Download Effects of the Anticholinesterase Edrophonium on Spectral Analysis

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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics
JPET 300:112–117, 2002
Vol. 300, No. 1
4561/952621
Printed in U.S.A.
Effects of the Anticholinesterase Edrophonium on Spectral
Analysis of Heart Rate and Blood Pressure Variability in
Humans
ALAIN DESCHAMPS, STEVEN B. BACKMAN, VERA NOVAK, GILLES PLOURDE, PIERRE FISET, and DANIEL CHARTRAND
Department of Anesthesia, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada (A.D., S.B.B., G.P., P.F., D.C.); and
Department of Neurology, The Ohio State University, Columbus, Ohio (V.N.).
Received September 24, 2001; accepted November 11, 2001
This paper is available online at http://jpet.aspetjournals.org
Anticholinesterase drugs are used clinically to facilitate
cholinergic transmission. Edrophonium and neostigmine are
anticholinesterases commonly used postoperatively to reverse the neuromuscular block induced by nondepolarizing
muscle relaxants. An undesirable effect of the anticholinesterase is activation of parasympathetic target organs, resulting in a variety of responses including bradycardia.
It is assumed that the bradycardia results from the anticholinesterase activity, which prevents the hydrolysis of ACh
released tonically from parasympathetic neurons innervating the heart (Baraka, 1968). However, recent studies suggest that anticholinesterases may have additional effects at
cholinergic synapses within the autonomic peripheral pathway. For example, in vivo and in vitro animal studies suggest
that neostigmine and edrophonium directly activate (Backman et al., 1993a, 1996a) and inhibit (Backman et al., 1997;
Supported by grants from La Foundation d’Anesthésiologie et Réanimation
du Québec and Associated Anaesthetists Group, Royal Victoria Hospital. Preliminary results described in this paper were presented in part at the Society
for Neuroscience 1999 Annual Meeting October 23–28, 1999, in Miami, FL (Soc
Neurosci Abstr 25:877.1).
1.0 mg 䡠 kg⫺1, P ⬍ 0.01]. HFP of the RRI increased at low doses
(0.2– 0.4 mg 䡠 kg⫺1; maximum increase to 111.0 ⫾ 58.2% baseline; P ⬍ 0.01) but decreased (⫺49.5 ⫾ 35.5% baseline; P ⬍
0.01) at higher (1.0 mg 䡠 kg⫺1) doses. Edrophonium had no
effect on SBP and DBP. HFP of SBP decreased with increasing
doses (maximal decrease to ⫺26.2 ⫾ 7.5% baseline, P ⬍ 0.01,
1.0 mg 䡠 kg⫺1). LFP of SBP was also decreased (⫺46.3 ⫾
10.9% baseline, P ⬍ 0.01, 1.0 mg 䡠 kg⫺1). Edrophonium may
enhance (lower dose) or reduce (higher dose) cardiovascular
autonomic drive in humans, as evidenced by the significant
changes it evokes in HFP of the RRI (parasympathetic drive),
and in the HFP and LFP of SBP (sympathetic drive). These
observations may account for the modest autonomic side effects of edrophonium when this drug is used clinically.
Stein et al., 1998), respectively, these cholinergic receptors.
Thus, the parasympathomimetic action of the anticholinesterases must be understood within the context of their anticholinesterase activity on the one hand, and their direct
interaction with cholinergic receptors on the other. For example, it is well established clinically that the fall in heart
rate produced by edrophonium is significantly smaller than
that produced by neostigmine (Fogdall and Miller, 1973;
Cronnelly et al., 1982). It has been proposed that the modest
bradycardic effect of edrophonium occurs because the enhancement of parasympathetic drive, secondary to the anticholinesterase action, is diminished by the inhibitory effect of
the drug on autonomic cholinergic transmission (Backman et
al., 1997; Stein et al., 1998). Animal studies suggest that the
enhancement (anticholinesterase action) occurs at lower
doses compared with the reduction (block of cholinergic receptors) of autonomic cholinergic transmission that occurs at
high doses (Backman et al., 1996a; Stein et al., 1998).
