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Sugammadex. Nuevo fármaco reversor del bloqueo neuromuscular
Abstract
Significant progress in the management of aminosteroid nondepolarizing neuromuscular blockers will follow the introduction of sugammadex (Org 25969). Safety and rapid recovery of muscle force will improve and the adverse effects of acetylcholinesterase inhibitors will be avoided. Sugammadex is a modified γ-cyclodextrin agent developed for the specific reversal of rocuronium and, to a lesser extent, vecuronium. This novel drug functions by means of encapsulation (chelation). Sugammadex was recently approved by the European Medicines Evaluation Agency and became available in Spain in 2009, leading to a series of changes related to patient safety and surgical conditions. We review the literature on sugammadex published to date.
The use of anticholinesterases to reverse residual neuromuscular block is efficacious only if recovery is already established.
It was originally advised that at least the second twitch (T2) of the train-of-four response should be detectable before neostigmine
is administered. Even in these circumstances, the full effect of anticholinesterases takes up to 10 min to achieve. Anticholinesterases
also have muscarinic side-effects that require an antimuscarinic to be administered concomitantly. An ideal reversal agent
could be given at any time after the administration of a neuromuscular blocking agent (NMBA), and should have no muscarinic
side-effects. The gamma cyclodextrin, sugammadex, has been demonstrated to effectively antagonize even profound block produced
by the aminosteroid NMBAs, rocuronium and vecuronium, by chelating them. The complex is then excreted in the urine. Sugammadex
is ineffective in antagonizing the benzylisoquinolinium NMBAs. The dose should be adjusted according to the degree of residual
block: sugammadex 16 mg kg−1 for immediate reversal; 4–8 mg kg−1 for antagonizing profound block (post-tetanic count 1–2); and 2 mg kg−1 to antagonize moderate block (when T2 is detectable). As yet, the extent of any side-effects that may occur with this new
antagonist is not fully known, although rarely adverse cardiovascular effects (hypotension, hypertension, prolonged QT interval)
have already been reported.
Steroidal neuromuscular blocking agents (NMBAs), such as rocuronium, are widely used in clinical anesthesia and emergency medicine to facilitate endotracheal intubation and artificial ventilation and to allow surgical access to body cavities. Reversal of neuromuscular blockade is important for the acceleration of patient recovery and prevention of postoperative residual neuromuscular blockade and reduces the incidence of severe morbidity and mortality associated with anesthesia management. Sugammadex is the first selective relaxant binding agent (SRBA) and has been designed to reverse the steroidal neuromuscular blocking drug rocuronium. Encapsulation of the rocuronium molecule by sugammadex results in a rapid decrease in free rocuronium in the plasma and subsequently at the nicotinic receptor at the motor endplate. After encapsulation, rocuronium is not available to bind to the nicotinic receptor in the neuromuscular junction. This promotes the liberation of acetylcholine receptors, and muscle activity reappears. This new concept of reversal of neuromuscular block induced by rocuronium (or vecuronium) led to impressive results in animal and phase 1 and 2 studies. Sugammadex is currently in phase 3 clinical studies and may be commercially available by 2008.
Org 25969 is a cyclodextrin compound designed to reverse a rocuronium-induced neuromuscular block. The aim of this study was to explore the efficacy, dose-response relation and safety of Org 25969 for reversal of a prolonged rocuronium-induced neuromuscular block.
Thirty anaesthetized adult patients received rocuronium 0.6 mg kg(-1) as an initial dose followed by increments to maintain a deep block at a level of <10 PTCs (post-tetanic counts) recorded every 6 min. Neuromuscular monitoring was carried out using accelerometry, in a train-of-four (TOF) mode using TOF-WatchSX. At recovery of T2, following at least 2 h of neuromuscular block, patients received their randomly assigned dose of 0.5, 1.0, 2.0, 4.0 or 6.0 mg kg(-1) of Org 25969. Anaesthesia and neuromuscular monitoring were continued for a minimum period of 30 min after Org 25969 administration. The main end-point of the study was the time to achieve a sustained recovery of TOF ratio to 0.9. Patients were followed up for 7 days after anaesthesia.
The results showed a dose-related decrease in the average time taken to attain a TOF ratio of 0.9 from 6:49 (min:s) with the 0.5 mg kg(-1) dose to 1:22 with the 4.0 mg kg(-1) dose. Weighted non-linear regression analysis showed the fastest achievable time to TOF ratio of 0.9 to be 1:35. Org 25969 produced no major adverse effects.
Org 25969 effectively reversed a deep and prolonged neuromuscular block induced by rocuronium. The effective reversal dose appears to be 2-4 mg kg(-1).
At present, reversal of neuromuscular block induced by steroidal neuromuscular blocking agents (NMBAs) is achieved by administration of cholinesterase inhibitors. Chemical encapsulation of steroidal NMBAs, such as rocuronium, by a cyclodextrin is a new concept in neuromuscular block reversal. The present study evaluates the capacity of nine synthetic cyclodextrin derivatives (Org 25288, Org 25289, Org 25467, Org 25168, Org 25169, Org 25555, Org 25166, Org 26142, and Org 25969) to reverse constant neuromuscular block of approximately 90%, induced by rocuronium infusion in the Rhesus monkey, using single twitch stimulation. The ability of these cyclodextrin derivatives to reverse neuromuscular block was compared with the reversal of the same neuromuscular block by the commonly used combination of neostigmine and atropine.
After a bolus injection of rocuronium, continuous infusion was started to reduce twitch contractions to approximately 10% of baseline values. After a steady state block of at least 10 min the infusion was stopped and the preparation was allowed to recover spontaneously. This process was repeated, but at the time the infusion was stopped, either one of the nine cyclodextrin derivatives or a combination of neostigmine and atropine was given.
Recovery with cyclodextrin derivatives Org 26142 and Org 25969 was faster than after a combination of neostigmine and atropine (P<0.05). Injection of these cyclodextrin derivatives did not affect blood pressure or heart rate. Signs of residual block or recurarization were not observed in any of these experiments. In the experiments in which a combination of neostigmine and atropine was given, two animals showed signs of abdominal discomfort as frequently seen after the administration of neostigmine and significant changes in circulatory variables.
Chemical encapsulation or chelation of rocuronium is a new concept in reversing neuromuscular block induced by rocuronium.
