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Summary

  1. Top of page
  2. Summary
  3. Pharmacology of the neuromuscular blocking and reversal agents in disease states
  4. Reversal agents
  5. Efficacy and safety of sugammadex in patients with organ disease
  6. Conclusions
  7. Conflicts of interest
  8. References

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.


Pharmacology of the neuromuscular blocking and reversal agents in disease states

  1. Top of page
  2. Summary
  3. Pharmacology of the neuromuscular blocking and reversal agents in disease states
  4. Reversal agents
  5. Efficacy and safety of sugammadex in patients with organ disease
  6. Conclusions
  7. Conflicts of interest
  8. References

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 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 non-depolarising 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 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.

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.
DrugSystemic clearanceVolume of distribution at steady state; l.kg−1 T1/2β; minReference
ControlsChronic kidney diseaseControlsChronic kidney diseaseControlsChronic kidney disease
Benzylisoquinoliniums
d-Tubocurarine    231330Miller et al. 1977 [12]
 Atracurium6.1 ml.min−1.kg−16.7 ml.min−1.kg−10.1820.22420.623.7Fahey et al. 1984 [19]
5.5 ml.min−1.kg−15.8 ml.min−1.kg−10.1530.14119.320.1Ward et al. 1987 [26]
 Cisatracurium293 ml.min−1254 ml.min−130.034.2 p < 0.05Eastwood et al. 1995 [22]
Mivacurium       
 Ciscis3.8 ml.min−1.kg−12.4 ml.min−1.kg−1 p < 0.010.2270.22468.080.0Head-Rapson et al. 1995 [27]
 Cis–trans106 ml.min−1.kg−180 ml min−1.kg−10.2780.4752.04.3Head-Rapson et al. 1995 [27]
 Trans–trans57 ml.min−1.kg−147 ml.min−1.kg−10.2110.2702.34.2Head-Rapson et al. 1995 [27]
Aminosteroids
Pancuronium74 ml.min−120 ml.min−1 p < 0.0050.1480.236 p < 0.05100489 p < 0.05McLeod et al. 1976 [29]
122.9 ml.min−153.0 ml.min−1 p < 0.0010.2610.296132.5257.3 p < 0.01Somogyi et al. 1977 [30]
Vecuronium5.29 ml.min−1.kg−13.08 ml.min−1.kg−1 p < 0.050.1990.2452.683.1 p < 0.05Lynam et al. 1988 [35]
Rocuronium4.5 ml.min−1.kg−12.7 ml.min−1.kg−1 p < 0.00010.1940.2257.070.0Robertson et al. 2005 [42]
3.7 ml.min−1.kg−12.5 ml.min−1.kg−1 p < 0.050.2070.21297.2104.4Cooper et al. 1993 [43]
Table 2.   Pharmacodynamic changes in NMBs associated with renal failure. Bolus doses unless otherwise stated.
DrugOnsetDuration; minRecovery index; minTrain-of-four (TOF) ratio 0.7; minReference
ControlsChronic kidney diseaseControlsChronic kidney diseaseControlsChronic kidney diseaseControlsChronic kidney disease
Benzylisoquinoliniums
 Atracurium 0.5 mg.kg−1Injection to max T1:T0 depressionInjection to 95% T1:T0 recovery25–75% T1:T0 Fahey et al. 1984 [19]
1.8 min2.0 min69.577.410.513.1  
 Cisatracurium 0.1 mg.kg−1Injection to 90% T1:T0 depressionInjection to 25% T1:T0 recovery25–75% T1:T0 Boyd et al. 1995 [23]
2.4 min3.7 min p < 0.0545.944.017.323.570.472.5
 Mivacurium 150 μg.kg−1 bolus, then 10 μg.kg−1.min−1 infusionInjection to 95% T1:T0 depressionInjection to 5% T1:T0 recovery25–75% T1:T0 recovery after stopping infusionTime to 70% recovery of T4/T1 after stopping infusionPhillips and Hunter 1992 [1]
2.7 min2.1 min9.815.3 p < 0.017.712.2 p < 0.0512.513.7
Aminosteroids
 Pancuronium 6 mg   Onset to 5% T1:T0 recovery    Somogyi et al. 1977 [30]
  37–160 (range, n = 7)41–234 (range, n = 6)    
 Vecuronium 0.1 mg.kg−1Injection to max T1:T0 depressionInjection to 25% T1:T0 recovery    Lynam et al. 1988 [35]
1.8 min1.9 min54.198.6 p < 0.05    
 Rocuronium 0.6 mg.kg−1Injection to max T1:T0 depressionInjection to 25% T1:T0 recovery25–75% T1:T0 Robertson et al. 2005 [42]
116 s137 s3249 p < 0.0041219 p < 0.0015488 p < 0.001

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.

