Recently, a new drug called sugammadex (Bridion, MSD, USA) has been introduced to clinical practice. Sugammadex is the first and only selective relaxant binding agent (SRBA), which selectively binds steroid relaxants (rocuronium, vecuronium) and reverses the neuromuscular blockade. The drug is a modified gamma-cyclodextrin, which encapsulates and inactivates molecules of steroid ring compounds, including relaxants, forming complexes, which are subsequently excreted by kidneys [1, 2].

Cyclodextrins are cyclic carbohydrates, first described by Villiers in 1891. The most common forms of these compounds include: alpha, beta and gamma cyclodextrins, composed of 6, 7 and 8 glucose monomers, respectively. Due to high solubility in water, the compounds have been used for many years in pharmaceutical industry as drug carriers as well as in the cosmetics and food industry. Cyclodextrin increases the drug bioavailability [3, 4]. The idea to use cyclodextrins to encapsulate steroid relaxants was introduced by Anton Bom. Initially, scientists searched for a substance that could increase the solubility of rocuronium in water; however, the chemical properties of sugamadex determined its new application [4].

Cyclodextrins are externally hydrophilic which guarantees high solubility in water, whereas their core is hydrophobic which creates favourable conditions for steroid molecules to penetrate their interior. Hydrophobic interactions between a molecule of a steroid compound and cyclodextrin result in formation of the host-guest complex. Sugammadex is a gamma-cyclodextrin modified by addition of side chains, which increases its lipophilicity [4].

Sugammadex uptakes and encapsulates the relaxant present in plasma and tissues, thus decreasing its concentration; as a result, the remaining agent molecules continue to detach from nicotinic receptors and inactivate. The postsynaptic receptor becomes once again available to acetylcholine. Cyclodextrins bind relaxants with a 1:1 ratio, with the highest affinity to rocuronium, weaker to vecuronium and the lowest one to pancuronium [4, 5].

Since the affinity to the above-mentioned agents is very strong (120-700 times stronger than that to other agents), there is no risk of sugammadex binding other drugs of steroid structure used during general anaesthesia.

Sugammadex administered in an appropriate dose reverses the neuromuscular blockade regardless of its depth. Its action does not interfere with acetylcholine metabolism thus anticholinergic drugs are not required and their side effects are avoided [2, 3, 4].

The administration of relaxants during general anaesthesia carries the risk of their residual effects after surgery. Based on numerous studies, the incidence of this risk was estimated at 20-40%. Such residual effects induce complications that prolong hospitalization. The most frequent include apnoea, atelectasis, hypoxia and pneumonia. For these reasons, the guidelines for residual curarisation prevention should be followed, e.g. the use of short- and intermediate-acting relaxants, monitoring of neuromuscular transmission and routine reversal of neuromuscular blockade [6].

It is currently recommended to monitor the depth of neuromuscular blockade each time relaxants are administered [7]. In most cases, acceleromiography is used, which measures the acceleration of movement (e.g. of a thumb) in response to electric stimulation (e.g. of the ulnar nerve). The train-of-four (TOF) and post-tetanic count (PTC) stimulations are most frequently used during anaesthesia [8].

In the TOF method, a series of individual stimuli is generated at 2 Hz frequency, i.e. 4 stimuli per 2 sec. This enables semi-quantitative evaluation of the blockade. The reversal of relaxant-induced neuromuscular blockade is assessed using the T4/T1 ratio, (TOFr) [9]. Until recently, TOFr of 0.7 was considered safe and allowing to avoid residual curarisation. However, numerous studies have demonstrated that such a value is associated with decreased sensitivity of peripheral chemoreceptors to hypoxia, upper airway collapse, dysphagia, visual disturbances and prolonged muscular weakness [10, 11, 12]. At present, it is believed that only TOFr >0.9 indicates sufficient reversal of neuromuscular blockade which allows safe extubation and avoidance of residual blockade [6].

The PTC method is used to differentiate the depth of neuromuscular blockade when non-depolarizing relaxants are administered. This involves stimulation with a tetanic stimulus of 50 Hz frequency for 5 sec, followed by the 3-second interval and stimulation with single stimuli. The number of induced muscle responses is counted until they have disappeared [9]. Immediately after the relaxant administration, in the intensive block both TOF and PTC are 0, in the deep block TOF = 0 but PTC = 1-2 or more, whereas in the moderate block TOF = 1-3. PTC enables to differentiate the intensive (no response to stimulation) and the deep block phase, which is essential for selection of the appropriate dose of sugammadex. The immediate reversal of muscle relaxation is achieved with 16 mg kg-1 in intensive, 4 mg kg-1 in deep, and 2 mg kg-1 in moderate neuromuscular blockade [2, 4].