Binding of the steroidal molecule of rocuronium by a cyclodextrin is a new concept for reversal of neuromuscular block. The present study evaluated the ability of Sugammadex Org 25969, a synthetic gamma-cyclodextrin derivative, to reverse constant neuromuscular block of about 90% induced by rocuronium or the non-steroidal neuromuscular blocking drugs, mivacurium or atracurium, in the anaesthetized Rhesus monkey.
After a bolus injection of rocuronium, mivacurium or atracurium, a continuous infusion of these drugs was started to maintain the first twitch contraction of the train-of-four at approximately 10% of its baseline value. After a steady state block of at least 10 min the infusion was stopped and the preparation was allowed to recover spontaneously. This process was repeated, but at the time the infusion was stopped, either sugammadex 0.5 or 1.0 mg kg(-1) was given in the rocuronium-induced blockade and sugammadex 1.0 mg kg(-1) was given in the mivacurium- and atracurium-induced blockade.
Sugammadex caused a rapid and complete reversal of rocuronium-induced neuromuscular block. The recovery time to train of four ratio=0.9 after spontaneous recovery was 14.4 min (sd=3.4 min; n=14). This was reduced significantly (P<0.001) to 3.7 min (sd=3.3 min; n=4) with sugammadex 0.5 mg kg(-1) and to 1.9 min (sd=1.0 min; n=4) with sugammadex 1.0 mg kg(-1). Signs of residual blockade or re-curarization were not observed. Reversal of mivacurium- or atracurium-induced neuromuscular block (n=2 in each experiment) by sugammadex (1.0 mg kg(-1)) was not effective. In all experiments, injection of sugammadex had no effects on blood pressure or heart rate.
Sugammadex is effective in reversing rocuronium, but not mivacurium- or atracurium-induced neuromuscular block.
In this review, we summarize the new drugs in development in the anaesthesia field.
There are some interesting approaches, including pro-drugs of propofol such as Aquavan (MGI Pharma, Bloomington, Minnesota, USA) and novel 'soft-drug' sedatives and hypnotics (e.g. CNS-7259X and TD-4756) as well as a novel approach to terminate the action of steroidal neuromuscular blockers (sugammadex). There is also significant activity in the field of novel analgesics. Particularly addressing the fields of sedatives, hypnotics and neuromuscular blockers, however, there is relatively little drug discovery activity currently. Part of the reason for this may be that the mechanisms of action of anaesthetics are not fully understood. This cannot be the whole story, however, since attractive new targets have recently been identified. For example, an agent with selective actions at the beta3-containing subunit of the gamma-amino butyric acid-A receptor is likely to have the hypnotic effects of propofol without the cardiac depressant side-effects.
We consider the main reason for low activity is the perception in industry that there is little need for new drugs in anaesthesia because the needs are well addressed by existing agents. If this is not the case then anaesthesiologists need to be more effective in communicating their requirements.
Reversal of neuromuscular block can be accomplished by chemical encapsulation of rocuronium by sugammadex (Org 25969), a synthetic gamma-cyclodextrin derivative. The present study determined the time course of the reversal action of sugammadex on rocuronium-induced block in the anaesthetized Rhesus monkey using train-of-four stimulation.
A bolus injection of rocuronium 100 microg kg(-1) (about 1xED(90)) was given to determine the degree of neuromuscular block reached by this dose. After complete spontaneous recovery, a rapid bolus injection of sugammadex, 1 mg kg(-1), was given and at different time intervals (15, 30 or 60 min, in three different experiments) the effect of another rocuronium bolus injection of 100 microg kg(-1) was determined.
Injection of the first dose of rocuronium resulted in a mean neuromuscular block (depression of first twitch) of 93 (SEM=1.6)%. Fifteen minutes after injection of sugammadex the same rocuronium dose resulted in 17% (SEM=5.6) block. After 30 and 60 min these maximum blocks amounted to 49% (SEM=7.6) and 79% (SEM=4.2), respectively. The estimated half-life of sugammadex in Rhesus monkey is 30 (SEM=4.9) min.
The half-life of sugammadex (Org 25969), a new fast and efficient reversal agent for rocuronium-induced block, is relatively short in the Rhesus monkey, implying the possibility to perform neuromuscular block by rocuronium shortly after reversal of a prior block. In translation to the human situation differences in rocuronium sensitivity and kinetics should be taken into account.
Background and Objective
Sugammadex reverses neuromuscular blockade induced by aminosteroid agents by encapsulating these agents. The objective of this study was to compare the efficacy and safety of sugammadex to reverse a rocuronium-induced neuromuscular blockade in long-duration surgery in association with inhaled or intravenous anesthesia.
Patients and Methods
We performed a randomized, double-blind, multicenter trial of 20 ASA 1–3 patients aged between 18 and 69 years and scheduled for elective surgery lasting at least 120 minutes. Anesthesia was induced with remifentanil and rocuronium at a dosage of 0.6 mg·kg−1, and neuromuscular function was monitored by means of acceleromyography. After randomization, anesthesia was maintained with sevoflurane or with propofol for total intravenous anesthesia. Patients in both groups also received an infusion of remifentanil for analgesia and rocuronium to maintain a block of greater than 90%. After surgery, sugammadex was administered at a dosage of 2 mg·kg−1 on reappearance of the second train-of-four (TOF) twitch (T2) and the times until recovery of T4/T1 ratios of 0.7, 0.8, and 0.9 (main endpoints). Mean arterial pressure and heart rate were recorded at baseline and after 2, 5, 10, and 30 minutes (secondary outcome measures).
Results
Although less rocuronium was consumed in the sevoflurane group than in the propofol group and the time between the start of sugammadex administration until recovery of a TOF ratio of 0.9 was shorter for the sevoflurane group than for propofol group (mean [SD], 1.46 [0.30] minutes and 1.89 [0.62] minutes, respectively), these differences were not significant. No signs of recurarization or associated adverse effects were observed.
Conclusions
Sugammadex effectively and safely reverses a rocuronium-induced neuromuscular blockade in less than 2 minutes in long-duration surgery performed under both inhaled and intravenous anesthesia. The interaction of neuromuscular blocking agents with sevoflurane appears not to affect the reversal time of sugammadex in such operations.