Table 3.   Pharmacokinetic changes in neuromuscular blocking drugs associated with liver disease.
DrugPathologySystemic clearanceVolume of distribution at steady state T1/2βReference
Controls; ml.min−1.kg−1Liver disease; ml.min−1.kg−1Controls; ml.kg−1Liver disease; ml.kg−1Controls; minLiver disease; min
Benzylisoquinoliniums
 AtracuriumHepatic cirrhosis N = 86.68.0202.1281.8 p < 0.0520.924.5Parker and Hunter 1989 [20]
 CisatracuriumEnd-stage liver disease undergoing transplantation N = 145.76.6 p < 0.05161195 p < 0.0523.524.4De Wolf et al. 1996 [24]
 Mivacurium Hepatic cirrhosis N = 11      Head-Rapson et al. 1994 [2]
 Cis–trans9544 p < 0.052101881.52.5 p < 0.05
 Trans–trans7032 p < 0.052001992.311.1 p < 0.001
 Cis–cis5.24.226623750.360.8
Aminosteroids
 PancuroniumHepatic cirrhosis N = 141.861.45 p < 0.05279416 p < 0.05114208 p < 0.005Duvaldestin et al. 1978 [28]
 VecuroniumHepatic cirrhosis N = 124.262.73 p < 0.012462535884 p < 0.01Lebrault et al. 1985 [39]
Hepatic cirrhosis and alcoholic hepatitis N = 104.54.418022057.751.4Arden et al. 1988 [37]
 RocuroniumHepatic cirrhosis N = 173.72.66 p < 0.005210.7247.992143 p < 0.05Van Miert et al. 1997 [46]
Hepatic cirrhosis N = 102.792.4118423487.596.0Khalil et al. 1994 [10]
Table 4.   Pharmacodynamic changes in NMBs associated with liver disease. (Bolus doses unless otherwise stated.)
DrugOnsetDuration; minRecovery index; minTrain-of-four (TOF) 70%; minReference
ControlsLiver diseaseControlsLiver diseaseControlsLiver diseaseControlsLiver disease
Benzylisoquinoliniums
 Atracurium 0.5 mg.kg−1Injection to max T1:T0 depressionInjection to 20% T1:T0 recovery    Bell et al. 1985 [21]
109.7 s186.3 s p < 0.00143.134.1 p < 0.05    
 Cisatracurium 0.1 mg.kg−1Injection to max T1:T0 depressionInjection to 25% T1:T0 recovery25–75% T1:T0T4:T1 = 0.7De Wolf et al. 1996 [24]
3.3 min2.4 min p < 0.0546.953.512.815.480.479.0
 Mivacurium 15 μg.kg−1.min−1 infusion for 10 minInjection to 90% T1:T0 depressionInjection to 25% T1:T0 recovery25–75% T1:T0T4:T1 = 0.7Head-Rapson et al. 1994 [2]
5.9 min6.8 min p < 0.0512.819.87.411.8 p < 0.0124.140.1 p < 0.05
Aminosteroids
 VecuroniumInjection to max T1:T0 depressionInjection to 20% T1:T0 recovery     
 0.1 mg.kg−1172.7 s248.7 s33.527.3 p < 0.05    Bell et al. 1985 [21]
 0.15 mg.kg−1111.0 s143.0 s48.9549.4    Hunter et al. 1985 [38]
 0.2 mg.kg−198.8 s108.3 s6590.5 p < 0.05    Hunter et al. 1985 [38]
   Injection to 50% T1:T0 recovery25–75% T1:T0   
 0.2 mg.kg−1  62130 p < 0.012144 p < 0.05  Lebrault et al. 1985 [39]
 Injection to 100% T1:T0 depressionInjection to 50% T1:T0 recovery     
 0.1 mg.kg−11.9 min2.8 min p < 0.00566.159.8    Arden et al. 1988 [37]
 RocuroniumInjection to max T1:T0 depressionInjection to 75% T1:T0 recovery25–75% T1:T0T4:T1 = 0.7 
 0.6 mg.kg−1108 s158 s p < 0.015777 p < 0.051735 p < 0.016993Khalil et al. 1994 [10]
 Injection to 90% T1:T0 depressionInjection to 25% T1:T025–75% T1:T0T4:T1 = 0.7 
 0.6 mg.kg−163.6 s60.3 s42.353.7 p < 0.0526.038.276.1114.9 p < 0.01Van Miert et al. 1997 [46]
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 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 μg.ml−1 induce epileptiform EEG changes in anaesthetised dogs, whilst plasma concentrations > 17 μg.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 μg.ml−1 in renal failure patients and 0.19 μg.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 μg.ml−1 in renal failure patients and 0.023 μg.ml−1 in controls [22].