The action of muscle relaxants can subside spontaneously due to their metabolism and elimination yet the process is slow and differs depending on the agents used. Mivacurium is characterized by the shortest action; the drug is decomposed by non-specific plasma cholinesterase and generally does not require the use of agents reversing its effects.

Neostigmine, an acetylcholinesterase inhibitor, stimulates muscarinic receptors found in smooth muscles, glands or heart and nicotinic receptors present in autonomic ganglia, causing adverse side effects, most frequently decreased cardiac output and ptyalism [9]. Its efficacy depends on many factors such as: acid-base and electrolyte balance, type of anaesthesia, patient’s body weight, and can be impaired by some antibiotics. If overdosed, neostigmine alone may induce the neuromuscular blockade [6]. To prevent its side effects, parasympathicolytic drugs are used (mostly atropine and glycopyrrolate). The administration of neostigmine does not reverse the deep block, hence cannot be used in emergencies [2].

Sugammadex is distributed in the extracellular space [4]. When administered by an iv bolus, it exhibits linear kinetics for 1-16 mg kg-1 doses [2]. Following its use, tightly bound molecules of cyclodextrin and muscle relaxant are excreted by kidneys (96%), with only a small percentage (<0.02%) excreted in faeces and expired air, demonstrating no significant biological activity. The molecules do not bind with plasma proteins or erythrocytes. The excretion was observed to be fast – 70% of the administered dose during 6 h, >90% in 24 h. The agent’s half-life ranges from 1 to 4 h, with the mean value of 1.8 h. The plasma clearance for sugammadex is estimated at approximately 88 mL min-1 for adults [4]. Neither preclinical nor clinical studies showed any sugammadex metabolites, only unchanged complexes excreted by kidneys [2, 4].

Patients with mild or moderate renal failure (creatinine clearance – 30-80 mL min-1) can receive sugammadex without dose modification. In severe renal failure (including dialyzed patients) and hepatic failure, the drug is not recommended [2]. Nevertheless, there are reports, which demonstrate the efficacy and safety of sugammadex in patients with severe renal failure [13] yet they concern only a limited group of patients.

Current clinical trials confirm that the administration of sugammadex is safe regardless of age and does not require dose modification in paediatric, elderly and obese patients [2, 4]. Nevertheless, given the limited number of clinical trials in children <2 years of age, it is presently not recommended to administer sugammadex in this age group. Moreover, in paediatrics, it is advised not to use the agent to reverse the intensive block (i.e. in emergencies or immediately after intubation), which is also associated with insufficient data evaluating the 16 mg kg-1 dose [14, 15].

In elderly patients (>65 years) the time for complete reversal of neuromuscular blockade after sugammadex is slightly longer in comparison to younger patients. The differences are not, however, significant [16].

Human studies concerning the safety of sugammadex (including 1700 patients and 120 volunteers) did not show any significant side effects. Sugammadex in the dose higher than recommended resulted in sporadic unpleasant taste in the mouth and cough. There is only one documented case of allergic reaction in a healthy, adult volunteer, in which sugammadex 8.4 mg kg -1 resulted in flush and tachycardia. The reaction was mild. Moreover, no prolonged QT interval in ECG was observed [1]. Nevertheless, the drug failed to obtain the FDA approval due to insufficient number of examined patients.

The main criterion in sugammadex trials is time of muscle relaxation reversal (T1) based on recovery of TOFr to 0.9.

The use of sugammadex (doses 2 mg kg-1 and 4 mg kg-1) in patients with severe cardiac conditions undergoing anaesthesia for non-cardiac surgical procedures with rocuronium was found to be completely safe and efficient [17].

The first study on sugammadex administration included a group of 29 healthy volunteers, who received the agent in 0.1-8 mg kg-1 doses, with or without previous muscle relaxation with rocuronium (0.6 mg kg-1). Its findings demonstrated that sugammadex administered in an appropriate dose, i.e. 4-8 mg kg-1 reversed the rocuronium-induced neuromuscular blockade during 2-3 min.

In all cases, the agent was well tolerated; transient paraesthesia was observed only in one patient (dose of 8 mg kg-1) [5].

