Download Neuromuscular blocking drugs and their antagonists in patients with

Anaesthesia, 2009, 64 (Suppl. 1), pages 55–65
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Neuromuscular blocking drugs and their antagonists in
patients with organ disease
R. G. Craig1 and J. M. Hunter2
1
Specialist Registrar in Anaesthesia, 2Professor of Anaesthesia, Division of Clinical Science (Anaesthesia), University
Clinical Department, University of Liverpool, Liverpool, UK
Summary
The pharmacodynamics and pharmacokinetics of the currently available neuromuscular blocking
and reversal drugs may be altered by organ disease. Adverse effects such as prolonged neuromuscular block, postoperative residual curarisation, recurarisation, the muscarinic effects of the anticholinesterases, and the side-effects of the antimuscarinics are encountered more frequently. This
review will consider these potential problems and assess the role of sugammadex in enabling the
anaesthetist to avoid them. It will also present the latest knowledge regarding the safety and efficacy
of sugammadex in patients with renal, hepatic, cardiovascular and pulmonary disease.
. ......................................................................................................
Correspondence to: R. G. Craig
E-mail: [email protected]
Accepted: 15 December 2008
Pharmacology of the neuromuscular blocking
and reversal agents in disease states
In renal and hepatic disease a number of factors contribute to alterations in the pharmacokinetics and pharmacodynamics of the neuromuscular blocking drugs
(NMBs). These include: reduced elimination of the drug,
accumulation of active metabolites, altered fluid compartment size, acid–base disturbances, reduced plasma
cholinesterase activity, and an increased likelihood of
drug interactions.
Depolarising neuromuscular blocking drugs
Suxamethonium
Both renal failure and liver disease are associated with
reduced plasma cholinesterase activity [1, 2]; prolonged
neuromuscular block following suxamethonium is possible in these conditions [3, 4]. Suxamethonium administration results in a mild and transient increase in serum
potassium concentration. In individuals with normal renal
function, the serum potassium increases by 0.5–1
mmol.l)1 within 3–5 min of a dose of suxamethonium
and returns to normal after 10–15 min [5]. Patients with
chronic kidney disease do not demonstrate an exaggerated
hyperkalaemic response, and suxamethonium may be
safely administered in the absence of pre-operative
hyperkalaemia or any myopathy or neuropathy [6], but
2009 The Authors
Journal compilation 2009 The Association of Anaesthetists of Great Britain and Ireland
suxamethonium causes myoglobinaemia, albeit rarely,
and has been reported to cause acute rhabdomyolytic
renal failure [7]. Both chronic kidney and liver disease
patients are at risk of developing acute renal failure in the
peri-operative period; it is prudent therefore to avoid
nephrotoxic insults where possible. Nevertheless, if the
airway is at risk and the serum potassium is normal,
suxamethonium can be used in these patients.
Non-depolarising neuromuscular blocking drugs
In patients with chronic kidney disease, as well as those
with hepatic cirrhosis, the initial dose of a non-depolarising neuromuscular blocking drug (NMB) required to
produce block is larger than in normal subjects [8].
Patients with hepatic cirrhosis have long been considered
to be resistant to NMBs, although studies have shown that
neither the sensitivity of the neuromuscular junction nor
protein binding are altered [9, 10]. A delayed onset of
action is evident, which is thought to relate to an
increased volume of distribution and a reduced cardiac
output [10, 11].
When considering the impact of hepatic or renal
dysfunction on the pharmacodynamics of the nondepolarising NMBs, it is important to appreciate that
recovery from a single bolus is due to intercompartmental
distribution. For those drugs that are dependent on organ
function for elimination, prolonged neuromuscular block
55
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R. G. Craig and J. M. Hunter
Pharmacodynamics and pharmacokinetics of NMBs in health and disease
Anaesthesia, 2009, 64 (Suppl. 1), pages 55–65
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Patients with hepatic cirrhosis have an increased total
volume of distribution and clearance of atracurium, but
the elimination half-life does not differ significantly from
controls (Table 3) [20]. A bolus of atracurium
0.5 mg.kg)1 has a slower onset of neuromuscular block
and a shorter duration of action in patients with cirrhosis
than controls (Table 4) [21]. This may be explained by
the larger volume of distribution.
only becomes apparent with repeated bolus doses,
overdosage or the use of continuous infusions of NMB.
