Full text of DOI:10.1007/BF03018917

REPORTS OF INVESTIGATION
225
Intubating conditions
and blockade after
mivacurium, rocuronium
and their combination in
young and elderly adults
C. Motamed MD,
F. Donati PhD MD FRCPC
Purpose: Mivacurium-rocuronium combinations have been demonstrated to be more potent than either drug
given alone. Combinations were compared with mivacurium and rocuronium, with respect to onset, intubating
conditions, and duration of action in young and elderly adults.
Methods: Fentanyl-propofol-N2O-isoflurane anesthesia was given to ASA I and II adults aged 18-65 yr (45
patients) and over 66 yr (45 patients). In this blinded randomized study, we compared accelerographic adductor
pollicis response and visual assessment of response to facial nerve stimulation after 0.25 mg·kg–1 mivacurium, 0.6
mg·kg–1 rocuronium, and a combination of 0.08 mg·kg–1 mivacurium plus 0.2 mg·kg–1 rocuronium. Intubating con-
ditions at 2.5 min were rated as excellent, good, fair or poor.
Results: Onset times were similar for all drugs regimens and for both age groups (204-276 sec at the thumb;
142-196 sec at the eye) (P < 0.05 between muscles). Intubating conditions were similar in all groups, and rated
good or excellent, except in two subjects. In young patients duration to 25% recovery was longer (P < 0.05) for
rocuronium (mean ± SD) (39 ± 11 min) than for either mivacurium (23 ± 6 min), or the combination (27 ± 7
min). Duration was prolonged in the elderly for rocuronium (54 ± 17 min), and the combination ( 35 ± 11 min),
but not for mivacurium (24 ± 6 min).
Conclusions: Mivacurium-rocuronium combinations yield onset times and intubating conditions similar to either
parent agent with only two thirds as much total drug. Duration for such a mixture is similar to that of mivacurium
in young adults and slightly prolonged in the elderly.
Objectif : Le mélange de rocuronium et de mivacurium est plus puissant que l’un ou l’autre de ses composants
donné seul. On a comparé ce mélange au mivacurium et au rocuronium quant au délai d’installation, aux condi-
tions d’intubation et à la durée d’action chez des adultes jeunes et âgés.
Méthode : Une anesthésie au fentanyl, propofol, N2O et isoflurane a été administrée à 45 patients de 18 à 65
ans et à 45 sujets de plus de 65 ans. De façon randomisée et aveugle, on a comparé la réponse accélérographique
de l’adducteur du pouce et l’évaluation visuelle de la réponse à la stimulation du nerf facial après 0,25 mg·kg–1 de
mivacurium, 0,6 mg·kg–1 de rocuronium ou un mélange de 0,08 mg·kg–1 de mivacurium et 0,2 mg·kg–1 de
rocuronium. Les conditions d’intubation à 2,5 min ont été classifiées comme excellentes, bonnes, passables ou
inadéquates.
Résultats : Les délais d’installation étaient semblables pour tous les myorelaxants et pour les deux groupes d’âge
(204-276 sec au pouce, 142-196 sec près de l’œil (P < 0,05 entre les muscles). Les conditions d’intubation
étaient semblables dans tous les groupes et cotées bonnes ou excellentes, excepté chez deux sujets. Chez les
jeunes, la durée d’action jusqu’à 25 % de récupération était plus longue (P < 0,05) pour le rocuronium (moyenne
± ET) (39 ± 11 min) que pour le mivacurium (23 ± 6 min), ou le mélange (27 ± 7 min). Chez les sujets âgés,
la durée était prolongée pour le rocuronium (54 ± 17 min) et le mélange ( 35 ± 11 min), mais pas pour le miva-
curium (24 ± 6 min).
Conclusion : Le mélange de mivacurium et de rocuronium produit des délais d’installation et des conditions d’in-
tubation semblables à ceux de l’un ou l’autre myorelaxant avec une quantité totale réduite au deux tiers. La durée
du mélange est semblable à celle du mivacurium chez les jeunes, mais un peu plus longue chez les sujets âgés.