From the above, it is anticipated that in humans edrophonium produces a dose-dependent biphasic effect on autonomic drive. That is, the drive is augmented by lower doses
ABBREVIATIONS: ACh, acetylcholine; HFP, high frequency power; LFP, low frequency power; RRI, R-R interval; SBP, systolic blood pressure;
DBP, diastolic blood pressure; SA, sinoatrial; EDRO, edrophonium-treated patients; CONT, control patients who received saline.
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ABSTRACT
Edrophonium, an anticholinesterase, exerts a biphasic effect on
cardiovascular autonomic drive in humans (lower doses enhance; higher doses reduce). Twenty-five anesthetized, mechanically respired (10 breaths 䡠 min⫺1, constant tidal volume)
patients were given either saline (n ⫽ 10) or edrophonium
(0.01–1.0 mg 䡠 kg⫺1, n ⫽ 15) following surgery. ECG, radial
arterial pressure, and respiratory rate were sampled at 250 Hz
to obtain time series for consecutive R-R intervals (RRIs), and
systolic (SBP) and diastolic blood pressure (DBP). A Wigner
distribution was used for time frequency mapping of spectral
powers at high (HFP, 0.15– 0.5 Hz) and low (LFP, 0.0 – 0.05 Hz)
frequency. Edrophonium produced a dose-dependent decrease in heart rate [baseline 66.8 ⫾ 1.9 (S.E.M.) beats per
minute; maximum decrease to 55.8 ⫾ 1.4 beats per minute with
Edrophonium and the Autonomic Nervous System
Materials and Methods
Subjects. This study was approved by the Ethics Committee at
the Royal Victoria Hospital, and informed consent was obtained from
every subject. This report includes data from 25 patients (13 male, 12
female; 25– 63 years old) who underwent abdominal, urological, gynecological, head and neck, or plastic surgery under general anesthesia using a standardized regimen. Exclusion criteria included
major cardiovascular, pulmonary, neurological, or endocrine disease,
metabolic disorders, recent exposure to medications that could affect
heart rate (e.g., beta blockers or agonists, muscarinic agonists or
antagonists), age ⬍ 18 or ⬎ 70 years, patients undergoing emergency
procedures, and patients receiving major conduction anesthesia (spinal or epidural) because of possible interference with sympathetic
cardiovascular outflow. Patients were also excluded if they demonstrated a cardiac rhythm other than sinus, if premature ventricular
beats were present, or if heart rate was less than 55 beats/min prior
to the start of the experiment (see below).
Experimental Set-Up. Patients received no premedication. Monitoring in the operating room included ECG (lead II), noninvasive
systemic arterial pressure, pulse oximetry, end-tidal carbon dioxide
and concentration of volatile anesthetic agents, ventilation pressure,
and train-of-four ratio. General anesthesia was induced using fentanyl (1–1.5 ␮g 䡠 kg⫺1) and propofol (1.5–2.0 mg 䡠 kg⫺1). Tracheal
intubation was facilitated by muscle paralysis with rocuronium (0.6 –
1.0 mg 䡠 kg⫺1). Anesthesia was maintained using a mixture of isoflurane (0.4 –1.2%) and 50% N2O/O2. Drugs with an antimuscarinic
(e.g., pancuronium, atropine, glycopyrrolate) or beta-blocking effects
were avoided. The rate of the respirator was set at 10 breaths 䡠 min⫺1
(0.17 Hz). Tidal volume was initially set at 10 ml 䡠 kg⫺1 and was then
adjusted to maintain end-tidal CO2 between 30 and 35 mm Hg.
Respiratory parameters were unaltered during the study period.