Benzylisoquinoliniums
The long-acting benzylisoquinoliniums, d-tubocurarine,
metocurine, alcuronium and doxacurium, are dependent
upon renal excretion for elimination [12–15]. When
given to patients with renal failure they have a duration of
action that is not only prolonged but also considerably less
predictable than in health [16]. Furthermore, their use in
renal patients has resulted in the return of neuromuscular
block after initial antagonism by neostigmine (recurarisation) [17]. This prompted the search for NMBs with
organ-independent routes of elimination. Atracurium,
cisatracurium and mivacurium all undergo breakdown in
the plasma.
Cisatracurium
The 1 R cis-1’R cis isomer of atracurium, cisatracurium, is
more potent and produces less histamine release than
atracurium. Due to its stereochemistry, it is subject to
more Hofmann degradation (80%) and less ester hydrolysis. About 15% of a bolus dose is excreted in the urine
over 24 h in healthy patients [22]. In patients with renal
failure, cisatracurium clearance is reduced by 13% and the
terminal elimination half-life is prolonged by 4.2 min
(Table 1) [22]. The onset is slower, mean time to 90%
depression of the first twitch of the train-of-four response
(T1 ⁄ T0) being 3.7 min vs 2.4 min in controls, but
recovery variables are unchanged (Table 2) [23]. In
patients undergoing liver transplantation the volume of
distribution at steady-state is increased by 21% and the
clearance is increased by 16%, with no change in the
terminal elimination half-life (Table 3) [24]. The onset of
Atracurium
Atracurium undergoes Hofmann degradation, a process of
spontaneous breakdown at body temperature and pH
(45%), as well as metabolism by non-specific esterases in
the plasma (45%). Only about 10% of a bolus dose is
excreted in the urine over 24 h in healthy patients [18].
The pharmacokinetics and pharmacodynamics of atracurium are not altered by chronic kidney disease (Tables 1
and 2) [19].
Table 1 Pharmacokinetic changes in NMBs associated with renal failure.
Volume of distribution at
steady state; l.kg)1
Systemic clearance
Drug
Controls
Benzylisoquinoliniums
d-Tubocurarine
Atracurium
6.1 ml.min)1.kg)1
5.5 ml.min)1.kg)1
Cisatracurium 293 ml.min)1
Mivacurium
Cis–cis
Cis–trans
Trans–trans
Aminosteroids
Pancuronium
3.8 ml.min)1.kg)1
106 ml.min)1.kg)1
57 ml.min)1.kg)1
74 ml.min)1
122.9 ml.min
Vecuronium
Rocuronium
)1
5.29 ml.min)1.kg)1
)1
4.5 ml.min .kg
)1
3.7 ml.min)1.kg)1
56
T1 ⁄ 2b; min
Chronic kidney
disease
Controls
Chronic kidney
disease
Controls
6.7 ml.min)1.kg)1
5.8 ml.min)1.kg)1
254 ml.min)1
0.182
0.153
–
0.224
0.141
–
231
20.6
19.3
30.0
2.4 ml.min)1.kg)1
p < 0.01
80 ml min)1.kg)1
47 ml.min)1.kg)1
0.227
0.224
68.0
80.0
Head-Rapson et al. 1995 [27]
0.278
0.211
0.475
0.270
2.0
2.3
4.3
4.2
Head-Rapson et al. 1995 [27]
Head-Rapson et al. 1995 [27]
20 ml.min)1
p < 0.005
53.0 ml.min)1
p < 0.001
3.08 ml.min)1.kg)1
p < 0.05
2.7 ml.min)1.kg)1
p < 0.0001
2.5 ml.min)1.kg)1
p < 0.05
0.148
0.261
0.236
p < 0.05
0.296
0.199
0.24
52.6
0.194
0.22
0.207
0.212
100
Chronic kidney
disease
330
23.7
20.1
34.2
p < 0.05
Reference
Miller et al. 1977 [12]
Fahey et al. 1984 [19]
Ward et al. 1987 [26]
Eastwood et al. 1995 [22]
McLeod et al. 1976 [29]
57.0
489
p < 0.05
257.3
p < 0.01
83.1
p < 0.05
70.0
97.2
104.4
Cooper et al. 1993 [43]
132.5
Somogyi et al. 1977 [30]
Lynam et al. 1988 [35]
Robertson et al. 2005 [42]
2009 The Authors
Journal compilation 2009 The Association of Anaesthetists of Great Britain and Ireland
2009 The Authors