From the Department of Anaesthesia, Hôtel-Dieu, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada.
Address correspondence to: François Donati PhD MD FRCPC, Département d’anesthésie, Centre Hospitalier de l’Université de Montréal,
Hôtel- Dieu, 3840, rue Saint Urbain, Montréal, Québec, H2W 1T8 Canada. Phone: 514-843-2611 X 4636; Fax: 514-543-2690;
E-mail: donatif@medclin.umontreal.ca
This work was presented in part at the European Society of Anaesthesiologists meeting in Barcelona, Spain, April 1998.
Accepted for publication November 14, 1999
CAN J ANESTH 2000 / 47: 3 / pp 225–231

226
CANADIAN JOURNAL OF ANESTHESIA
IXTURES of two nondepolarizing
blocking drugs are additive when the
effect is the sum of equipotent doses of
either drug given alone, for example,
those aged 66-90 yr (elderly group). Patients with a
history of renal, hepatic, or neuromuscular disease
were excluded, as those with diabetes or an anticipat-
ed difficult airway. Premedication was at the discretion
of the anesthesiologist.
M
the combination of d-tubocurarine with gallamine,1
pancuronium and gallamine,1 pipecuronium and
vecuronium,2 pancuronium and vecuronium,3 rocuro-
nium with other steroidal muscle relaxants,4 and
atracurium with cistracurium.5 When the effect of the
mixture is greater than the equipotent dose of either
drug, synergism is observed. This has been reported in
the case of pancuronium-metocurine,6 pancuronium
with d-tubocurarine,6 gallamine-metocurine,1 d-
tubocurarine-vecuronium,7 mivacurium with rocuro-
nium,8 and cistracurium with rocuronium,5, 9
mivacurium,9 or vecuronium.9
After the patient arrived in the operating room, an
intravenous line was inserted. Standard monitoring
was applied and consisted of ECG, pulse oximetry and
non-invasive arterial pressure. Neuromuscular func-
tion was measured at the adductor pollicis by a TOF-
GUARD accelerometer (Biometer International,
Odense Denmark). Two surface electrodes were
applied over the ulnar nerve at the wrist and a piezo-
electric device measuring acceleration was placed on
the corresponding thumb. Another set of two surface
electrodes was applied over the temporal branch of the
facial nerve and connected to the stimulator unit of
another TOF-GUARD accelerometer, without using
the probe. Anesthesia was induced with 1.5-3 µg·kg– 1
fentanyl and 1.5-3 mg·kg–1 propofol, titrated to loss of
consciousness and loss of eyelash reflex. Then, supra-
maximal train-of-four stimulation (2 Hz, 2 sec) was
applied every 15 sec to both the ulnar nerve at the
wrist (60 mA), and to the temporal branch of the
facial nerve lateral and posterior to the eye (30 mA).
The lungs were ventilated manually with oxygen 100%
via a face mask.
Patients in the young and elderly groups were fur-
ther randomized into three subgroups. They were
assigned to receive, in a random fashion, 0.25 mg·kg–1
mivacurium, 0.6 mg·kg–1 rocuronium, or a combina-
tion of 0.08 mg·kg–1 mivacurium, plus 0.2 mg·kg–1
rocuronium, iv over 10 sec, as soon as both stimulators
were functioning. Laryngoscopy and tracheal intuba-
tion were performed 2.5 min after injection of the neu-
romuscular blocking agent. Intubating conditions were
assessed by an observer who was unaware of which drug
or combination had been given. They were rated as
excellent, good, fair or poor (Table I). After intubation,
The main advantages of synergistic mixtures are the
decreased likelihood of side effects of either drug and
decreased overall cost, provided that equipotent doses
of both drugs have comparable price. For mivacuri-
um-rocuronium combinations, there could be an
additional advantage. Onset has been reported to be
as rapid as that of rocuronium and duration as short as
for mivacurium.7 In other words, the mixture keeps
the desirable features of each agent.7
However, it is difficult to extrapolate results from
an onset and duration study performed during steady-
state anesthesia to clinical practice. The adductor pol-
licis response depends on the stabilization time. Onset
is shorter if stimulation has been applied for 15-20
min, than for one minute,10,11 as is the case in clinical
practice. Furthermore, the response of the adductor
pollicis is a poor predictor of intubating conditions. In
this respect, visual inspection of the loss of response of
muscles surrounding the eye is a better guide.1 2 In
addition, onset and duration data might be different
in the elderly13,14 who constitute a growing part of
anesthetic practice.
