Full text of DOI:10.1007/BF03016828

532
GENERAL ANESTHESIA
Desflurane reduces the effective therapeutic infu-
sion rate (ETI) of cisatracurium more than isoflu-
rane, sevoflurane, or propofol
[Le desflurane, comparé à l’isoflurane, au sévoflurane ou au propofol, réduit
davantage la vitesse de perfusion thérapeutique utile (PTU) du cisatracurium]
Thomas M. Hemmerling MD DEAA, Juergen Schuettler MD, Helmut Schwilden MD PhD
Purpose: The present study investigated the interaction between
the cumulative dose requirements of cisatracurium and anesthesia
with isoflurane, sevoflurane, desflurane or propofol using closed-
loop feedback control.
Objectif : Rechercher l’interaction entre la dose cumulative néces-
saire de cisatracurium et l’anesthésie avec de l’isoflurane, du
sévoflurane, du desflurane ou du propofol, en utilisant un système
de rétroaction en boucle fermée.
Methods: Fifty-six patients (18–85 yr, vitrectomies of more than
one hour) were studied. In the volatile anesthetics groups, anes-
thesia was maintained by 1.3 MAC of isoflurane, sevoflurane or
desflurane; in the propofol group, anesthesia was maintained by a
Méthode : L’étude a porté sur 56 patients (18–85 ans, vitrectomie
de plus d’une heure). Chez les patients qui ont reçu un
anesthésique volatil, l’anesthésie a été entretenue avec 1,3 CAM
d’isoflurane, de sévoflurane ou de desflurane; chez ceux qui ont eu
du propofol, on a administré une perfusion continue de 6–8
–1
–1
continuous infusion of 6–8 mg·kg ·hr propofol. After bolus appli-
–1
–1 –1
cation of 0.1 mg·kg cisatracurium, a T1%-level of 10% of control
level (train-of-four stimulation every 20 sec) was maintained using
closed-loop feedback controlled infusion of cisatracurium. The
effective therapeutic infusion rate (ETI) was estimated from the
asymptotic steady-state infusion rate I The I was derived from fit-
mg·kg ·h de propofol. Après l’administration d’un bolus de 0,1
–1
mg·kg de cisatracurium, une première réponse T1à 10 % (d’une
stimulation en train-de-quatre répétée toutes les 20 s) a été main-
tenue au moyen d’une perfusion de cisatracurium contrôlée par un
système de rétroaction en boucle fermée. La vitesse de perfusion
thérapeutique utile (PTU) a été évaluée à partir de la vitesse de per-
fusion asymptotique àl’équilibre P . La P a été dérivée de l’ajuste-
ss.
ss
ting an asymptotic line to the measured cumulative dose require-
ment curve. The ETI of the different groups was compared using
Kruskal-Wallis- test, followed by rank sum test, corrected for the
number of comparisons, P <0.05 was regarded as showing signifi-
cant difference.
e
e
ment d’une ligne asymptotique à la courbe de la dose cumulative
nécessaire. La PTU des différents groupes a été comparée à l’aide
du test de Kruskal-Wallis, suivi du test de la somme des rangs, ajusté
en fonction du nombre de comparaisons, P<0,05 a été considéré
comme une différence significative.
–2
–1
Results: ETI in the isoflurane group was 35.6 ± 8.6 µg·m ·min ,
–2
–1
in the sevoflurane group 36.4-± 11.9 µg m ·min , in the desflu-
–2
–1
rane group 23.8 ± 6.3 µg·m ·min . The ETI of the volatile anes-
thetic groups were all significantly lower than the ETI in the
Résultats : La PTU associée à l’isoflurane a été de 35,6 ± 8,6
–
2
–1
–2
–1
mg·m ·min ; au sévoflurane, 36,4 ± 11,9 mg m ·min et au
–2
–1
–2
–1
propofol group at 61.7 ± 25.3 µg·m ·min (P <0.002). The ETI
in the desflurane group was significantly lower than in all other
groups (P <0.02).
desflurane, 23,8 ± 6,3 mg·m ·min . La PTU associée aux
anesthésiques volatils a été significativement plus basse que celle qui
–2
–1
est associée au propofol, 61,7 ± 25,3 mg·m ·min (P <0,002).
