Br. J. Anaesth. (1988), 60, 74-80
EFFECTS OF ATRACURIUM, VECURONIUM OR
PANCURONIUM PRETREATMENT ON LIGNOCAINE
SEIZURE THRESHOLDS IN CATS
W. L. LANIER, F. W. SHARBROUGH AND J. D. MICHENFELDER
WILLIAM L. LANIER, M.D., JOHN D. MICHENFELDER, M.D.
(Department of Anesthesiology); FRANK W. SHARBROUGH,
M.D. (Department of Neurology); Mayo Clinic and Mayo
Medical School, Rochester, Minnesota 55905, U.S.A. Accepted for Publication: August 26, 1987.
Correspondence to W.L.L.
SUMMARY
Among the non-depolarizing neuromuscular
blocking drugs, atracurium appears to be unique
in its ability to produce cerebral stimulation in
lightly anaesthetized animals. This effect is
attributed to the atracurium metabolite, laudanosine. The following studies were performed
to determine if pretreatments with the nondepolarizing neuromuscular blockers pancuronium, atracurium or vecuronium would differ in
their effects on the seizure threshold of lignocaine. Adult mongrel cats were anaesthetized
with 1.0 MAC halothane in oxygen and
nitrogen. Ventilation, blood-gas tensions, acidbase balance and temperature were controlled.
Cats received pancuronium 0.2 mg kg'1 i.v. (n =
7), atracurium 1.0 mg kg'1 i.v. (n — 7) or vecuronium 0.2 mg kg'1 i.v. (n = 7). Ten minutes
after the administration of the myoneural blocker,
all cats received lignocaine 4 mg kg'1 min'1 i.v.
until the onset of EEG evidence of generalized
seizure activity. At seizure onset, there were no
statistically significant differences among the
cumulative lignocaine doses or the serum lignocaine concentrations in cats pretreated with
pancuronium. atracurium or vecuronium.
unknown if the cerebral stimulating effects of
atracurium, as demonstrated by the EEG, correlate with alterations in seizure thresholds of any
origin.
Generalized seizure activity is a well appreciated complication of excessive local anaesthetic administration, including the local anaesthetic lignocaine [10]. Furthermore, neuromuscular blocking drugs may be used in many
patients in whom lignocaine is used for the
induction of a regional anaesthetic technique, as
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Neuromuscular blocking drugs are large, charged
molecules which do not readily cross the bloodbrain barrier [1—3]; however, cerebral effects of
i.v. administered depolarizing and non-depolarizing myoneural blockers have been reported. In general, when neuromuscular blocking
drugs are given to lightly anaesthetized subjects,
depolarizing drugs tend to produce cerebral
stimulation, while non-depolarizing drugs tend to
depress cerebral function. This depression of
cerebral function by non-depolarizing neuromuscular blockers has been manifested as EEG
synchronization following i.v. gallamine [4] and as
a reduction in the minimum alveolar anaesthetic
concentration (MAC) in man following i.v. pancuronium [5]. Although the cerebral effects of
vecuronium are not as thoroughly denned as those
of many of the other commonly used drugs,
vecuronium would be expected to affect cerebral
function in a manner similar to pancuronium.
Both myoneural blockers produce a non-depolarizing blockade, while neither has cerebralactive metabolites or an effect on circulating
histamine, all of which are proposed mechanisms
whereby myoneural blocking drugs may affect
cerebral function [6].
In contrast to the effects of other nondepolarizing neuromuscular blocking drugs,
atracurium, when given in large i.v. doses
(l.Omgkg" 1 ) to lightly anaesthetized dogs, produces EEG arousal [6]. This arousal response has
been attributed to the atracurium metabolite
laudanosine [6], a known cerebral stimulant
[7] and seizure-producing agent [8, 9]. It is
RELAXANTS AND LIGNOCAINE SEIZURES
MATERIALS AND METHODS
Formal approval for these studies was obtained
from the Institutional Animal Care and Use
Committee. Subjects were 21 unmedicated mongrel cats weighing 3.7 + 0.2 kg (mean + SEM).