At the conclusion of surgery and wound dressing, no attempt was
made to lighten the level of anesthesia or reverse neuromuscular
blockade, and stimulation of the patient (oral suctioning, patient
transfer from OR table to stretcher, etc.) was avoided. Fifteen
minutes were allotted for stabilization of cardiovascular parame-
ters. After this interval, a 20 gauge catheter was inserted into a
radial arterial to record systemic arterial pressure if heart rate
was above 55 beats 䡠 min⫺1 (three patients were excluded for low
heart rates).
Continuous ECG (lead II), systemic arterial blood pressure, and
ventilation pressure were recorded on a personal computer via an
analog-to-digital converter at a sampling rate of 250 Hz per channel
(Windaq; Dataq Instruments, Akron, OH). After the 15-min stabilization interval (see above), a 5-min period of recording of baseline
physiological parameters was initiated (baseline ⫽ condition 1). Following recording of baseline parameters, in one set of patients (edrophonium, EDRO, n ⫽ 15) edrophonium chloride (Zeneca Pharma,
Mississauga, Ontario, Canada) was injected at 5-min intervals to
obtain cumulative doses of 0.01, 0.05, 0.1, 0.2, 0.4, and 1.0 mg 䡠 kg⫺1
(conditions 2–7, respectively) with the maximal dose constituting a
full reversing dose (Breen et al., 1985). Five-minute intervals were
chosen because in a previous study in humans, we demonstrated
that the edrophonium-induced bradycardia began within 30 sec after
edrophonium injection and reached a plateau within 2 min (Backman et al., 1997). Atropine sulfate (Abbott Laboratories, Ltd., Montreal, Quebec, Canada) 10 ␮g 䡠 kg⫺1 was administered 5 min after
the last dose of edrophonium. In a second set of patients (control,
CONT, n ⫽ 10), following an initial 5-min period for recording of
baseline data (condition 1), six doses of saline (conditions 2–7, respectively), each of a volume matched to the corresponding dose of
edrophonium, were injected at 5-min intervals. In this CONT group,
1.0 mg 䡠 kg⫺1 edrophonium and 10 ␮g 䡠 kg⫺1 atropine were coadministered 5 min following the last dose of saline.
Data Management. Consecutive RRIs, and systolic and diastolic
blood pressures (SBP, DBP) were acquired from the ECG and blood
pressure signals and converted to their respective time series. These
were linearly interpolated at 4 Hz to obtain equal samples within
each time series. A moving fourth order polynomial function, comprising a nonlinear bandpass filter, was used to remove baseline
trends. This filtering excludes the very low frequency nonstationary
components (⬍0.005 Hz) but leaves the faster frequencies of interest
intact. Time frequency mapping and beat-to-beat spectral estimation
was achieved using a discrete Wigner distribution that decomposes
signals expressed as a function of time into signals expressed as a
function of both time and frequency. The modified Wigner distribution has been demonstrated to be a good estimation method for short
nonstationary time series, and its resolution was enhanced by independent time and frequency smoothing using a moving 128-event
data window. The time-frequency distributions were computed with
the same parameter set for all signals. A detailed description of the
Wigner function can be found elsewhere (Novak and Novak, 1993).
The cross-time frequency distributions were calculated for each signal and each condition to determine common frequency contents
between consecutive RRIs and SBPs. The spectral power was calculated at high frequency (HFP, 0.15– 0.50 Hz) and low frequency
(LFP, 0.0 – 0.05 Hz). Spectral powers were averaged over 4-min intervals starting 1 min following each injection of edrophonium or
saline.
Statistics. Heart rate [HR], SBP, DBP and RRI changes, in
addition to the high- and low frequency power of RRI and SBP
following injection of either edrophonium or saline, were assessed
using a two-way repeated-measures analysis of variance. Logtransformed high- and low-frequency powers were analyzed to
ensure a normal distribution of data. When differences between
the groups were significant (P value ⱕ 0.05), a Tukey test was
performed for post hoc comparison. Data are expressed as mean ⫾
S.E.M. unless indicated otherwise. To permit direct comparison of
the magnitude of change in high and low frequency between
individuals, percentage changes from baseline were used for
graphical representation of these data.