La PTU associée au desflurane a été significativement plus basse
que celles qui concernent tous les autres anesthésiques (P<0,02).
Conclusion: In comparison to propofol, isoflurane, sevoflurane
and desflurane reduce the cumulative dose requirements of
cisatracurium to maintain a 90% neuromuscular blockade by 42%,
Conclusion : Comparés au propofol, l’isoflurane, le sévoflurane et
41% and 60%, respectively.
le desflurane réduisent de 42 %, 41 % et 60 %, respectivement,
From the Department of Anesthesiology, University of Erlangen-Nuremberg, Germany.
Present correspondence address: Dr. Thomas M Hemmerling, Department of Anesthesiology, University of Montreal, CHUM - Hôtel-
Dieu, 3840, rue Saint-Urbain, Montreal, Quebec H2W 1T8, Canada. Phone: 514-843-2611, ext. 4570; Fax: 514-843-2690;
E-mail: thomashemmerling@hotmail.com
Accepted for publication February 6, 2001.
Revision accepted March 26, 2001.
CAN J ANESTH 2001 / 48: 6 / pp 532–537

Hemmerling et al.: DESFLURANE REDUCES ETI OF CISATRACURIUM
533
la dose cumulative nécessaire de cisatracurium pour maintenir un
blocage neuromusculaire à 90 %.
all patients before application of cisatracurium). The
TOF sequence was assessed every 20 sec; the degree
of neuromuscular blockade was defined as the ratio of
the first twitch in the TOF-ratio compared to the cor-
responding control value (T1%).
ISATRACURIUM is the 1-R-cis-1’R-cis
isomer of atracurium; in comparison to
Neuromuscular blockade then was induced by
1
–1
atracurium, it has a slower onset time and
less propensity to liberate histamine.
injecting 0.1 mg·kg cisatracurium (2 x ED ) intra-
9
5
C
2,3
venously. After complete neuromuscular blockade
(T1% <5%), endotracheal intubation was performed.
Body temperature was monitored at the hand and
kept above 35.6C using a heating blanket (Bair
Hugger, MN, USA).
The reduction of the cumulative dose requirements of
atracurium by volatile anesthetics has been shown in
4
, 5
several studies. The cumulative dose requirements
of cisatracurium have not yet been determined nor has
the effect of desflurane on any non-depolarizing neu-
romuscular blocking drug.
Patients were randomly assigned to one of the four
groups: in the isoflurane, sevoflurane, desflurane
groups (groups I, S, D), general anesthesia was main-
tained by end-tidal 1.3 MAC of each volatile anes-
thetic in oxygen/air (30% oxygen). In the propofol
group (group P), anesthesia was maintained by a con-
6
A recent study has shown that volatile anesthetics
lower ED5 0 and ED9 5 of cisatracurium significantly in
comparison to propofol. However, data about the
influence of volatile anesthetics on the clinical dura-
tion of the neuromuscular blockade after cisatracuri-
um were inconclusive. During surgery requesting a
high and steady level of neuromuscular blockade (e.g.,
eye surgery) the non-depolarizing muscle relaxant can
easily be applied via continuous infusion and the effect
repetitively controlled.
We used a closed-loop feedback control model-dri-
ven system to administer cisatracurium to maintain a
neuromuscular blockade of 90% in patients undergo-
ing vitrectomy; the effect of desflurane, isoflurane,
sevoflurane, or propofol on the infusion requirements
of cisatracurium was measured by calculating the
effective therapeutic infusion rate (ETI) to maintain a
level of neuromuscular blockade at 90% of control
twitch height of the first twitch amplitude (T1).