The peak laudanosine concentration after atracurium 0.6 mg.kg−1 is 0.149 μg.ml−1 in patients with cirrhosis and 0.198 μg.ml−1 in controls [20]. The elimination half-life and volume of distribution of laudanosine are increased in patients with cirrhosis [20]. There is, however, no change in its clearance.

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 half-lives 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-hydroxypancuronium, 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 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 steady-state [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

  1. Top of page
  2. Summary
  3. Pharmacology of the neuromuscular blocking and reversal agents in disease states
  4. Reversal agents
  5. Efficacy and safety of sugammadex in patients with organ disease
  6. Conclusions
  7. Conflicts of interest
  8. References

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 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 guest-host 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 rocuronium-induced 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 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

  1. Top of page
  2. Summary
  3. Pharmacology of the neuromuscular blocking and reversal agents in disease states
  4. Reversal agents
  5. Efficacy and safety of sugammadex in patients with organ disease
  6. Conclusions
  7. Conflicts of interest
  8. References

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 β2-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 pre-operative 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 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 γ-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 γ-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 sugammadex 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.

Conclusions

  1. Top of page
  2. Summary
  3. Pharmacology of the neuromuscular blocking and reversal agents in disease states
  4. Reversal agents
  5. Efficacy and safety of sugammadex in patients with organ disease
  6. Conclusions
  7. Conflicts of interest
  8. References

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 vecuronium-induced 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

  1. Top of page
  2. Summary
  3. Pharmacology of the neuromuscular blocking and reversal agents in disease states
  4. Reversal agents
  5. Efficacy and safety of sugammadex in patients with organ disease
  6. Conclusions
  7. Conflicts of interest
  8. References

JMH received funding from Organon over 2 years ago to undertake phase III studies on sugammadex. RGC has declared no conflicts of interest.

