHFresponse to passive tilt
of 40? to 80? (n=8)
SBPLFresponse to passive tilt of 40?
to 80? (n=6)
Norepinephrine response to modified
Oxford technique (n=3)
Koh et al.51
Houtman et al.99
Wecht et al.96
New York City
Wecht et al.64
n=7 high lesion
n=7 low lesion
Aslan et al.93
n=5 high lesion
n=5 low lesion
Claydon and Krassioukov73
n=9 high lesion level
n=8 paraplegic (T2–T11)
SBPLFresponse to HUT
SBPLFresponse to progressive HUT
RRILF/RRIHFresponse to progressive
RRILF/RRIHFafter 45? HUT
SBPLFresponse to progressive HUT
SBPLFwas decreased in the high-
lesion group during HUT, was
similar in the low-lesion group,
and was increased in AB
SBPLFduring sit-up test
RRILF/RRIHFduring sit-up test
RRILF/RRIHFwas increased in AB,
but not high- or low-level lesion
groups in response to sit-up
testing; SBPLFduring sit-up
testing was lowest in the high-
level, and intermediate in the
low-level groups compared to
Handrakis et al.97
Bluvshtein et al.68
n=11 high lesion
n=10 low lesion
SBPLFresponse after combined
inhibitor and 45? HUT
RRILF/RRIHFresponse to 35? HUT
Had reduced SBPLFafter tilt, while
AB individuals had increased
RRILF/RRIHFwas increased in both
groups similarly to non-injured
controls; trend toward a decrease
in RRILFin the high-lesion group
Y=Significant decrease compared to able-bodied controls;& = no difference compared to able-bodied controls.
High lesion level refers to those with injuries at or above the T6 spinal segment; low lesion level denotes those with injures below the T6 level unless
SCI, spinal cord injury; RRI, RR-interval; RRILF/RRIHF, ratio of LF power of RRI to HF power of RRI; HUT, head-up tilt; SBPLF, spectral power of
blood pressure in the LF region; AB, able-bodied; HF, high frequency; LF, low frequency.
2440 PHILLIPS ET AL.
activation is contentious. While originally reported to be signifi-
cantly related using group data during lower body negative pres-
sure,75Ryan and associates recently showed that on an individual
basis, low-frequency power of systolic blood pressure (SBPLF)
does not correlate with recordings of MSNA.76Similarly, the low-
frequency component of the ratio of low-frequency RRI power to
high-frequency RRI power (LFRRI/HFRRI) was shown to be related
to MSNA in two early articles, although both have limitations, in
that either (1) the statistical analysis may not be suitable,75or (2)
only 40% of participants reported a significant relationship.77Also
in opposition of using LFRRI/HFRRI, Cooke and colleagues dem-
onstrated in able-bodied individuals that the changes in LFRRI/
HFRRIthat occur during sympathetic activation are more due to
decreases in the HF denominator (thought to arise primarily from
respiratory-mediated increases in vagal efferent activity), and not
the LF numerator.79Taking into consideration the controversy
surrounding these measures, studies examining spectral-derived
indicators of sympathetic tone in those with high-level SCI still
deserve discussion, and indeed SBPLFand LFRRI/HFRRIare re-
duced in those with high-level SCI during orthostatic challenges
(Table 2). As the amplitude of vagal withdrawal is usually the
same,64or increased,73in this population, reduced LFRRI/HFRRI
may indicate an attenuation of the sympathetic cardiac response
during an orthostatic challenge. These studies, which employed
indirect indicators of sympathetic activity, are supported more di-
rectly by work showing that the norepinephrine response to a ni-
troprusside bolus (rapid decrease in blood pressure) was severely
reduced in high-level lesion SCI. Taken together, there is com-
pelling evidence for a dysfunctional sympathetic response to blood
pressure changes and orthostatic challenges in this population.51
studies do not necessarily show a mitigated baroreflex-mediated
sympathetic response (which would occur within 5sec after ortho-
static challenge), as much as they highlight the functional inade-
quacy of the sympathetic autonomic branch during hemodynamic
challenges in those with high-level SCI.