–
1
–1
tinuous infusion of 6–8 mg·kg ·hr of propofol; as
breathing gas an oxygen/air mixture (30% oxygen)
was used. Alfentanil was given at the discretion of the
–1
anesthesiologist (not more than 1 mg alfentanil·hr of
surgery). Patients were kept in normoventilation with
an end-tidal carbon dioxide of 30–40 mmHg.
After the bolus administration, cisatracurium was
infused intravenously according to a model-driven,
closed-loop feedback system. The Infusomat CP®
(Fresenius, Bad Homburg, Germany) and the
Relaxograph® were connected to a Toshiba® T
1850C laptop via a serial RS 232 C interface. The set
point of neuromuscular blockade was defined as
T1%=10%; the controller performance was calculated
as the mean offset of the measured T1% from the set
point during feedback control.
Materials and methods
Statistical analysis
After obtaining approval by the local Ethics
Committee and written informed consent, 56 patients
Difference of means and standard deviation of I (4,5)
s s
was used to determine group size for a power of more
–
2
(
ASA I–III) undergoing vitrectomy of an anticipated
than 0.9 (beta error=10%). The ETI (µg x m body sur-
–
1
duration of more than one hour were studied. Patients
with neuromuscular disorders or patients on medica-
tion known to interact with neuromuscular blockade
were excluded from the study. Ten milligrams of chlo-
razepatedipotassium was given orally at 22:00 hr on
the evening before the operation and one hour prior
to the start of anesthesia. Anesthesia was induced with
face area x min ) maintaining 90% of neuromuscular
blockade was estimated from the asymptotic steady-state
infusion rate I . I was calculated by fitting an asymptot-
s s s s
ic line to the measured cumulative dose requirement
curve using least square fitting (see appendix).
Parameters were compared using Kruskal-Wallis-
test, followed by rank sum test, corrected for the num-
ber of comparisons, P <0.05 was regarded as showing
statistical significance. Correlation between anthropo-
metric data and ETI for each group was tested by
Spearman’s test (P <0.05).
–1
–1
0
.3 mg·kg etomidate and 10 µg·kg alfentanil. The
Relaxograph® (Datex Instrumentarium, Helsinki,
Finland) was used to measure the train-of-four (TOF)
response from the adductor pollicis muscle over the
thenar area via surface skin electrodes. After induction
of anesthesia the Relaxograph® was automatically cal-
ibrated by setting optimum signal levels at supramaxi-
mal stimulation (TOF stimulation for five minutes in
Results
The anthropometric data, the duration of feedback
control and the controller performance for each group

534
CANADIAN JOURNAL OF ANESTHESIA
TABLE Patient data, feedback, control period and controller performance (mean offset from set-point: 90% blockade of control value)
Groups
ASA
I, II, III
Sex
(m/f)
Age
(y)
Weight
(kg)
Body surface
area (m)
Feedback
control
Mean offset
from set point
2
I
S
D
P
2,5,7
2,5,7
4,5,5
2,4,8
9/5
6/8
8/6
8/6
56 (19)
61 (17)
61/20
83 (15)
72 (13)
74 (9)
1.93 (0.19)
1.81 (0.21)
1.86 (0.12)
1.93 (0.21)
118 (41)
83 (22)
97 (35)
88 (20)
3.19 (1.78)
2.06 (1.56)
2.00 (1.51)
2.49 (1.65)
51 (18)
81 (14)
Values are mean ± SD.
cisatracurium bolus application and start of the closed
loop control was 22 ± 5 min. The mean duration of
cisatracurium-infusion was longest in the isoflurane
group (118 min) without being statistically significant-
ly different from the other groups. The neuromuscular
–1
blockade after bolus administration of 0.1 mg·kg
cisatracurium achieved levels of more than 95% block-
ade of T1% in all patients at a mean of 210 ± 55 sec,
thus providing good conditions for intubation.