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and is reduced with higher doses. In humans, however, there
is little information concerning the effect of edrophonium on
cardiovascular autonomic responses when this drug is administered without a muscarinic antagonist (van Vlymen and
Parlow, 1997). Thus, the purpose of the present study was to
characterize the effect of edrophonium on autonomic control
of the cardiovascular system in humans. This was achieved
by measuring sensitive indices of sympathetically and parasympathetically mediated cardiovascular responses (timefrequency analyses of heart rate and systemic arterial pressure variability) in anesthetized patients following
incremental doses of edrophonium. Time frequency mapping
based on a Wigner distribution enables simultaneous assessment of signals in both time and frequency domains. High
frequency power of R-R intervals (RRIs) is a quantitative
indicator of parasympathetic influence on the SA node
(Brown et al., 1993; Task Force of the European Society of
Cardiology and the North American Society of Pacing and
Electrophysiology, 1996; Novak et al., 1997b). It is established that the low frequency power of the systolic component
of systemic arterial pressure may be employed as a quantitative indicator of sympathetic outflow (Pagani et al., 1996).
The high frequency power of the systolic component may also
be used for this purpose, but it is markedly influenced by
mechanical factors such as tidal volume and respiratory rate
(Madwed et al., 1989; Pagani et al., 1996; Novak et al.,
1997a.)
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Results
Fig. 2. Relationship between condition (abscissa) and high frequency
power of heart rate variability (HFP, ordinate), expressed as percentage
change from baseline value. Each histogram represents the average
response from patients who received saline (control, n ⫽ 10, black) or
edrophonium (n ⫽ 15, white). ⴱ, change in HFP that was significantly
different from control (P ⬍ 0.01).
Fig. 3. Relationship between condition (abscissa) and blood pressure
(ordinate). Each point represents averaged responses of systolic (solid
symbols) or diastolic (open symbols) blood pressure, respectively, of patients who received saline (control; F, E, n ⫽ 10) or edrophonium (f, 䡺,
n ⫽ 15).
condition 7; maximal decrease to ⫺26.2 ⫾ 7.5% baseline, P ⬍
0.01, Fig. 4). This decrease contrasts greatly from the
changes observed in the CONT group, where the power did
not change significantly (Fig. 5).
Discussion
Fig. 1. Relationship between condition (abscissa) and R-R interval (ordinate). Each point represents averaged responses of patients who received
saline (control; F, n ⫽ 10) or edrophonium (䡺, n ⫽ 15). * t, change in R-R
interval that was significantly different from baseline (P ⬍ 0.01) or from
matched saline injection (P ⬍ 0.01), respectively. Bars indicate S.E.M.
The main finding of this study is that clinically relevant
doses of edrophonium block cardiovascular autonomic drive
in humans, as evidenced by the significant decrease it produces in HFP of the RRI, and HFP and LFP of SBP. The
observations are at odds with the widely held view that
anticholinesterase drugs simply augment cardiac autonomic
drive (Cronnelly et al., 1982). However, the findings from the
present study are in accordance with results obtained from
previous animal studies which demonstrated that edrophonium blocks autonomic ganglionic cholinergic transmission
and which predicted such a diminution of cardiovascular
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In the EDRO and CONT groups, the distribution of males/
females (8:7, 5:5, respectively) and ages (47.3 ⫾ 10.7, 43.7 ⫾
16.2, respectively) were similar.
R-R Intervals. Baseline RRI of patients in the CONT
(936 ⫾ 36.0 ms; 65.3 ⫾ 2.7 beats 䡠 min⫺1) and EDRO (897 ⫾
23.9 ms; 66.8 ⫾ 1.9 beats 䡠 min⫺1) groups were similar. With
the patients who received saline (CONT), RRI did not change
significantly during the study. In contrast, with the patients
who received edrophonium, RRI increased with increasing
doses of edrophonium and a plateau was reached after the
fifth dose of edrophonium. The maximum increase, to 1072 ⫾
30.4 ms (P ⬍ 0.01), occurred after the last dose of edrophonium (cumulative dose of 1.0 mg 䡠 kg⫺1, condition 7; Fig. 1).