Anaesthesia was induced with 3 % inspired halothane in oxygen, and the trachea was intubated
without the use of a neuromuscular blocking
drug. Anaesthesia was maintained with 1.5%
inspired halothane in 30-40 % oxygen and nitrogen during the preparatory period. Ventilation
was controlled with a Harvard ventilator and
adjusted along with the inspired oxygen concentration to maintain control values of blood-gas
tensions (Instrumentation Laboratory, Inc. electrodes at 37 °C) at PaOa 20.3 + 0.3 kPa (mean
±SEM) and PaCOi 4.7 + 0.0 kPa. Cannulae were
placed in a femoral artery for continuous pressure
measurements and blood sampling, and in femoral
and forelimb veins for fluid and drug administration. During the preparatory period, cats were
given i.v. infusions of lactated Ringer's solution
10±3mlkg~ 1 (two cats in each group) or 5%
dextrose in lactated Ringer's solution 7 + 1 ml kg"1
(five cats in each group). Sodium bicarbonate
was given i.v., if needed, to maintain the buffer
base (BB + ) around 40 mmol litre"1. Since the
infusions of lignocaine decreased mean arterial
pressure (MAP) during the study period, phenylephrine 0.04 mg ml"1 i.v. was used in 20 of 21 cats
to maintain MAP ^ 60 mm Hg. Rectal temperature was measured with a thermistor and maintained near 38 °C with heating lamps and pads.
Inspired and end-expired halothane concentrations were measured with an infra-red analyser
calibrated for halothane (Beckman Medical Gas
Analyser LB-2). Heart rate (HR) was determined
from a lead II ECG which was continuously
recorded using skin needle electrodes. A six-lead,
three-channel bi-frontal, bi-parietal, and bi-occipital EEG was recorded from gold electrodes
glued to the calvarium. A 10-kfi "dummy"
circuit was also recorded to detect electrical
artefacts. Electroencephalographic filter settings
were such that the linear frequency response
range was between 1 and 70 Hz.
Fifteen minutes before the definitive study
period, the halothane concentration was decreased
to 0.83 + 0.00 % end-expired (1.0 MAC). The cats
were then divided into three groups and, over a 1min period, given i.v. infusions of atracurium
1.0 mg kg"1 (w = 7), pancuronium 0.2 mg kg"1 (n
= 7), or vecuronium 0.2 mg kg"1 (« = 7). These
doses were chosen to represent twice the intubating dose of the various drugs in man. Ten
minutes after the completion of the administration, lignocaine hydrochloride 4 mg kg"1 min"1
in 0.9% saline solution 3.6 ml min"1 was infused
to a forelimb vein at a Y-piece to which an
additional "flush" of 0.9% saline solution was
infused. The flush solution was begun at a rate of
3.6 ml min"1 before the lignocaine infusion and
continued for 30 s after the cessation of the
lignocaine infusion. Assuming the pharmacokinetics of atracurium and its metabolite laudanosine are similar in cats, dogs and man [13, 14],
this sequence of neuromuscular blocker followed
in 10 min by lignocaine would produce near
maximum increases in brain laudanosine concentration at the time of seizure onset [6].
EEG activity was recorded before and during
the infusion of the myoneural blocker, and at 2.5,
5.0 and 7.5 min after the infusion; and continuously, beginning 1 min before the infusion of
lignocaine until the end of the study.
Since all study subjects were paralysed, it was
necessary to define seizure onset using EEG
criteria. The infusion of lignocaine was discontinued with the onset of seizure activity, which
was denned as the appearance of electrical attenuation in all three EEG leads > 1.0 s followed by
polyspike or polyspike and wave activity (fig. 1).
These criteria were determined by observing the
most frequent seizure pattern that was readily
reproducible and easily recognized prospectively
in real time as determined by pilot studies. The
EEG criteria used to define the onset of seizure
activity were similar to those used in previous
studies [12, 15, 16].
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an i.v. general anaesthetic supplement, or as an
antiarrhythmic agent. Previous studies have demonstrated that the seizure threshold of lignocaine
may be altered by gallamine [11] and suxamethonium [12]. The effects of pancuronium,
vecuronium and atracurium on the lignocaine
seizure threshold have not been reported.
The following study was designed to test the
hypothesis that, since EEG evidence of cerebral
arousal following i.v. atracurium differs uniquely
from the cerebral response to other non-depolarizing myoneural blocking drugs, atracurium
will also differ in its effect on lignocaine-seizure
thresholds when compared with pancuronium
and vecuronium.