Journal compilation 2009 The Association of Anaesthetists of Great Britain and Ireland
)1
)1
Rocuronium 0.6 mg.kg
Vecuronium 0.1 mg.kg
Aminosteroids
Pancuronium 6 mg
Mivacurium
150 lg.kg)1 bolus,
then 10 lg.kg)1.min)1
infusion
Cisatracurium 0.1 mg.kg)1
Benzylisoquinoliniums
Atracurium 0.5 mg.kg)1
Drug
Injection to max
T1:T0 depression
116 s
137 s
Injection to max
T1:T0 depression
1.8 min
1.9 min
Injection to 25%
T1:T0 recovery
32
Injection to 25%
T1:T0 recovery
54.1
Onset to 5%
T1:T0 recovery
37–160 (range, n = 7)
9.8
2.1 min
2.7 min
Injection to 95%
T1:T0 recovery
69.5
Injection to 25%
T1:T0 recovery
45.9
Controls
Injection to 5%
T1:T0 recovery
Chronic kidney
disease
Duration; min
Injection to max
T1:T0 depression
1.8 min
2.0 min
Injection to 90%
T1:T0 depression
2.4 min
3.7 min
p < 0.05
Injection to 95%
T1:T0 depression
Controls
Onset
Chronic kidney
disease
49
p < 0.004
98.6
p < 0.05
41–234
(range, n = 6)
15.3
p < 0.01
17.3
44.0
12.2
p < 0.05
12
19
p < 0.001
25–75% T1:T0
7.7
25–75% T1:T0 recovery after
stopping infusion
23.5
10.5
13.1
25–75% T1:T0
25–75% T1:T0
Controls
77.4
Chronic kidney
disease
Recovery index; min
Table 2 Pharmacodynamic changes in NMBs associated with renal failure. Bolus doses unless otherwise stated.
72.5
Chronic kidney
disease
54
88
p < 0.001
Time to 70% recovery of
T4 ⁄ T1 after stopping infusion
12.5
13.7
70.4
Controls
Train-of-four (TOF)
ratio 0.7; min
Robertson et al.
2005 [42]
Lynam et al.
1988 [35]
Somogyi et al.
1977 [30]
Phillips and
Hunter 1992 [1]
Boyd et al.
1995 [23]
Fahey et al.
1984 [19]
Reference
Anaesthesia, 2009, 64 (Suppl. 1), pages 55–65 R. G. Craig and J. M. Hunter
Pharmacodynamics and pharmacokinetics of NMBs in health and disease
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Pharmacodynamics and pharmacokinetics of NMBs in health and disease
Anaesthesia, 2009, 64 (Suppl. 1), pages 55–65
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Table 3 Pharmacokinetic changes in neuromuscular blocking drugs associated with liver disease.
Systemic clearance
Drug
Pathology
Benzylisoquinoliniums
Atracurium
Hepatic cirrhosis N = 8
6.6
70
Cis–cis
5.2
Aminosteroids
Pancuronium
Hepatic cirrhosis N = 14
1.86
Vecuronium
Hepatic cirrhosis N = 12
4.26
4.5
Rocuronium
Hepatic cirrhosis and
alcoholic hepatitis
N = 10
Hepatic cirrhosis
N = 17
Hepatic cirrhosis
N = 10
3.7
2.79
8.0
202.1
281.8
p < 0.05
195
p < 0.05
20.9
24.5
23.5
24.4
6.6
p < 0.05
161
44
p < 0.05
32
p < 0.05
4.2
210
188
1.5
200
199
2.3
266
237
50.3
1.45
p < 0.05
2.73
p < 0.01
4.4
279
246
416
p < 0.05
253
180
220
57.7
2.66
p < 0.005
2.41
210.7
247.9
92
184
234
87.5
action is more rapid but the recovery profile is unchanged
(Table 4) [24]. The rapid onset may reflect a hyperdynamic circulation in this group of patients with severe
liver disease.
Laudanosine is a product of Hofmann degradation and is
known to be epileptogenic in animals [25]. Plasma
laudanosine concentrations > 10 lg.ml)1 induce epileptiform EEG changes in anaesthetised dogs, whilst plasma
concentrations > 17 lg.ml)1 result in prolonged seizures
[25]. However, the mean peak plasma laudanosine
concentration 2 min after atracurium 0.3–0.4 mg.kg)1 is
only 0.27 lg.ml)1 in renal failure patients and
0.19 lg.ml)1 in controls (not statistically significant)
[26]. Similarly, the elimination half-life and clearance of
laudanosine are not significantly altered by renal failure
[26]. After cisatracurium 0.1 mg.kg)1, the mean peak
plasma laudanosine concentration is much lower at 0.031
lg.ml)1 in renal failure patients and 0.023 lg.ml)1 in
controls [22].
