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Published online http://www.ajcconline.org 2009 American Association of Critical-Care Nurses

doi: 10.4037/ajcc20098832009;18:439-445Am J Crit CareShiva Gautam, Atul Malhotra and Matthias EikermannPhilipp Fassbender, Gtz Geldner, Manfred Blobner, Rainer Hofmockel, Christopher Rex,Administered Long-TermClinical Predictors of Duration of Action of Cisatracurium and Rocuronium

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By Philipp Fassbender, MD, Gtz Geldner, MD, Manfred Blobner, MD, RainerHofmockel, MD, Christopher Rex, MD, Shiva Gautam, PhD,Atul Malhotra, MD,and Matthias Eikermann, MD

Background The duration of action of neuromuscular block-

ing drugs (NBDs) varies between individuals and even within

individuals in different settings.

Objectives To define predictors of variance in duration of

action of rocuronium and cisatracurium administered long-term.

Methods A prospective, double-blind, multicenter trial that

included 113 patients scheduled for major abdominal surgery

and postoperative admission to the intensive care unit.

Patients received repetitive (median, 7) equipotent doses of

rocuronium or cisatracurium to maintain deep relaxation

(twitch height of the adductor pollicis muscle


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Uncontrolled neuromuscular blockade may

increase the morbidity of critically ill patients. In fact,

even a minimal degree of partial

paralysis that cannot be detected

without quantitative neuromuscular

transmission monitoring (train-of-4

ratio, 0.5-1.0) can put a patient with

an unsecured upper airway at risk of

severe respiratory complications7

such as upper airway obstruction.8-10

Moreover, long-term administration

of NBDs is a risk factor for the

development of critical illness

polyneuropathy.11-14 Finally, recent

animal data suggest that a constant

neuromuscular blockade with rocuronium andcisatracurium over only a single day evokes a myopa-

thy that significantly decreases diaphragmatic force.12,14

Therefore, we feel it is important for clinicians

to get information about variables that predict the

duration of action of NBDs administered long-term.

We aimed at determining predictors of duration of

action of cisatracurium and rocuronium administered

long-term. Both of these NBDs are often used in

anesthesia and intensive care medicine.4 On the basis

of published data, we thought that weight,15,16 age,17

sex,18American Society of Anesthesiologists (ASA)

risk score,19 blood loss (suggesting instability of

cardiac output),20,21 lowest core body temperature,22

duration of NBD administration,23 and tobacco

smoking history24-26 might contribute to the vari-

ance in the mean duration of action of cisatracurium

and rocuronium.

MethodsThis randomized, double blinded, multicenter

trial was performed at 5 German hospitals. After

approval was gained from the local ethics commit-

tees, we evaluated 400 patients scheduled for major

abdominal surgery of at least 3 hours duration and

subsequent admission to an intensive care unit

(Figure 1). Informed consent was obtained from

338 patients who met the preoperative inclusion

criteria and did not have a history of neuromuscu-

lar, cardiovascular, pulmonary, or neurological dis-

order or acute renal or hepatic failure. Patients werethen included if they met a final intraoperative

inclusion criterion: intraoperative administration

of at least 4 doses of NBD before admission to the

ICU. Patients were randomly assigned to 2 groups

to receive either rocuronium or cisatracurium.

Acceleromyography (TOF-WatchSX Monitor,

Organon Teknika, Eppelheim, Germany) of the

adductor pollicis muscle was used to monitor neu-

romuscular transmission.9,27After calibration of the

device, the ulnar nerve was stimulated supramaximally

N

euromuscular blocking drugs (NBDs) are commonly used in anesthesia and

to treat critically ill patients in intensive care units (ICUs),1,2 but few clinicians

use neuromuscular transmission monitoring.3-5 In the United Kingdom, 31%

of critically ill children are likely to receive NBDs, but the depth of the block-

ade is routinely assessed in only 16% of patients.2 Results of a recent survey4

indicated that only 22% of Canadian ICUs use standardized protocols for NBD applicationand that 16% of all Canadian intensive care providers do not use neuromuscular transmission

