Sympathetic Nervous System

Abstract

For more than 100 yr, scientists have studied the sympathetic nervous system and its cardiovascular control mechanisms. Muscle sympathetic activity is the most important direct and rapidly responding variable for evaluation of sympathetic neural outflow. Because of its significance in response to environmental challenges and its role in cardiovascular control, great attention has been paid to the sympathetic nervous system in both health and disease and, more recently, also during general anesthesia. In fact, general anesthesia can also be considered as an investigational tool to assess mechanisms of cardiovascular regulation. This review evaluates different methods for determination of sympathetic nervous system activity and describes its role in human neurohumoral circulatory control. Furthermore, the effects of general anesthesia on sympathetic nervous system activity and their relevance for clinical anesthesia are discussed.

Full text

䡵REVIEW ARTICLE
David S. Warner, M.D., and Mark A. Warner, M.D., Editors
Anesthesiology 2008; 109:1113–31 Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
Sympathetic Nervous System
Evaluation and Importance for Clinical General Anesthesia
Martin Neukirchen, M.D.,*Peter Kienbaum, M.D.†
For more than 100 yr, scientists have studied the sympathetic
nervous system and its cardiovascular control mechanisms.
Muscle sympathetic activity is the most important direct and
rapidly responding variable for evaluation of sympathetic neu-
ral outflow. Because of its significance in response to environ-
mental challenges and its role in cardiovascular control, great
attention has been paid to the sympathetic nervous system in
both health and disease and, more recently, also during general
anesthesia. In fact, general anesthesia can also be considered as
an investigational tool to assess mechanisms of cardiovascular
regulation. This review evaluates different methods for deter-
mination of sympathetic nervous system activity and describes
its role in human neurohumoral circulatory control. Further-
more, the effects of general anesthesia on sympathetic nervous
system activity and their relevance for clinical anesthesia are
discussed.
MORE than a century ago, Langley
1
defined the autonomic
nervous system as the neural outflow from the central
nervous system to the vasculature and viscera and distin-
guished between a sympathetic (thoracolumbar) and a
parasympathetic (craniosacral) system. This separation was
based on embryologic development, distribution of inner-
vation to target organs, and opposing effects of electrical
nerve stimulation or exogenously applied drugs such as
epinephrine, pilocarpine, or atropine. The spinal segments
of neural outflow to different organs were defined by ex-
amining organ function in response to ventral root stimu-
lation. Furthermore, ganglionic synapses were localized by
topical application of nicotine. These studies indicated that
organs received both sympathetic and parasympathetic in-
nervation and that the stimulatory effects of the systems are
often opposed.
1,2
Around the same time, Cannon
3,4
hypothesized that
the autonomic nervous system served the body’s ho-
meostasis. He considered the sympathetic nervous sys-
tem (SNS) to mobilize forces during struggle, whereas
the parasympathetic system regulated hollow organ
function and reproduction. In fact, animals from which
the entire sympathetic paravertebral chain was removed
survived in a protected environment but could not main-
tain normal body temperature, arterial and cerebral per-
fusion pressures, or constant extracellular fluid volume,
in particular in response to challenges.
5
Although these
observations suggest a uniform reaction of the SNS to
stress, the autonomic nervous system is nevertheless
highly differentiated, and each organ system seems to be
controlled separately.
6,7
Accordingly, a general state of
increased or decreased sympathetic activity, as often
assumed by clinicians, is unlikely. Rather, one has to
consider sympathetic outflow to each individual organ
system separately.
8
Because of its significance in response to environmen-
tal challenges and its role in cardiovascular control, great
attention has been paid to the SNS in both health and
disease and, more recently, also during general anesthe-
sia. In fact, anesthesia can also be considered as an
investigational tool to assess mechanisms of cardiovas-
cular regulation. This review evaluates the methodology
for assessing SNS activity in humans, its role in cardio-
vascular regulation, and the significance of SNS integrity
during general anesthesia.
Mechanisms and Evaluation of Sympathetic
Nervous System
Methods of Assessment of Sympathetic Activity
Direct Assessment of Sympathetic Activity by Mi-
croneurography. Sum action potentials induced by
transdermal electrical nerve stimulation can be recorded
from human peripheral nerves with surface electrodes.
In contrast, evaluation of spontaneous nerve traffic re-
quires more sophisticated methods. A technique for re-
cording neural activity via percutaneously inserted in-
traneural electrodes was introduced approximately
three decades ago by Hagbarth and Vallbo
9
obtaining
direct recordings of mechanoreceptive activity from hu-
man peripheral nerves. Concurrently, spontaneous intra-
neural activity was discovered and recognized as efferent
sympathetic nerve traffic.
10
Since then, microneurogra-
*Resident in Anesthesiology and Research Fellow, †Staff Anesthesiologist and
Vice Chairman.
Received from the Klinik fu¨r Ana¨sthesiologie, Universita¨tsklinikum Du¨sseldorf,
Du¨sseldorf, Germany. Submitted for publication March 17, 2008. Accepted for
publication August 6, 2008. Support was provided solely from institutional
and/or departmental sources.
Mark A. Warner, M.D., served as Handling Editor for this article.
Address correspondence to Dr. Neukirchen: Klinik fu¨r Anaesthesiologie, Uni-
versita¨tsklinikum Du¨sseldorf, Moorenstrasse 5, 40225 Du¨ sseldorf, Germany.
martin.neukirchen@med.uni-duesseldorf.de. Information on purchasing reprints
may be found at www.anesthesiology.org or on the masthead page at the
beginning of this issue. ANESTHESIOLOGY’s articles are made freely accessible to all
readers, for personal use only, 6 months from the cover date of the issue.
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phy has been increasingly used to investigate human
sympathetic nerve traffic under physiologic and patho-
physiologic conditions.
11
Tungsten electrodes (diameter: 200
␮
m) with a tip
diameter of a few microns are used for recordings of
sympathetic neural outflow. A peripheral nerve is local-
ized by transcutaneous electrical stimulation (30–50 V,
100–200 mA, 2 ms) evoking motor or sensory effects.
Afterward, a recording electrode is inserted intraneu-
rally, and a reference electrode is placed subcutaneously
a couple of centimeters apart. A suitable electrode posi-
tion for intraneural recordings is found by minor adjust-
ments of the electrode tip. The correct needle position is
confirmed by a low threshold of intraneural electrical
stimulation (0.2–1.0 V, 100–200 mA, 2 ms) evoking
muscle contractions or paresthesias as well as by record-
ing of muscle (stretching of muscle tissue)– or cutaneous
(light stroking or scratching of the skin)–derived affer-
ent activity. Peak-to-peak amplitudes of multiunit raw
signals usually range from 10 to 20
␮
V, with a signal-to-
noise ratio of 3–5 to 1. The detected signal is amplified
(gain ⫻50,000) and filtered (700- to 2,000-Hz band-pass
filter). To obtain a mean voltage neurogram, a resistance-
capacitance integrating circuit with a time constant of
0.1 s is used.
12
The multiunit nerve recording is com-
posed of several single nerve fiber discharges, which are
grouped. These groups can be counted as bursts in the
mean voltage neurogram.
The mean amplitude or the area under the curve of
single bursts in the integrated signal is dependent on the
number of recorded single unit discharges (neural re-
cruitment) and also on the location of the needle relative
to the nerve bundles. Therefore, slight movement may
alter the needle tip location within the nerve so that area
under the curve calculations should be analyzed cau-
tiously. Finally, for the same reason, it is difficult to use
these data on the same subject for comparisons between
different days or experimental sessions.
10,13
In peripheral nerves, efferent sympathetic activity to
skin (skin sympathetic activity [SSA]) and to muscle
vasculature (muscle sympathetic activity [MSA]) can be
distinguished. In the supine position, the same resting
MSA can be determined at different nerve recording sites
(e.g., peroneal and median nerve), which is very repro-
ducible in a given subject over more than 10 yr. Never-
theless, MSA tends to increase with age so that higher
MSA at rest is observed in healthy patients older than
60 yr.
14,15
This observation contrasts with a large intra-
individual variability of less than 10 to more than 90
bursts/100 heartbeats between different healthy sub-
jects.
16
Because of this great intraindividual variability,
there is no defined pathologic level of MSA.