Chemical modification of γ-cyclodextrin afforded Org-25969 that has a cavity dimension capable of forming a binary host-guest complex with the steroidal neuromuscular blocker rocuronium bromide with high affinity. In this complex, rocuronium is encapsulated inside the cavity of Org-25969. As a consequence, the neuromuscular blocking activity of rocuronium can be reversed by Org-25969. The reversal produced by Org-25969 is more efficacious than the standard combination of acetylcholinesterase inhibitor and muscarinic receptor antagonist, e.g., neostigmine + atropine. Unlike neostigmine + atropine, Org-25969 does not interfere with the acetylcholine homeostasis. At the effective reversal dose (0.5 μmol/kg i.v.), Org-25969 produced negligible changes in hemodynamic parameters in anesthetized guinea pigs, cats and monkeys. Org-25969 is also effective in reversing profound block induced by 3 times the ED90 of rocuronium in guinea pigs at a rate at least 3 times faster than neostigmine + atropine. Therefore, Org-25969 is also potentially useful for early or escape reversal of rocuronium, for instance, in a "cannot intubate, cannot ventilate" situation.
Sugammadex (Org 25969), a novel, selective relaxant binding agent, was specifically designed to rapidly reverse rocuronium-induced neuromuscular blockade. The efficacy and safety of sugammadex for the reversal of profound, high-dose rocuronium-induced neuromuscular blockade was evaluated.
A total of 176 adult patients were randomly assigned to receive sugammadex (2, 4, 8, 12, or 16 mg/kg) or placebo at 3 or 15 min after high-dose rocuronium (1.0 or 1.2 mg/kg) during propofol anesthesia. The primary endpoint was time to recovery of the train-of-four ratio to 0.9. Neuromuscular monitoring was performed using acceleromyography.
Sugammadex administered 3 or 15 min after injection of 1 mg/kg rocuronium decreased the median recovery time of the train-of-four ratio to 0.9 in a dose-dependent manner from 111.1 min and 91.0 min (placebo) to 1.6 min and 0.9 min (16 mg/kg sugammadex), respectively. After 1.2 mg/kg rocuronium, sugammadex decreased time to recovery of train-of-four from 124.3 min (3-min group) and 94.2 min (15-min group) to 1.3 min and 1.9 min with 16 mg/kg sugammadex, respectively. There was no clinical evidence of reoccurrence of neuromuscular blockade or residual neuromuscular blockade. Exploratory analysis revealed that prolongation of the corrected QT interval considered as possibly related to sugammadex occurred in one patient. Another two patients developed markedly abnormal arterial blood pressure after sugammadex that lasted approximately 15 min.
Sugammadex provides a rapid and dose-dependent reversal of profound neuromuscular blockade induced by high-dose rocuronium (1.0 or 1.2 mg/kg) in adult surgical patients.
Sugammadex, a specifically designed gamma-cyclodextrin, is a selective relaxant binding drug that rapidly reverses rocuronium-induced and, to a lesser extent, vecuronium-induced neuromuscular blockade. In this study, we compared the efficacy of sugammadex and neostigmine for the reversal of vecuronium-induced neuromuscular blockade in patients scheduled for elective surgery.
Patients aged > or = 18 yr, ASA Class I-III, and scheduled for a surgical procedure under sevoflurane/opioid anesthesia received an intubating dose of vecuronium (0.1 mg/kg) and maintenance doses of 0.02-0.03 mg/kg at reappearance of the second twitch (T(2)) of train-of-four (TOF) if required. Neuromuscular blockade was monitored using acceleromyography (TOF-Watch SX, Schering-Plough Ireland, Dublin, Ireland). At end of surgery, at reappearance of T(2) after the last dose of vecuronium, patients were randomized to receive either sugammadex (2 mg/kg) or neostigmine (50 microg/kg) plus glycopyrrolate (10 microg/kg) i.v.. The primary efficacy end-point was time from start of administration of sugammadex or neostigmine to recovery of TOF ratio to 0.9.
The geometric mean time to recovery of the TOF ratio to 0.9 was significantly faster with sugammadex compared with neostigmine (2.7 min [95% confidence interval {CI}]: 2.2-3.3) versus 17.9 min [95% CI: 13.1-24.3], respectively; P < 0.0001). The mean recovery times to a TOF ratio of 0.8 and 0.7 were also significantly shorter with sugammadex. No serious adverse events or unexpected side effects were reported with either drug.
Sugammadex provided significantly faster reversal of vecuronium-induced neuromuscular blockade compared with neostigmine.
The present randomized, safety-assessor blinded, placebo-controlled trial was designed to assess safety and efficacy of sugammadex, a novel selective relaxant-binding agent, in patients with underlying cardiovascular disease undergoing noncardiac surgery.
Overall, 116 patients (New York Heart Association class II-III) were randomized and received sugammadex 2.0 mg kg (n = 38), sugammadex 4.0 mg kg (n = 38) or placebo (n = 40) for reversal of rocuronium-induced neuromuscular blockade at reappearance of T2. Safety variables included heart rate, blood pressure and electrocardiogram characteristics, including rate-corrected QT (QTc Fridericia and QTc Bazett) interval. Efficacy was evaluated as time to recovery of the T4/T1 ratio to 0.9 after administration of sugammadex or placebo.
There were no significant differences between groups in terms of QTc (Fridericia) interval. Three serious adverse events, one in each treatment group, considered to be possibly drug-related according to the investigator, were cases of mild QTc (Bazett) interval prolongation. Blood pressure and heart rate decreased after initiation of anaesthesia and remained stable in all groups up to 10 min after administration of study drug. Blood pressure was significantly higher (P < 0.05) in both sugammadex dose groups compared with placebo at 30 min. The decrease in heart rate from baseline (prestudy drug) was significantly greater in the 2.0 mg kg sugammadex group at 2 and 5 min, and, for both sugammadex groups, the increase at 30 min was greater compared with placebo. Both sugammadex doses resulted in considerably shorter time to recovery of the T4/T1 ratio to 0.9 compared with placebo.
The findings indicate sugammadex 2.0 and 4.0 mg kg can be given safely and effectively for the reversal of rocuronium-induced neuromuscular blockade in patients with cardiovascular disease undergoing noncardiac surgery.