The peak laudanosine concentration after atracurium
0.6 mg.kg)1 is 0.149 lg.ml)1 in patients with cirrhosis
and 0.198 lg.ml)1 in controls [20]. The elimination halflife and volume of distribution of laudanosine are
increased in patients with cirrhosis [20]. There is,
however, no change in its clearance.
58
T1 ⁄ 2b
Liver disease; Controls; Liver disease; Controls; Liver disease;
Controls;
ml.kg)1
min
min
ml.min)1.kg)1 ml.min)1.kg)1 ml.kg)1
Reference
5.7
Cisatracurium End-stage liver disease
undergoing
transplantation
N = 14
Mivacurium
Hepatic cirrhosis N = 11
Cis–trans
95
Trans–trans
Volume of distribution
at steady state
114
58
2.5
p < 0.05
11.1
p < 0.001
60.8
Parker and Hunter
1989 [20]
De Wolf et al.
1996 [24]
Head-Rapson
et al. 1994 [2]
208
p < 0.005
84
p < 0.01
51.4
Duvaldestin
et al. 1978 [28]
Lebrault et al.
1985 [39]
Arden et al.
1988 [37]
143
p < 0.05
96.0
Van Miert et al.
1997 [46]
Khalil et al.
1994 [10]
Mivacurium
Mivacurium consists of three isomers: cis–trans (37%),
trans–trans (57%), and cis–cis (6%). Clearance of the cis–cis
isomer, which contributes only slightly to neuromuscular
block, is significantly reduced in renal failure patients and
it may accumulate (Table 1) [27]. Chronic kidney disease
may be associated with an acquired decrease in plasma
cholinesterase activity and this correlates with time to
recovery from mivacurium induced block [1]. Spontaneous recovery is slower, and lower infusion rates are
required (Table 2) [1]. In patients with liver cirrhosis,
reduced plasma cholinesterase activity results in a 54%
decrease in the clearance of the trans–trans and cis–trans
isomers, with an increase in the terminal elimination halflives compared with healthy subjects: trans–trans 11.1 min
vs 2.3 min; and cis–trans 2.5 min vs 1.5 min (Table 3) [2].
The clearance and terminal elimination half-life of the
cis–cis isomer are unaffected. Recovery from neuromuscular block is delayed (Table 4) [2].
Aminosteroids
Pancuronium
Pancuronium is excreted mainly in the urine, although
35% undergoes hepatic metabolism with biliary excretion
of the metabolites. One of the metabolites, 3-hydroxy 2009 The Authors
Journal compilation 2009 The Association of Anaesthetists of Great Britain and Ireland
2009 The Authors
Journal compilation 2009 The Association of Anaesthetists of Great Britain and Ireland
0.6 mg.kg
0.6 mg.kg
)1
)1
Rocuronium
0.1 mg.kg)1
108.3 s
Injection to 100%
T1:T0 depression
1.9 min
2.8 min
p < 0.005
Injection to max
T1:T0 depression
108 s
158 s
p < 0.01
Injection to 90%
T1:T0 depression
63.6 s
60.3 s
98.8 s
0.2 mg.kg)1
143.0 s
Injection to max
T1:T0 depression
172.7 s
248.7 s
111.0 s
0.2 mg.kg)1
Liver
disease
Injection to max
T1:T0 depression
109.7 s
186.3 s
p < 0.001
Injection to max
T1:T0 depression
3.3 min
2.4 min
p < 0.05
Injection to 90%
T1:T0 depression
5.9 min
6.8 min
p < 0.05
Controls
0.15 mg.kg)1
0.1 mg.kg)1
Aminosteroids
Vecuronium
Mivacurium
15 lg.kg)1.min)1
infusion for 10 min
Cisatracurium 0.1 mg.kg)1
Benzylisoquinoliniums
Atracurium 0.5 mg.kg)1
Drug
Onset
Liver
disease
90.5
p < 0.05
Injection to 75%
T1:T0 recovery
57
77
p < 0.05
Injection to 25%
T1:T0
42.3
53.7
p < 0.05
Injection to 50%
T1:T0 recovery
62
130
p < 0.01
Injection to 50%
T1:T0 recovery
66.1
59.8
65
Injection to 20%
T1:T0 recovery
33.5
27.3
p < 0.05
48.95
49.4
Injection to 25%
T1:T0 recovery
12.8
19.8
Injection to 20%
T1:T0 recovery
43.1
34.1
p < 0.05
Injection to 25%
T1:T0 recovery
46.9
53.5
Controls
Duration; min
26.0
25–75% T1:T0
17
25–75% T1:T0
21
38.2
35
p < 0.01
44
p < 0.05
76.1
T4:T1 = 0.7
69
T4:T1 = 0.7
24.1
7.4
25–75% T1:T0
T4:T1 = 0.7
25–75% T1:T0
11.8
p < 0.01
80.4
12.8
Controls
T4:T1 = 0.7
15.4
Liver
disease
114.9
p < 0.01
93
40.1
p < 0.05
79.0
Liver
disease
Train-of-four (TOF)
70%; min
25–75% T1:T0
Controls
Recovery index; min
Table 4 Pharmacodynamic changes in NMBs associated with liver disease. (Bolus doses unless otherwise stated.)