Forearm venous norepinephrine plasma concentration
significantly correlates with peroneal MSA. This relation
is probably due to the large contribution of cardiac
output to muscle blood flow (anywhere from 25% to
40%).
17
Surprisingly, total-body norepinephrine spill-
over, as well as renal and cardiac norepinephrine spill-
over, correlates well with MSA despite the proposed
differential control of sympathetic organ innervation at
rest.
18–20
Muscle sympathetic activity does not correlate with
arterial pressure between different subjects as indicated
by hypertensive patients with low MSA, hypotensive
subjects with high MSA, and vice versa. Moreover, an
insulin-induced increase in MSA is not associated with a
change in arterial pressure.
21
These observations suggest
that other variables exert major influences on the indi-
vidual level of arterial blood pressure and MSA.
16,22,23
A relaxed subject at a comfortable ambient tempera-
ture has virtually no detectable SSA.
24–26
By exposing a
subject to warm (43°) or cold (15°) environments, a
selective activation of either the sudomotor or the vaso-
constrictor neural system is usually obtained, with sup-
pression of spontaneous activity in the other system.
25,27
In a comfortably warm subject, a deep spontaneous
inspiration is followed by a strong increase of SSA, which
consists of both sudomotor and vasoconstrictor activity.
28,29
Similarly, a sudden arousal stimulus elicits a burst of
SSA
24,25,30
whereas, in contrast, MSA is not affected by
such stimuli.
12,30
With these findings, the traditional view of a whole-
body activation of sympathetic outflow in response to
stimuli is no longer tenable, though striking correlations
between kidney, muscle, and cardiac sympathetic activ-
ity were observed at rest. Instead, it is suggested that the
SNS has the capacity to selectively activate different
subdivisions. This makes it difficult to generalize data
derived from one subdivision to other effector organs or
conditions without direct experimental evidence.
Therefore, microneurography is the only technique
available to directly assess sympathetic neural activity in
humans. Its advantage is the ability to detect rapid
changes in nerve traffic. Accordingly, it is suitable to
study not only static but also dynamic situations, e.g.,
determination of the offset and the gain in situations of
sympathetic activation induced by certain challenges. In
contrast, this technique is limited by its invasiveness, by
motion artifacts, and by the fact that it is site specific so
that it may reflect only regional effects.
Assessment of Baroreflex Sensitivity. Although
MSA at rest does not correlate to the individual “normal”
resting blood pressure, alterations in arterial blood pres-
sure are associated with increases or decreases in MSA.
The relation between spontaneous or induced (e.g.,
pharmacologically, neck chamber technique) arterial
pressure changes to MSA can be used to describe barore-
flex sensitivity (BRS).
31–35
Different methods have been used to quantify the
arterial baroreflex influence on MSA. The relation be-
tween spontaneous variations of blood pressure and
nerve traffic in terms of threshold (i.e., whether a sym-
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pathetic burst is generated) and BRS (i.e., the slope of
the relation between the strength of a burst and the
diastolic pressure in the corresponding heartbeat) has
already been the subject of early studies.
36
Obviously,
there is a good correlation between diastolic pressures
and the occurrence of sympathetic bursts so that low
diastolic pressures usually and high diastolic pressures
rarely are associated with a burst. These kinds of thresh-
old variability diagrams are conveniently characterized
by the blood pressure value at which 50% of the heart-
beats were associated with a burst and the slope of the
regression line, which gives a measure of the variability
range of the blood pressure threshold. On the other
hand, the number of activated sympathetic fibers (as
indicated by the area of a burst) does not correlate with
blood pressure.
35
The sensitivity of the arterial baroreceptor reflex can
also be calculated during arterial blood pressure changes
during application of positive or negative pressure to the
area of the neck over the carotid sinus receptors using
the neck chamber technique.
37
The correlation between
heart rate (HR) and sympathetic neuronal response to
arterial pressure changes was taken as a measure for
reflex sensitivity.
Apart from these nonpharmacologic testing proce-
dures, baroreflex influences on the SNS have been quan-
tified by relating HR and/or sympathetic nerve activity to
mild temporary alterations in arterial pressure induced
by (sequential) intravenous administrated pharmaco-
logic vasoconstrictors (phenylephrine) or vasodilators
(sodium nitroprusside [SNP]) (Oxford technique)
38
(fig.
1). Accordingly, distances between two R waves in the
electrocardiogram can be plotted as a function of pre-
ceding systolic pressures during pressure perturbations.
The slope of the (linear part) of this regression analysis
provide an index of cardiac baroreflex responsiveness or
sensitivity, which is also modulated by parasympathetic
innervation. In contrast, MSA (bursts or burst incidence)
can be plotted as a function of preceding diastolic pres-
sure, giving an index of arterial sympathetic baroreflex
responsiveness or sensitivity that is free of parasympa-
thetic modulation
23
(fig. 2).
Muscle sympathetic BRS during rest differs from BRS
during evoked hypotension. The relation between mean
MSA burst incidence and diastolic arterial pressure was
compared before and after a pressure decrease caused
Fig. 1. Original trace from an experiment
investigating baroreflex sensitivity show-
ing the effects of a bolus injection of so-
dium nitroprusside (SNP, 3
␮
g/kg) on arte-
rial pressure (determined by volume
plethysmography) and muscle sympa-
thetic activity (MSA). Bursts are indicated
by dots. The decrease in diastolic pressure
of 20 mmHg is followed by a marked in-
crease in MSA. Correlating MSA burst area
with diastolic arterial pressure during the
decrease in blood pressure on a beat-to-
beat basis allows determination of barore-
flex sensitivity. ECG ⴝelectrocardiogram.
Fig. 2. Baroreflex control: Examples of baroreflex threshold dia-
grams for mean arterial pressure and cardiac interval (A) and
diastolic arterial pressure and muscle sympathetic nerve activity
(MSNA; B). Independent variables were averaged in 2- to 3-mmHg
intervals, and regression analyses were applied to the linear por-
tion of each response curve. The Xon each graph is located at the
operating point for each variable, determined from the average of
10 cardiac cycles before injection of sodium nitroprusside.
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by SNP (2–3
␮
g/kg intravenous) yielding an average
baroreflex gain. Average baroreflex gain assessed by this
conventional method was compared with baroreflex
gain assessed during spontaneous arterial pressure fluc-
tuations. Resting MSA was 28 bursts/100 heartbeats at a
diastolic pressure of 71 mmHg. Baroreflex gain during
spontaneous arterial pressure fluctuations was 4.0%/
mmHg and was significantly greater than the average
gain assessed during evoked hypotension (2.1%/mmHg).
Baroreflex gain during spontaneous arterial pressure
fluctuations differs from that assessed during SNP-
evoked hypotension, possibly because of intrinsic effects
of SNP on the baroreflex.
39
Method of Assessment of Sympathetic Activity by
Heart Rate Oscillations. Sympathetic traffic to the
heart may be addressed by analysis of the power spec-
trum of HR oscillations. Changes of HR in time depend
on physiologic control systems, including sympathetic
and parasympathetic influences. When distances be-
tween R waves, derived from an electrocardiographic
recording, are transformed into instantaneous HR and a
fast Fourier transformation is applied to these data, a
power spectrum with very low (around 0.03 Hz)–, low
(around 0.05–0.15 Hz)–, and high (around 0.3–0.4 Hz)–
frequency oscillations (frequency bands) can be ob-
tained.
40
Whereas most researchers agree that the area
under the high-frequency oscillations relates to parasym-
pathetic modulation, some authors have speculated that
the area under the low-frequency oscillation or the “low-
frequency to high-frequency power ratio” represents
cardiac sympathetic drive.
40–48
If this were true, HR
spectral variability would be an easy and noninvasive
way to assess cardiac sympathetic innervation. However,
several clinical studies question the validity of HR spec-
tral variability data.
49–52
Despite sensory blockade from dermatomes C6 to T6
by thoracic epidural anesthesia (0.75% bupivacaine), the
low-frequency band and the low-frequency to high-fre-
quency power ratio did not change during supine rest
and head-up tilt in humans. Accordingly, there was an
incomplete blockade of cardiac sympathetic nerve traffic
by epidural anesthesia, there was a lack of cardiac sym-
pathetic activity at rest and during sympathetic chal-
lenge by tilt, or the low-frequency band and low-fre-
quency to high-frequency ratio may not be an adequate
measure of cardiac sympathetic function.