75
76
BRITISH JOURNAL OF ANAESTHESIA
100 ^V o/*»V>-'vv^>'MNWWN*VyvYrfA^^
1s
An attempt was made to compare seizure
thresholds in treated cats with those in unparalysed, placebo-treated cats; however, this was
not technically possible. During the infusion of
lignocaine in unparalysed cats in pilot studies,
muscle twitching often preceeded EEG evidence
of seizures. This phenomenon has been described
previously in man [17]. The lignocaine-induced
muscle twitching, along with ocular and lingual
movements, produced EEG artefacts which made
accurate assessment of the onset of seizure activity
impossible using electrodes glued to the calvarium.
Arterial blood samples that would be used for
blood-gas analysis and serum lignocaine determinations were drawn at the the time of the onset
of seizure activity in all cats. Samples for the
measurement of serum lignocaine concentration
were frozen at — 70 °C until analysed using an
enzyme immunoassay technique (EMIT: Syva
Company, Palo Alto) [18]. All samples were
serially diluted until dilutions were obtained
which provided EMIT measurements within the
0-12-ug ml"1 calibration standards. This methodology has a reported coefficient of variation of
3.4%, and results from this technique correlate
well with values obtained by gas-liquid chromatography (r = 0.976) [18]. At the completion of
study, cats were killed with i.v. potassium chloride, and the isoelectric EEG was evaluated for
artefacts. Retrospective EEG analysis was performed by a blinded observer (F.W.S.).
Comparison of data was made using paired t
tests and Bonferroni's correction of unpaired t
tests. P < 0.05 was considered significant when
comparing paired data, and, because multiple
comparisons were made, a Bonferroni's corrected
P value of 0.05/3 = < 0.016 was considered
significant when comparing unpaired data. The
correlation between the duration of the lignocaine
infusion and serum lignocaine concentration was
assessed by determining the Pearson productmoment correlation coefficient. Data are presented as the mean + SEM.
RESULTS
Values for physiological variables during the
control period and at the onset of seizures are
listed in table I. There were no significant
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FIG. 1. The pre-lignocaine control EEG (A) was typical of an "anaesthetic" pattern [6] in all cats, both
before and after administration of the neuromuscular blocking drug. The predominant EEG rhythm was
of 4-6 Hz, 150-300 uV rhythmic theta activity, while individual cats had superimposed rhythms of
10-14 Hz, 60-120 uV rhythmic fast activity, intermittent high voltage delta activity (2-4 Hz, 200-400
UV), or both. Consistent with previous reports [30], lignocaine infusion initially produced an increase
in EEG amplitude and a decrease in frequency, typical of increasing anaesthetic depth, until evidence
of seizure activity was noted. The seizure "marker" used to determine seizure threshold in the current
study was denned as the complex of electrical attentuation of 35 1.0 s followed by polyspike or polyspike
and wave activity (B and c). EEG attenuation between periods of polyspike activity frequently resembled
the isoelectric or "flat" EEG (B), as has been previously described [12, 17]. However, in other cats
during the periods of attenuation there was low amplitude activity (c) which was clearly distinguishable
from both electrical artefact and polyspike and wave activity. All of the above recordings are from
biparietal electrodes.