Therefore, the aim of the study was to compare
intubating doses of mivacurium, rocuronium, and
their combinations on adductor pollicis response mea-
sured by accelerometry, on the response to facial nerve
stimulation observed visually, and on intubating con-
ditions, both in young and elderly adults.
the lungs were ventilated mechanically with N O 60%
2
in O2 and isoflurane 1.0-1.5 % (inspired). Ventilation
was adjusted to keep PETCO2 in the range 32-38
TABLE I Assessment of intubating conditions
Intubating conditions Laryngoscopy
Patients and methods
1= excellent
vocal cords open, no coughing, easy
laryngoscopy
The study was approved by the hospital Ethics
Committee and written informed consent was
obtained from each patient. Ninety patients of both
sexes scheduled for elective surgery requiring tracheal
intubation were enrolled into the study. They were
divided into two groups of 45 individuals each accord-
ing to age: patients aged 18-65 yr (young group), and
2= good
vocal cords moving, coughing with
diaphragm, fair laryngoscopy
vocal cords closing, clear coughing,
difficult laryngoscopy
3= poor
4= inadequate
vocal cords closed, severe coughing,
laryngoscopy impossible

Motamed & Donati: MIVACURIUM-ROCURONIUM COMBINATIONS
TABLE II Patient characteristics, (young group), (mean SD) TABLE IV Onset, duration and intubating conditions
227
Mivacurium Combination
Rocuronium
(n=13)
Young patients
Mivacurium Combination Rocuronium
(n=14)
(n=18)
(n=15)
(n=15)
(n=15)
Age (yr)
44 14
7/7
41 15
12/6
70 12
47 15
8/5
63 16
Onset 95% thumb
(sec; mean SD)
Onset of maximum
blockade thumb
(sec; mean SD)
Onset eye
(seconds; mean SD) 142 54
Duration 25 %
(min; mean SD)
Intubating conditions
(1/2/3/4)
Sex: male/female
Weight (kg)
Height (cm)
Propofol (mg)
Fentanyl (µg)
180 120
210 165
160 100
67
171
8
5
172
8
172
8
203 20
175 35
209 35
177 33
192 18
173 37
271 103
276 102
151 49
253 132
158 67
39 11*
10/5/0/0
No statistically significant difference was found among subgroups.
23
6
25
7
TABLE III Patient characteristics, (elderly group), (mean SD)
7/6/2/0
8/7/0/0
Mivacurium Combination
Rocuronium
(n=15)
Elderly patients
Mivacurium Combination Rocuronium
(n=15)
(n=15)
(n=15)
(n=15)
(n=15)
Age (yr)
74 10
7/8
69 12
77 13
11/4
72 15
75 10
6/9
64 11
Onset 95% thumb
(sec; mean SD)
Onset of maximum
blockade thumb
(sec; mean SD)
Onset eye
(sec; mean SD)
Duration 25%
(min; mean SD)
Intubating conditions
(1/2/3/4)
Sex: male/female
Weight (kg)
Height (cm)
Propofol (mg)
Fentanyl (µg)
176 78
213 71
152 52
169
6
170
4
169
7
162 28
140 45
158 35
126 45
149 26
131 39
223 108
147 66
273 88
174 62
35 11*†
11/4/0/0
204 102
196 93
No statistically significant difference was found among subgroups.
23
6
54 17*§†
13/2/0/0
11/4/0/0
mmHg. Isoflurane concentration was kept at 0.8-1%
end-tidal and fentanyl (50-100 µg iv) was given to
increase the depth of anesthesia if required.
