A Comparison of Cisatracurium and Atracurium: Onset of

Neuromuscular Block After Bolus Injection and Recovery

After Subsequent Infusion
Hermann Mellinghoff, MD, Lukas Radbruch, MD, Christoph Diefenbach, MD, and
Walter Buzello, MD
Department of Anesthesiology, University of Cologne, Cologne, Germany

Cisatracurium is a new nondepolarizing muscle relax- rates for a 95% t 4% neuromuscular block were 1.5 i
ant. In patients randomized to receive either cisatra- 0.4 pg * kg- ’ * mini ’ for cisatracurium and 6.6 i
curium (n = 40) or atracurium (n = 20) we compared 1.7 PELg* kg-’ * mini’ for atracurium, 3.3 times those of
the time course of neuromuscular block. The initial bo- cisatracurium when referenced to the active cations. Af-
lus dose of cisatracurium was 0.1 mg/kg, that of atra- ter the infusion, the spontaneous recovery intervals
curium 0.5 mg/kg. Neuromuscular block, maintained 25%-75% of 18 +- 11 min and 18 + 8 min for cisatra-
with an infusion of either drug, was reversed with curium and atracurium (P = 0.896) were shortened to
neostigmine 45 pg/kg and atropine 20 pg/kg in one 5 -f 2 min and 4 -t 3 min (P = 0.921) after neostigmine.
half of the patients. Neuromuscular transmission was While attributing different onset times also to differ-
assessed by recording the mechanical twitch re- ences in the initial doses, we conclude that time profiles
sponse to train-of-four nerve stimulation. Onset times for neuromuscular block of both muscle relaxants,
were 3.1 i 1.0 min with cisatracurium and 2.3 2 when given in equipotent doses, are not different.
1.1 min with atracurium (P = 0.008). The infusion (Anesth Analg 1996;83:107225)

C
isatracurium (51W89) is the purified form of one not provide comparable data and thus do not allow a
of the 10 stereoisomers of atracurium, account- final recommendation for clinical practice. Further-
ing for about 15% of the total mixture (1,2). In more, none of these studies included a randomized
adult patients, after single bolus doses (2 X 95% effec- patient allocation schedule (5). Therefore, we per-
tive dose) of cisatracurium and atracurium, one group formed a comparison of neuromuscular block in terms
of investigators found a significant, 1.5 min slower, of the times to onset after bolus injection and of the
onset from the end of intravenous (IV) injection to rates of recovery after a two-hour infusion of cisatra-
complete neuromuscular block (8 ? 2 versus 6 ? curium or atracurium in patients randomized to re-
1 min), as well as a significant, 8 min slower, recovery ceive either drug.
to 25% twitch recovery (46 ? 7 versus 38 ? 9 min)
with cisatracurium (3). By contrast, in another study
(4), using a larger single bolus dose of cisatracurium
and the same dose of atracurium, no significant dif- Met hods
ference was found with respect to the time to 25%
After approval by the institutional ethical committee,
twitch recovery, while the time to onset was again
35 male and 25 female adult patients, scheduled for
slower with cisatracurium than with atracurium. On
maxillofacial surgery of an anticipated duration of at
the other hand, in cats (2), onset times of cisatracurium
and atracurium were not different. These reports do least 3.5 h, gave their written, informed consent to
participate in the study. Inclusion criteria were: age
over 18 yr and ASA physical status I or II. Pregnant
The study was supported by a grant of The Wellcome Foundation
Ltd., London, England.
women were excluded, as were patients with neuro-
Presented in part at the Annual Meeting of the International muscular, hepatic, or renal disease, or those taking
Anesthesia Research Society, Orlando, FL, March 1994. medication known to interact with neuromuscular
Accepted for publication July 5, 1996. blocking drugs. According to a predetermined ran-
Address correspondence and reprint requests to Hermann
Mellinghoff, MD, Department of Anesthesiology, University of domization code, the patients were assigned to receive
Cologne, Koeln, Germany. either cisatracurium (n = 40) or atracurium (n = 20).