In order to determine the appropriate dose of sugammadex, the drug was administered in 0.5-4 mg kg-1 doses during reversal of blockade induced by the rocuronium intubation dose of 0.6 mg kg-1. The recovery of TOFr to 0.9 showed variability. The dose-dependent shortening of block reversal time was observed – from 4.3 min for 0.5 mg kg-1 to 1.1 min for 4 mg kg-1. Sugammadex was administered during moderate block (2 responses to TOF stimulation) [18].

Subsequent studies confirmed that administration of sugammadex in ≥2 mg kg-1 dose resulted in complete reversal of neuromuscular blockade in <3 min, with the mean of 1.3-1.7 min for 2 mg kg-1 and 1.1-1.5 min for 4 mg kg-1 [2].

The administration of 2 mg kg-1 of sugammadex resulted in significantly quicker reversal of moderate rocuronium-induced block compared to neostigmine 50 µg kg-1. In the first case, TOFr 0.9 was achieved after 1.9 min, whereas in the second one the reversal took 17.6 min. No residual curarisation was observed in either case [2].

If surgery has to be completed erlier than anticipated the block cannot be reversed using acetylcholinesterase inhibitors. The concentration of relaxant molecules requires an increased dose of sugammadex in order to inactivate them [2]. The appropriate dose of sugammadex in such cases was 4 mg kg-1, allowing reversal of rocuronium-induced T1 block after 1.6-3.3 min [19].

Comparative studies showed that deep rocuronium-induced neuromuscular blockade was reversed much quicker after sugammadex 4 mg kg-1 (2.9 min) compared to neostigmine 70 mg kg-1 or glycopyrronium 14 mg kg-1 (50.4 min); its action was about 17 times faster than that of neostigmine. Moreover, the administration of sugammadex did not result in residual block [20].

In cases of anticipated difficult intubation, suxamethonium is the treatment of choice (fast and short action). Due to its numerous side effects, the search for alternative substances is being continued. Currently, rocuronium is most suitable. Its onset of action following the intubation dose of 1.2 mg kg-1 is comparable with that of suxamethonium, and so are the intubation conditions. When immediate reversal of rocuronium effects is needed (intubation failure, immediate awakening required), the appropriate dose of sugammadex is 16 mg kg-1 [1, 2], at which the blockade reversal time was quicker compared to spontaneous reversal following suxamethonium 1 mg kg-1 [2].

Studies on effective doses and muscle relaxation blockade reversal times after vecuronium  revealed that the time was slightly longer than for rocuronium – 3.4 min for 2 mg kg-1 of sugammadex in moderate block, and approximatelly 3 min for 4 mg kg-1 of sugammadex in deep block [16].

The multicentre randomized study demonstrated that the recovery of TOF to 0.9 in moderate and deep neuromuscular blockades induced by vecuronium was shorter after sugammadex (2.7 min) than after neostigmine and glycopyrrolate (17.9 min). No side effects of the agents were observed [22].

It is well known that sevoflurane may prolong the action of muscle relaxants [2]. Studies have been undertaken in which anaesthesia was induced with propofol and maintained with sevoflurane, and muscles were relaxed with vecuronium or rocuronium. The intubation dose was 0.9 mg kg-1 for rocuronium and 0.1 mg kg-1 for vecuronium, with maintenance doses typical of both agents. The blockade was reversed in deep phase using the sugammadex doses ranging from 0.5 to 8 mg kg-1. Recovery of TOFr to 0.9 was as follows: in the rocuronium group – from 79.8 min (sugammadex dose – 0.5 mg kg-1), 1.7 min (for 4 mg kg-1) to 1.1 min (for 8 mg kg-1); in the vecuronium group – 68.4 min, 3.3 min, 1.7 min, respectively. Interestingly, monitoring of neuromuscular transmission revealed the presence of persistent blockade in 5 patients from the rocuronium group; however, these patients received subclinical doses of sugammadex (2 patients – 0.5 mg kg-1, and 3 – 1 mg kg-1). None of the persistent blockades manifested clinically [23]. Other studies have confirmed that the effect of sugammadex did not depend on the kind of anaesthesia (propofol or sevoflurane) [24].

Furthermore, the efficacy of sugammadex depending on the kind of anaesthesia (propofol/sevoflurane) using continuous rocuronium infusion was compared. It was demonstrated that the agent was well tolerated and similarly effective in both types. In one case hypotension developed, which was considered a possible side effect of rocuronium [25].

Another study revealed that in the group anesthetized with sevoflurane, requirement for rocuronium was lower, and time of TOFr recovery to 0.9 was shorter than in the propofol group; however, the differences were not significant (1.46 min vs 1.89 min) [26].