Van Miert et al.
1997 [46]
Khalil et al.
1994 [10]
Arden et al.
1988 [37]
Lebrault et al.
1985 [39]
Bell et al.
1985 [21]
Hunter et al.
1985 [38]
Hunter et al.
1985 [38]
Head-Rapson
et al. 1994 [2]
De Wolf et al.
1996 [24]
Bell et al.
1985 [21]
Reference
Anaesthesia, 2009, 64 (Suppl. 1), pages 55–65 R. G. Craig and J. M. Hunter
Pharmacodynamics and pharmacokinetics of NMBs in health and disease
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Pharmacodynamics and pharmacokinetics of NMBs in health and disease
Anaesthesia, 2009, 64 (Suppl. 1), pages 55–65
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pancuronium, has half the neuromuscular blocking
potency of the parent compound. Five to 10% of a dose
is metabolised to 3-hydroxypancuronium [28]. The
clearance of pancuronium is reduced and the half-life
prolonged in patients with chronic kidney disease
(Table 1) [29, 30]. Numerous case reports describe
prolonged neuromuscular block after pancuronium in
patients with renal failure [31, 32].
In patients with hepatic cirrhosis, the total apparent
volume of distribution of pancuronium is increased by
50%, clearance is reduced by 22%, and the elimination
half-life increases from 114 to 208 min (Table 3) [28].
Patients require a large initial dose but elimination is
slower. There is, therefore, a risk of a very prolonged
block. Prolonged neuromuscular block and postoperative
residual curarisation has been described after pancuronium in patients with chronic liver disease and severe biliary
obstruction [33].
Vecuronium
Vecuronium predominantly undergoes biliary excretion,
although up to 30% may be excreted in the urine [34].
Only a small fraction of the drug undergoes hepatic
metabolism to 3-hydroxyvecuronium, which is active at
the neuromuscular junction. In patients with renal failure,
clearance is reduced, terminal elimination half-life is
increased, and the duration of action is prolonged
(Tables 1 and 2) [35]. Accumulation occurs with repeat
boluses or infusions [36].
In patients with liver cirrhosis the duration of action
of vecuronium is related to the dose; the action of a
small dose is terminated mainly by redistribution, but
the termination of action of the drug in larger doses is
also dependent on hepatic clearance. A dose of
vecuronium 0.1 mg.kg)1 has a slower onset and shorter
duration of action in patients with cirrhosis compared
to healthy patients (Table 4) [21, 37]. A dose of
0.15 mg.kg)1 has a similar onset and duration of action
in cirrhotics and controls [38]. A dose of 0.2 mg.kg)1
has a similar onset time (108.3 s in cirrhotic patients
vs 98.8 s in healthy controls) but a significantly longer
duration of action (90.5 min in cirrhotic patients
vs 65 min in healthy patients) [38, 39]. The
slower onset and more rapid recovery from a small
dose of vecuronium in patients with cirrhosis would
be consistent with an increase in its volume of
distribution.
Rocuronium
The elimination of rocuronium is dependent upon biliary
excretion of the unchanged drug, although up to 33% is
excreted in the urine within 24 h [40]. Only a small
fraction is metabolised in the liver producing a metabolite
60
with insignificant neuromuscular blocking activity [41].
The clearance of rocuronium is reduced by 39% in renal
failure (Table 1) [42, 43]. The time to recovery of the
train-of-four (TOF) ratio to 0.7 is significantly prolonged
in patients with renal failure compared to controls: 88 vs
54 min (Table 2) [42]. Interindividual variability is
increased in renal failure patients, resulting in a less
predictable duration of action.