01996 by the International Anesthesia Research Society

1072 An&h Amlg 1996;83-1072-S 00032999/96/$5.00
ANESTH ANALG
1996;83:1072-5
Table 1. Demographic Data
Age (yr)
Cisatracurium
Spontaneous recovery 35 + 14 (18-61)
Induced recovery 38 -+ 16 (19-71)
Atracurium
Spontaneous recovery 35 5 16 (21-63)
Induced recovery 37 -c 18 (18-66)
Values are mean 2 SD and (range).
After oral administration of flunitrazepam (l-2 mg)
and hyoscine (0.5 mg), anesthesia was induced 1 h
later with fentanyl (2-8 pg/kg), midazolam (0.05-
0.10 mg/kg), and thiopental (4-8 mg/kg) IV. Endo-
tracheal intubation was performed without the use of
a muscle relaxant. Mechanical ventilation was main-
tained with nitrous oxide (70%) in oxygen in a re-
breathing circuit. The ventilation was adjusted to
achieve 28 -53 mm Hg ETco, partial pressure. As nec-
essary to maintain mean arterial pressure within 20%
of baseline values, IV increments of fentanyl (0.05-
0.10 mg) and midazolam (l-2 mg) were administered
for maintenance of anesthesia. Neuromuscular trans-
mission was monitored by recording the evoked
twitch tension of the left adductor pollicis muscle in
response to supramaximal train-of-four (TOF) stimuli
(2 Hz/2 s; pulse width 0.2 ms) every 17 s to the ulnar
nerve at the wrist via surface electrodes. After a stable
baseline period of at least 15 min, a predetermined
(approximately 2 X 95% effective dose) initial dose of
0.1 mg/kg cisatracurium (dose reported with refer-
ence to the cation, molecular weight 929) or 0.5 mg/kg
atracurium (dose reported with reference to the besy-
late salt, molecular weight 1245) was injected IV
within 5-10 s into a fast-flowing infusion. An infusion
of cisatracurium or atracurium was initiated when the
first twitch response in the TOF (Tl) attained 5% of its
control value. The initial rates of infusion of cisatra-
curium and atracurium were 3 FLg* kg-’ * mini and
10 PLg* kg-’ * mini, respectively. The rates of infu-
sion were adjusted manually to maintain a 95% 2 4%
depression of Tl. Following the end of infusion, one
half of the randomly selected patients (cisatracurium,
y1= 20; atracurium, n = 10) received 45 pg/kg neostig-
mine and 20 pg/kg atropine IV as soon as Tl attained
10% of its control value, while in the remaining pa-
tients neuromuscular transmission was allowed to re-
cover spontaneously. Monitoring of the neuromuscu-
lar transmission was continued until no change of Tl
was detected for at least 5 min. All measurements
were recorded on a polygraph. Skin temperature of
the left hand was maintained between 33 and 35°C by
means of warmed IV fluids and warming blankets.
The twitch recordings, always given with reference
to the control values recorded before the administration
MELLINGHOFF ET AL. 1073
CISATRACURIUM AND ATRACURIUM COMPARED
Duration of
Weight (kg) Height (cm) infusion (min)
71 ? 16 (46-103) 173 + 10 (159-190) 112 + 32 (78-192)
72 -c 10 (53-93) 175 L 10 (154-192) 108 + 21 (75-150)
73 2 7 (60-84) 174 + 7 (167-187) 100 + 13 (83-120)
70 ? 11 (57-96) 174 5 9 (156-184) 119 + 35 (88-183)
of the neuromuscular blocking drugs, were evaluated
for the following variables: time from the end of in-
jection of the initial dose of the muscle relaxant to 90%,
95%, and the maximum twitch depression (onset 90%,
95%, maximum block); maximum twitch depression
after the initial dose; time from the end of injection of
the initial dose to the beginning of twitch recovery as
well as the time when the twitch recovered to 5%;
twitch depression at the time of neostigmine admin-
istration; time from the end of infusion to neostigmine
administration as well as the time when twitch recov-
ered to 25%, 75%, and 90% of control twitch tension
and the TOF ratio reached 0.7; time from 25% to 75%
recovery of control twitch tension (recovery interval,
RI25-75). The results are expressed as mean t SD and
range. Comparison between groups was performed
using Student’s t-test. Variability of data was assessed
by the coefficient of variation (SD/mean).
Results
All groups were comparable with respect to age, body
weight, height, and duration of infusion (Table 1). The
administration of either muscle relaxant resulted in
complete neuromuscular block in nearly all patients.
The time from the end of injection of the bolus dose to
the onset of maximal twitch suppression was almost
1 min shorter after atracurium than after cisatra-
curium (Table 2). No significant difference was noted
in the time from the end of the injection of the bolus
dose until recovery of twitch tension to 5% of control
(Table 2). The average rate of infusion for a constant
95% 5 4% neuromuscular block was 1.5 ? 0.4 (range,
l-3) pg * kg-’ * min-’ and 6.6 -t 1.7 (range, 3-11)
pg * kg-’ * min-’ for cisatracurium and atracurium,
respectively. In terms of the cations, these rates repre-
sent a 3.3 times larger infusion requirement of atra-
curium than of cisatracurium. The total cumulative
dose of cisatracurium varied between 0.2 and
0.5 mg/kg and that of atracurium between 0.9 and
2.4 mg/kg. All indices of recovery appear to be almost
identical between atracurium and cisatracurium (Ta-
ble 3). The coefficients of variation (so/mean) and
ranges were of similar magnitudes for all values ex-
cept RI and the time to TOF ratio of 0.7.
1074 MELLINGHOFF ET AL. ANESTH ANALG
CISATRACURIUM AND ATRACURIUM COMPARED 1996;83:1072-5