Figure 1 demonstrates an example of the time
course of neuromuscular blockade and the cumulative
dose requirements for one representative patient.
Figure 2 shows the ETI to maintain the desired level
of neuromuscular blockade for each group. The ETI
FIGURE 1 Data for one representative patient; the figure shows
the time course of the neuromuscular blockade and the cumulative
dose requirements; I is calculated by non-linear curve fitting
ss
–
2
– 1
(least square fitting, dotted straight line). ETI: 32 µg·m ·min ,
isoflurane group.
–2
–1
was lowest in group D at 23.8 ± 6.3 µg m ·min (P
–2
–1
<
0.02), and highest at 61.7 ± 25.3 µg·m ·min in
group P (P <0.002). The ETI in groups I and S did
not differ statistically. There was no correlation
between the age and weight of patients and the ETI.
Discussion
Isoflurane, sevoflurane and desflurane at 1.3 MAC
reduce the cumulative dose requirements of cisatracuri-
um by 42%, 41% and 60% in comparison to propofol at
–1
–1
6
–8 mg·kg ·hr . Desflurane significantly reduced the
cumulative dose requirements of cisatracurium in com-
parison to sevoflurane and isoflurane.
Cisatracurium has widely replaced atracurium
2
,3
because of the absence of histamine liberation.
–1
FIGURE 2 Shows the ETI for all groups. #P <0.002: ETI
Using 0.1 mg·kg cisatracurium for intubation fol-
lowed by a closed-loop feedback controlled infusion,
no sign of histamine liberation such as skin rash or
changes in hemodynamics were noticed. The onset
(propofol) vs ETI (volatile anesthetics); *P <0.02: ETI (desflu-
rane) vs ETI (propofol, sevoflurane, isoflurane).
–
1
time of the bolus application of 0.1 mg·kg
cisatracurium at the adductor pollicis muscle was
between three to five minutes, comparable to results
in other studies.
The controller performance was regarded as suffi-
cient at an average difference from 2.0% (group D) to
3.2% (group I) between the set point of T1%=10% and
the measured degree of neuromuscular blockade. The
controller performance for cisatracurium was different
are shown in the Table. There were no significant dif-
ferences in sex distribution, age, and weight or ASA
classification between the groups. The controller per-
formance was not different between the groups. All
patients completed the study according to the protocol,
there were no technical problems with the closed loop
delivery system. The mean duration between
7–9

Hemmerling et al.: DESFLURANE REDUCES ETI OF CISATRACURIUM
535
from those found for other non-depolarizing muscle
study, all volatile anesthetics were compared in a breath-
ing gas mixture consisting of air/oxygen (30% oxygen).
It could be assumed that the significant 20% reduc-
tion of the cumulative cisatracurium dose requirement
of desflurane in comparison to isoflurane and sevoflu-
rane is due to a different depth of anesthesia achieved
by 1.3 MAC of desflurane. Kansanaho et al. studied
the influence of several doses of enflurane on the
cumulative dose requirements of atracurium to main-
tain a constant 90% neuromuscular block; this study
showed that enflurane decreased the atracurium
requirements in a dose-dependant manner: 0.5 MAC
of enflurane reduced the atracurium requirements by
10,11
12,13
relaxants such as vecuronium,
atracurium
or
rocuronium.1 4 In the latter study, Olkkola et al. inves-
tigated the interaction of rocuronium with several iv
anesthetics or isoflurane; the best controller perfor-
mance values were achieved at 0.2% to 0.8% average
offset from set point. The controller performance
found in our study could have been anticipated
because cisatracurium shows a more marked hysteresis
and slower onset time than the other three non-depo-
13
6
larizing muscle relaxants. Wulf et al. recently showed
a significant decrease of ED5 0 and ED9 5 of cisatracuri-
um during anesthesia with 1.5 MAC (in a mixture of
7
0% nitrous oxide/30% oxygen) of desflurane,
20%, 1 MAC by 25% and 1.3 MAC reduced the I of
ss
sevoflurane or isoflurane in comparison to propofol. It
is interesting to note that the time to reach 25% of
control level of
atracurium by 28%. The assumption that 1 MAC of
desflurane might create a different depth of anesthesia
than 1 MAC of sevoflurane or isoflurane cannot, how-
ever, be supported by a recent study by Rehberg et
TOF stimulation was not statistically different
between the groups, but recovery index and time to
reach a TOF ratio of 0.7 were significantly prolonged
during anesthesia with desflurane and sevoflurane in
comparison to propofol, but not so for isoflurane.