In patients with liver cirrhosis, the central volume of
distribution of rocuronium is expanded by 33%, with a
43–75% increase in the volume of distribution at steadystate [10, 44, 45]. The increased volume of distribution
correlates with a slower onset of neuromuscular block in
cirrhotic patients compared to controls: mean (SD)
onset = 158 (56)s vs 108 (33)s (Table 4) [10]. Khalil
et al. [10] using old controls did not find a significant
difference in plasma clearance and elimination half-life in
cirrhotic patients; whilst van Miert et al. [46] demonstrated a 28% reduction in clearance and a 55% increase
in elimination half-life in the cirrhotic group (Table 3).
The latter study had the advantage of a larger sample size
and more frequent and prolonged estimation of the
rocuronium plasma concentration. The time taken for
recovery of the TOF ratio to 70% is increased from
76.1 min in healthy patients to 114.9 min in patients
with cirrhosis (Table 4) [46]. Patients with liver cirrhosis
also demonstrate greater interpatient variability in
response to rocuronium.
Reversal agents
Anticholinesterases
Inhibition of acetylcholinesterase at the neuromuscular
junction prolongs the half-life of acetylcholine and
potentiates its action on nicotinic receptors, thereby
overcoming the competitive antagonistic effect of residual
non-depolarising NMB. However, the inhibition of
acetylcholinesterase also results in muscarinic side-effects
such as bradycardia, vomiting, and bronchoconstriction.
Anticholinesterases are combined with an antimuscarinic
agent such as atropine or glycopyrronium to counteract
these effects. The use of glycopyrronium is thought to
result in better control of secretions and a lower incidence
of arrhythmias than atropine [47].
Fifty percent of the plasma clearance of neostigmine is
dependent on renal excretion; it also undergoes breakdown by esterases in the plasma [48]. Neostigmine has a
prolonged half-life and reduced clearance in patients with
renal failure; it may precipitate bradycardia or atrioventricular block, especially when combined with the
shorter-acting atropine [48]. The absence of renal function also significantly reduces the clearance of edrophonium [49]. Its elimination half-life is significantly
2009 The Authors
Journal compilation 2009 The Association of Anaesthetists of Great Britain and Ireland
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Anaesthesia, 2009, 64 (Suppl. 1), pages 55–65 R. G. Craig and J. M. Hunter
Pharmacodynamics and pharmacokinetics of NMBs in health and disease
...............................................................................................................................................................................................................................................................................................
prolonged; 206 min in anephric patients compared to
114 min in controls.
Sugammadex
The mechanism of action of sugammadex differs from
that of the anticholinesterases. It chelates rocuronium in
the plasma, precipitating a decrease in the concentration
of free rocuronium and passive diffusion of the drug away
from the neuromuscular junction. It is also capable of
encapsulating vecuronium. Sugammadex is water soluble
and does not bind to plasma proteins [50]. Its volume of
distribution is 18 l, clearance 84–93 ml.min)1 and terminal elimination half-life 136 min [51, 52].
Sugammadex is excreted unchanged in the urine: the
mean cumulative percentage over 24 h is 48–86% [52].
There is no relationship between the dose of sugammadex
given and the percentage excreted in the urine [52].
Interestingly, the renal excretion of rocuronium is
increased by the use of sugammadex. This phenomenon
is consistent with the urinary excretion of the sugammadex–rocuronium complex. The median cumulative
excretion of rocuronium in the urine over 24 h increases
from 26% to 58–74% of the administered dose after
sugammadex 4–8 mg.kg)1 [52]. The total clearance of
rocuronium in the presence of sugammadex is less than
that of rocuronium alone; rocuronium encapsulated by
sugammadex is not subjected to biliary excretion.
Sugammadex reversal of rocuronium-induced neuromuscular blockade results in faster recovery of the TOF
ratio to 0.9 and less interpatient variability compared to
neostigmine [53, 54]. Sugammadex is also able to reverse
profound block [55, 56]. Given the greater inter-patient
variability in response to rocuronium in patients with
renal failure and hepatic cirrhosis the ability to reverse
profound block in such patients would be a considerable
advantage.