53
In healthy
volunteers during supine rest, HR variability did not
correlate with HR, arterial pressure, norepinephrine
plasma concentration, or peroneal MSA.
54
When arterial
pressure was decreased by SNP, changes in the low-
frequency band of the power spectrum correlated with
peroneal MSA but, interestingly, not during an increase
in arterial pressure induced by phenylephrine.
54
This
observation was explained by a model of HR control in
which low-frequency fluctuations of HR result from
changing levels of both the sympathetic and parasympa-
thetic inputs to the sinoatrial node. Furthermore, the
low-frequency spectral power did not correlate with
cardiac norepinephrine spillover in healthy volunteers
or in patients with increased MSA activity because of
cardiac failure.
55
It was concluded that the low-fre-
quency spectral power, in addition to cardiac sympa-
thetic nerve traffic, depends on other factors, including
multiple neural reflexes, cardiac adrenergic receptor
sensitivity, postsynaptic signal transduction, and electro-
chemical coupling, and is not related to cardiac norepi-
nephrine spillover, the latter being a more direct mea-
sure of sympathetic nerve traffic.
55
Furthermore, during
general anesthesia, HR variability may be altered by pos-
itive-pressure ventilation, changing carbon dioxide ten-
sion, and respiratory frequency.
Together, determination of HR variability may be suit-
able to assess parasympathetic influences on HR, but it
does not reflect cardiac sympathetic innervation.
Methods of Assessment of Norepinephrine Plasma
Concentration and Norepinephrine Kinetics
Norepinephrine Plasma Concentration. From the
time of von Euler’s
56
demonstration that norepinephrine
is the sympathetic postganglionic neurotransmitter, the
potential value of measuring norepinephrine plasma
concentrations as an index of nerve activity has been
recognized. Plasma norepinephrine is derived largely
from transmitter release by sympathetic nerve terminals
with only approximately 2% released from the adrenal
medulla (fig. 3).
57,58–60
Lacking an acceptable compart-
ment model to determine whole-body norepinephrine
kinetics, investigators used norepinephrine plasma con-
centration as a crude overall index of SNS activity.
61–64
However, norepinephrine plasma concentrations de-
pend on the rate of immediate norepinephrine reuptake
as well as norepinephrine clearance from the circula-
tion, the latter depending on cardiac output, organ
blood flow, and regional norepinephrine clearance ca-
pabilities.
65–68
During anesthesia, cardiac output is often
depressed and organ blood flow is altered, which may be
particularly important when trying to relate norepineph-
rine plasma concentration to sympathetic outflow.
For norepinephrine analysis, either a single isotope
radioimmunoassay or electrochemical detection after
high-pressure liquid chromatography is used.
61,69–72
The
main advantage of the radioimmunoassay is its sensitivity
of approximately 100 pMin 50-
␮
l samples, permitting
catecholamine determination in very small sample vol-
umes. Concentrations of less than 100 pMcan be de-
tected by high-pressure liquid chromatography only
with larger sample volumes. In contrast, high-pressure
liquid chromatography is less time-consuming and has
the advantage that occasional problems with interfer-
ences or poor sensitivity appear immediately on the
chromatograms and may be identified or even corrected
before final analysis.
72
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Usually, there are large intraindividual differences in
norepinephrine plasma concentrations between arterial
and different venous sampling sites.
57
Norepinephrine
plasma concentrations in supine young subjects under
resting conditions are around 1–2 nMin forearm venous
plasma. Arterial concentrations are as much as 25%
lower than mixed venous concentrations because of
norepinephrine clearance by the lungs during pulmo-
nary transit.
57
These norepinephrine plasma concentrations are
thought to be devoid of important hormonal metabolic
and hemodynamic effects. Norepinephrine plasma con-
centration typically has to be increased at least fivefold
by infusion of norepinephrine to achieve a hemody-
namic effect.
73
However, neurally released norepi-
nephrine contributing to norepinephrine plasma con-
centration may not be comparable to similar increases
in norepinephrine plasma concentration by infusion
of norepinephrine.
Although norepinephrine plasma concentrations can
provide crude estimates of overall sympathetic activa-
tion, they do not indicate the dominant source of nor-
epinephrine release in a given situation. Furthermore,
increased norepinephrine plasma concentrations may
result from decreased norepinephrine clearance rather
than increased release.
Plasma Norepinephrine Kinetics.
Total-body Norepinephrine Spillover. As mentioned in
the previous section, norepinephrine plasma concentra-
tion does not depend solely on neurotransmitter release
but also on the uptake of neurally released norepineph-
rine by the sympathetic neuron itself and by extraneural
structures. Norepinephrine plasma clearance and nor-
epinephrine spillover rate into plasma (the fraction of
endogenously released norepinephrine that appears in
plasma) can be calculated by using steady state infusions
of tracer amounts of tritium-labeled norepinephrine.
66,67,74
In
humans, total-body norepinephrine spillover is 10–20%
of total norepinephrine release.
68,75
The mean nervous
system norepinephrine production rate in healthy hu-
mans at rest is approximately 20 nmol/min with a mean
norepinephrine spillover into plasma of 2–4 nmol/min
and a mean norepinephrine plasma clearance of 1.5–2.5
l/min.
76–80
With an extraction rate of 0.9, the liver has
an important role in norepinephrine clearance as indi-
cated by increased norepinephrine plasma concentra-
tions in liver disease.
76,79
Single-organ Norepinephrine Spillover. To locate the
source for an increased total-body norepinephrine spill-
over or to evaluate sympathetic activity of particular
organs, it is most useful to determine single-organ spill-
over as calculated from Fick’s principle as the product of
the venoarterial plasma norepinephrine concentration
difference across the organ corrected for the organ’s
norepinephrine uptake and the plasma flow according to
the following equation:
Organ norepinephrine spillover rate
⫽关
共
Norepinephrinevenous ⫺Norepinephrinearterial
兲
⫹
共
Norepinephrinearterial
⫻H关3H兴Norepinephrineextraction
兲
兴
⫻organ plasma flow,
where norepinephrine
venous
and norepinephrine
arterial
rep-
resent the organ’s venous and arterial plasma concentra-
tion, respectively, and [
3
H]norepinephrine
extraction
repre-
sents the fractional extraction of titrated norepinephrine in
passage through the organ. The contribution of major or-
gan systems to total-body norepinephrine spillover is illus-
trated in figure 4.
81
Possible important determinants be-
sides the sympathetic nerve traffic are sympathetic nerve
density, organ mass, blood flow, and norepinephrine re-
uptake and metabolism. The fractional norepinephrine
spillover of total norepinephrine released varies substan-
tially between different organ systems (kidneys, 1:3; skele-
tal muscle, 1:12; heart, ⬍1:20).
59
This should be consid-
Fig. 3. Diagram of an arteriole in cross
section showing norepinephrine release
reuptake (U1 ⴝuptake 1; U2 ⴝuptake 2),
metabolism (M), and diffusion (D).
␣
1
ⴝ
␣
1
-adrenergic receptor;
␣
2
ⴝ
␣
2
-adrenergic
receptor. Derived from and used with per-
mission from Goldstein et al.
57
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ered when evaluating the degree of sympathetic neural
activation to single organs by the organ norepinephrine
spillover technique.
67,68,82
There has been particular interest in cardiac norepineph-
rine spillover, which contributes only 2–3% (50 –150 pmol/
min) to total norepinephrine spillover under supine resting
conditions in healthy, young volunteers. This value in-
creases substantially with age (beyond age 40–60 yr by
approximately 90%) and more than 3-fold in patients with
cardiac failure (to 200–400 pmol/min) at rest.
55,83,84
Fur-
thermore, cardiac norepinephrine spillover increases more
than 10-fold (to 1.3–1.6 nmol/min) during moderate dy-
namic exercise in young, healthy subjects.
55,85
Therefore, the norepinephrine spillover technique is
useful for determining whole-body and in particular sin-
gle-organ norepinephrine release at rest and during sym-
pathetic activation. The main disadvantages of this
method are certain logistic requirements (e.g., isotopes)
and its invasiveness, particularly for single-organ deter-
minations. Furthermore, instantaneous changes in SNS
activity cannot be assessed because a stimulus must last
for a few minutes to allow detection of altered norepi-
nephrine release and clearance.