References

  1. Top of page
  2. Summary
  3. Pharmacology of the neuromuscular blocking and reversal agents in disease states
  4. Reversal agents
  5. Efficacy and safety of sugammadex in patients with organ disease
  6. Conclusions
  7. Conflicts of interest
  8. References
  • 1
    Phillips BJ, Hunter JM. Use of mivacurium chloride by constant infusion in the anephric patient. British Journal of Anaesthesia 1992; 68: 4928.
  • 2
    Head-Rapson AG, Devlin JC, Parker CJ, Hunter JM. Pharmacokinetics of the three isomers of mivacurium and pharmacodynamics of the chiral mixture in hepatic cirrhosis. British Journal of Anaesthesia 1994; 73: 6138.
  • 3
    Ryan DW. Preoperative serum cholinesterase concentration in chronic renal failure. Clinical experience of suxamethonium in 81 patients undergoing renal transplant. British Journal of Anaesthesia 1977; 49: 9459.
  • 4
    Viby-Mogensen J, Hanel HK. Prolonged apnoea after suxamethonium: an analysis of the first 225 cases reported to the Danish Cholinesterase Research Unit. Acta Anaesthesiologica Scandinavica 1978; 22: 37180.
  • 5
    Yentis SM. Suxamethonium and hyperkalaemia. Anaesthesia and Intensive Care 1990; 18: 92101.
  • 6
    Thapa S, Brull SJ. Succinylcholine-induced hyperkalemia in patients with renal failure: an old question revisited. Anesthesia and Analgesia 2000; 91: 23741.
  • 7
    Blanc VF, Vaillancourt G, Brisson G. Succinylcholine, fasciculations and myoglobinaemia. Canadian Anaesthetic Society Journal 1986; 33: 17884.
  • 8
    Gramstad L. Atracurium, vecuronium and pancuronium in end-stage renal failure. Dose-response properties and interactions with azathioprine. British Journal of Anaesthesia 1987; 59: 9951003.
  • 9
    Duvaldestin P, Henzel D. Binding of tubocurarine, fazadinium, pancuronium and Org NC 45 to serum proteins in normal man and in patients with cirrhosis. British Journal of Anaesthesia 1982; 54: 5136.
  • 10
    Khalil M, D’Honneur G, Duvaldestin P, Slavov V, De Hys C, Gomeni R. Pharmacokinetics and pharmacodynamics of rocuronium in patients with cirrhosis. Anesthesiology 1994; 80: 12417.
  • 11
    Donati F. Onset of action of relaxants. Canadian Journal of Anaesthesia 1988; 35: S528.
  • 12
    Miller RD, Matteo RS, Benet LZ, Sohn YJ. The pharmacokinetics of d-tubocurarine in man with and without renal failure. Journal of Pharmacology and Experimental Therapeutics 1977; 202: 17.
  • 13
    Brotherton WP, Matteo RS. Pharmacokinetics and pharmacodynamics of metocurine in humans with and without renal failure. Anesthesiology 1981; 55: 2736.
  • 14
    Diefenbach C, Kunzer T, Buzello W, Theisohn M. Alcuronium: a pharmacodynamic and pharmacokinetic update. Anesthesia and Analgesia 1995; 80: 3737.
  • 15
    Cashman JN, Luke JJ, Jones RM. Neuromuscular block with doxacurium (BW A938U) in patients with normal or absent renal function. British Journal of Anaesthesia 1990; 64: 18692.
  • 16
    Hunter JM, Jones RS, Utting JE. Comparison of vecuronium, atracurium and tubocurarine in normal patients and in patients with no renal function. British Journal of Anaesthesia 1984; 56: 94151.
  • 17
    Miller RD, Cullen DJ. Renal failure and postoperative respiratory failure: recurarization? British Journal of Anaesthesia 1976; 48: 2536.
  • 18
    Shearer ES, O’Sullivan EP, Hunter JM. Clearance of atracurium and laudanosine in the urine and by continuous venovenous haemofiltration. British Journal of Anaesthesia 1991; 67: 56973.
  • 19
    Fahey MR, Rupp SM, Fisher DM, et al. The pharmacokinetics and pharmacodynamics of atracurium in patients with and without renal failure. Anesthesiology 1984; 61: 699702.
  • 20
    Parker CJ, Hunter JM. Pharmacokinetics of atracurium and laudanosine in patients with hepatic cirrhosis. British Journal of Anaesthesia 1989; 62: 17783.
  • 21
    Bell CF, Hunter JM, Jones RS, Utting JE. Use of atracurium and vecuronium in patients with oesophageal varices. British Journal of Anaesthesia 1985; 57: 1608.
  • 22
    Eastwood NB, Boyd AH, Parker CJ, Hunter JM. Pharmacokinetics of 1R-cis 1’R-cis atracurium besylate (51W89) and plasma laudanosine concentrations in health and chronic renal failure. British Journal of Anaesthesia 1995; 75: 4315.
  • 23
    Boyd AH, Eastwood NB, Parker CJ, Hunter JM. Pharmacodynamics of the 1R cis-1’R cis isomer of atracurium (51W89) in health and chronic renal failure. British Journal of Anaesthesia 1995; 74: 4004.