monitoring at all. Absence of neuromuscular transmission monitoring during repetitive

administration of NBDs may be a patient safety issue, because partial paralysis is difficult to

detect without neuromuscular transmission monitoring6 and has been known to persist more

than 72 h in critically ill patients.1

About the AuthorsPhilipp Fassbender is a resident in anesthesiology atUniversitt Duisburg-Essen and UniversittsklinikumEssen, Germany. Gtz Geldner is an anesthesiologist atKlinikum Ludwigsburg and Philipps-Universitt, Mar-burg, Germany. Manfred Blobner is an anesthesiologistat Klinikum rechts der Isar and Technische UniversittMnchen, Munich, Germany. Rainer Hofmockel is ananesthesiologist at Universittsklinikum Rostock, Ger-

many. Christopher Rex is an anesthesiologist atKlinikum am Steinenberg, Reutlingen, Germany. ShivaGautam is a statistician at Beth Israel Deaconess Med-ical Center, Boston, Massachusetts. Atul Malhotra is apulmonary intensivist at Brigham and Womens Hospitaland Harvard Medical School in Boston, Massachusetts.Matthias Eikermann is an anesthesiologist and inten-sivist at Massachusetts General Hospital and HarvardMedical School, Boston, Massachusetts.

Corresponding author: Philipp Fassbender, Klinik frAnsthesiologie und Intensivmedizin, Universittskli-nikum Essen, Hufelandstrae 55, 45122 Essen, Germany(e-mail: [email protected]).

Uncontrolled

neuromuscular

blockade

increases

morbidity in

critically ill

patients.

440 AMERICAN JOURNAL OF CRITICAL CARE, September 2009, Volume 18, No. 5 www.ajcconline.org

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that only duration of NBD administration (mean

[95% confidence interval, CI], 4.6 [3.6-5.3] h) is

predictive of (P< .001) the duration of action of

rocuronium and explains 44% of its variance. The

dur 25 (mean [SD], 13.3 [4.1] min) was calculated

to increase by 1.68 (95% CI, 0.60-2.76) min with

each hour of NBD administration.

For cisatracurium, only lowest body tempera-

ture (mean [95% CI], 35.7C [35.3C -36.2C]) is

predictive of (P< .005) its duration of action and

explains 17% of its variance. Thedur 25 of cisatracurium increased

by 2.4 (95% CI, 0.66-4.13) min per

degree Celsius decrease in body

temperature and had a mean (SD)

of 15.1 (4.3) min (Figure 2).

We wondered whether the same

variables that were predictive of the

dur 25 would be predictive of the

dur TOF 0.9, a variable that might

be more clinically relevant. Linear

regression revealed that duration of

NBD administration is predictive of(P< .001) dur TOF 0.9 of rocuro-

nium and explains 57% of its variance. The dur

TOF 0.9 was calculated to increase by a mean of

12.4 (95% CI, 8.3-16.5) min per hour of NBD

administration. In turn, lowest body temperature is

predictive of (P< .001) dur TOF 0.9 of cisatracurium

and explains 37% of its variance. The dur TOF 0.9

of cisatracurium increased by 9.8 (95% CI, 6.25-

13.36) min per degree Celsius decrease in lowest

body temperature (Figure 3).

DiscussionResults of this study show that the duration of

action of cisatracurium and rocuronium administered

long-term can be predicted by means of different

variables. Duration of rocuroniums effects increases

with increasing duration of its administration,

whereas the lowest body temperature is predictive

of the duration of action of cisatracurium.

Rocuroniums elimination half-life (83 min) is

longer than that of cisatracurium (26 min).28The

differences in elimination half-life, however, do notnecessarily translate into a longer duration of action

of rocuronium if single doses or short-term infu-

sions are given. Results of several studies29-31 indicate

that the clinical durations of cisatracurium and

rocuronium do not significantly differ under those

conditions. Rocuronium is taken up by the liver

and excreted into bile in high concentrations, and

the major routes of elimination of unchanged

rocuronium are in the feces and urine.32 Redistribu-

tion plays an important role as a patient recovers

from rocuronium-induced neuromuscular block-

ade.33

In contrast, cisatracurium is removed by Hof-mann elimination and has an intermediate clearance

(0.3 L/kg per hour).28These differences in elimina-

tion of NBDs may explain our observation that

rocuroniums duration of action increases with dura-

tion of its administration, whereas cisatracuriums

duration of action remains unchanged over time.