Conclusion
Despite the widespread studying of norepinephrine
plasma concentrations, determination of regional SNS
activity by microneurography or norepinephrine kinet-
ics is most appropriate to yield reliable data on sympa-
thetic outflow values.
Role of the Sympathetic Nervous System in
Human Neurohumoral Circulatory
Regulation
Neurohumoral cardiovascular regulation, apart from
brain and spinal cord, involves both afferent and efferent
nerves as recognized since the original description of the
depressor nerve.
86
The presence of cardiodepressing
nerves arising from the region of the aortic arch and
great vessels was demonstrated in 1903.
87
Both baroreceptors in the aortic arch and barorecep-
tors in the carotid sinus are “high-pressure” stretch re-
ceptors, which respond quickly to changes in wall ten-
sion to maintain an adequate blood pressure (fig. 5).
88
Arterial baroafferent activity in the aortic arch and
carotid sinuses reaches the nucleus tractus solitarius via
Fig. 4. Regional rates of norepinephrine spillover to plasma, expressed as a percentage of total spillover for lungs, kidneys, skeletal
muscle, hepatomesenteric circulation, skin, heart, adrenals, and brain. Adapted from and used with permission from Esler et al.
81
Fig. 5. Arterial baroreflex pathways that control vasomotor tone
and heart rate. (1) Carotid sinus and aortic arch “high-pressure”
stretch receptors. (2) Unmyelinated fibers running in glossopha-
ryngeal and vagus nerve synapsing at nucleus tractus solitarii
(NTS). (3) Parasympathetic preganglionic fibers running in vagus
nerve emerging from nucleus ambiguus. (4) Intermediate neu-
rons. (5) Inhibitory neuron from caudal ventrolateral medulla
(CVLM) to rostral ventrolateral medulla (RVLM). (6) Afferent path-
way for release of vasopressin. (7) Sympathetic cardiac and vaso-
motor fibers passing intermediolateral column of spinal cord and
sympathetic chain ganglia. Adapted from and used with permis-
sion from Smit et al.
88
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the glossopharyngeal and vagal nerves, and changes nu-
cleus tractus solitarius activity by N-methyl-D-aspartate–
and non-N-methyl-D-aspartate receptor–mediated effects.
Secondary neurons activate neurons of the caudal ven-
trolateral medulla, where baroreceptor and nonbarore-
ceptor input, e.g., from chemoreceptors or pulmonary
afferents, are integrated. Neurons in the caudal ventro-
lateral medulla, in turn, inhibit or stimulate neurons in
the rostral ventrolateral medulla, where sympathetic
preganglionic neurons originate. Axons of these first
sympathetic neurons pass through the lateral column of
the spinal cord and reach sympathetic paravertebral gan-
glia, where a second postganglionic neuron is activated
by acetylcholine release. Postganglionic sympathetic fi-
bers reach their effector organs along with mixed pe-
ripheral nerves, sympathetic rami, or blood vessels.
89,90
An increase in arterial pressure activates these “high-
pressure” baroreceptors. In response, sympathetic neu-
ral outflow, e.g., to muscle vasculature, immediately de-
creases, resulting in decreased norepinephrine release as
well as decreased regional vascular resistance and arte-
rial pressure.
89–94
The occurrence of MSA bursts is determined mainly by
fluctuations of arterial pressure and respiration. Pauses
between successive bursts correspond to increasing sys-
tolic pressure inhibiting sympathetic nerve traffic.
The importance of these “high-pressure” baroreceptor
afferents from the great vessels for blood pressure con-
trol was demonstrated by administration of local anes-
thesia to the vagal and glossopharyngeal nerves in
humans. In this study, blockade of vagal and glossopha-
ryngeal afferents induced a strong increase in MSA ac-
companied by temporal hypertension and tachycardia.
Moreover, cardiac rhythmicity disappeared and MSA be-
came similar to SSA.
95
On the other hand, “low-pressure” baroreceptors are
located in the great veins as well as in the walls of the
atria and the ventricles of the heart. Baroafferents reach
the brain stem via the vagal nerve (fig. 5). These recep-
tors are also linked to the release of atrial natriuretic
peptide, controlling blood volume, which determines
the static filling pressure of the system. Increased (right)
cardiac filling activates “low-pressure” baroreceptors. In
turn, similar to activation of “high-pressure” barorecep-
tor sympathetic outflow is decreased while parasympa-
thetic tone is increased, which may result in changes in
vasomotor tone, stroke volume, and HR.
Both “high-pressure” baroafferents and “low-pressure”
baroreceptors play an important role in regulating MSA.
Moderate levels of “lower body negative pressure” (up to
⫺20 cm H
2
O) decrease central blood volume and central
venous pressure without affecting arterial pressure.
Therefore, this technique was thought to be an appro-
priate method to examine the cardiopulmonary barore-
flex.
96–99
Under these conditions, MSA increased up to
250% of baseline during supine rest in healthy volun-
teers. However, the selectivity of low levels of lower
body negative pressure in unloading cardiopulmonary
baroreceptors has been questioned because computed
tomographic scans have revealed small changes in aortic
root diameter during mild lower body negative pressure,
suggesting a possible involvement of aortic barorecep-
tors as well.
100,101
In healthy subjects, a slight pharmacologic decrease in
diastolic pressure from 78 mmHg to 70 mmHg rapidly
increased MSA to as much as 300% of baseline.
32
However, how does an increase in MSA change arterial
blood pressure? MSA correlates well with muscle vascu-
lar resistance determined by occlusion plethysmogra-
phy.
102
A 50% increase in MSA (induced by lower body
negative pressure) correlated linearly with significant
decreases in both forearm and calf blood flow.
96,97
Therefore, increased MSA may counteract arterial hypo-
tension by increasing systemic vascular resistance,
which in turn increases arterial blood pressure.
Analysis of spontaneous threshold for occurrence of
MSA bursts and their strength (burst area) indicate that
the baroreflex mechanisms that regulate occurrence and
strength of MSA bursts are not identical. Therefore, dif-
ferent sites within the central nervous system may con-
trol the generation of MSA bursts and the strength of the
single bursts.
103
However, the physiologic meaning for
this differential control of occurrence and strength of
MSA bursts remains unclear so far.
During the past years, the modulation of arterial BRS
and the control of MSA came to the scientific fore.
In patients with vasovagal syncope, resting MSA was
increased, whereas baroreflex activation in response to
lower body negative pressure is impaired. These data
provide new recent insights into mechanisms of vasova-
gal syncope. The authors suggest that pharmacologic
modulation of baroreceptor sensitivity may be a promis-
ing treatment strategy for neuromediated syncope.
104
Improved arterial BRS could be achieved by physical
training in these patients, decreasing the incidence of
syncope.
105
Moreover, exercise training also restored baroreflex
control of MSA and HR in untreated hypertensive pa-
tients and normalized MSA and blood pressure in these
patients.
106
Therefore, physical training acts as a non-
pharmacologic therapeutic alternative on sympathetic
outflow and blood pressure control in patients with
cardiovascular disease.
Often, there is an obvious respiratory periodicity in
MSA with maximum activation during end-expiration
and the first half of inspiration in spontaneously breath-
ing subjects.
107–109
However, maximum MSA also paral-
lels the lowest blood pressure during the respiratory
cycle. Because of these oscillations of arterial pressure
with respiration, it is difficult to distinguish between
primary central modulation and secondary baroreceptor
reflex or lung receptor–induced changes in MSA.
110,111
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A study in four patients after combined heart and lung
transplantation–induced denervation of cardiopulmo-
nary baroreceptors indicated that during normal tidal
breathing, most of the respiratory influence on MSA
observed is, at least in these patients, independent of
baroreceptor-sensed fluctuations of intrathoracic or in-
tracardiac pressures. Furthermore, stimulation of vagal
afferents by lung inflation does not account for the
observed changes. In turn, during hyperpneic states,
vagally mediated feedback of lung inflation is the pri-
mary mechanism augmenting the within-breath variation
of MSA in healthy humans.