Moreover, the effectiveness of reversal of rocuronium-induced neuromuscular blockade using sugammadex versus cisatracurium-induced blockade using neostigmine was compared. The findings demonstrated that the action of sugammadex was 4.7 times faster compared to neostigmine. No significant side effects were detected in either group [27].

Another report concerned a patient with myasthenia who received 2 mg kg-1 of sugammadex during the moderate phase of neuromuscular rocuronium-induced blockade. The recovery of TOFr to 0.9 was observed within 210 sec [28]. Still another documented case described successful administration of sugammadex in a child with Duchenne muscular dystrophy [29].

According to the available randomized controlled clinical trials in adult patients, side effects associated with sugammadex were observed in less than 1% of all cases. The agent proved to be effective and safe; nevertheless, further studies on larger populations are necessary [30].

By decreasing the number of residual and recurrent recurarisations, sugammadex considerably improves the patients` safety. It can be used for emergency reversal of neuromuscular blockade in “can’t intubate /can`t ventilate” situations [31].

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REFERENCES

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15.    Plaud B, Meretoja O, Hofmockel R, Raft J, Stoddart PA, van Kuijk JH, Hermens Y, Mirakhur RK: Reversal of rocuronium-induced neuromuscular blockade with sugammadex in pediatric and adult surgical patients. Anesthesiology 2009; 110: 284-294.

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17.    Dahl V, Pendeville PE, Hollmann MW, Heier T, Abels EA, Blobner M: Safety and efficacy of sugammadex for the reversal of rocuronium-induced neuromuscular blockade in cardiac patients undergoing noncardiac surgery. Eur J Anaesth 2009; 26: 874-884.

18.    Sorgenfrei IF, Norrild K, Larsen PB, Stensballe J Ostergaard D, Prins ME, Viby-Mogensen J: Reversal of rocuronium induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study. Anesthesiology 2006; 104: 667-674.

19.    Sparr HJ, Vermeyen KM, Beaufort AM, Rietbergen H, Proost JH, Saldien V, Velik-Salchner C, Wierda JM: Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study: efficacy, safety and farmacokinetics. Anesthesiology 2007; 106: 935-943.

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25.    Rex C, Wagner S, Spies C, Scholz J, Rietbergen H, Heeringa M, Wulf H: Reversal of neuromuscular blockade by sugammadex after continous infusion of rocuronium in patients randomized to sevoflurane or propofol maintenance anesthesia. Anesthesiology 2009; 111: 30-35.

26.    Vega-Ruiz G, Dominguez N, Orozco J, Janda M, Hofmockel R, Alvarez- Gomez JA: Efficacy of sugammadex in the reversal of neuromuscular blockade induced by rocuronium in long-duration surgery: under inhaled vs. intravenous anesthesia. Rev Esp Anestesiol Reanim 2009; 56: 349-354.

27.    Flocton EA, Mastronardi P, Hunter JM, Gomar C, Mirakhur RK, Aguilera L, Giunta FG, Meistelman C, Prins ME: Reversal of rocuronium – induced neuromuscular block with sugammadex is faster than reversal of cisatracurium – induced block with neostigmine.Br J Anaesth 2008; 100: 622-630.

28.    Unterbuchner C, Fink H, Blobner M: The use of sugammadex in patient with myasthenia gravis. Anaesthesia 2010; 65: 302-305.

29.    de Boer HD, van Esmond J, Booij LH, Driessen JJ: Reversal of rocuronium-induced profound neuromuscular block by sugammadex in Duchenne muscular dystrophy. Pediatr Anesth 2009; 19: 1226-1228.

30.    Abrishami A, Ho J, Wong J, Yin L, Chung F: Sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade. Cochrane Database Syst Rev 2009 Oct 7: (4):CD007362.http://www.ncbi.nlm.nih.gov/pubmed/.

31.    Debaene B, Meistelman C: Indications and clinical use of sugammadex. Ann Fr Anesth Réanim. 2009; 28 (Suppl. 2): 57-63.

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Address:

*Lidia Glinka
Oddział Anestezjologii i Intensywnej Terapii
Wojewódzki Szpital Specjalistyczny w Olsztynie
ul. Żołnierska 18, 10-561 Olsztyn
tel.: 89-538 64 42
e-mail: szpital@wss.olsztyn.pl

Received: 27.03.2010
Accepted: 07.06.2010