Sugammadex (Bridion (R)), a modified gamma-cyclodextrin, is the first selective relaxant binding agent indicated to reverse the neuromuscular blockade induced during general anaesthesia to facilitate surgical procedures. The mechanism of action of sugammadex differs from that of other commonly used reversal agents, such as neostigmine and edrophonium. In the EU, sugammadex is recommended for use in the reversal of rocuronium- or vecuronium-induced moderate or deep muscle relaxation in adult (including elderly) patients and reversal of rocuronium-induced moderate muscle relaxation in paediatric patients (aged 2-17 years). Sugammadex is also approved in Australia, Iceland, New Zealand and Norway. In clinical trials in adult surgical patients with relatively good health, sugammadex at recommended doses provided rapid reversal of rocuronium- or vecuronium-induced neuromuscular blockade with a low incidence of residual or recurrent neuromuscular blockade and was generally well tolerated. In paediatric patients, sugammadex effectively reversed rocuronium-induced neuromuscular blockade and was generally well tolerated. Several factors associated with the use of sugammadex have yet to be determined, such as the efficacy and safety in patients with poorer health or in those with neuromuscular disorders, the incidence of infrequent adverse events in larger patient populations and the cost effectiveness of the drug relative to existing reversal agents. Nevertheless, sugammadex is a useful addition to the reversal agents commonly employed in anaesthetic practice.
Postoperative residual curarization is still a problem of the modern anesthesia. Neostigmine is not the safest drug that allows a safe decurarization, especially when neuromuscular transmission monitoring is not used. Sugammadex is a A-cyclodextrin designed to encapsulate rocuronium bromide, providing a rapid reversal of neuromuscular blockade. It has not cardiovascular, respiratory and cholinergic effects. It has been used in renally impaired patients with no neuromuscular blockade recurrence. Sugammadex reverses either a shallow or a deep neuromuscular block. Volatile agents such as sevoflurane seems not to influence the sugammadex ability to reverse the rocuronium neuromuscular blockade. There is no difference in the sugammadex pharmacokinetic in children and adults. Sugammadex would be able to have a role in the future in reversing a non depolarizing steroidal neuromuscular block.
Rocuronium in intubation doses provides similar intubation conditions as succinylcholine, but has a longer duration of action. This study compared time to sugammadex reversal of profound rocuronium-induced neuromuscular block with time to spontaneous recovery from succinylcholine.
One hundred and fifteen adult American Society of Anesthesiologists Class I-II surgical patients were randomized to this multicenter, safety-assessor-blinded, parallel group, active-controlled, Phase IIIa trial. Anesthesia was induced and maintained with propofol and an opioid. Neuromuscular transmission was blocked and tracheal intubation facilitated with 1.2 mg/kg rocuronium or 1 mg/kg succinylcholine. Sugammadex (16 mg/kg) was administered 3 min after rocuronium administration. Neuromuscular function was monitored by acceleromyography. The primary efficacy endpoint was the time from the start of relaxant administration to recovery of the first train-of-four twitch (T(1)) to 10%.
One hundred and ten patients received study treatment. Mean times to recovery of (T(1)) to 10% and (T(1)) to 90% were significantly faster in the rocuronium-sugammadex group (4.4 and 6.2 min, respectively), as compared with the succinylcholine group (7.1 and 10.9 min, respectively; all P < 0.001). Timed from sugammadex administration, the mean time to recovery of (T(1)) to 10%, (T(1)) to 90%, and the train-of-four (T(4)/T(1)) ratio to 0.9 was 1.2, 2.9, and 2.2 min, respectively. Reoccurrence of the block was not observed. There were no serious adverse events related to study treatments.
Reversal of profound high-dose rocuronium-induced neuromuscular block (1.2 mg/kg) with 16 mg/kg sugammadex was significantly faster than spontaneous recovery from 1 mg/kg succinylcholine.
Since the introduction of nondepolarizing neuromuscular blocking agents, acetylcholinesterase inhibitors have been used to increase the speed of recovery from neuromuscular blockade. The major disadvantages of acetylcholinesterase inhibitors are their lack of activity against profound neuromuscular blockade and their activity outside the neuromuscular junction resulting in unwanted side effects, requiring cotreatment with a muscarinic antagonist. An alternative to acetylcholinesterase inhibitors is the encapsulating agent sugammadex. This agent has been specifically designed to encapsulate the steroidal neuromuscular blocking agents rocuronium and vecuronium. This review describes the effects of sugammadex in in vitro tissue and in vivo animal experiments. The encapsulation approach allows reversal of any degree of neuromuscular blockade because the dose of sugammadex can be adjusted to encapsulate sufficient neuromuscular blocking molecules to cause effective reversal. Because this interaction is a drug-drug interaction, reversal can be achieved very fast but is limited by the circulation time. Sugammadex is also effective against neuromuscular blockade under conditions with reduced acetylcholine release, which potentiate the action of neuromuscular blocking agents. Sugammadex does not cause cholinergic side effects, preventing the need of coadministration of muscarinic antagonists. Because of these properties, sugammadex has the potential to become a very useful drug for the management of neuromuscular blockade.
The first part of this article presents an update of the basic considerations of neuromuscular monitoring. It emphasises the need to assure supramaximal stimulation, to place the stimulating electrodes correctly and to use appropriate sites for nerve stimulation as well as appropriate stimulation patterns. The second part focuses on current developments and ongoing discussion. The authors describe the performance of acceleromyography and the need for initial calibration when using these quantitative devices.
No drugs in anaesthesia are more problematic than suxamethonium. Yet, no drugs have survived as suxamethonium does in spite of crisis after crisis, and attempt after attempt at its replacement. For decades, suxamethonium has taught us neuromuscular pharmacology and provided us with an encyclopaedia of side effects, while benefiting millions and millions of our anaesthetised patients. With the arrival of sugammadex, it finally appears that suxamethonium can be retired. Suxamethonium has done its job and seen its days! The present review is intended to offer a eulogy for suxamethonium.
Sugammadex is a cyclodextrin molecule that encapsulates and inactivates rocuronium and vecuronium. As a result, any degree of neuromuscular block produced by rocuronium or vecuronium can be rapidly and completely reversed without autonomic effects. Because sugammadex is optimised for reversing rocuronium it is most likely to be used in conjunction with this drug. Sugammadex will allow deep levels of block to be maintained until the very end of surgery, and will allow block to be reversed at any time after rocuronium administration, even just a few minutes. The recommended dose-range is 2-16 mg.kg-1 (ascender), depending on the level of block. The availability of sugammadex reversal may increase the use of rocuronium, and decrease the use of suxamethonium and benzylisoquinoline neuromuscular blocking drugs. In addition, it will certainly increase pharmacy costs, which may be offset by faster recovery and discharge from the post-anesthesia recovery unit. Sugammadex may also change monitoring practices in that post-tetanic count will be required to quantify deep block, and quantitative monitoring of recovery may be driven by cost concerns in order to allow the use of the smallest dose of sugammadex that gives a satisfactory train-of-four ratio. Alternatively, monitoring may essentially be abandoned since a large dose of sugammadex will reliably reverse any degree of rocuronium-induced block. The ultimate clinical utility of sugammadex will be clear only after large-scale clinical use.