112
In a meta-analysis, major
changes in the pattern of MSA were not observed com-
paring spontaneous breathing with mechanical ventila-
tion. It was concluded that an inspiratory inhibition of
MSA does not depend on increases in arterial pressure
and baroreceptor output.
108
Both hypoxia and hypercarbia activate MSA via pe-
ripheral and central chemoreceptors.
113–115
Isocapnic
hypoxia (10% O
2
, 90% N
2
) significantly increased MSA by
21% after 5 min, hyperoxic hypercapnia (7% CO
2
, 93%
O
2
) by 53%, and a combination of both (10% O
2
,7%CO
2
,
83% N
2
) by 108% in a synergistic fashion.
29
After 4 min
of severe hypoxia (8% O
2
), an increase in MSA by as
much as 298% was reported, indicating that the maxi-
mum effect of sympathetic reflex activation induced by
hypoxia is moderately delayed.
116
Surprisingly, both nor-
epinephrine spillover (⫹40) and norepinephrine clear-
ance (⫹20) significantly increased during 20–30 min of
hypoxia (10% O
2
), resulting in an only minor but signif-
icant increase in arterial norepinephrine of 20%.
117
This
observation is a good example that norepinephrine
plasma concentration often does not mirror sympathetic
activity.
In contrast to the effects on parasympathetic arm of
baroreflex, baroreflex control of sympathetic outflow is
not impaired with age. Collectively, changes in barore-
flex function with age are associated with an impaired
ability of the organism to buffer changes in blood pres-
sure. This is evidenced by the reduced potentiation of
the pressor response to bolus infusion of a pressor drug
after compared with before systemic ganglionic block-
ade in older as compared with young adults.
118
On the other hand, a recent study revealed insights on
sex differences in sympathetic nervous activity. Women
with hypertension had increased MSA compared with
their normotensive counterparts, and MSA was signifi-
cantly related to blood pressure but not to body mass
index. MSA in men with hypertension was no different
from that in normotensive subjects, but MSA was signif-
icantly related to body mass index. Diet resulted in
similar weight loss in men and women but induced a
decrease in MSA only in men.
119
Table 1 summarizes the conditions that are known to
cause an increase or decrease in resting MSA, subcatego-
rized as perioperative and nonperioperative.
120,121
Effects of General Anesthesia on Sympathetic
Nervous System Activity
General anesthesia is usually associated with changes
in sympathetic activity that may be due to mechanical
ventilation, specific anesthetic drugs, the direct circula-
tory effects they induce, and/or their effects on central
or peripheral nervous system.
Role of Mechanical Ventilation
Mechanical ventilation, in particular positive end-expi-
ratory pressure, often decreases cardiac filling, cardiac
output, and arterial pressure by displacing blood from
the thorax to the gut and liver.
122
This raises the ques-
tion of whether and to what extent these alterations are
counterregulated by the SNS, both in the conscious state
and during anesthesia.
123
Reflex activation of the SNS is thought to be important
for compensatory responses to mechanical ventilation.
Sympathetic activation increased systemic vascular resis-
tance
124–127
and possibly also tone of capacitance ves-
sels,
128,129
and activated the renin–angiotensin sys-
tem.
130
Mechanical ventilation with increasing positive
end-expiratory pressure (0–20 cm H
2
O) in conscious
volunteers increased MSA by up to 82%. This response
was paralleled by an increase in calf vascular resistance
and in forearm venous norepinephrine plasma concen-
tration (fig. 6).
131
Table 1. Influences on MSA Level
Increase of MSA Decrease of MSA
Perioperative Nonperioperative Perioperative Nonperioperative
Hypoxia Aging Most anesthetics Chronic exercise
Hypercapnia Obesity Diet/weight loss
Positive end-expiratory pressure Obstructive sleep apnea syndrome
Laryngoscopy Heart failure
Intubation
Surgical stimulation
MSA ⫽muscle sympathetic activity.
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Several receptor populations can be considered to
mediate such effects. Besides “high-pressure” barorecep-
tors in the carotid sinus region and aortic arch,
132,133
“low-pressure” cardiopulmonary receptors are consid-
ered to be responsible for the cardiovascular reflex acti-
vation, but their respective roles have not been fully
clarified.
131
Because continuous positive airway pressure
(10–12 cm H
2
O) breathing in awake subjects decreases
cardiac and intrathoracic blood volume by approxi-
mately 10% at unchanged arterial pressure,
122
unloading
of cardiopulmonary “low-pressure” baroreceptors may
contribute to the observed increase in MSA during me-
chanical ventilation.
Intravenous Anesthetics
Ketamine. Ketamine is the only injectable anesthetic
that increases arterial pressure and HR.
134,135
This car-
diovascular stimulation is associated with increased cat-
echolamine plasma concentrations.
136
Because even
small amounts of ketamine when injected into the cere-
bral circulation in goats induced a similar increase in
arterial pressure and cardiac output (by increased HR) as
a larger dose given intravenously, central sympathetic
activation was proposed to be responsible for cardiovas-
cular stimulation during ketamine anesthesia.
137
In healthy volunteers, racemic ketamine increased ar-
terial blood pressure and norepinephrine plasma con-
centrations, whereas MSA was markedly decreased (fig.
7A). However, when increased arterial pressure was
normalized to awake baseline, MSA did not differ in
comparison with values obtained in the awake state. At
the same time, the MSA response to arterial hypotension
was not altered by racemic ketamine.
138
It can be con-
cluded that during anesthesia with racemic ketamine,
MSA was reduced because of baroreflex inhibition. Nor-
epinephrine plasma concentrations may be increased
because of inhibition of norepinephrine uptake by ket-
amine or increased sympathetic outflow to organs other
than muscle.
In contrast, anesthesia with S(⫹)-ketamine increased
sympathetic outflow to muscle and increased norepi-
nephrine plasma concentration, resulting in increased
arterial pressure.
139
The effects on resting MSA contrasts
with earlier observations during anesthesia with racemic
ketamine where sympathetic neural outflow to muscle
Fig. 6. Effects of positive end-expiratory pressure (PEEP: 0–20 cm
H
2
O) on muscle sympathetic activity (MSA) in spontaneously
breathing (SB), awake volunteers (mean ⴞSEM from eight healthy
volunteers). Note the pressure-dependent (0–20 cm H
2
O) increase
in MSA resulting in a 100% increase of MSA with 20 cm H
2
O PEEP.
Recovery to baseline conditions was achieved within a few min-
utes after discontinuation of PEEP. Therefore, a further increase in
intrathoracic pressure during mechanical ventilation with in ad-
dition PEEP is associated with increased efferent sympathetic ac-
tivity to the vasculature of muscles. * P<0.05. ** P<0.001. Derived
from and used with permission from Sellde´n et al.
131
Fig. 7. (A) Muscle sympathetic activity (MSA) burst incidence in the
awake state, during ketamine anesthesia, and during ketamine
anesthesia with arterial pressure adjusted to baseline by infusion
of sodium nitroprusside infusion (SNP). Mean ⴞSD from six
healthy subjects. MSA markedly and significantly decreased after
induction of anesthesia with ketamine. When arterial pressure
was decreased during ketamine anesthesia to awake baseline by
SNP, as to inhibit baroreflex afferents, MSA normalized, indicating
preserved muscle sympathetic activity during ketamine anesthe-
sia. * P<0.01 versus baseline awake. (B) Relations between dia-
stolic arterial pressure and MSA burst incidence before and after
injection of SNP in the awake state and during ketamine anesthe-
sia. Mean ⴞSD from six healthy subjects. The muscle sympathetic
response to hypotensive challenges as indicated by the slope of
the regression line was maintained during ketamine anesthesia
even at a higher arterial pressure level. Derived from and used
with permission from Kienbaum et al.
138
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decreased during increased arterial pressure, thus dem-
onstrating stereoselective effects on MSA.
138,139
Similar
to racemic ketamine, the MSA response to hypotensive
challenges was fully maintained during anesthesia with
S(⫹)-ketamine even at higher arterial pressures (fig. 7B).
In contrast to racemic ketamine, barbiturates, propo-
fol, and etomidate, S(⫹)-ketamine, therefore, is the only
intravenous anesthetic that increases MSA despite an
increase in arterial pressure.