Incomplete reversal
Sugammadex encapsulates rocuronium to form a guesthost complex that exists in equilibrium with a very low
dissociation rate. The complex is tight and provided an
adequate dose is given, recurarisation is unlikely and has
not been reported. A case in which a temporary decrease
in train-of-four response was observed in an obese but
otherwise healthy patient after reversal of rocuroniuminduced block was the result of the administration of a
small and inadequate dose of sugammadex (0.5 mg.kg)1)
[57]. The train-of-four ratio initially peaked at between
0.6 and 0.7 before decreasing to 0.3 and then gradually
increasing to > 0.9. This may have occurred because of
redistribution of unbound rocuronium from the peripheral compartments with insufficient sugammadex available for additional complex formation. It is not due to
2009 The Authors
Journal compilation 2009 The Association of Anaesthetists of Great Britain and Ireland
dissociation of the encapsulated rocuronium. Similarly,
incomplete reversal was reported in two healthy patients
who were given a small dose of sugammadex 0.5 mg.kg)1
during profound rocuronium-induced neuromuscular
blockade [55]. Time to recovery decreases with increasing
doses of sugammadex and at least 2 mg.kg)1 should be
given, increasing to higher doses if the block is deep at the
time of the reversal.
Efficacy and safety of sugammadex in patients
with organ disease
Chronic kidney disease
An animal study involving cats with bilateral renal artery
ligation demonstrated the rapid and complete reversal of
rocuronium-induced block by sugammadex in the
absence of renal function [58]. More recently, Staals
et al. [59], in a small study of 15 renal patients,
demonstrated the efficacy of sugammadex in patients
with a creatinine clearance of < 30 ml.min)1. The time
to recovery of the TOF ratio to 0.9 after sugammadex
2 mg.kg)1 given at reappearance of the second twitch of
the TOF was compared to 15 controls; there was no
significant difference, with a mean time to recovery of
2.0 min and 1.65 min respectively. The estimated mean
absolute difference in time from the start of administration
of sugammadex to recovery of the TOF ratio to 0.9
between renal patients and controls was 20.1 s (95% CI:
)12.1 to + 52.3 s). There was no evidence of recurarisation.
Urinary N-acetyl-glucosaminidase (NAG) is a measure
of proximal tubule damage. Sorgenfrei et al. [60] documented abnormal values in five out of 22 patients who
received sugammadex. Sparr et al. [52] administered
sugammadex to 88 healthy patients and reported abnormal values for urinary N-acetyl-glucosaminidase in two
cases. This study also documented microalbuminuria in
four cases and abnormal urine b2-microglobulin concentration in three patients. In a study comparing sugammadex reversal of rocuronium-induced block with
neostigmine after cisatracurium-induced block, seven of
the 34 patients who were given sugammadex had
increased urinary levels of NAG [53]. This was considered
to be drug-related in two cases in which the level
increased above the upper safety limit from a previously
normal level. In contrast, only one of the 39 patients who
received neostigmine demonstrated an increased urinary
NAG level. However, the difference between preoperative and postoperative NAG levels was not statistically significant and did not seem to be of clinical
relevance. It is as yet uncertain how these urinary findings
should be interpreted. Elevated plasma creatinine phosphokinase (CK) has been described in one healthy patient
61
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Pharmacodynamics and pharmacokinetics of NMBs in health and disease
Anaesthesia, 2009, 64 (Suppl. 1), pages 55–65
...............................................................................................................................................................................................................................................................................................
who received sugammadex 8 mg.kg)1(CK 5400 U l)1
24 h post-dose) [55]. Cammu et al. [61] also reported
elevated aspartate aminotransferase and c-glutamyltransferase levels 6 h after the administration of sugammadex
20 mg.kg)1 with vecuronium 0.1 mg.kg)1 to a healthy
volunteer. Aspartate aminotransferase levels increased
from 21 U.l)1 pre-dose to 54 U.l)1 post-dose (normal
range 10–37 U.l)1), and c-glutamyltransferase levels
increased from 22 U.l)1 pre-dose to 73 U.l)1 (normal
range 10–66 U.l)1). The significance of these findings is
unknown and these have not been associated with any
clinical evidence of dysfunction.
Hepatic disease
To date, no animal studies or clinical trials have been
conducted in subjects with hepatic impairment. However, a population pharmacokinetic–pharmacodynamic
interaction model of sugammadex has been used to
simulate the reversal of rocuronium-induced neuromuscular block in patients with hepatic impairment (data on
file with Schering-Plough). Scenarios representing immediate reversal, reversal of profound neuromuscular block,
and reversal at reappearance of T2 were simulated in
subjects with hepatic impairment. Worst case scenarios,
which assume that sugammadex is affected by hepatic
impairment, demonstrated that recovery following sugammadex 4 mg.kg)1 administered 15 min after rocuronium 1.2 mg.kg)1 may take up to 4.12 min longer in
patients with severe hepatic impairment than normal
patients. When sugammadex 2 mg.kg)1 is given at the
reappearance of T2, the model predicts that the recovery
time will be prolonged by 2.55 min in severe hepatic
impairment. Hepatic impairment had little effect on the
predicted recovery time after sugammadex 16 mg.kg)1
given 3 min after rocuronium. Thus, in patients with
hepatic impairment, it could be speculated that recovery
after sugammadex will still be faster than after neostigmine, although not as quick as in healthy subjects. The
explanation for the findings from these simulations is not
yet understood.