Table 2. Onset of Neuromuscular Block After the Initial Bolus Doses of Cisatracurium and Atracurium

Cisatracurium (n = 40) Atracurium (n = 20)

Onset 90%” (min) 2.2 -+ 0.6 (14) 1.5 t o.t3* (14)
Onset 95%” (min) 2.5 5 0.7 (l-5) 1.8 * 1.0* (l-5)
Onset maximum block” (min) 3.1 2 1.0 (2-7) 2.3 + l.l* (l-5)
Maximum block (%) 99.9 t 0.5 (97-100) 99.9 t 0.7 (97-100)
Beginning of recoveryb (min) 27 t 6 (11-39) 30 2 6 (1547)
DUR 5%” (min) 32 ? 6 (1546) 34 5 7 (18-54)
Values are mean i SD and (range).
a Time from end of injection to 90%, 95%, or maximum neuromuscular block.
b First visible recovery of twitch response.
’ Time from end of injection of bolus dose until recovery of twitch tension to 5% of control.
*P < 0.01 versus cisatracurium.

Table 3. Times of Recovery from Neuromuscular Block Follow Termination of Infusion of Cisatracurium or Atracurium

Cisatracurium Atracurium
Spontaneous recovery Induced recovery Spontaneous recovery Induced recovery
62 = 20) (n = 20) (72 = 10) (n = 10)
Recovery to 25% 16.5 ? 3.5 (10-24) 11.3 + 3.4 (3-18) 15.4 ? 3.6 (9-21) 12.8 ? 3.3 (9-18)
Recovery to 75% 33.7 2 11.9 (24-74) 15.9 + 4.2 (10-25) 33.8 -c 10.4 (22-53) 17.3 + 5.5 (12-29)
Recovery to 90% 37.7 -c 9.8 (31-70) 19.2 + 5.4 (13-30) 41.2 -+ 12.1 (25-57) 18.6 t 4.7 (12-24)
RI (25%-75%) 17.9 -c 10.9 (11-58) 4.6 + 2.3 (2-10) 18.4 t 8 (10-34) 4.4 t 2.7 (2-12)
TOF ratio = 0.7” 38.7 ? 6.4 (22-51) 18.2 + 3.9 (13-26) 42.1 2 6.7 (33-57) 19.9 2 7.9 (11-25)
Values are mean 2 sD (range); times are given in minutes.
RI = recovery interval; TOF = train-of-four.
a Time from termination of infusion until TOF ratio = 0.7.

Neostigmine was administered at the same level of to 12 minutes longer after cisatracurium than after
neuromuscular transmission of 11% 2 1% of baseline, atracurium. The authors themselves attribute this dif-
an average of 11 min after termination of the infusion ference in part to the respective initial bolus doses not
of either muscle relaxant. The use of neostigmine re- being equipotent (3). Randomized allocation of 60 pa-
sulted in a 14-min reduction of the RI25-75 and an ll- tients in our study versus 30 nonrandomly assigned
to 12-min reduction of the time from the end of infu- patients in the other study (3) avoids possible bias in
sion to a TOF ratio of 0.7 for both cisatracurium and patient selection and adds statistical significance to
atracurium. No correlation was noticed between the our results (5).
spontaneous RI25-75 (11-58 min) and the duration of In our study, we did not detect a positive correlation
infusion (75-192 min) for either cisatracurium or between the offset of neuromuscular block and the total
atracurium. cumulative dose with either cisatracurium (0.2-0.5 mg/
kg) or atracurium (0.9-2.4 mg/kg). This is in keeping
with previously published simulations (6), where the
Discussion RI25-75 of atracurium did not depend on the size of the
The results of our study show that the spontaneous bolus dose (0.2-0.4 mg/kg). Our results are also in line
rates of recovery after an approximately three-hour with those of an earlier clinical report (4).
constant neuromuscular block produced by cisatra- In keeping with previous clinical reports (3,4,7), two
curium or atracurium were almost the same, as were of them using the same dose ratio for the initial bolus
the neostigmine-facilitated rates of recovery. These doses (0.1 versus 0.5 mg/kg) (4,7), the times from end
data are new even when compared with a previous of the injection of the bolus doses to the onset of
study (4), demonstrating almost equal times to 25% maximum neuromuscular block were significantly
twitch recovery after infusion of either cisatracurium longer (1 min) after cisatracurium than after atra-
or atracurium. In that study (4), recovery of twitch curium. This finding has been explained with an
tension beyond 25% twitch recovery was reported inverse relationship between onset and potency
only for cisatracurium but not for atracurium. On the (4,8-10). However, the doses of cisatracurium and
other hand, our results differ from the previous obser- atracurium in our study as well as in the other studies
vation (3) that the times from the end of the injection have not been determined, and thus the bolus doses
of a bolus dose to twitch recoveries to 25%, 50%, and we used may not have been exactly equipotent.
75% of control, as well as to the TOF ratio of 0.7, are up Hence, the faster onset of neuromuscular block after
ANESTH ANALG MELLINGHOFF ET AL. 1075
1996;83:1072-5 CISATRACURIUM AND ATRACURIUM COMPARED