Power analysis of the RRI at the high frequency band
(HFP, 0.15– 0.50 Hz) in patients receiving anticholinesterase
demonstrated significant increases following the fourth (cumulative dose of 0.2 mg 䡠 kg⫺1, condition 5) and fifth doses
(maximal increase 111.0 ⫾ 58.2% baseline, P ⬍ 0.05, cumulative dose 0.4 mg.kg⫺1, condition 6, Fig. 2). However, a
sharp decrease to ⫺49.5 ⫾ 35.5% baseline, P ⬍ 0.01, occurred
following the last dose (1.0 mg 䡠 kg⫺1, condition 7). In contrast, the HFP of the CONT group demonstrated no significant changes during the study.
Systemic Arterial Blood Pressure. Baseline SBP and
DBP of patients were similar in the two groups, CONT
(113.5 ⫾ 18.9 mm Hg, 60.4 ⫾ 13.3 mm Hg, respectively) and
EDRO (109.9 ⫾ 17.2 mm Hg, 61.2 ⫾ 11.8 mm Hg, respectively). Neither edrophonium nor saline infusion had a significant effect on SBP and DBP (Fig. 3). Spectral analysis of
SBP, however, demonstrated significant differences between
the two groups. Spectral powers at low frequency tended to
increase, although not significantly, after the third to fifth
doses of edrophonium, followed by a precipitous decrease
after the final dose (1.0 mg 䡠 kg⫺1, condition 7, ⫺46.3 ⫾ 10.9%
baseline, P ⬍ 0.01, Fig. 4). This decrease was not observed in
the CONT group (Fig. 4).
Spectral powers at high frequency decreased with edrophonium in a dose-dependent manner following the fourth (0.2
mg 䡠 kg⫺1, condition 5; P ⬍ 0.01) to sixth doses (1.0 mg 䡠 kg⫺1,
Edrophonium and the Autonomic Nervous System
Fig. 5. Relationship between condition (abscissa) and high frequency
power of systolic blood pressure (HFP, ordinate) expressed as percentage
change from baseline value. Each histogram represents the average
response from patients who received saline (control, n ⫽ 10, black) or
edrophonium (n ⫽ 15, white). ⴱ, change in power that was significantly
different from control (P ⬍ 0.05).
autonomic output in humans (Backman et al., 1997; Stein et
al., 1998).
The evidence for a ganglion-blocking effect of edrophonium
was obtained from studies in the rat sympathetic superior
cervical ganglion, where clinically relevant doses of edrophonium [10 –500 ␮M, ED50 163 ␮M; clinical peak serum concentration 50 – 60 ␮M with bolus dose of 1.0 mg 䡠 kg⫺1 edrophonium (Stein et al., 1998; Wachtel, 1990)] decreased the
compound action potential amplitude recorded from the postganglionic axons in the internal carotid nerve in response to
electrical stimulation of preganglionic axons in the cervical
sympathetic trunk (Stein et al., 1998). Block of the synaptic
transmission was shown to occur postsynaptically, as edrophonium inhibited postganglionic cell firing in response to
exogenously administered ACh (Stein et al., 1998). It is relevant that in other models of cholinergic transmission,
mouse tumor cells (Wachtel, 1990), and Xenopus laevis oocytes (Yost and Maestrone, 1994) with expressed nicotinic
receptors, clinically relevant doses of edrophonium (ED50 3.8
and 82 ␮M, respectively) decrease ACh-activated channel
open time (Wachtel, 1990) and DMPP (a selective nicotinic
agonist)-activated currents (Yost and Maestrone, 1994), indicating a postsynaptic blocking effect. Edrophonium may
also block transmission in the peripheral autonomic pathway
by blocking release of ACh from preganglionic terminals in
the autonomic ganglia (Stein et al., 1998) and by blocking
inhibitory cardiac muscarinic (M2) receptors (Endou et al.,
1997). The inhibitory effect of edrophonium on autonomic
outflow, regardless of the site of action, is reminiscent of the
model of autonomic failure achieved with blockage of cholinergic ganglionic transmission (Jordan et al., 1998; Shannon
et al., 1998). Although the findings from the present study
offer no further insight into the mechanisms by which edrophonium blocks autonomic cardiovascular drive, they are the
first demonstration that such blockage occurs when this drug
is administered to patients and are entirely consistent with
the results from previous animal and cellular studies cited
above.