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.
The availability of sugammadex allows greater flexibility in the use of rocuronium and vecuronium during anaesthesia and surgery. The neuromuscular block induced by both drugs can be reversed from both superficial and deep levels of block by adjusting the dose of sugammadex. The dose of sugammadex for reversal of shallow block produced by these neuromuscular blocking drugs is approximately 2 mg.kg(-1) and for deep block the dose is 4 mg.kg(-1). A larger dose of sugammadex (16 mg.kg(-1)) administered 3 min after the neuromuscular blocking drug allows rapid reversal of a neuromuscular block induced by 1-1.2 mg.kg(-1) of rocuronium, thereby raising the possibility of using rocuronium as a replacement for suxamethonium. The use of sugammadex has not been reported to be associated with recurrence of block provided a dose that is adequate for reversal has been used. Sugammadex appears to have an acceptable safety profile. There are no requirements for dose adjustment for age or the use of potent volatile anaesthetic agents.
A review is presented of animal studies of the selective steroidal neuromuscular blocking drug binding agent sugammadex. These studies demonstrate that sugammadex is faster in onset than the currently used acetylcholinesterase inhibitors, has no muscarinic effects, and is characterised by lack of adverse effects on other organs. These results offer support for the further development of sugammadex for clinical use in humans.
Residual paralysis, with its subsequent postoperative pulmonary sequelae, is one of the major complications of anaesthesia, and was recognised shortly after the introduction of neuromuscular blocking drugs into routine clinical practice. Although its incidence decreased with the introduction of intermediate duration drugs, and further diminished with routine neuromuscular monitoring and reversal with cholinesterase inhibitors, residual paralysis still remained a problem. In the search for alternatives to stop the effect of neuromuscular blocking drugs and to match their duration of action to clinical need, chelation of the non-depolarising neuromuscular blocking drugs was considered. It was recognised that cyclodextrins could encapsulate steroidal molecules and thereby inactivate the aminosteroidal neuromuscular blocking drugs. In order to improve the binding of rocuronium to the cyclodextrin and to increase the compound's water solubility, the molecule was modified. This led to the development of sugammadex (Org 25969), a modified gamma-cyclodextrin. The modification of the molecule and the initial in vitro studies that led to in vivo and later human studies of this conceptually new drug for anaesthesia are described.
There is now mounting evidence that even small degrees of postoperative residual neuromuscular block increases the incidence of adverse respiratory events in the Post Anaesthesia Care Unit and may increase longer-term morbidity as well. In the absence of quantitative neuromuscular monitoring, residual block is easily missed. A very strong case can be made for the routine administration of a non-depolarising antagonist unless it can be objectively demonstrated that complete recovery has occurred spontaneously. However, the use of acetylcholinesterase inhibitors is associated with the potential for cardiovascular and respiratory side-effects, so there are cogent reasons for using low doses when the level of neuromuscular block is not intense. As little as 0.015-0.025 mg.kg(-1) of neostigmine is required at a train-of-four count of four with minimal fade, whereas 0.04-0.05 mg.kg(-1) is needed at a train-of-four count of two or three. If only a single twitch or none at all can be evoked, neostigmine should not be expected to promptly reverse neuromuscular block, and antagonism is best delayed till a train-of-four-count of two is achieved.
Neuromuscular blocking drugs are designed to bind to the nicotinic receptor at the neuromuscular junction. However, they also interact with other acetylcholine receptors in the body. Binding to these receptors causes adverse effects that vary with the specificity for the cholinergic receptor in question. Moreover, all neuromuscular blocking drugs may cause hypersensitivity reactions. Often the symptoms are mild and self-limiting but massive histamine release can cause systematic reactions with circulatory and respiratory symptoms and signs. At the end of anaesthesia, no residual effect of a neuromuscular blocking drug should be present. However, the huge variability in response to neuromuscular blocking drugs makes it impossible to predict which patient will suffer postoperative residual curarization. This article discusses the undesirable effects of the currently available neuromuscular blocking drugs including the definitions, diagnosis and causes of hypersensitivity reactions and postoperative residual curarisation.
Neuromuscular transmission at the skeletal muscle occurs when a quantum of acetylcholine from the nerve ending is released and binds to the nicotinic acetylcholine receptors on the postjunctional muscle membrane. The nicotinic acetylcholine receptors on the endplate respond by opening channels for the influx of sodium ions and subsequent endplate depolarisation leads to muscle contraction. The acetylcholine immediately detaches from the receptor and is hydrolysed by acetylcholinesterase enzyme. Suxamethonium is a cholinergic agonist stimulating the muscle nicotinic acetylcholine receptors prior to causing neuromuscular block. Non-depolarising neuromuscular blocking drugs bind to the nicotinic acetylcholine receptors preventing the binding of acetylcholine. Non-depolarising neuromuscular blocking drugs also inhibit prejunctional alpha3beta2 nicotinic acetylcholine autoreceptors, which can be seen in the clinical setting as train-of-four fade. In some pathological states such as denervation, burns, immobilisation, inflammation and sepsis, there is expression of other subtypes of nicotinic acetylcholine receptors with upregulation of these receptors throughout the muscle membrane. The responses of these receptors to suxamethonium and non-depolarising neuromuscular blocking drugs are different and explain some of the aberrant responses to neuromuscular blocking drugs.
Sugammadex is a modified gamma cyclodextrin compound which encapsulates rocuronium resulting in rapid reversal of residual neuromuscular blockade. We performed a post hoc analysis of data from a multicenter study designed to mimic standard clinical practice which would test the hypothesis that the presence (versus the absence) of a twitch response to neuromuscular stimulation at the time of reversal drug administration would influence the speed and completeness of the reversal effect of sugammadex.
One-hundred-seventy-one consenting patients undergoing general anesthesia with a volatile-based anesthetic technique were enrolled in a multicenter observational study. All patients received rocuronium, 0.6 mg/kg i.v. for tracheal intubation and maintenance boluses of 0.15 mg/kg i.v. as needed during surgery. The degree of rocuronium-induced blockade was assessed during anesthesia using a TOF-Watch-SX acceleromyograph to record the train-of-four (TOF) responses on a laptop computer from induction of anesthesia until the TOF ratio returned to > or = 0.9 after completion of the surgical procedure. The patients received sugammadex, 4 mg/kg i.v., for reversal of neuromuscular blockade > 15 min after the last dose of rocuronium. Recovery data were compared in patients with either no (0) (n = 89) or > or = 1 twitch (n = 82) in response to TOF stimulation at the time of reversal drug administration.