There are, however, several limitations to that study.
The cumulative dose technique might underestimate
the potency of the neuromuscular blocking drugs.
Diffusion of the inhaled anesthetic requires more than
1
8
al. In a study of pharmacodynamic modelling of the
EEG slowing effect of isoflurane, sevoflurane and des-
flurane, these authors have shown that MAC and
MAC multiples are valid representations of the con-
centration response curve for the anesthetic suppres-
th
sion of the 95 percentile of the power spectrum with
no significant difference of the EC values.
5
0
The effect of desflurane on cumulative dose
requirements using closed loop feedback systems had
not been studied previously. Several studies, however,
have determined the effect of desflurane on the recov-
3
0 min to reach equilibrium and this time span is dif-
ferent for the volatile anesthetic tested. Hendricks et
1
5
al. showed that uptake for desflurane and isoflurane
might even take up to an hour. These findings limit at
least the interpretation of the degree of ED5 0 or ED9 5
reductions. Wulf et al. admit themselves that the appli-
cation of the total dose in increments could have under-
estimated the effect of the duration of action of
cisatracurium during continuous infusion of propofol.
Finally, in contrast to the current study, which used the
1
9
ery of neuromuscular blockade of vecuronium,
20
2 1
mivacurium and rapacuronium. Desflurane pro-
longed the recovery of neuromuscular blockade of
those non-depolarizing blocking drugs in a degree
similar to sevoflurane or isoflurane.
One reason for the significantly higher ETI reduc-
tion by desflurane in comparison to sevoflurane or
isoflurane might be the need for a much higher partial
pressure to achieve the same MAC multiples because
of its weaker anesthetic potency.
16
algorithm presented by Mapleson to calculate the age-
related adaptation of MAC value for each patient, the
Vol % equalling MAC was not adjusted to age.
However, 1 MAC of desflurane in 100% oxygen for a
In our study, isoflurane, sevoflurane and desflurane
at 1.3 MAC reduced the cumulative dose require-
ments of cisatracurium by 42%, 41% and 60% in com-
4
5
0-yr-old patient would be 6.6 Vol % in comparison to
.1 Vol % for an 80-yr-old patient, a difference of 25%.
In contrast to the present study, most studies have
–1
– 1
parison to propofol at 6–8 mg·kg ·hr . Our findings
did not differ from other investigators who - in con-
compared cumulative dose requirements of volatile
anesthetics in breathing gas mixtures including nitrous
22,23
trast to animal studies -
could not show any inter-
1
7
oxide. A recent study, however, shows by calculating
isoboles for desflurane and cumulative doses of nitrous
oxide, that the decrease of the required desflurane con-
centrations by the administration of nitrous oxide
might be less than expected from their MAC values.
This could mean that for different volatile anesthetics,
the additive effect of nitrous oxide might be different,
limiting the comparability of the studies. In the current
action between iv anesthetic agents such as
midazolam, etomidate, thiopental or fentanyl and
1
4
muscle relaxants. Propofol seems to show an inter-
action similar to these other agents.