The decrease edrophonium produces in HFP of the RRI,
and HFP and LFP of SBP, as shown in the present study,
may be accounted for by the inhibitory effect this anticholinesterase drug has on transmission in the peripheral autonomic nervous system (see above). However, at cumulative
doses less than 1.0 mg 䡠 kg⫺1, augmentation of the HFP of the
RRI was apparent (Fig. 2). Presumably, this reflects the
enhancement of cholinergic transmission in the parasympathetic autonomic ganglia, or at the SA node, as a consequence
of the inhibition of cholinesterase and subsequent accumulation of ACh at these sites. This is reminiscent of observations
in animal studies in which lower doses of edrophonium augment the bradycardia evoked by electrical stimulation of the
vagus nerve, whereas higher doses block the bradycardia
(Backman et al., 1997). It may be anticipated that cholinergic
transmission in the peripheral cardiac parasympathetic
pathway is particularly sensitive to the facilitatory effect of
cholinesterase inhibition because of an additive effect at both
the ganglion and the SA node. Moreover, blockage of cholinesterase activity may affect the ACh released spontaneously from intrinsic cardiac parasympathetic postganglionic
neurons in addition to that released as a consequence of
ongoing cardiac parasympathetic drive (Backman et al.,
1993a, 1996a, 1997). In contrast, the peripheral sympathetic
pathway has only the one cholinergic synapse, at the autonomic ganglion, and this may account for the lack of a clear
facilitatory effect of edrophonium on the HFP and LFP of
SBP (Figs. 4 and 5), which are indices of sympathetic outflow.
An additional consideration may be that as a consequence of
inhibition of cholinesterase, overflow of ACh from the synaptic cleft may activate extrasynaptic postganglionic inhibitory
M2 receptors in the sympathetic ganglion, which would block
ganglionic cholinergic transmission (Bachoo and Polosa,
1992). Finally, data from animal studies indicate that the
dose-response relationships for inhibition of cholinesterase
activity and for block of cholinergic ganglionic transmission
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Fig. 4. Relationship between condition (abscissa) and low frequency
power of systolic blood pressure (LFP, ordinate) expressed as percentage
change from baseline value. Each histogram represents the average
response from patients who received saline (control, n ⫽ 10, black) or
edrophonium (n ⫽ 15, white). ⴱ, change in power that was significantly
different from control (P ⬍ 0.01).
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and end-tidal CO2 were kept constant during the study period.
The diminution of cardiovascular autonomic drive by edrophonium may explain the clinical observation of the modest
cardiac parasympathomimetic side effect of this drug (Cronnelly et al., 1982). In addition, it may account for the observation that less muscarinic antagonist is required to blunt
the bradycardia produced by edrophonium than is required
for neostigmine (Fogdall and Miller, 1973; Cronnelly et al.,
1982). Although neostigmine has been shown to block cholinergic activation of nicotinic receptors expressed in mouse
tumor cells (Wachtel, 1990) and in X. laevis oocytes (Yost and
Maestrone, 1994), and to block cholinergic responses in the
rat sympathetic superior cervical ganglion (S. B. Backman,
R. D. Stein, and C. Polosa, unpublished observations), these
effects are observed at concentrations (ED50 4.6, 46, and 82.0
␮M, respectively) much higher than those achieved clinically
[peak serum concentration 0.9 ␮M (Wachtel, 1990)]. In fact,
unlike edrophonium, neostigmine appears to directly activate cholinergic muscarinic receptors in the peripheral cardiac parasympathetic pathway (Backman et al., 1993a,
1996a; Endou et al., 1997), and this may contribute to the
enhanced parasympathomimetic action of neostigmine compared with edrophonium. Such direct cholinergic activation
may also account for the bradycardia neostigmine produces
in patients who have undergone cardiac transplantation
(Backman et al., 1993b, 1996b,c). Consideration should be
given to the possibility that the direct interaction of anticholinesterase drugs with cholinergic receptors may mediate
other effects such as analgesia, which are assumed to be
produced as the consequence of cholinesterase inhibition
(Eisenach, 1999).