The patients without a twitch response were more likely to be female (60% vs 40%) and had a shorter time interval between the last bolus dose of rocuronium and the administration of the reversal drug (31+/-18 vs 45+/-23 min, P < 0.05). The time to achieve a TOF ratio of 0.9 was prolonged in the 0 twitch group compared with the > or = 1 twitch response group (173+/-162 vs 104+/-73 s, P < 0.05). Overall, 84% of the patients in the 0 twitch group recovered to a TOF of 0.9 in < or = 5 min compared to 91% of the patients in the group with > or = 1 twitch (P < 0.05). The times to achieve a TOF of 0.9 varied from 0.8 to 22.3 and 0.7 to 8.5 min in the 0 twitch and > or = 1 twitch groups, respectively.
Reversal of rocuronium-induced neuromuscular blockade by sugammadex was influenced by the degree of residual blockade at the time the reversal drug was administered. Despite the wide variability, reversal of the TOF ratio to 0.9 occurred < or = 5 min in more than 80% of the patients regardless of the number of twitches at the time of reversal drug administration.
Sugammadex reverses neuromuscular blockade by chemical encapsulation of rocuronium. This phase IIIA study explored efficacy and safety of sugammadex in infants (28 days to 23 months), children (2-11 yr), adolescents (12-17 yr), and adults (18-65 yr).
Anesthetized patients (American Society of Anesthesiologists class 1-2) received 0.6 mg/kg rocuronium and were randomized to receive sugammadex (0.5, 1.0, 2.0, or 4.0 mg/kg) or placebo at reappearance of T2. Neuromuscular monitoring was performed using acceleromyography. Primary endpoint was time from sugammadex/placebo administration to recovery of the train-of-four ratio to 0.9. Adverse events and electrocardiograms were recorded, and blood samples were collected for safety and determination of sugammadex and rocuronium plasma concentrations.
A dose-response relation was demonstrated in children (n = 22), adolescents (n = 28), and adults (n = 26), but not infants because of the small sample size (n = 8). After placebo, median recovery time of train-of-four to 0.9 was 21.0, 19.0, 23.4, and 28.5 min in infants, children, adolescents, and adults, respectively. After 2.0 mg/kg sugammadex train-of-four 0.9 was attained in 0.6, 1.2, 1.1, and 1.2 min, respectively. The sugammadex plasma concentrations were similar for the children, adolescent, and adult age groups across the dose range. Sugammadex was well tolerated: No reoccurrence of blockade, inadequate reversal, significant QT prolongation, or other abnormalities were observed.
Sugammadex is a new reversal agent that rapidly, effectively, safely, and with similar recovery times reverses rocuronium-induced neuromuscular blockade in children, adolescents, adults, and the small number of infants studied.
Traditionally, reversal of nondepolarizing neuromuscular blocking agents was achieved using acetylcholinesterase inhibitors, but these are unable to adequately reverse profound blockade. Sugammadex is a novel reversal agent, reversing the effects of rocuronium by encapsulation. This study assessed the efficacy and safety of sugammadex versus neostigmine for reversal of profound rocuronium-induced neuromuscular blockade.
This phase III, randomized study enrolled surgical patients, aged 18 yr or older with American Society of Anesthesiologists physical status I-IV. Patients were randomized to receive sugammadex (4.0 mg/kg) or neostigmine (70 microg/kg) plus glycopyrrolate (14 microg/kg). Anesthetized patients received an intubating dose of rocuronium (0.6 mg/kg), with maintenance doses (0.15 mg/kg) as required. Neuromuscular monitoring was performed by acceleromyography. Sugammadex or neostigmine was administered at reappearance of 1-2 posttetanic counts (profound neuromuscular blockade). The primary efficacy parameter was the time from sugammadex or neostigmine-glycopyrrolate administration to return of the train-of-four ratio to 0.9.
In the intent-to-treat population (n = 37 in each group), geometric mean time to recovery to a train-of-four ratio of 0.9 with sugammadex was 2.9 min versus 50.4 min with neostigmine-glycopyrrolate (P < 0.0001) (median, 2.7 min vs. 49.0 min). Most sugammadex patients (97%) recovered to a train-of-four ratio of 0.9 within 5 min after administration. In contrast, most neostigmine patients (73%) recovered between 30 and 60 min after administration, with 23% requiring more than 60 min to recover to a train-of-four ratio of 0.9.
Recovery from profound rocuronium-induced neuromuscular blockade was significantly faster with sugammadex versus with neostigmine, suggesting that sugammadex has a unique ability to rapidly reverse profound rocuronium neuromuscular blockade.
The frequency and duration of postoperative residual neuromuscular block on arrival of 150 patients in the recovery ward following the use of vecuronium (n = 50), atracurium (n = 50) and rocuronium (n = 50) were recorded. Residual block was defined as a train-of-four ratio of <0.8. An additional group of 10 patients received no neuromuscular blocking drugs during anaesthesia. The incidence of postoperative residual neuromuscular block was 64%, 52% and 39% after the use of vecuronium, atracurium and rocuronium, respectively. Similar numbers of patients were not able to maintain a sustained head or leg lift for 5 s on arrival in the recovery ward. The mean [range] times to attaining a train-of-four ratio of > or =0.8 after arrival in the recovery ward were 9.2 [1-61], 6.9 [1-24] and 14.7 [1.5-83] min for vecuronium, atracurium and rocuronium, respectively. None of the 10 patients who did not receive neuromuscular blocking drugs had train-of-four ratios <0.8 on arrival in the recovery ward. It is concluded that a large proportion of patients arrive in the recovery ward with a train-of-four ratio <0.8, even with the use of intermediate-acting neuromuscular blocking drugs. Although the residual block is relatively short lasting, it may occasionally be prolonged, requiring close observation and monitoring of such patients in the recovery ward.