Due to the loss of sympathetic vasomotor tone below the lesion
level and the susceptibility to orthostatic hypotension, those with
high-level SCI rely disproportionately on the renin-angiotensin-
aldosterone system to regulate blood pressure.78As such, larger
increases in renin have been found during orthostatic challenge in
tetraplegics.80The increase in renin-angiotensin dependency,
however, appears to be more related to blood pressure responses
due to poor vasomotor response, and less to baroreflex function
specifically. Improving blood pressure response through nitro-
l-arginine methyl ester administration led to mitigated increases in
aldosterone (a trend toward smaller increases in renin) during or-
thostatic challenge in those with high-level lesion SCI.81
It should be noted that one study did not find a reduced response
of SBPLF during orthostatic challenge in high-level lesions, a
finding potentially explained by a weaker orthostatic stimulus than
that used in other studies.68Collectively, the overall findings in this
field of study can be explained by the work done by Stjernberg and
associates, whichshowsthat resting MSNAinthe peronealnerve is
extremely low and nearly non-existent in those with SCI.71This
highlights that the ability to produce effective vasomotor tone is
lost below the level of SCI. Severely reduced vasomotor control
was also shown by the work by Houtman and colleagues, who
demonstrated an essentially passive blood pressure and cerebral
blood flow response to lower-body negative pressure in those with
high-level SCI, while in able-bodied individuals with intact vaso-
motor control mean arterial pressure was well maintained.67In that
study, it was illustrated that blood pressure and cerebral blood flow
decreased in a remarkably linear fashion in relation to the suction
applied to the legs.67The most interesting aspect of that article was
the finding that cerebral oxygenation was markedly decreased in
the high-lesion group compared to able-bodied individuals; how-
ever, both groups reported a similar prevalence of syncope, sug-
gesting that downstream mechanisms related to the hypoxic
threshold for syncope may have adapted. Other work from our
group has highlighted this possibility, showing that subtle markers
of cerebral hemodynamic adaptation (dynamic cerebral auto-
regulation as well as cerebral blood flow pulsatility index) occur in
those with high-level SCI.82This association provides support for
the fundamental inverse relationship between BRS and cerebral
It is unfortunate that so few studies have investigated the sym-
pathetic branch of the baroreflex system in those with high-level
lesions, as this would provide insight into the functioning of the
baroreflex branch most important to the widespread orthostatic
intolerance present within this population. Interestingly, sympa-
thetic vasomotor tone of the brachial artery is innervated from the
such, it would be possible to evaluate the sympathetic baroreflex
sensitivity directly. More studies of this topic may shed light on
why blood pressure is so drastically reduced after orthostatic
challenge, and why a-agonist administration not only improves
resting blood pressure, but also mitigates the blood pressure re-
duction seen during orthostatic challenge.83
Low lesion level
Marked variability exists within the seven articles reviewed that
examined cardiovagal baroreflex function in low-level SCI (Table
1). For example, three studies showed a reduction in cardiovagal
BRS. Of these, two employed the Valsalva technique to measure
BRS, while the remaining article used a spontaneous indicator of
BRS.84As such, 80% ofthe studies using spontaneous indicators of
BRS failed to show a significant reduction in those with low-lesion
in studies investigating spontaneous baroreflex function in humans
with low-level SCI. Taking into account the variability in the
available evidence, it is still notclear if cardiovagal BRS is reduced
in those with low-level SCI. Again, the two studies employing
phase IV Valsalva for BRS evaluation reported high Cohen’s d
values of 2.3 and 1.0.84,85
Similarly to high lesions, those with low-level SCI tend to be
more physically inactive compared to able-bodied individuals.54
Furthermore, lower resting supine vagal tone has been shown in
those with low-level SCI.73Therefore, following the same princi-
ples outlined for the high-level lesion SCI group (i.e., physical
activity and resting vagal tone), there is a strong rationale for
finding reduced sensitivity of the baroreflex.62From a hemody-
namic perspective, cerebral perfusion is likely maintained in low-
level SCI, and cardiovagal tone is preserved.67,68Following this,
the neural pathway of the baroreflex is likely not disrupted.73Both
studies using phase IV Valsalva derived-values reported reduced
BRS in low-level lesion SCI. It is difficult to synthesize these
findings with the overall trends found using spontaneous BRS
measures. Published work86comparing the Valsalva technique to
the modified Oxford method have shown the two measures to be
correlated, but not to provide similar results. When compared to
spontaneous BRS techniques, the values from the Valsalva tech-
nique were not associated with those reported using the spectral
BAROREFLEX FUNCTION IN SPINAL CORD INJURY2441
method, and related significantly only to Gdownof the sequence
method.86It has been suggested that BRS markers derived from the
Valsalva maneuver provide different information regarding the
baroreflex comparedtospontaneous-derived markers.Spontaneous
BRS is thought to be representative of tonic cardiovagal activity,
whereas BRS measures derived from perturbed blood pressure
(Valsalva and modified Oxford) are associated with the phasic re-
lationship between vagal tone and blood pressure changes.87
Therefore, it may be the case that phasic BRS is influenced after
SCI, whereas tonic BRS is not. The clinical value of phasic versus
tonic BRS has yet to be determined.