* P < 0.05 compared with mivacurium;
§ P < 0.05 compared with combination
† P < 0.05 compared with young group
Onset time at the adductor pollicis was defined as
the interval between injection and maximum blockade
of first twitch (T1) in a train-of-four as measured by
accelerometry. Onset time at the eye was defined as
the time from injection until total disappearance of
muscular activity around the eye. Duration of action
was defined as the time from injection of the neuro-
muscular blocking agent until 25% T1 recovery as
measured by accelerometry at the adductor pollicis.
The presence or absence of cutaneous reaction (rash)
was noted after injection of the neuromuscular block-
ing drug.
pare gender distribution and intubation conditions,
Chi Square test or Fisher exact test was used.
Results
Within each age group, each subgroup was compara-
ble with respect to age, weight, height, sex distribu-
tion and dose of induction anesthetics (Tables II, III).
The elderly received less fentanyl and less propofol
than young patients. All subjects had at least 95%
blockade at the adductor pollicis. Six patients did not
achieve 100% blockade at the adductor pollicis. Seven
others did not demonstrate complete abolition of
response following facial nerve stimulation, in which
case onset time was set arbitrarily at five minutes.
For each drug or drug combination given, onset
time was similar in young and elderly subjects (Table
IV). Within each age group, there were no differences
in onset time among mivacurium, rocuronium, and
the combination (Table IV). Onset of neuromuscular
blockade was shorter at the orbicularis oculi than at
the adductor pollicis (P < 0.05; Table IV). Intubating
conditions were all excellent or good, except for two
Comparisons were made among drug regimens
within the same age group, and for the same drug reg-
imen between the young and elderly. Results of con-
tinuous variables are presented as mean
SD. For
statistical analysis, a Jandel Sigmastat statistical soft-
ware was used. The sample size was determined to
detect a minimum difference of 60 sec in the onset
times with an expected standard deviation of 50 sec
and a desired power of 0.8. A P value less than 0.05
was considered to indicate a statistically significant dif-
ference. To compare patients characteristics, dose of
anesthetics, onset, duration one way ANOVA or
Kruskall Wallis ANOVA on ranks was used. To com-

228
CANADIAN JOURNAL OF ANESTHESIA
urium or 0.6 mg·kg– 1rocuronium). For the combina-
tion of 0.0375 mg·kg– 1mivacurium plus 0.15 mg·kg– 1
rocuronium, which represents one ED9 5 in terms of
patients in the mivacurium subgroup (young
patients), who had poor conditions. The type of relax-
ant used did not influence intubating conditions
(Table IV). Excellent intubating conditions were
observed in 25/45 patients in the young group, com-
pared with 35/45 in the elderly (N.S.).
In young patients, duration of action of the combi-
nation was similar to that of mivacurium, approxi-
mately 15 min shorter than that of rocuronium (P <
0.05 when compared with mivacurium or the combi-
nation) (Table IV). In the elderly, the duration of
action of the combination and of rocuronium was pro-
longed compared with that in young adults (Table
IV). Thus, in the elderly, the duration of action of the
combination was longer than that of mivacurium, but
still shorter to that of rocuronium (Table IV).
Cutaneous rash was seen only in the mivacurium
group. It was observed in 6/15 young patients and
6/15 elderly subjects. No bronchospasm was
observed.