In summary, ketamine does not increase sympa-
thetic outflow in a generalized fashion but shows
differential effects of both ketamine isomers on the
SNS. Interestingly, despite increased arterial pressure,
the MSA responses to arterial hypotension were al-
ways maintained with both racemic and S(⫹)-ket-
amine, which may contribute to cardiovascular stabil-
ity during ketamine anesthesia.
Opioids. Opioid receptors are ubiquitously present in
the heart, vasculature, and ganglia.
140,141
␮
-Opioid re-
ceptor agonists are the subgroup of opioids most fre-
quently used during general anesthesia and periopera-
tive analgesia. Nevertheless, the acute effects of
pharmacologic doses of
␮
-opioid receptor agonists on
the SNS are difficult to evaluate because baseline anes-
thesia, sedation, and respiratory depression by opioids
alter SNS activity as well.
In spontaneously breathing, awake humans, fentanyl
induces a dose-dependent increase in norepinephrine
plasma concentration by 70% and in epinephrine plasma
concentration by 180%.
142–144
In contrast, fentanyl ad-
ministered to healthy volunteers and awake, premedi-
cated patients did not alter MSA during a 5-min observa-
tion period.
120,145
This first view contradiction may be
resolved considering opioid-induced respiratory depres-
sion responsible for sympathetic activation in the first
study. When hypoventilation is avoided in anesthetized
dogs, high doses of fentanyl even decreased HR, arterial
pressure, left ventricular dp/dt, and norepinephrine and
epinephrine plasma concentrations due to decreased
sympathetic outflow.
146
Second, as classically shown for meperidine and mor-
phine, some opioids can exert both a probably direct
and also unspecific histamine release–related vasodilata-
tion with a consecutive decrease in arterial pressure.
147–149
This decrease in arterial pressure may also induce the
reflex activation of sympathetic neural outflow observed
in some studies.
23
Moreover, effects of endogenous opioids have been
studied by administration of opioid receptor antagonists.
When
␮
-opioid receptors were blocked by administra-
tion of the
␮
-opioid receptor antagonist naloxone, he-
modynamics, catecholamine plasma concentrations,
MSA, and arterial baroreflexes were not changed at
rest.
150–156
In contrast, cardiopulmonary baroreflexes
and the MSA response to exercise were augmented after
administration of naloxone in humans.
152–158
Finally, chronic
␮
-opioid receptor stimulation, as ob-
tained in opioid-addicted patients, markedly decreases
MSA, norepinephrine plasma concentration, and arterial
baroreflexes, whereas arterial blood pressure and HR did
not differ from those in healthy volunteers (fig. 8). More-
over, when opioid receptors were blocked by acute
administration of naloxone for detoxification from opi-
oids, MSA, norepinephrine plasma concentration, and
BRS increased despite deep general anesthesia.
159–161
Therefore, chronic opioid receptor stimulation mark-
edly depresses sympathetic outflow at rest and during
cardiovascular challenges.
Moreover, chronic
␮
-opioid receptor stimulation mark-
edly decreased the MSA response to hypotension com-
pared with healthy subjects despite similar arterial blood
pressure and HR at rest. In contrast, the HR response to
hypotension did not differ between addicted patients
and healthy subjects. Opioid receptor blockade during
Fig. 8. Average resting muscle sympathetic
activity (MSA) and catecholamine plasma
concentrations in six unpremedicated, opi-
oid-addicted patients and six healthy,
matched controls. Chronic
␮
-opioid recep-
tor stimulation was associated with a
marked parallel decrease in both MSA and
norepinephrine plasma concentration. In
contrast, epinephrine plasma concentra-
tion increased. However, the mechanism
underlying the increased epinephrine con-
centration in plasma remains unclear. Pos-
sibly, adrenal epinephrine release is less
sensitive to the inhibitory effects of
chronic opioid agonist administration, or
opposite to the decrease in MSA, shows a
compensatory increase. Derived from and
used with permission from Kienbaum
et al.
160
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propofol anesthesia markedly increased the MSA re-
sponse to hypotension even beyond awake values,
whereas the HR response remained unchanged. There-
fore, chronic
␮
-opioid receptor stimulation results in
uncompensated depression of cardiovascular sympa-
thetic neural regulation and exerts differential effects on
efferent sympathetic nerve activity to muscle and on HR
control in response to arterial hypotension.
162
In summary, acute administration of opioids alone has
little effect on sympathetic outflow and cardiovascular
variables in uncompromised volunteers. However, when
opioids are given for an extended period, depression of
SNS may be expected.
Sedative Hypnotics
Barbiturates. The central nervous system–depressive
effect of barbiturates has been known for more than 40 yr.
Tachycardia after induction is most likely due to inhibition
of cardiac vagal outflow rather than sympathetic activa-
tion.
34,127,163
Depressant effects on myocardial contractility
and arterial pressure are probably attributable to both a
direct negative inotropic effect and decreased efferent sym-
pathetic drive. SSA is abolished within 1 min after in-
duction of anesthesia with thiopental.
164
Further-
more, MSA was suppressed after methohexital
administration (fig. 9). When BRS was determined by
sequential bolus injections of SNP and phenylephrine,
baroreflex slopes relating MSA to induced changes in
arterial pressure were almost abolished.
34,145,165
Nevertheless, intense stimulation, e.g., by laryngoscopy
or intubation, is still accompanied by an increased MSA,
indicating that sympathetic reflex activation from stimula-
tion of laryngeal and tracheal receptors is not fully sup-
pressed by barbiturates in clinically used dosages.
In conclusion, barbiturates depress both SSA and MSA
and decrease BRS substantially, indicating marked inhi-
bition of sympathetic outflow and reflex activation.
Benzodiazepines. In resting patients, intravenous ad-
ministration of benzodiazepines usually induces only mi-
nor cardiovascular changes. Nevertheless, diazepam, or
flunitrazepam, when given to healthy volunteers, de-
creased catecholamine plasma concentrations and atten-
uated baroreflex responses.
166–168
A study that observed the effects of benzodiazepines in
patients with panic disorder demonstrated that anxio-
lytic therapy with alprazolam increases MSA and HR not
only in patients with panic disorder but also in healthy
controls.
169
In contrast, several studies suggested that diazepam
reduces both arterial blood pressure and MSA. After
diazepam administration, systolic and mean blood pres-
sure and MSA decreased significantly. In conclusion, the
hypotensive effect of diazepam in human is mainly due
to the central mechanism.
170
However, direct recordings of efferent sympathetic
nerve activity in humans have not been reported.
In contrast to direct negative inotropic effects of diaz-
epam in isolated rat heart muscle,
171
diazepam given to
dogs anesthetized with chloralose did not change base-
line renal sympathetic nerve activity. However, BRS,
when determined as changes in renal sympathetic nerve
activity in response to arterial pressure perturbations,
was markedly decreased.
146
Whereas midazolam in rab-
bits had no effect on mean arterial pressure or HR at
baseline, HR response after bilateral carotid occlusion
was significantly attenuated. In contrast, no effects on
mean arterial pressure response were observed, suggest-
ing differential effects on cardiac and baroreflex con-
trol.
172
Moreover, when diazepam was combined with
Fig. 9. Muscle sympathetic activity (MSA)
and arterial pressure during induction of
anesthesia with a bolus dose of methohexi-
tal. Bottom panels show selected passages
of records from top panels on an ex-
panded time scale. Note inhibition of nerve
traffic with induction despite decreased ar-
terial pressure and sympathetic activation
during intubation. Therefore, methohexi-
tal anesthesia clearly reduces MSA, but the
sympathetic nervous system can still be ac-
tivated at least to some extent, e.g., by tra-
cheal intubation or surgical stress. Derived
from and used with permission from Sell-
gren et al.
145
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opioids (e.g., fentanyl, morphine), decreases in arterial
pressure, cardiac output, systemic vascular resistance,
and catecholamine concentrations in plasma were ob-
served in dogs anesthetized with thiopental, in healthy
volunteers, and in patients before coronary artery bypass
graft surgery, which did not occur when fentanyl was
given alone.
143,173–175
In summary, benzodiazepines may decrease baseline
SNS activity and the ability to respond to arterial pres-
sure changes. Moreover, it has to be emphasized that a
combination of benzodiazepines with opioids typically
results in profound reduction of SNS activity associated
with decreases in systemic vascular resistance and arte-
rial pressure. These cardiovascular changes are even
more pronounced when SNS activity is increased, e.g.,
during cardiac failure.