Cardiovascular disease
Dahl et al. [62] studied the efficacy of sugammadex for
the reversal of rocuronium-induced neuromuscular block
in 76 patients with cardiovascular disease manifesting as
ischaemic heart disease, chronic heart failure or arrhythmia (New York Heart Association Class II or III); all
patients were undergoing non-cardiac surgery. The
control group consisted of patients with a similar degree
of cardiovascular disease who were given a placebo (there
was no neostigmine group). The study drug was administered at reappearance of T2: 38 patients were given
sugammadex 2 mg.kg)1, 38 patients were given sug62
ammadex 4 mg.kg)1, and 40 patients were given placebo.
The geometric mean time from the start of administration
of the drug to recovery of the TOF ratio to 0.9 was
1.7 min, 1.4 min, and 34.3 min respectively.
Gijsenberg et al. [51], in a study of the first human
exposure to sugammadex in 29 volunteers, noted three
cases of QT interval prolongation after sugammadex
administration. However, this study also documented five
cases of QT interval prolongation after placebo. The
study by Dahl et al. [62] specifically examined the safety
of sugammadex compared to placebo in cardiac patients
with regard to the QT interval [62]. A 12-lead ECG was
recorded at screening, before administration of rocuronium, before and at 2, 5, 10, and 30 min after administration of the study drug (sugammadex or placebo),
during the post-anaesthetic visit and at least 10 h after the
study drug. With one exception, the QT interval had
decreased slightly from baseline values measured immediately before administration of the study drug, at each
time point following sugammadex administration. The
sole exception was at 5 min following sugammadex
4 mg.kg)1, when the mean QT interval was prolonged
by 5.3 ms. Importantly, there were no statistically
significant differences compared to placebo [62].
In two studies of the effect of sugammadex on the QT
interval in healthy volunteers, either alone or in combination with rocuronium or vecuronium (n = 62 and
n = 84), the upper limit of the 95% confidence interval
for the largest time-matched mean difference in QTc
compared with placebo was less than 10 ms [63, 64]. In
none of the studies was the QTc interval reported to be
above the upper limit of the normal values.
Pulmonary disease
Amao et al. [65] administered sugammadex to reverse
rocuronium-induced neuromuscular block in 77
patients with pulmonary disease (ASA physical status
2–3). Thirty-nine patients were given sugammadex
2 mg.kg)1 and 38 patients were given sugammadex
4 mg.kg)1, administered at the reappearance of T2. The
geometric mean time from the start of sugammadex
administration to recovery of the TOF ratio to 0.9 was
1.8 min in the sugammadex 4 mg.kg)1 group, and
2.1 min in the sugammadex 2 mg.kg)1 group.
Of the 77 patients with pulmonary disease who
received sugammadex, two developed bronchospasm
[65]. These were both asthmatic patients; in one case
the bronchospasm occurred 1 min after tracheal extubation and lasted 4 min, and in the other it occurred 55 min
after sugammadex. It is possible that bronchospasm in
these patients was related to sugammadex administration.
There was no evidence of residual neuromuscular block
or recurarisation.
2009 The Authors
Journal compilation 2009 The Association of Anaesthetists of Great Britain and Ireland
Æ
Anaesthesia, 2009, 64 (Suppl. 1), pages 55–65 R. G. Craig and J. M. Hunter
Pharmacodynamics and pharmacokinetics of NMBs in health and disease
...............................................................................................................................................................................................................................................................................................
Conclusions
In the context of organ disease, the advantage of
sugammadex is that it is able to reverse even profound
and prolonged neuromuscular block, whilst acting more
rapidly and with less interindividual variability than
neostigmine. It effectively reverses rocuronium-induced
neuromuscular blockade in patients with renal failure; the
use of sugammadex for the reversal of vecuroniuminduced neuromuscular blockade in patients with chronic
kidney disease has yet to be studied. Sugammadex is well
tolerated with few side effects. The safety and efficacy of
sugammadex in patients with hepatic dysfunction has yet
to be investigated, and further research into its potential
for drug interactions is required.
Conflicts of interest
JMH received funding from Organon over 2 years ago to
undertake phase III studies on sugammadex. RGC has
declared no conflicts of interest.
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