A series of secondary face modified cyclodextrins (CDs) were synthesised with the aim of constructing host molecules capable of forming host-guest complexes with neuromuscular blockers, especially with rocuronium bromide. Perfacial 2-O-substitution of gamma-CD with 4-carboxybenzyl resulted in a CD host molecule 1 that forms a 1:1 binary complex with rocuronium bromide (K(a) 6.2 x 10(5) M(-1)). The biological activities of this compound and other derivatives as reversal agents of rocuronium bromide were examined in vitro (mouse hemi-diaphragm) and in vivo (anaesthetized guinea pigs). The host molecule 1 was found to exert potent reversal activity (ED(50) 0.21 micromol/kg, iv) against rocuronium-induced neuromuscular block, and thus proved the viability of using host molecules as antidotes of a biologically active compound.
A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.
A sensitive and specific liquid chromatography/mass spectrometry (LC/MS) method has been developed and validated for the quantification of the modified gamma-cyclodextrin Org 25969 and Rocuronium bromide (Roc or Org 9426) in the plasma and urine of guinea pigs. The assay was linear and reproducible over the range 25-10000 ng/mL for both compounds. The lowest limit of quantification (LLOQ) for both compounds in urine was 25 ng/mL. In plasma, the LLOQ was 25 ng/mL for Org 9426 and 50 ng/mL for Org 25969. The inter- and intra-day variation was lower than 20%. The physicochemical properties of both compounds imposed different modes of extraction from plasma. The modified gamma-cyclodextrin was extracted by trifluoroacetic acid (TFA) precipitation while Rocuronium was extracted by acetonitrile precipitation. Both compounds were quantified in urine by direct injection onto the column. The LC/MS analyses of Org 25969 and Org 9426 were performed using two different assay conditions. It was not possible to quantify the complex of cyclodextrin and Roc as it dissociated on the LC column. The use of LC/MS conferred great advantage to the quantification of both Org 25969 and Org 9426, as they were not chromogenic enough to afford the sensitivity and specificity required for the assay.
Stark wirksam bei geringen Nebenwirkungen: In der Anästhesie dienen Muskelrelaxantien zum Einstellen guter Intubationsbedingungen über eine tiefe neuromuskuläre Blockade; am häufigsten wird hierfür Rocuroniumbromid verwendet. Die hierdurch hervorgerufene neuromuskuläre Blockade wird durch die Bildung eines fest gebundenen, binären Komplexes (Ka≈ 107 M−1) zwischen dem Gastmolekül Rocuroniumbromid und einer synthetischen Wirtverbindung auf Cyclodextrinbasis (siehe Struktur im Kristall) aufgehoben. Im Hinblick auf Wirksamkeit und geringe Nebenwirkungen ist dieses Wirkstoff-System den derzeit klinisch verwendeten überlegen.
Although numerous reversal agents for neuromuscular block (NMB) have been known for some time, investigations on new approaches were initiated only recently. The different approaches used in an attempt to avoid the muscarinic side effects associated with the antagonists of NMB that are currently available are reviewed.
Residual neuromuscular blockade remains a problem even after short surgical procedures. The train-of-four (TOF) ratio at the adductor pollicis required to avoid residual paralysis is now considered to be at least 0.9. The incidence of residual paralysis using this new threshold is not known, especially after a single intubating dose of intermediate-duration nondepolarizing relaxant. Therefore, the aim of the study was to determine the incidence of residual paralysis in the postanesthesia care unit after a single intubating dose of twice the ED(95) of a nondepolarizing muscle relaxant with an intermediate duration of action.
Five hundred twenty-six patients were enrolled. They received a single dose of vecuronium, rocuronium, or atracurium to facilitate tracheal intubation and received no more relaxant thereafter. Neuromuscular blockade was not reversed at the end of the procedure. On arrival in the postanesthesia care unit, the TOF ratio was measured at the adductor pollicis, using acceleromyography. Head lift, tongue depressor test, and manual assessment of TOF and DBS fade were also performed. The time delay between the injection of muscle relaxant and quantitative measurement of neuromuscular blockade was calculated from computerized anesthetic records.
The TOF ratios less than 0.7 and 0.9 were observed in 16% and 45% of the patients, respectively. Two hundred thirty-nine patients were tested 2 h or more after the administration of the muscle relaxant. Ten percent of these patients had a TOF ratio less than 0.7, and 37% had a TOF ratio less than 0.9. Clinical tests (head lift and tongue depressor) and manual assessment of fade showed a poor sensitivity (11-14%) to detect residual blockade (TOF < 0.9).
After a single dose of intermediate-duration muscle relaxant and no reversal, residual paralysis is common, even more than 2 h after the administration of muscle relaxant. Quantitative measurement of neuromuscular transmission is the only recommended method to diagnose residual block.
The purpose of this study was to determine the changes in the plasma concentration of rocuronium and the reversal of its neuromuscular blockade after the intravenous infusion of Org 25969, the novel neuromuscular block-reversal agent, in anesthetized guinea pigs.
Rocuronium was infused for 1 h at a rate of 12-19 nmol.kg-1.min-1 to produce a steady-state 90% neuromuscular block. After 30 min, a concomitant infusion of either the reversal agent Org 25969 at a rate of 50 nmol.kg-1.min-1 or an infusion of an equivalent volume of saline was started. The time course of plasma concentrations of rocuronium was determined by use of liquid chromatography-mass spectrometry/mass spectrometry.
In both treatment groups, a steady-state plasma concentration of rocuronium was obtained after 30 min. In the saline-treated group, the plasma concentration of rocuronium and depth of block remained constant. In the Org 25969 group, neuromuscular block was reversed while the rocuronium infusion was ongoing. Simultaneously, an increase in the total plasma concentration of rocuronium (free and complexed) was observed, even though the infusion rate of rocuronium was not changed. Compared with the saline-treated group, a small increase in the postmortem bladder concentration of rocuronium was detected.
The authors propose that the capture of rocuronium by Org 25969 causes the rapid reversal of neuromuscular block. The reversal can be explained by the rapid transfer of free rocuronium from the effect compartment (neuromuscular junction) to the central compartment, in which it is bound to Org 25969. This explains the increase in total plasma concentration of rocuronium (free and bound to Org 25969).
Quantitative estimates of how anesthesia management impacts perioperative morbidity and mortality are limited. The authors performed a study to identify risk factors related to anesthesia management for 24-h postoperative severe morbidity and mortality.
A case-control study was performed of all patients undergoing anesthesia (1995-1997). Cases were patients who either remained comatose or died during or within 24 h of undergoing anesthesia. Controls were patients who neither remained comatose nor died during or within 24 hours of undergoing anesthesia. Data were collected by means of a questionnaire, the anesthesia and recovery form. Odds ratios were calculated for risk factors, adjusted for confounders.