The clinical implication of this study is that the
dose of cisatracurium required to maintain a given
degree of neuromuscular blockade is influenced by
volatile anesthetics as much as for other muscle relax-

536
CANADIAN JOURNAL OF ANESTHESIA
ants such as vecuronium, rocuronium or atracurium
and needs to be adjusted accordingly. It is noteworthy
that desflurane reduced the ETI of cisatracurium in
comparison to sevoflurane or isoflurane by a further
9 Mellinghoff H, Radbruch L, Diefenbach C, Buzello W. A
comparison of cisatracurium and atracurium: onset of
neuromuscular block after bolus injection and recovery
after subsequent infusion. Anesth Analg 1996; 83:
1072–5.
2
0%; this might have economic implications in surg-
eries such as neurosurgical procedures where a high
degree of neuromuscular blockade must be main-
tained for a long period of time but short awakening
times are desirable. Large interindividual differences,
however, and the absence of any correlation between
patient characteristics, such as age, weight or even
body surface area, and the ETI to maintain the desired
level of neuromuscular blockade make monitoring of
the neuromuscular function mandatory. When moni-
toring neuromuscular blockade at the adductor polli-
cis muscle, one should remember the shorter onset,
faster recovery and less intense block at the orbicularis
oculi muscle2 4 for appropriate site-related relaxation.
10 Olkkola KT, Schwilden H. Adaptive closed-loop feed-
back control of vecuronium-induced neuromuscular
relaxation. Eur J Anaesth 1991; 8: 7–12.
11 Olkkola KT, Kansanaho M. Quantifying the interaction
of vecuronium with enflurane using closed-loop feed-
back control of vecuronium infusion. Acta Anaesthesiol
Scand 1995; 39: 489–93.
12 Olkkola KT, Schwilden H. Quantitation of the interac-
tion between atracurium and
succinylcholine using
closed-loop feedback control of infusion of atracurium.
Anesthesiology 1990; 73: 614–8.
13 Kansanaho M, Olkkola KT. Quantifying the effect of
enflurane on atracurium infusion requirements. Can J
Anaesth 1995; 42: 103–8.
References
14 Olkkola KT, Tammisto T. Quantifying the interaction
of rocuronium (Org 9426) with etomidate, fentanyl,
midazolam, propofol, thiopental, and isoflurane using
closed-loop feedback control of rocuronium infusion.
Anesth Analg 1994; 78: 691–6.
15 Hendrickx JFA, Soetens M, Van der Donck A, Meeuwis
H, Smolders F, De Wolf AM. Uptake of desflurane and
isoflurane during closed-circuit anesthesia with sponta-
neous and controlled mechanical ventilation. Anesth
Analg 1997; 84: 413–8.
16 Mapleson WW. Effect of age on MAC in humans: a
meta-analysis. Br J Anaesth 1996; 76: 179–85.
17 Ropcke H, Wartenberg HC, Konen-Bergmann M. The
interaction of desflurane and nitrous oxide on EEG
during surgical stimulation is additive. Anesthesiology
1998; 89: A108 (abstract).
18 Rehberg B, Bouillon T, Zinserling J, Hoeft A.
Comparative pharmacodynamic modeling of the elec-
troencephalography-slowing effect of isoflurane,
sevoflurane, and desflurane. Anesthesiology 1999; 91:
397–405.
19 Ghouri AF, White PF. Comparative effects of desflurane
and isoflurane on vecuronium-induced neuromuscular
blockade. J Clin Anesth 1992; 4: 34–8.
20 Gan TJ, Quill TJ, Pressley C, Parrillo S, Glass PSA. A
comparison of mivacurium dosage requirements during
isoflurane and desflurane anesthesia. J Clin Anesth
1996; 8: 301–6.
21 Zhou TJ, Coloma M, White PF, et al. Spontaneous
recovery profile of rapacuronium during desflurane,
sevoflurane, or propofol anesthesia for outpatient
laparoscopy. Anesth Analg 2000; 91: 596–600.