  • 24
    De Wolf AM, Freeman JA, Scott VL, et al. Pharmacokinetics and pharmacodynamics of cisatracurium in patients with end-stage liver disease undergoing liver transplantation. British Journal of Anaesthesia 1996; 76: 6248.
  • 25
    Chapple DJ, Miller AA, Ward JB, Wheatley PL. Cardiovascular and neurological effects of laudanosine. Studies in mice and rats, and in conscious and anaesthetized dogs. British Journal of Anaesthesia 1987; 59: 21825.
  • 26
    Ward S, Boheimer N, Weatherley BC, Simmonds RJ, Dopson TA. Pharmacokinetics of atracurium and its metabolites in patients with normal renal function, and in patients in renal failure. British Journal of Anaesthesia 1987; 59: 697706.
  • 27
    Head-Rapson AG, Devlin JC, Parker CJ, Hunter JM. Pharmacokinetics and pharmacodynamics of the three isomers of mivacurium in health, in end-stage renal failure and in patients with impaired renal function. British Journal of Anaesthesia 1995; 75: 316.
  • 28
    Duvaldestin P, Agoston S, Henzel D, Kersten UW, Desmonts JM. Pancuronium pharmacokinetics in patients with liver cirrhosis. British Journal of Anaesthesia 1978; 50: 11316.
  • 29
    McLeod K, Watson MJ, Rawlins MD. Pharmacokinetics of pancuronium in patients with normal and impaired renal function. British Journal of Anaesthesia 1976; 48: 3415.
  • 30
    Somogyi AA, Shanks CA, Triggs EJ. The effect of renal failure on the disposition and neuromuscular blocking action of pancuronium bromide. European Journal of Clinical Pharmacology 1977; 12: 239.
  • 31
    Geha DG, Blitt CD, Moon BJ. Prolonged neuromuscular blockade with pancuronium in the presence of acute renal failure: a case report. Anesthesia and Analgesia 1976; 55: 3435.
  • 32
    Sangala W, Dixon J. Pancuronium and renal failure. Anaesthesia 1987; 42: 1236.
  • 33
    Ward ME, Adu-Gyamfi Y, Strunin L. Althesin and pancuronium in chronic liver disease. British Journal of Anaesthesia 1975; 47: 1199204.
  • 34
    Bencini AF, Scaf AH, Sohn YJ, et al. Disposition and urinary excretion of vecuronium bromide in anesthetized patients with normal renal function or renal failure. Anesthesia and Analgesia 1986; 65: 24551.
  • 35
    Lynam DP, Cronnelly R, Castagnoli KP, et al. The pharmacodynamics and pharmacokinetics of vecuronium in patients anesthetized with isoflurane with normal renal function or with renal failure. Anesthesiology 1988; 69: 22731.
  • 36
    Smith CL, Hunter JM, Jones RS. Vecuronium infusions in patients with renal failure in an ITU. Anaesthesia 1987; 42: 38793.
  • 37
    Arden JR, Lynam DP, Castagnoli KP, Canfell PC, Cannon JC, Miller RD. Vecuronium in alcoholic liver disease: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology 1988; 68: 7716.
  • 38
    Hunter JM, Parker CJ, Bell CF, Jones RS, Utting JE. The use of different doses of vecuronium in patients with liver dysfunction. British Journal of Anaesthesia 1985; 57: 75864.
  • 39
    Lebrault C, Berger JL, D’Hollander AA, Gomeni R, Henzel D, Duvaldestin P. Pharmacokinetics and pharmacodynamics of vecuronium (ORG NC 45) in patients with cirrhosis. Anesthesiology 1985; 62: 6015.
  • 40
    Wierda JM, Kleef UW, Lambalk LM, Kloppenburg WD, Agoston S. The pharmacodynamics and pharmacokinetics of Org 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl. Canadian Journal of Anaesthesia 1991; 38: 4305.
  • 41
    Mirakhur RK. Safety aspects of non-depolarizing neuromuscular blocking agents with special reference to rocuronium bromide. European Journal of Anaesthesiology Supplement 1994; 9: 13340.
  • 42
    Robertson EN, Driessen JJ, Booij LH. Pharmacokinetics and pharmacodynamics of rocuronium in patients with and without renal failure. European Journal of Anaesthesiology 2005; 22: 410.
  • 43
    Cooper RA, Maddineni VR, Mirakhur RK, Wierda JM, Brady M, Fitzpatrick KT. Time course of neuromuscular effects and pharmacokinetics of rocuronium bromide (Org 9426) during isoflurane anaesthesia in patients with and without renal failure. British Journal of Anaesthesia 1993; 71: 2226.
  • 44
    Magorian T, Wood P, Caldwell J, et al. The pharmacokinetics and neuromuscular effects of rocuronium bromide in patients with liver disease. Anesthesia and Analgesia 1995; 80: 7549.
  • 45