The cohort comprised 869,483 patients; 807 cases and 883 controls were analyzed. The incidence of 24-h postoperative death was 8.8 (95% confidence interval, 8.2-9.5) per 10,000 anesthetics. The incidence of coma was 0.5 (95% confidence interval, 0.3-0.6). Anesthesia management factors that were statistically significantly associated with a decreased risk were: equipment check with protocol and checklist (odds ratio, 0.64), documentation of the equipment check (odds ratio, 0.61), a directly available anesthesiologist (odds ratio, 0.46), no change of anesthesiologist during anesthesia (odds ratio, 0.44), presence of a full-time working anesthetic nurse (odds ratio, 0.41), two persons present at emergence (odds ratio, 0.69), reversal of anesthesia (for muscle relaxants and the combination of muscle relaxants and opiates; odds ratios, 0.10 and 0.29, respectively), and postoperative pain medication as opposed to no pain medication, particularly if administered epidurally or intramuscularly as opposed to intravenously.
Mortality after surgery is substantial and an association was established between perioperative coma and death and anesthesia management factors like intraoperative presence of anesthesia personnel, administration of drugs intraoperatively and postoperatively, and characteristics of delivered intraoperative and postoperative anesthetic care.
Gamma cyclodextrin and purified plasma cholinesterase are 2 novel pharmacological agents being investigated as to their suitability for antagonism of neuromuscular blockade. Both of these agents are devoid of cholinergic stimulation and the accompanying side effects because their action is independent of acetylcholinesterase inhibition. Gamma cyclodextrin antagonizes the steroidal neuromuscular blocker rocuronium via the chemical encapsulation of the molecule forming a "host-guest" complex through van der Waals and hydrophobic interactions in the plasma. Encapsulation decreases plasma drug concentrations, shifting the neuromuscular blocking drug molecules from the neuromuscular junction back to the plasma compartment resulting in a rapid recovery of the neuromuscular function. Org 25969, a modified gamma cyclodextrin, will antagonize profound neuromuscular block induced by rocuronium in approximately 2 minutes. A commercial preparation of purified human plasma cholinesterase has been shown to be effective in reversing succinylcholine or mivacurium-induced block. Administration of exogenous plasma cholinesterase also has been shown to be effective in antagonizing mivacurium-induced neuromuscular block, cocaine toxicity, and organophosphate poisoning.
Acetylcholinesterase inhibitors are widely used for the reversal of neuromuscular blocking agents. However, acetylcholinesterase inhibitors have several side effects and are not effective during profound block. Org 25969 is a modified gamma-cyclodextrin that encapsulates the neuromuscular blocking agent, rocuronium bromide (Esmeron/Zemuron, NV Organon, Oss, The Netherlands), forming a tightly bound complex with an association constant of approximately 10 m. Chemical encapsulation of rocuronium promotes dissociation of rocuronium from the acetylcholine receptor, thereby reversing the neuromuscular block without the side effects associated with acetylcholinesterase inhibitors.
Twenty-nine healthy male volunteers were enrolled to investigate the safety, pharmacokinetics, and efficacy of Org 25969. In part 1, Org 25969 or placebo was administered to 19 subjects during one to three treatment periods each. In part 2, a further 10 subjects received general anesthesia on two separate occasions, using an intubating dose of 0.6 mg/kg rocuronium. Three minutes after rocuronium administration, Org 25969 or placebo was given in random order. Six doses of 0.1-8.0 mg/kg Org 25969 were evaluated. Neuromuscular block was measured using an acceleromyograph, the TOF-Watch-SX (NV Organon, Oss, The Netherlands).
All adverse events related to Org 25969 treatment were of limited duration and mild intensity, except for a period of paresthesia, seen in one patient receiving 8 mg/kg Org 25969, which was of moderate intensity. No adverse events required any treatment, and all subjects recovered from them. When 8 mg/kg Org 25969 was given, the train-of-four ratio returned to 0.9 within 2 min after its administration. No signs of recurarization were observed.
Org 25969 was both well tolerated and effective in reversing neuromuscular block induced by rocuronium in 29 human volunteers.
This review is focused on recent advances in the application of cyclodextrins to new drug formulations, with emphasis on the field of anesthesia.
Cyclodextrins are well-known excipients in the pharmaceutical industry. Their recent application to the anesthetic induction agent propofol as a means of creating a non-lipid formulation may lead to their introduction into anesthesia pharmacology. The development of a novel cyclodextrin as specific reversal agent for the neuromuscular blocker rocuronium (that acts as an in-vivo scavenging system to bind free rocuronium in the circulation) will also increase the likelihood that cyclodextrins will have a greater clinical presence in anesthesiology in the future. Cyclodextrin-containing polymers are also finding a role in the delivery of nucleic acids and protein therapeutic agents.
Recent developments in cyclodextrins as excipients for anesthetics may soon culminate in their introduction into anesthesiology, although more research is necessary to better define their potential.
Reversal of neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a synthetic gamma-cyclodextrin derivative. The current study determined the feasibility of reversal of rocuronium-induced profound neuromuscular blockade with sugammadex in the anesthetized rhesus monkey using train-of-four stimulation.
Four female rhesus monkeys each underwent three experiments. In each experiment, first, a 100-microg/kg dose of rocuronium was injected and spontaneous recovery was monitored. After full recovery, a 500-microg/kg dose of rocuronium was injected. Up to this point, all three experiments in a single monkey were identical. One minute after this rocuronium injection, either one of the two tested dosages of sugammadex (1.0 or 2.5 mg/kg) was injected or saline was injected.
Injection of 100 microg/kg rocuronium resulted in a mean neuromuscular blockade of 93.0% (SD = 4%), and profound blockade was achieved by injection of 500 microg/kg. In all experiments, a 100% neuromuscular blockade was achieved at this dose. After injection of the high rocuronium dose, the 90% recovery of the train-of-four ratio took 28 min (SD = 7 min) after saline, 26 min (SD = 9.5 min) after 1 mg/kg sugammadex, and 8 min (SD = 3.6 min) after 2.5 mg/kg sugammadex. Signs of residual blockade or recurarization were not observed. Injection of sugammadex had no significant effects on blood pressure or heart rate.
Chemical encapsulation of rocuronium by sugammadex is a new therapeutic mechanism allowing effective and rapid reversal of profound neuromuscular blockade induced by rocuronium in anesthetized rhesus monkeys.