22 Khuenl-Brady KS, Agoston S, Miller RD. Interaction of
ORG 9426 and some of the clinically used intravenous
1
2
3
4
Lepage JY, Malinovsky JM, Malinge M, Cozian A,
Pinaud M. Comparison of equipotent doses of 51W89
and atracurium. Anesthesiology 1994; 81: A1090
(abstract).
Lien CA, Belmont MR, Abalos A, et al. The cardiovas-
cular effects and histamine-releasing properties of
51W89 in patients receiving nitrous oxide/opioid/bar-
biturate anesthesia. Anesthesiology 1995; 82: 1131–8.
Doenicke A, Soukup J, Hoernecke R, Moss J. The lack of
histamine release with cisatracurium: a double-blind
comparison with vecuronium. Anesth Analg 1997; 84:
6
23–8.
Vanlinthout LEH, Booij LHD, Van Egmond J,
Robertson EN. Effect of isoflurane and sevoflurane on
the magnitude and time course of neuromuscular block
produced by vecuronium, pancuronium and atracuri-
um. Br J Anaesth 1996; 76: 389–95.
5
6
7
8
O’Hara DA, Derbyshire GJ, Overdyk FJ, Bogen DK,
Marshall BE. Closed-loop infusion of atracurium with
four different anesthetic techniques. Anesthesiology
1991; 74: 258–63.
Wulf H, Kahl M, Ledowski T. Augmentation of the
neuromuscular blocking effects of cisatracurium during
desflurane, sevoflurane, isoflurane or total i.v. anaesthe-
sia. Br J Anaesth 1998; 80: 308–12.
Kim KS, Chung CW, Shin WJ. Cisatracurium neuro-
muscular block at the adductor pollicis and the laryn-
geal adductor muscles in humans. Br J Anaesth 1999;
83: 483–4.
Carroll MT, Mirakhur RK, Lowry DW, McCourt KC,
Kerr C. Neuromuscular blocking effects and train- of-
four fade with cisatracurium: comparison with other non-
depolarising relaxants. Anaesthesia 1998; 53: 1169–73.

Hemmerling et al.: DESFLURANE REDUCES ETI OF CISATRACURIUM
537
anaesthetic agents in the cat. Acta Anaesthiol Scand
1992; 36: 260–3.
23 Krieg N, Rutten JMJ, Crul JF, Booij LHDJ.
Preliminary review of the interactions of ORG NC 45
with anaesthetics and antibiotics in animals. Br J
Anaesth 1980; 52: 33S–6S.
2
4 de Rossi L, Fritz H, Krober L, Klein U. Cisatricurium in
the orbicularis oculi muscle. Comparisn of the neuro-
muscular action of cisatracurium and atracurium in the
orbicularis oculi muscle and the adductor pollicis mus-
cle. (German). Anaesthesist. 1999; 48: 602–6.
Appendix
Estimating the Effective Therapeutic Infusion rate (ETI)
Given a drug disposition function of the form
G(t) = Ae– t + Be– ß t + Ce– ....
a
(t
the cumulative drug requirement D(t) to maintain a
given plasma concentration c is given by
0
k12
k 21
t
k13
-
- k31t
D(t)=V c (1+k t +
(1- e
)+
(1- e
) +....
c
0
el
k 21
k31
whereby V denotes the central volume of distribution
c
and k the transfer micro-constants associated with the
ij
hybrid constants A, a , B, ß, C, (...
The asymptote A(t) to the cumulative drug require-
ment is a straight line.
A(t) = D +I t,
0
a s
the slope Ias of which defines an infusion rate. If D(t)
is measured at constant drug effect, than Ias denotes
the infusion rate which is effective to maintain that
effect at steady-state (I ). If the effect was chosen with-
s s
in the therapeutic window, I defines an effective ther-
a s
apeutic infusion (ETI).
This infusion rate can be estimated by least square
fitting the above formula for D (t) to the measured
cumulative drug requirement as identified by the closed
loop system.