total drug amount, but 1.58 × ED in terms of
9 5
potency, onset time was only slightly longer than for
0.6 mg·kg–1 rocuronium, (114 vs 99 sec) and duration
was approximately equal to that of 0.15 mg·kg– 1
mivacurium, (14.7 vs 14.5 min). Giving twice as much
of the combination, namely 2 × ED in drug amount,
9 5
or 3.16 × ED in drug potency, yielded a short onset
of action (699 5sec) but a longer duration (34 min),
comparable to that of 0.6 mg·kg– 1 rocuronium (36
min). The doses had to be modified for the purpose of
the present study. First, mivacurium, 0.15 mg·kg–1 has
been shown to yield poor intubating conditions.1 5
Better results are obtained with 0.2-0.25 mg·kg–1,
without producing a large increase in duration of
action.15,16 Thus a dose of 0.25 mg·kg– 1 was chosen,
in an attempt to obtain the best possible effect from
mivacurium. It is likely that smaller doses would have
produced longer onset times and poorer intubating
conditions. For rocuronium, the lowest dose reported
to be consistent with acceptable intubating condi-
tions, or 0.6 mg·kg– 1,17–19 was used, because larger
doses are associated with a prolonged duration of
action.1 8 The combination dose was based on the
reported value of 62% for the synergism between both
drugs, that is 31% of each drug given together pro-
duces an effect equivalent to 100% of either drug
given alone.8 This figure was rounded off to 2/3 (1/3
for each drug) for practical reasons.
In the present study, onset times at the adductor
pollicis for mivacurium and especially rocuronium
(3.5 - 4.5 min) were longer than usually reported for
these drugs. This might be explained by the short sta-
bilization time, which tends to increase measured
onset times. For example, onset time after 0.16
mg·kg–1 mivacurium was reported to be 198 sec if sta-
bilization time was one minute, and only 106 sec if
stabilization time was 20 min.1 0 For 0.6 mg·kg– 1
rocuronium, the differences appear even greater: 150
and 46 sec after one and 20 min respectively.1 1 In the
present study, onset times for mivacurium and rocuro-
nium were not statistically different. This finding is
usually present when neuromuscular monitoring is
applied immediately after induction. For example,
Pino et al.1 7 reported an onset time of 5.8 min for 0.6
mg·kg–1 rocuronium, not very different from the 4.3
min obtained for 0.25 mg·kg– 1 mivacurium. Similarly,
Audibert et al.1 8report values of 5.0 and 5.25 min for
0.6 mg·kg– 1 rocuronium and for 0.2 mg·kg–1 mivac-
urium, respectively. In both these studies, neuromus-
cular monitoring was started immediately after
Discussion
This study shows that, in adults aged 18-65 yr, a mix-
ture of 0.08 mg·kg–1 mivacurium, and 0.2 mg·kg– 1
rocuronium, provides onset characteristics and intu-
bating conditions comparable to those associated with
either mivacurium or rocuronium given alone. The
combination contains the equivalent of two thirds as
much drug as either parent drug administered alone.
In adults younger than 65 yr, the duration of action of
the mixture is similar to that of the shorter-acting
drug, mivacurium. In the elderly (>66 yr), the dura-
tion of action of the mivacurium-rocuronium combi-
nation was prolonged and became slightly longer than
that of mivacurium. Duration of action of rocuronium
alone was also prolonged in the elderly. Giving the
combination offers two advantages: only two thirds as
much drug is given so that costs are reduced, and the
incidence of cutaneous side effects is less. Under the
conditions of this study, onset time and intubating
conditions were similar for mivacurium, rocuronium,
and their combination.
A previous study described the interaction between
mivacurium and rocuronium.8 Dose response rela-
tionships were first established. The ED s for mivac-
urium and rocuronium administered alo5n0e were 38.8
and 125 µg·kg–1, respectively. The ED for the com-
bination was 11.4 µg·kg–1 mivacuri5u0m plus 38.8
µg·kg–1 rocuronium, that is 62 % as much drug (in
equipotent doses) was required to produce the same
effect. In the same study, onset and duration for the
combination were measured and compared with 2 ×
ED9 5 doses of the parent drugs (0.15 mg·kg–1 mivac-

Motamed & Donati: MIVACURIUM-ROCURONIUM COMBINATIONS
229
induction. To obtain a fast onset, one could increase
the dose of rocuronium to 0.9 mg·kg–1, but the dura-
tion of action would be increased considerably.19,20
Intubating conditions were assessed at 2.5 min in the
present study. The time chosen for this procedure
appears rather arbitrary, as intervals varying between
one minute and three minutes have been chosen by var-
ious investigators.15,17,19–23 It is expected that intubating
conditions would have been less optimal if a shorter
interval had been used. Conditions reported here might
appear worse than in most published studies. This is
probably because, in the present investigation, any
movement meant that conditions were not excellent.