In summary, data from the present study demonstrate that
clinically relevant doses of edrophonium block cardiovascular
autonomic drive in humans, as evidenced by the significant
decrease it produces in HFP of the RRI, and HFP and LFP of
SBP. These observations may account for the modest autonomic side effects of edrophonium.
Acknowledgments
We are grateful for the help provided by Dr. L. Quintin who read
an earlier version of the manuscript.
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overlap (Backman et al., 1996a, 1997), such that facilitation
in autonomic outflow may be masked (Stein et al., 1998).
Edrophonium was administered as bolus doses and steady
state plasma concentrations were not achieved. However,
since the objective of this study was to assess the effect of
clinically relevant doses of edrophonium on cardiovascular
autonomic outflow, a dose-response study best mimics the
clinical situation where the drug is administered as a bolus.
Yet, the data from the present study do not reveal the dose at
which edrophonium reduces cardiac autonomic outflow. In
all likelihood, with the experimental paradigm used, the
dose-response data provided in Figs. 2, 4, and 5 overestimate
this dose. After the initial injection of edrophonium, each
subsequent injection was separated by an interval of ⬃5 min.
Given a t1/2␣ of approximately 7 min (Morris et al., 1981), it
is anticipated that the final plasma concentration of edrophonium achieved with the cumulative dose of 1 mg 䡠 kg⫺1 is
considerably less than that which would be produced by the
single bolus dose of 1 mg 䡠 kg⫺1 that is used in clinical practice. Incremental doses of edrophonium, as used in the
present study, were necessary to be able to demonstrate any
dose-response changes in cardiovascular autonomic outflow.
Had edrophonium been administered as a single bolus dose of
1 mg 䡠 kg⫺1, responses could only have been compared with
baseline values, and changes in autonomic parameters may
have been missed. Of course, there are issues of patient
safety that have to be considered; although we have administered edrophonium in incrementally increasing bolus doses
in previous clinical studies without adverse effect (Backman
et al., 1997), this may not be the case with a larger bolus dose.
Spectral components of autonomic target organ responses
may be influenced by a variety of factors including gender,
age (Bigger et al., 1995; Jensen-Urstad et al., 1998), and
choice of volatile anesthetic agent (Galletly et al., 1994; Widmark et al., 1998). The influences of these factors were balanced in the present study by using the same anesthetic
agent for each patient in each group and by the equal distribution of age and gender between the groups. Possibly, variations in power observed over time in the controls and in
those who received edrophonium may have been additionally
influenced by a time-dependent effect of the anesthetic agent
(Galletly et al., 1994; Widmark et al., 1998). Graphical representation of the power spectral data as a percentage
change from baseline helps to compare the magnitude of the
changes for each individual studied as well as between the
groups.
There is ample evidence to suggest that HFP of heart rate
variability may be used as an index of parasympathetic outflow at the sinoatrial node (Task Force of the European
Society of Cardiology and the North American Society of
Pacing and Electrophysiology, 1996). With regard to LFP of
systolic blood pressure, there is good evidence to suggest that
it reflects sympathetic outflow, which may control vasomotor
tone (Novak et al., 1997a; Pagani et al., 1996). HFP of systolic
blood pressure appears to reflect sympathetic outflow, although this has been shown to be strongly influenced by
mechanical factors such as respiratory rate and tidal volume
on blood pressure (Novak et al., 1997a; Madwed et al., 1989;
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