RELAXANTS AND LIGNOCAINE SEIZURES
77
TABLE I. Systemic variables (mean ± SEM) during the control period and at seizure onset, n = 7 for all groups. * Significantly different from control value (P < 0.05). There were no significant differences among study groups during either measurement period
Seizure onset
Control
Vecuronium Pancuronium
Atracurium
Vecuronium Pancuronium
3.6±0.2
20.4 + 0.4
4.5 ±0
7.38 ±0.01
42 + 0
27±2
37.9 ±0.1
121+5
186±14
0.83 ±0.00
—
3.5 ±0.3
20.3 + 0.5
4.7±0.1
7.37 ±0.02
41 + 1
28±1
38.0±0.1
129±8
174±17
0.83 ±0.00
—
4.0 + 0.4
20.0±0.5
4.7±0.0
7.37 + 0.01
20.5 + 0.5
4.4±0.3
7.36 + 0.02
41 ±1
27±1
40±0*
— •
37.9 + 0.1
123 ±6
196±14
0.83±0.01
—
37.9 + 0.1
103 ±7
129 ±7*
0.84 ±0.01
42.1 ±4.8
21.6±0.8
4.7 ±0.1
7.35 + 0.02
40±l
—
37.8 ±0.0*
91 ±7*
138±10
0.84 ±0.00
47.6±5.2
20.8 ±0.9
4.4±0.3
7.36 + 0.02
40+1
—
37.9 ±0.1
89 ±7*
123 ±10*
0.84±0.01
68.2 ±11.6
—
235±21
284 ±14
258 ±20
—
15.7± 1.5
19.0±1.0
17.2±1.4
—
—
—
differences among groups at either measurement
period. Infusion of the various neuromuscular
blocking drugs during 1.0 MAC halothane anaesthesia had no apparent independent effect on the
EEC
At seizure onset, several variables had changed
from control values by quantities that were
physiologically acceptable but statistically significant. Mean arterial pressure and HR tended to
decrease in all groups; however, the changes in
MAP were significant only in pancuronium- and
vecuronium-treated cats, while the decreases in
HR were significantly different only in atracurium- and pancuronium-treated cats. A decrease in BB + of 2 mmol litre"1 in atracuriumtreated cats and a mean decrease in temperature of
0.2 °C in vecuronium-treated cats were both
statistically significant.
Serum lignocaine concentrations obtained at
the onset of seizure activity did not significantly
differ among groups of cats pretreated with
atracurium 42.1 ±4.8 ugml"1, pancuronium 68.2
+ 11.6 ngml"1 or vecuronium 47.6 + 5.2 ugml"1.
The mean cumulative lignocaine dose at the onset
of seizure activity for all cats was 17.3 + 0.8 mg kg"1
and did not differ significantly among the
groups (table I). There were no significant
differences among the groups regarding the
durations of lignocaine infusions (table I), and
there was no meaningful correlation between the
durations of the infusions of lignocaine and
measured serum lignocaine concentrations (r
140
•- 120 •
o
100-
o
8 0 --
• o
60 •
o
o
c
g>
E
•o
•
o
•
40
•
20
S
50
100 150 200 250 300 350 400
Infusion duration (s)
FIG. 2. The relationship between the durations of the lignocaine infusion and serum lignocaine concentrations. There
was no meaningful correlation between the durations of lignocaine infusions—and thus cumulative lignocaine doses—v.
the measured serum lignocaine concentrations (r = —0.03;
P > 0.8). • = Atracurium; O = pancuronium; • = vecuronium.
= - 0 . 0 3 , P> 0.8) (fig. 2). Mean phenylephrine
dose for all cats was 0.16 + 0.04 mg and did not
significantly differ among groups.
DISCUSSION
Neuromuscular blocking drugs are large charged
molecules that are reported either not to cross the
blood-brain barrier [2, 3] or to cross the blood-
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Wt (kg)
Pa o (kPa)
Pa
(kPa)
PH
BB+ (mmol litre"1)
Haematocrit (%)
Rectal temp. (°C)
MAP (mm Hg)
HR (beat min"1)
Expired halothane (%)
Serum lignocaine (pg ml"1)
Duration of lignocaine
infusion (s)
Cumulative lignocaine dose
(mg kg"1)
Atracurium
78
produced complete non-depolarizing neuromuscular blockade, and their effects on cerebral
function, as predicted by the afferentation theory,
should not differ.
Contrary to the cerebral effects of non-depolarizing drugs predicted by the afferentation
theory, atracurium in large doses (l.Omgkg"1)
produced EEG arousal in dogs receiving subMAC concentrations of halothane [6]. This
arousal response has been attributed to the
metabolite laudanosine, a known cerebral stimulant [7] and seizure-producing agent [8, 9].
Although the production of laudanosine by clinical doses of atracurium is much less than the
laudanosine doses previously reported to produce
seizures in animals [6], we hypothesized that the
atracurium-induced production of laudanosine
might be sufficient to alter the lignocaine seizure
threshold. The current data do not support that
hypothesis.