We thought that blood loss and hypothermia,

conditions that affect hepatic function, would increase

rocuroniums duration of action. In fact, both vari-

ables correlated with the dur 25 of rocuronium.

Figure 2 Individual mean values of the duration of recovery of the single twitch height to 25% of baseline (dur 25) asa function of its predictors. A, Cisatracurium. Lowest core body temperature is predictive of duration of action ofcisatracurium. B, Rocuronium. Duration of rocuronium administration is predictive of the duration of action of therocuronium.

Core body temperature, C

Meandur25,min

Meandur25,min

Duration of rocuronium administration, min

B

4

100 150 200 250

r=0.73

300 350 400 450 500

6

8

10

12

14

16

18

20

22

A

5

33 34 35

r=0.44

36 37 38

10

15

20

25

30

35

Neuromuscular

transmission

monitoring with

cisatracurium

is particularly

important in

hypothermic

patients.




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we did not find a correlation of age with the dura-

tion of action of either of the 2 muscle relaxants we

studied. Absence of a significant age effect may be

explained by the relatively low age range of our

patients, which in turn may reflect the typical age

range of patients admitted to a surgical ICU.38,39The

patients sex also was not predictive of the duration

of action of NBDs. In contrast, Xue et al18 reported a

significantly longer dur 25 of rocuronium in women

than in men. This difference may

be explained by the different meanage of the patients included in that

study. The mean age of participants

in the study by Xue et al was 30

years, whereas the mean age in our

study was approximately 60 years.

Thus it is likely that most of the

women included in our study were

postmenopausal, and the differ-

ence in sexual hormone levels between the partici-

pants in the 2 studies may explain the different

results relating to steroid metabolism.40

The ASA physical status classification is a scor-ing system designed to stratify patients according to

their perioperative risk. It is assigned either in the

preoperative period or at the time of surgery by the

anesthesiologist. The ASA classification score is

included in the Department of Veterans Affairs

National Surgical Quality Improvement Program

database and is predictive of patients outcome after

surgical procedures such as liver resection.41 However,

much like Blobner et al,19we did not find evidence

for the predictive value of the ASA risk score with

However, multiple regression analysis revealed that

only the duration of NBD administration was an

independent predictor of the duration of action of

rocuronium. Thus, high blood loss and low core

body temperature correlated with a longer dur 25

of rocuronium are most likely epiphenomena of an

increased duration of rocuronium administration,

which was an independent predictor of the dur 25

of rocuronium in the multivariate analysis. The

increase in duration of action with time of adminis-

tration may at least partially explain why the neuro-muscular blockade effects of steroidal NBDs can

last extremely long in critically ill patients.1

Cisatracurium is eliminated organ-independ-

ently by Hofmann degradation, which is dependent

on temperature and pH. The influence of hypother-

mia on the time course of action of cisatracurium is

in accordance with observations on cisatracuriums

effects during deep hypothermia for cardiac surgery.22,34

Our data support the view35 that body temperature

already explains significant variation in cisatracuriums

duration of action when varied in a moderate tem-

perature range that is likely to occur in intensivecare patients.36,37 Moderate hypothermia may occur

as a consequence of accidental or controlled intra-

operative hypothermia, or hypothermia may even

be applied as a neuroprotective treatment approach

after cardiopulmonary resuscitation.36,37 Our data

suggest that neuromuscular transmission monitoring

is particularly important when cisatracurium is being

used in critically ill patients with hypothermia.