There were only two patients (of 90) with poor intu-
bating conditions. Time to disappearance of response to
facial nerve stimulation was shorter in all groups, when
compared with the adductor pollicis. A more rapid
onset at the orbicularis oculi was observed before with
vecuronium,2 4 atracurium,12,25 and mivacurium.26,27
The response of the orbicularis oculi was recom-
mended as a guide to intubating conditions because
disappearance of response, as evaluated visually, was
found to correlate with maximum blockade of laryngeal
muscles.1 2 Other evidence includes the fast onset and
short duration of both the mechanical responses at the
larynx and the EMG data recorded near the eyebrow
after the same doses of vecuronium in two separate
studies.24,28 However, a more recent study reported late
recovery of accelerographic response of the orbicularis
oculi measured over the eyelid after vecuronium,
atracurium and mivacurium, similar to that of the
adductor pollicis.2 9 This suggests that muscles supplied
by the facial nerve have different sensitivities to neuro-
muscular blocking drugs. The palpebral part of the
orbicularis oculi, located on the eyelid, is sensitive,
whereas the muscles located near the eyebrow, such as
the corrugator supercilii, is resistant.3 0Visual inspection
detects movement of the latter.
selection of patients (ASA I and II) might have
excluded most subjects with decreased circulation
time, or that younger adults had a greater decrease in
circulation time because they received a larger dose of
induction agent.
The mechanisms accounting for synergism between
two neuromuscular blocking drugs are unclear.
However, this phenomenon occurs more frequently
with two drugs having different chemical structures, for
example metocurine-pancuronium,6 d-tubocurarine-
pancuronium,6 d-tubocurarine-vecuronium,7 cistracuri-
um-rocuronium,5,9
and
mivacurium
and
rocuronium.8,21 Drug combinations have been pro-
posed to decrease the incidence of side effects and cost.
In the present study minor cutaneous rash was seen
only in the mivacurium group. When cost is considered,
using a mixture of drugs is advantageous if both agents
are within the same price range. If one drug is consid-
erably cheaper than the other, then it is more econom-
ical to use only the less expensive drug. Mid-1999
prices (in Canadian dollars) at our institution were
$0.26 and $0.55 per milligram for rocuronium ($13.00
for 50 mg) and mivacurium ($10.75 for 20 mg),
respectively. The cost of the intubating doses given in
the present study to a 70-kg patient would be $10.92,
$9.62 and $6.72. The cost advantage of the combina-
tion must be balanced against the greater possibility of
wastage as two vials are open. Nevertheless, the main
advantage of using two drugs with different onset times
and duration of action, such as mivacurium and rocuro-
nium, appears to be, from this study and others,8,21 that
a judicious combination can be chosen for its neuro-
muscular properties, that is to obtain onset of one drug
with the duration of an other.
In summary, combinations of mivacurium and
rocuronium can be used to obtain acceptable onset
times with duration of action similar to that of mivac-
urium, at least in adults younger than 65 yr. This is
achieved by using 1/3 less drug and cutaneous side
effects of mivacurium are likely to be avoided. Such a
combination might be considered especially when the
anticipated duration of the anesthetic is 20-30 min.
The elderly group was studied because the pharma-
codynamics of rocuronium are altered1 4and mivacuri-
um has been reported to have a slightly increased
duration in this age group.3 1 This increased duration
of mivacurium is small and was not found in the pre-
sent study probably because of the small number of
patients. The duration of rocuronium blockade was
longer in the elderly (54 vs 39 min), which corre-
sponds to earlier observations.1 4 The mivacurium-
rocuronium combination also has an increased
duration of action in the elderly, according to the pre-
sent study. It was expected that the onset at the adduc-
tor pollicis and the orbicularis oculi would be longer
in the elderly patient, because of longer circulation
time. This was not the case. It is possible that our
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