atracurium than after cisatracurium may also be ex- of cisatracurium and atracurium appear to be the
plained with a relatively higher initial bolus dose of same.
atracurium than of cisatracurium.
Larger groups of patients and equal sizes of the
groups might have revealed differences in the rates of References
recovery of neuromuscular transmission after cisatra- 1. Tsui D, Graham GG, Torda TA. The pharmacokinetics of atra-
curium or atracurium. Estimation of sample sizes nec- curium isomers in vitro and in humans. Anesthesiology 1987;
essary for this purpose demonstrates that the number 67~722-8.
2. Wastila WB, Maehr RB. The pharmacological profile of 51W89,
of patients required is beyond the scope of clinical the R, CIS- R’, CIS isomer of atracurium in cats [abstract].
studies: for all variables, the study of more than 140 to Anesthesiology 1993;79:A946.
several thousand patients would be required to estab- 3. Boyd AH, Eastwood NB, Parker CJR, Hunter JM. Pharmacody-
namics of the 1R cis-1’R cis isomer of atracurium (51W89) in
lish that the differences in the recovery data of the health and chronic renal failure. Br J Anaesth 1995;74:400-4.
magnitude we have observed were statistically signif- 4. Belmont MR, Lien CA, Quessy S, et al. The clinical neuromus-
icant. Even then, such differences would have no rel- cular pharmacology of 51W89 in patients receiving nitrous
evance to clinical practice. On the other hand, given oxide/opioid/barbiturate anesthesia. Anesthesiology 1995;82:
1139-45.
the similar variability for most sets of data, our sample 5. McPeek B, Mosteller F, McKneally MF, Neugebauer EAM. Ex-
sizes were large enough to detect clinically relevant oerimental methods: clinical trials. In: Troidl H. Suitzer WO.
differences, i.e., a difference between the means of McPeek B, et al. eds. Principles and practice of research: strat:
+ 1 SD. egies for surgical investigators. 2nd ed. New York: Springer,
1991;114-25.
In conclusion, after a 75- to 192-min infusion for a 6. Fisher DM, Rosen JI. A pharmacokinetic explanation for increas-
constant 95% ~fr 4% neuromuscular block during ni- ing recovery time following larger or repeated doses of nonde-
trous oxide-narcotic anesthesia, we found identical polarizing muscle relaxants. Anesthesiology 1986;65:286-91.
7. Lepage JY, Malinovsky JM, Malinge M, et al. 51W89: Dose-
recovery characteristics with both cisatracurium and response, neuromuscular blocking profile and cardiovascular
atracurium. Neostigmine was equally effective in ac- effects [abstract]. Anesthesiology r993;79:A0945.
celerating the recovery from neuromuscular block 8. Bowman WC, Rodner ”
IW, Houston I, et al. Structure:action
_.

produced by either muscle relaxant. On a molar basis, relationships among some desacetoxy analogues of pancuro-
nium and vecuronium in the anesthetized cat. Anesthesiology
during infusion, cisatracurium was 3.3 times more 1988;69:57-62.
potent than atracurium. The one-minute slower onset 9. Feldman SA, Wu X, England A. Rate of “onset” and “offset” of
with cisatracurium than with atracurium in our study four non-depolarizing neuromuscular blocking drugs. Anaes-
thesia 1995;50:510-3.
may also be explained with a relatively larger initial
10. Law Min JC, Bekavac I, Glavinovic MI, et al. Iontophoretic study
dose of atracurium. Thus, under clinical circum- of speed of action of various muscle relaxants. Anesthesiology
stances, the pharmacodynamics of equipotent doses 1992;77:351-6.