Age is a factor that may influence the duration

of action of steroidal muscle relaxants.17 However,

Figure 3 Individual mean values of the duration of recovery of the train-of-4 ratio to 90% after the last administrationof a nueromuscular blocking drug (dur TOF 0.9) as a function of its predictors. A, Cisatracurium. Lowest core bodytemperature is predictive of dur TOF 0.9 of cisatracurium. B, Rocuronium. Duration of rocuronium administration is

predictive of dur TOF 0.9 of the rocuronium.

Core body temperature, C

Meandur

TOF0.9,min

A

30

33 34

r=0.62

40

50

60

70

80

3590

100

35 36 37 38

Duration of rocuronium administration, min

Meandur

TOF0.9,min

B

20

0 100

r=0.77

40

50

60

70

90

100

200 300 400 500

www.ajcconline.org AMERICAN JOURNAL OF CRITICAL CARE, September 2009, Volume 18, No. 5 443

Neuromuscularblocking drugs

may cause

polyneuropathy

and myopathy.

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respect to duration of action of NBD. Therefore,

our data do not support the view that NBD dose

should be decreased in patients with serious med-

ical comorbid conditions.

In our study, a tobacco smoking history corre-

lated with the duration of action of rocuronium,

but smoking was not an independent predictor ofrocuroniums dur 25. The existing data on the effects

of smoking on rocuroniums effects are contradic-

tory. Rautoma and Svartling25 reported a significantly

increased requirement for rocuronium in smokers,

and Reisli et al24 reported a significantly longer dur

25 in children with a history of exposure to second-

hand smoke than in children without such exposure.

Phringer et al,26 however, did not find any differ-

ences between tobacco smokers and nonsmokers

in rocuroniums onset time, peak neuromuscular

blockade, and duration of action. Our findings

indicate that tobacco smoking history is not anindependent predictor of the duration of action of

rocuronium, suggesting that the reported association

between smoking and increased duration of action

of rocuronium24,25 is not causative.

Muscle weakness is common in critically ill

patients and may persist in a clinically relevant

fashion even 1 year after patients hospital discharge.42

NBDs have been defined as a risk factor for critical

illness polyneuropathy and myopathy, conditions

manifested by muscle weakness in critically ill

patients.11-14,42 Moreover, infusion of rocuronium12

and cisatracurium14 for a single day in rats compro-

mises diaphragmatic function by a myopathic

mechanism that does not involve neuromuscular

transmission failure.12 Moreover, the combination

of 18 to 69 hours of complete diaphragmatic inac-

tivity and mechanical ventilation results in marked

atrophy of myofibers in the diaphragm of humans.43

Therefore, we advocate that all effort be made

to avoid immobilizing patients unnecessarily by

administering NBDs. If, however, NBDs are required

in the ICU to protect a patient against the potential

risk of high transpulmonary pressures they may

generate, the dose should be titrated by means of

neuromuscular transmission monitoring, takinginto account that the duration of action varies from

patient to patient, particularly during long-term

administration. Quantitative neuromuscular trans-

mission monitoring may be helpful in detecting an

increased duration of action of NBD1 and conse-

quently may even help clinicians reduce the incidence

of muscle weakness in ICU patients.

We could not conduct a study directly in the

ICU because it is very difficult to obtain informed

consent from ICU patients. Furthermore, long-term

administration of NBDs is rarely indicated in ICU

patients. Therefore, we included patients scheduled

for major abdominal surgery with subsequent

admission to an ICU. Our patients did not have

hepatic and renal dysfunction, conditions that will

markedly influence the duration of rocuronium.1,44

We speculate that the association between the dura-tion of rocuronium administration and its duration

of action will be even stronger in patients with

hepatic44 or renal1 failure.

In summary, our data show that core body tem-

perature is an independent predictor of the dura-

tion of action of cisatracurium, whereas the duration

of administration of rocuronium is predictive of the

duration of action of rocuronium.

FINANCIAL DISCLOSURESMatthias Eikermann has provided advice to Schering-Plough, United States.

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www.ajcconline.org AMERICAN JOURNAL OF CRITICAL CARE, September 2009, Volume 18, No. 5 445

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