Several researchers have attempted to measure the sympa-
thetic branch of the baroreflex system in those with low-level
SCI. These articles have shown that the orthostatic response in
SBPLFand LFRRI/HFRRIwas also reduced in those with low-level
SCI (Table 2). Those with low-level SCI also do not have tonic
vasomotor outflow below the lesion level, and therefore would
have reduced amplitude of SBP oscillations. Indeed, this group is
expected to have more systemic vasomotor tone compared to
those with higher lesion levels, as they have less vascular tissue
undergoing disrupted sympathetic control.71Bluvshtein and as-
sociates reported that LFRRI/HFRRI was similar for low-lesion
level SCI and able-bodied controls; however, the sample size was
quite small, and the study may have been under-powered.68
These findings highlight that the cardiac and vasomotor response
to orthostatic challenge is disrupted, even after low-level SCI.
Interpretation of these studies should be made with caution, as
neither of the markers of SNS activity truly represents BRS, as
they are simply measures of resting autonomic tone in different
is not as severe as in those with high-level lesions (Fig. 9). This is
thought to be due to the aforementioned mitigating factors, such as
greater physical activity levels, preservation of some sympathetic
vasomotor tone, and maintenance of cerebral perfusion.
To focus clinical and research efforts on improving BRS, the
issue of whether dysfunctional BRS after SCI is due primarily to
increases in arterial stiffening or to a more downstream neural
component needs to be elucidated. The resolution of this issue
would also aid in the development of new technologies, and the
advancement of techniques currently undergoing testing such as a
transcutaneous bionic baroreflex system.88It should be noted that a
number of articles are insufficiently powered to assess baroreflex
function in SCI. This issue should be more widely acknowledged
and discussed in articles when sample size is an issue.
The physical activity levels of the low-level SCI groups were not
much more access to, and participation from, SCI participants who
are highly active, while it is exceedingly difficult to recruit SCI
subjects with a more physically-inactive lifestyle. Physically-active
individuals with SCI tend to have reduced arterial stiffness, and
would also be expected to have increased gravitational challenge
compared to their inactive counterparts (resulting from fewer
orthostatic challenges in daily living).58As both of these factors
are known to be related to reduced BRS, this selection bias may
have led to a more similar cardiovagal BRS.3In addition, spon-
taneous techniques for evaluating BRS, especially those derived
through the spectral method, are confounded by the feed-forward
relationship between increasing heart rateand blood pressure.5As
such, spontaneous BRS measures, particularly for the purpose of
stratifying cardiovascular risk, should be used with caution, while
non-spontaneous measures of BRS need to be more widely
As those with chronic hypotension and SCI are thought to have
decrements in cognitive function associated with reduced brain
blood perfusion, the relationship between baroreflex function, ce-
rebral hemodynamic regulation, and cognitive function in SCI also
dysfunction cannot be differentiated by the techniques used to examine cardiovagal baroreflex function. Note that spontaneous estimates
of cardiovagal baroreflex sensitivity did not detect differences in low-level spinal cord injury.
may occur after spinal cord injury. Numbers indicate references examining dysfunction in this pathway.
Summary of evidence examining baroreflex function in those with low-level spinal cord injury. *Indicates that the region of
denotes where baroreflex dysfunction
2442 PHILLIPS ET AL.
needs to be examined. Baroreflex sensitivity directly influences
mitigate reductions in cognitive function.90
In both high- and low-level SCI, direct measurement of the
sympathetic branch of the baroreflex is warranted to evaluate the
role reduced sensitivity plays in orthostatic hypotension. Although
peroneal nerve MSNA is not viable, brachial nerve MNSA or
brachial artery vascular resistance are potential sites to measure
vasomotor responses to blood pressure and/or arterial diameter
The available literature indicates that BRS is disrupted in those
consistently disrupted in those with high-level lesions, due to se-
vere dysfunction of the sympathetic as well as parasympathetic
branches. The overall findings are hampered by small sample sizes,
and several spontaneous and ramped BRS techniques that detect
different components of the baroreflex. Baroreflex sensitivity in
those with low-level SCI is less clear. Arterial stiffening has been
shown to be increased in both high- and low-level SCI, although it
is interesting that BRS is not consistently reduced in these popu-
lations. It is plausible that increased vagal tone, which has been
shown to improve cardiovagal BRS,72may ameliorate the decline
resulting from increased arterial stiffening. Our focus should be
directed on examining the sensitivity of the sympathetic branch of
the baroreflex due to the lack of information currently available.
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Aaron A. Phillips, M.Sc.
University of British Columbia
Room 205, Unit II Osborne Centre
6108 Thunderbird Boulevard
Vancouver, British Columbia, Canada V6T 1Z3
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