    Servin FS, Lavaut E, Kleef U, Desmonts JM. Repeated doses of rocuronium bromide administered to cirrhotic and control patients receiving isoflurane. A clinical and pharmacokinetic study. Anesthesiology 1996; 84: 1092100.
  • 46
    Van Miert MM, Eastwood NB, Boyd AH, Parker CJ, Hunter JM. The pharmacokinetics and pharmacodynamics of rocuronium in patients with hepatic cirrhosis. British Journal of Clinical Pharmacology 1997; 44: 13944.
  • 47
    Suresh D, Carter JA, Whitehead JP, Goldhill DR, Flynn PJ. Cardiovascular changes at antagonism of atracurium. Effects of different doses of premixed neostigmine and glycopyrronium in a ratio of 5:1. Anaesthesia 1991; 46: 87780.
  • 48
    Cronnelly R, Stanski DR, Miller RD, Sheiner LB, Sohn YJ. Renal function and the pharmacokinetics of neostigmine in anesthetized man. Anesthesiology 1979; 51: 2226.
  • 49
    Morris RB, Cronnelly R, Miller RD, Stanski DR, Fahey MR. Pharmacokinetics of edrophonium in anephric and renal transplant patients. British Journal of Anaesthesia 1981; 53: 13114.
  • 50
    Naguib M. Sugammadex: another milestone in clinical neuromuscular pharmacology. Anesthesia and Analgesia 2007; 104: 57581.
  • 51
    Gijsenbergh F, Ramael S, Houwing N, Van Iersel T. First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology 2005; 103: 695703.
  • 52
    Sparr HJ, Vermeyen KM, Beaufort AM, et al. Early reversal of profound rocuronium-induced neuromuscular blockade by Sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics. Anesthesiology 2007; 106: 93543.
  • 53
    Flockton EA, Mastronardi P, Hunter JM, et al. Reversal of rocuronium-induced neuromuscular block with Sugammadex is faster than reversal of cisatracurium-induced block with neostigmine. British Journal of Anaesthesia 2008; 100: 62230.
  • 54
    Sacan O, White PF, Tufanogullari B, Klein K. Sugammadex reversal of rocuronium-induced neuromuscular blockade: a comparison with neostigmine–glycopyrrolate and edrophonium–atropine. Anesthesia and Analgesia 2007; 104: 56974.
  • 55
    Groudine SB, Soto R, Lien C, Drover D, Roberts K. A randomized, dose-finding, phase II study of the selective relaxant binding drug, sugammadex, capable of safely reversing profound rocuronium-induced neuromuscular block. Anesthesia and Analgesia 2007; 104: 55562.
  • 56
    Puhringer FA, Rex C, Sielenkamper AW, et al. Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by Sugammadex at two different time points. Anesthesiology 2008; 109: 18897.
  • 57
    Eleveld DJ, Kuizenga K, Proost JH, Wierda JM. A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with a small dose of sugammadex. Anesthesia and Analgesia 2007; 104: 5824.
  • 58
    Bom A, Van Egmond J, Hope F, Van de Pol F. Rapid reversal of rocuronium-induced neuromuscular blockade by Org 25969 is independent of renal function. Anesthesiology 2003; 99: A1158.
  • 59
    Staals L, Snoek M, Driessen J, Flockton E, Heeringa M, Hunter J. Multicentre, parallel-group, comparative trial evaluating the efficacy and safety of sugammadex in patients with end-stage renal failure or normal renal function. British Journal of Anaesthesia 2008; 101: 4927.
  • 60
    Sorgenfrei IF, Norrild K, Larsen PB, et al. Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study. Anesthesiology 2006; 104: 66774.
  • 61
    Cammu G, De Kam PJ, Demeyer I, et al. Safety and tolerability of single intravenous doses of sugammadex administered simultaneously with rocuronium or vecuronium in healthy volunteers. British Journal of Anaesthesia 2008; 100: 3739.
  • 62
    Dahl V, Pendeville PE, Hollman MW, Heier T, Blobner M. Reversal of rocuronium-induced neuromuscular blockade by sugammadex in cardiac patients. Anesthesiology 2007; 107: A1581.
  • 63
    De Kam P, Van Kuijk J, Smeets J, Thomsen T, Peeters P. Single IV sugammadex doses up to 32 mg/kg are not associated with Qt/QTc prolongation. Anesthesiology 2007; 107: A1580.
  • 64
    De Kam P, Van Kuijk J, Prohn M, Thomsen T, Peeters P. Single IV sugammadex doses up to 32 mg/kg alone or in combination with rocuronium or vecuronium are not associated with QTc prolongation. European Journal of Anaesthesiology 2008; 25: 9AP59.
  • 65
    Amao R, Zornow MH, Cowan RM, Cheng DCH, Allard M. Sugammadex safely reverses rocuronium-induced blockade in patients with pulmonary disease. Anesthesiology 2007; 107: A1582.