Propofol. Propofol induces hypotension, particularly
when injected rapidly. Responsible mechanisms have
been suggested to include myocardial depression,
176–178
decreased vascular resistance,
177,178
and diminished car-
diac preload and output.
179,180
The observed decrease of
peripheral vascular resistance in patients with artificial
hearts points to a direct vasodilatating effect of propofol
or a decrease in sympathetic vasoconstrictor activity.
109,181
In
contrast, propofol increases myofilament Ca
2⫹
sensitiv-
ity in pulmonary artery smooth muscles, and this effect
involves the protein kinase C signaling pathway, which
could in general serve as a target for anesthetic agents
that alter vasomotor tone.
182
If this observation was
clinically relevant, vasoconstrictor tone would be in-
creased at similar sympathetic outflow.
On the other hand, when propofol was infused in
the brachial artery, achieving local anesthetic plasma
concentrations, vasodilatation did not occur.
183
Ac-
cordingly, central mechanisms must be responsible
for the observed vasodilatation during propofol
anesthesia.
184,185
Propofol decreased mean arterial pressure from 100
mmHg to 73 mmHg, which was accompanied by a
66 ⫾7% decrease in MSA within 3 min and a threefold
to sevenfold increase in leg blood flow.
34,35,186,187
BRS, as determined by bolus injections of SNP, was
almost abolished.
35
Propofol in sedation dose significantly reduced sympa-
thetic nerve activity by 65% and 92% at moderate and
deep sedation. At the same time, forearm vascular resis-
tance significantly decreased. These effects resulted in
significant decreases in mean blood pressure at moder-
ate and deep sedation, respectively. Propofol also re-
duces reflex increases in sympathetic nerve activity. Re-
capitulatory sedation doses of propofol, which did not
compromise respiratory function, had substantial inhib-
itory effects on sympathetic nerve activity and reflex
responses to hypotension, resulting in vasodilatation and
significant decrease in mean blood pressure (fig. 10).
188
These data clearly demonstrate that propofol markedly
decreases SNS basal activity as well as the ability of the
SNS to respond to hypotensive challenges.
Etomidate. Etomidate is probably the induction anes-
thetic with the fewest hemodynamic effects and has
therefore been advocated in patients with cardiovascular
disease or hypovolemia. The mechanism for the hemo-
dynamic stability after etomidate administration has
been elucidated by direct recordings of MSA, demon-
strating that both sympathetic efferent activity and sym-
pathetic reflex activation by hypotensive challenges are
not impaired.
186
Sedative Hypnotics: Conclusion. Except for etomi-
date, barbiturates, benzodiazepine, and propofol all de-
crease resting SNS activity and attenuate baroreflex re-
sponses to changes in arterial pressure
189
(table 2).
Nevertheless, it is difficult to compare sedative hyp-
notics in their effects on SNS activity and baroreflex
function in a rigid manner, because dose–response rela-
tions are not available in humans and equi-potent seda-
tive effects are difficult to establish.
Nitrous Oxide
Nitrous oxide is a centrally acting stimulant of sympa-
thetic outflow. An increase in MSA by 60% paralleled by
an increase in forearm vascular resistance of 30% has
been observed during spontaneous breathing of subanes-
Fig. 10. Arterial blood pressure (BP), mus-
cle sympathetic nerve activity (MSNA), and
electrocardiographic recordings (ECG) in
the awake state as well as during moderate
and deep sedation with propofol in
healthy volunteers. Propofol decreases
MSNA even during moderate sedation, re-
sulting in arterial hypotension caused by
impaired sympathetic cardiovascular con-
trol. SBP ⴝsystolic blood pressure. De-
rived from and used with permission from
Ebert.
188
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thetic nitrous oxide concentrations.
190
In patients
breathing nitrous oxide, baroreflex-mediated tachycar-
dia decreased by approximately 39% during hypotension
induced by SNP.
Moreover, cardiovagal reflex response is not affected
by nitrous oxide, per se, and spontaneous baroreflex
responses closely reflect beat-to-beat dynamic modula-
tion of the cardiac cycle by the parasympathetic nervous
system during inhalation of 67% nitrous oxide.
191
Unlike the results demonstrated in adults, a study on
the use of nitrous oxide in children showed few cardio-
vascular effects of nitrous oxide. Furthermore, whereas
in adults nitrous oxide is associated with an excitatory
cardiovascular profile, in children this agent seems to be
associated with a depressant cardiovascular profile.
192
However, in adults the MSA increase in response to
arterial hypotension remained unchanged.
165
With-
drawal of nitrous oxide during isoflurane anesthesia
(0.6% end-tidal) in healthy volunteers was associated
with a substantial decrease in MSA (⫺40%), a slight
increase in HR, and unchanged mean arterial pressure,
despite the depth of anesthesia being reduced (mini-
mum alveolar concentration: 1.0–0.5; fig. 11).
187
Nitrous oxide, therefore, counteracts SNS depression
of volatile anesthetics when both drugs are administered
simultaneously. This mechanism may explain the classic
clinical observation that similar anesthetic depths can be
achieved with less cardiovascular depression by coad-
ministration of nitrous oxide–volatile anesthetic com-
pared with administration of a volatile anesthetic
alone.
193
Xenon
In contrast to the well-known volatile anesthetics
(chlorofluorocarbons), xenon does not cause circulatory
depression.
194–196
Even hints of circulatory activation
have been observed in animal models and patients.
197,198
Recent studies showed that xenon did not reduce heart
variability, indicating favorable cardiovascular stability in
patients with cardiac disease during xenon anesthe-
sia.
199
Whether xenon owes these inert cardiovascular
effects to a lack of effects on the SNS is not known.
Volatile Anesthetics
Cardiovascular effects of volatile anesthetics have been
investigated extensively, including evaluation of SNS ac-
Table 2. Development of MSA after Different Drug Applications
Dosage
Mean Arterial
Pressure, mmHg
Heart Rate,
beats/min
MSA, % vs.
Baseline Study
Ketamine 2 mg/kg ⫹30
␮
g·kg
⫺1
· min
⫺1
⫹37 ⫾19* ⫹38 ⫾26* ⫺58 ⫾26* Kienbaum et al.,
138
2000
Ketamine After blood pressure normalization (SNP) ⫹3⫾7⫹40 ⫾28* ⫹6⫾9 Kienbaum et al.,
138
2000
S(⫹)-Ketamine 670
␮
g/kg ⫹15
␮
g·kg
⫺1
· min
⫺1
⫹39 ⫾21* ⫹14 ⫾9* ⫹119 ⫾43* Kienbaum et al.,
139
2001
Fentanyl 2
␮
g/kg ⫺8⫾7* ⫺2⫾6⫹2⫾8 Sellgren et al.,
145
1992
Fentanyl 5
␮
g/kg ⫹1⫾5⫺2⫾8⫹1⫾2 Pacentine et al.,
120
1995
Thiopental 4 mg/kg ⫹8⫾6* ⫹11 ⫾11* ⫺54 ⫾65* Ebert et al.,
121
1990
Propofol 2 mg/kg ⫹100
␮
g·kg
⫺1
· min
⫺1
⫺27 ⫾10* ⫹11 ⫾8* ⫺66 ⫾7* Sellgren et al.,
187
1990
Propofol 3 mg/kg ⫹200
␮
g·kg
⫺1
· min
⫺1
⫺22 ⫾10* ⫺14 ⫾7* ⫺73 ⫾20* Ebert et al.,
186
1992
Etomidate 0.3 mg/kg ⫹15
␮
g·kg
⫺1
· min
⫺1
⫹23 ⫾10* ⫺4⫾7⫺13 ⫾12* Ebert et al.,
186
1992
Data are presented as value ⫾SD.
*P⫽0.01.
MSA ⫽muscle sympathetic activity; SNP ⫽sodium nitroprusside.