The release of histamine induced by certain
myoneural blockers may also affect cerebral
function and influence the amount of lignocaine
required to induce seizures. Histamine is a direct
cerebral vasodilator producing increases in cerebral blood flow [22], and there is some evidence
that histamine has a stimulating effect on cerebral
electrical activity [23]. In addition, histamine can
produce increases in PaCO2 secondary to an
increase in pulmonary deadspace [24], and increases in PaCO2can in turn produce increases in
cerebral blood flow [25] and cerebral electrical
excitation [26]. Atracurium is reported to release
histamine in approximately one-third the amount
noted following the administration of tubocurarine [27], while pancuronium and vecuronium
do not readily release histamine [28, 29]. Despite
histamine release after atracurium, we recently
demonstrated no significant alterations in CBF in
dogs given massive doses of either atracurium or
pancuronium during 1.0 MAC halothane anaesthesia [6]. There were no significant alterations in
PaCOj during the present study, so we can discount
histamine-induced carbon dioxide-mediated cerebral effects following atracurium; however, our
study design would not eliminate any direct
histamine-induced effects on either CBF or
cerebral electrical activity.
In the present study, we elected to administer
lignocaine as a continuous infusion until the onset
of seizures, as has previously been reported [11,
17, 30]. Since lignocaine acts as a general
anaesthetic at subconvulsant doses [31], this
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brain barrier in limited amounts [1]. In spite of
these considerations, alterations in cerebral function following the i.v. administration of neuromuscular blocking drugs are well documented.
Theoretically, the induced changes in cerebral
function may alter the lignocaine seizure threshold
either by modifying cerebral function in a manner
that is additive with the effects of lignocaine, or by
altering cerebral blood flow so that the distribution of lignocaine is changed. These alterations in cerebral function can be attributed to
four extracerebral mechanisms: changes in afferent muscle activity induced by the myoneural
blocking drug; release of cerebral-active metabolites; histamine release; and alterations in Paco .
The afferentation theory of cerebral arousal
predicts that agents or manoeuvres that actively or
passively cause muscle stretch or contraction or
stimulate afferent muscle spindles will stimulate
the brain [19-21]. Agents that inhibit muscle
stretch or contraction may decrease cerebral
activity [4, 5]. Induction of depolarizing neuromuscular blockade by suxamethonium, decamethonium and carbolonium have been shown to
induce EEG arousal [19, 20]. With suxamethonium, this EEG arousal is accompanied by
increases in cerebral blood flow [21]. In contrast,
gallamine-induced
non-depolarizing neuromuscular blockade produces electrocortical synchronization in cats [4], and pancuronium exerts
an anaesthesia augmenting effect in halothaneanaesthetized man [5].
The afferentation theory probably best explains
previous reports of the influence of gallamine and
suxamethonium on lignocaine seizures. Gallamine
has no known effect on cerebral blood flow, yet
gallamine-induced non-depolarizing neuromuscular blockade increases the lignocaine seizure
threshold in monkeys [11]. We must assume that
the gallamine-induced alterations in seizure threshold are the result of some functional interaction
between lignocaine and gallamine-induced cerebral electrical depression [4]. In contrast to the
increase in lignocaine seizure threshold produced
by gallamine, suxamethonium-induced depolarizing neuromuscular blockade decreases the
lignocaine seizure threshold in cats [12]. It is
unclear whether this effect is the result of a
functional interaction between suxamethonium
and lignocaine, or whether the seizure threshold
decrease was the result of an increase in cerebral
blood flow following suxamethonium [21]. All
three blocking drugs used in the current study
BRITISH JOURNAL OF ANAESTHESIA
RELAXANTS AND LIGNOCAINE SEIZURES
In summary, we could find no difference in
lignocaine seizure thresholds among groups of
halothane-anaesthetized cats pretreated with atracurium, vecuronium or pancuronium. Assuming
our data in cats are transferable to man, we
conclude that intubating doses of the three drugs
studied can be interchangeably administered in
patients also receiving lignocaine without increasing the relative risk of lignocaine-induced
convulsions.
ACKNOWLEDGEMENTS
This research was supported in part by Research Grant NS07507 from the National Institutes of Health, United States
Public Health Service.
The authors would like to thank Thomas P. Moyer PH.D.,
and William J. Gallagher for their technical assistance in
performing these studies.
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lignocaine seizure threshold after pretreatment
with atracurium v. vecuronium and pancuronium
may be attributable to a number of factors. First,
the production of laudanosine by the doses of
atracurium used may have been insufficient to
produce a change in seizure threshold [6]. Second,
histamine release following atracurium may have
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