Fig. 11. Mean arterial pressure (MAP), heart rate (HR), and muscle
sympathetic activity (MSA; total activity) in the awake state, after
induction of anesthesia with propofol, when patients were intu-
bated, and during maintenance of general anesthesia with nitrous
oxide (70% end-tidal), a combination of nitrous oxide and isoflu-
rane (0.3% and 0.6% end-tidal), and equianesthetic isoflurane
(1.2% end-tidal) alone. Data are mean ⴞSD. During anesthesia
with nitrous oxide, MSA increases in comparison with propofol
anesthesia. Isoflurane decreases MSA in a dose-dependent man-
ner. Equianesthetic doses of isoflurane combined with nitrous
oxide decrease MSA to a much lesser extent than when isoflurane
was administered alone. Symbols indicate statistical significance
(P<0.05) for comparisons with the awake control group (*), with
70% nitrous oxide (†), and with 0.6 vol% isoflurane plus 70% vol%
nitrous oxide (‚). Derived from and used with permission from
Sellgren et al.
187
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tivity and BRS. Halothane,
200–206
enflurane,
204,207,208
sevoflurane,
209
and isoflurane
187,204,210–213
decrease SNS
activity and baroreflex activation in animals. Most
components of the baroreflex loop (afferent and effer-
ent nerves, central nervous system, peripheral ganglia,
myocardium, smooth muscle) are suppressed by vol-
atile anesthetics. In contrast, carotid baroreceptor af-
ferent activity in rabbits increased with deeper halo-
thane anesthesia irrespective of cardiac filling and
output.
205
This mechanism, in addition to direct ef-
fects on the heart and vessels, may further contribute
to the decrease in arterial pressure observed during
halothane anesthesia.
Desflurane and isoflurane induce vasodilatation and
seem to have similar cardiodepressant effects.
214,215
Some data, however, indicate that there are substantial
differences between the actions of isoflurane and desflu-
rane with respect to the SNS.
216
Desflurane caused a
similar blood pressure decrease to isoflurane but was
associated with higher resting MSA at equianesthetic
steady state concentrations.
216–219
In addition, when the
inspired concentration of desflurane was rapidly in-
creased, a surge in sympathetic outflow was observed,
associated with a 2- to 3-min-lasting increase in HR and
blood pressure (fig. 12). That is why desflurane is not
recommended as the sole agent for anesthetic induction
of patients with coronary artery disease or any patient
where increases in HR or blood pressure are undesirable.
The increase in basal MSA at a high steady state concen-
tration of desflurane did not seem to be due to baroreflex
mechanism.
220
In contrast, BRS was preserved with low
concentrations (up to 1.0% end-tidal) of isoflurane but
not with desflurane. This finding could possibly explain
the isoflurane-induced tachycardia at low minimum alve-
olar concentrations. However, greater inspiratory con-
centrations were associated with similar depression of
BRS with both volatile anesthetics.
33
Investigators have
tried to identify a central or peripheral site, e.g., airway
irritation, involved in the aforementioned activation of
the SNS. It was demonstrated that central sites contrib-
ute more than pulmonary sites to the hemodynamic
activation associated with rapid increases in inspired
desflurane concentrations and that lower airway sites
dominate upper airway sites.
221,222
With sevoflurane, there is no neurocirculatory excita-
tion observed with rapid increases in inspiratory concen-
trations. At steady state, increasing sevoflurane concen-
trations were associated with lower MSA but similar
mean arterial pressure and HR when compared with
equianesthetic desflurane in humans.
223
Anesthetic Adjuvants
Ganglionic Blocking Drugs. Historically, N
N
-nico-
tinic receptor antagonists such as trimethaphan have
been administered in experimental and clinical settings
to achieve profound arterial hypotension by autonomic
ganglionic blockade. Ganglionic blockade results in near-
complete interruption of the efferent arc of the barore-
flex (sympathetic and parasympathetic), as indicated by
a variety of autonomic function tests. Intravenous admin-
istration of trimethaphan abolished resting MSA as well
as the MSA and HR response to induced changes in
arterial pressure. At the same time, norepinephrine
plasma concentrations decreased.
224
␣
2
-Receptor Agonists.
␣
2
-Receptor agonists, e.g.,
clonidine, dexmedetomidine, or mivazerol, have been used
to reduce dosages of opioids and volatile anesthetics.
Moreover, a reduction in ST-segment changes in pa-
tients undergoing peripheral vascular surgery was dem-
onstrated for clonidine, suggesting an improvement of
Fig. 12. Responses of muscle sympathetic activity (MSA), heart
rate, and mean arterial pressure to increasing inspiratory concen-
trations of either desflurane or isoflurane. Volatile anesthetic ad-
ministration began 2 min after thiopental (TP) anesthesia induction.
Transient sympathoexcitation, tachycardia, and hypertension were
observed in subjects receiving desflurane persisting for 15 min and
gradually abating with time but not during isoflurane (mean ⴞSEM
of 14 healthy volunteers). Therefore, desflurane in contrast to
isoflurane induces transient sympathoexcitation particularly
after rapid increases in inspiratory concentration. MAC ⴝmin-
imum alveolar concentration. Derived from and used with per-
mission from Ebert and Muzi.
216
* Differences between groups.
† Desflurane response different from thiopental value. ¥ Isoflu-
rane response different from thiopental value.
1126 M. NEUKIRCHEN AND P. KIENBAUM
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the ratio of myocardial oxygen supply and demand in
patient with coronary artery diseases.
225
In healthy volunteers, oral clonidine decreased resting
MSA and norepinephrine plasma concentration by
50%.
226
In contrast, the MSA response to changes in
arterial blood pressure was unchanged. When clonidine
was intravenously administered, arterial blood pressure
decreased and MSA tended to increase in response to
hypotension when clonidine plasma concentrations
were low.
227
Therefore, this decrease in arterial pressure
may be due to direct vasodilatating effects of clonidine.
However, with higher dosages, MSA decreased in paral-
lel to the decrease in arterial blood pressure, indicating a
resetting of arterial baroreflexes at a lower pressure
level.
Dexmedetomidine has been show to decrease MSA as
well. The combination of dexmedetomidine and glyco-
pyrrolate, a muscarinic receptor antagonist, mimics gan-
glionic blockade.
228
Clinical Correlations and Conclusions
Most anesthetics interfere with sympathetic neural
outflow and cardiovascular regulation. Accordingly, car-
diac output and systemic vascular resistance are destabi-
lized, causing arterial hypotension. These effects are
even more pronounced in states of chronically elevated
MSA, including normal aging, which places patients at
risk of profound hypotension when anesthetized with,
e.g., propofol, thiopental, or volatile anesthetics. At the
same, anesthetized patients with severely decreased
MSA and baroreflexes are prone to severe hypotension
in the presence of hypovolemia or systemic administra-
tion of vasodilators with only modest increases in HR.
Conversely, the
␣
-adrenoceptor agonist phenylephrine
increases arterial pressure, which in turn slows HR by
increased vagal outflow. Similar to certain anesthetics,
diseases that attack the SNS, e.g., multisystem atrophy
(Shy-Drager syndrome) and pure autonomic failure
(Bradbury-Eggleston syndrome), are associated with de-
creased sympathetic outflow and impaired cardiovascu-
lar control. Of interest, these patients present with su-
pine hypertension and postural hypotension, potentially
challenging blood pressure control in the perioperative
period. Patients with baroreflex failure may serve as a
clinical model of impaired sympathetic cardiovascular
control presenting with extreme arterial pressure
changes during cardiovascular challenges, e.g., mental
stress, painful stimuli.
229
Taken together, these patients
demonstrate the importance of sympathetic cardiovas-
cular control mechanisms in the awake state.
In patients with severe hypertension, physiologic
cardiovascular control mechanisms can be manipu-
lated. In these patients, carotid sinus stimulators were
implanted to further increase baroreceptor afferent
activity, which in turn decreases sympathetic outflow
and arterial pressure.
230
The authors thank Gunnar Wallin, M.D., Ph.D. (Professor, Department of
Clinical Neurophysiology, Sahlgren Hospital, University of Go¨teborg, Go¨teborg,
Sweden), for innumerable helpful discussions and Mikael Elam, M.D., Ph.D.
(Professor, Department of Clinical Neurophysiology, Sahlgren Hospital, Univer-
sity of Go¨teborg), for thorough review of the manuscript.
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1131EFFECTS OF GENERAL ANESTHESIA ON THE SYMPATHETIC SYSTEM
Anesthesiology, V 109, No 6, Dec 2008
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