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Anesthesiology:
Laboratory Investigations

Reversal of Profound Rocuronium Neuromuscular Blockade by Sugammadex in Anesthetized Rhesus Monkeys

de Boer, Hans D. M.D.*; van Egmond, Jan Ph.D.†; van de Pol, Francien Ing.‡; Bom, Anton Ph.D.§; Booij, Leo H. D. J. M.D., Ph.D.∥

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Abstract

Background: Reversal of neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a synthetic γ-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.
Methods: Four female rhesus monkeys each underwent three experiments. In each experiment, first, a 100-μg/kg dose of rocuronium was injected and spontaneous recovery was monitored. After full recovery, a 500-μg/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.
Results: Injection of 100 μg/kg rocuronium resulted in a mean neuromuscular blockade of 93.0% (SD = 4%), and profound blockade was achieved by injection of 500 μg/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.
Conclusions: 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.
REVERSAL of neuromuscular blockade induced by neuromuscular blocking agents is important for a safe postoperative recovery of the patient. Residual neuromuscular blockade and subsequent respiratory insufficiency have been reported as severe morbidity and even mortality.1–5 Reversal of neuromuscular blockade can be achieved with acetylcholinesterase inhibitors such as neostigmine, edrophonium, or pyridostigmine.6–8 In clinical practice, cholinesterase inhibitors are used in combination with muscarinic acetylcholine receptor antagonists such as atropine or glycopyrrolate. Both agents, acetylcholinesterase inhibitors as well as muscarinic acetylcholine receptor antagonists, have a number of well-known undesirable side effects.9–12 Moreover, cholinesterase inhibitors, as a consequence of their mechanism of action, are not able to reverse profound neuromuscular blockade.13,14
Pharmacologic reversal of neuromuscular blockade by cholinesterase inhibitors is only effective when the first twitch of the train-of-four (TOF) stimulation has already recovered spontaneously to at least 10% of the control twitch height.15,16 There is a need for a new reversal agent with minimal side effects and the capability to efficiently reverse neuromuscular blockade, independent of its depth. One of the possibilities is chemical encapsulation or chelation of the neuromuscular blocking agents. Sugammadex, a synthetic γ-cyclodextrin, has been designed to selectively bind the steroidal neuromuscular blocking drug rocuronium.17 The encapsulation of the rocuronium molecule results in a rapid decrease of its free concentration in plasma and its removal from the motor endplates, resulting in the reappearance of muscle activity.17,18 Sugammadex has been shown to reverse neuromuscular blockade induced by steroidal neuromuscular blocking agents in in vitro experiments in the mouse hemidiaphragm and in in vivo experiments in guinea pigs, cats, and monkeys.18,19 The current study was designed to determine the feasibility of reversal of profound neuromuscular blockade with sugammadex in a rocuronium-induced profound neuromuscular blockade in anesthetized rhesus monkeys, using TOF stimulation.
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Materials and Methods

In vivo experiments were performed in the experimental laboratories of the Department of Anesthesiology at the Radboud University Medical Centre in Nijmegen, The Netherlands. The experiments were approved by the regional ethical committee on animal experiments (Radboud University Medical Centre in Nijmegen, The Netherlands). Female rhesus monkeys (CSIMS, Beijing, China) with a body weight of 5.2–7.1 kg were sedated with 10 mg/kg ketamine (Nimatek Eurovet, Bladel, The Netherlands) intramuscularly. Two intravenous lines were placed: one for anesthetic administration, including rocuronium, the other for test drug administration. This was followed by intravenous injection of 25 mg/kg pentobarbitone sodium (Ceva Sante Animale, Libourne Cedex, France) and a subsequent continuous infusion of 5–10 mg · kg−1 · h−1. The monkeys were intubated endotracheally, and the lungs were ventilated with a mixture of oxygen and nitrous oxide (volume ratio of 2:3). Four animals were each studied on three different occasions. The occasions differed by the administration of either saline or a low (1.0 mg/kg) or high (2.5 mg/kg) dose of sugammadex. Between the experiments, the monkeys recovered for at least 6 weeks. Heart rate and oxygen saturation were determined at the ear with a pulse oximeter (Biox; Ohmeda, Madison, WI). Blood pressure was determined with a cuff placed around the tail (Finapres; Ohmeda). Body temperature was measured by a rectal probe and kept at 37°–38°C.
Fig. 1
Fig. 1
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For monitoring purposes, the median nerve of the right arm was stimulated supramaximally near the wrist using needle electrodes. Stimulation was performed with 2-ms square wave pulses in a TOF of 2 Hz with an interval of 15 s delivered by a Grass S88 Stimulator (Grass Medical Instruments, Quincy, MA). The resulting contractions of the thumb muscles were quantified with a force displacement transducer and recorded on a polygraph. The sequence of events during an actual experiment can be read from figure 1A. Before the profound blockade experiments were started, an initial dose of rocuronium bromide of 100 μg/kg (further named initial or “low dose”) was given as a rapid bolus to determine the degree of neuromuscular blockade it produced. This dose of rocuronium was chosen because it is close to the ED90 in our monkey population. Blockade was allowed to recover to full twitch spontaneously. After this, recovery was allowed for at least another hour. Then, a rapid bolus injection equal to 500 μg/kg (approximately 5 × ED90, further named “high dose”) rocuronium bromide was administered, producing profound neuromuscular block (100% blockade in all 12 instances), but at 1 min after this bolus injection, either vehicle (saline) or one of two dosages of sugammadex was intravenously administered as a rapid bolus. For each monkey, in three different experiments (at three dates, separated by at least 6 weeks), reversal was induced by either 0.9% saline, sugammadex at a dose of 1.0 mg/kg, or sugammadex at a dose of 2.5 mg/kg.
At the end of each experiment, the animals were allowed to recover from anesthesia.
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Statistical Analysis
Figure 1B depicts the tracings of recovery after the initial low dose of rocuronium in one particular monkey in the three experiments performed in this animal. Although the tracings are very similar, recovery times differ between the three experiments. This variance is to be expected on the basis of variation in pharmacokinetics and pharmacodynamics over such a long period of time (from 6 to 12 weeks between the experiments). These differences are taken into account by taking the ratio of the recovery after the high dose of rocuronium and those after the low dose. The rationale behind this ratio is that if the response to the first dose is faster on one occasion compared with another, the response to the second dose is likely to also be faster; we do not know whether this is explained by time-related changes in pharmacokinetics or pharmacodynamics.
Equation (Uncited)
Equation (Uncited)
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From the experimental traces at 50%, 75%, and 90%, TOF ratio recovery times from low-dose rocuronium block, 100 μg/kg (t50,low, t75,low, and T90,low), as well as from the high dose (t50,high, t75,high, and t90,high) with saline or sugammadex at both dosages were calculated at recovery. Then, the ratios were calculated of recovery times after high and low doses:
The significance of the effect of both dosages of sugammadex on these variables' R was tested in an analysis of variance procedure. P values less than 0.05 were considered statistically significant. Measurements regarding the recovery times, maximal blockade, and onset times are presented as mean (SD).
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Results

Neuromuscular Blockade
In all experiments, a bolus injection of 100 μg/kg rocuronium bromide (ED90 value for our rhesus monkey population) was administered, resulting in a mean neuromuscular blockade of 93% (4%), with a mean onset time of 1.2 (0.12) min. After full recovery, profound neuromuscular blockade was achieved by a bolus injection of 500 μg/kg rocuronium bromide, which always resulted in a 100% neuromuscular blockade, with a mean onset time of 0.51 (0.08) min.
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Reversal of Profound Blockade
Figure 1A shows typical tracings of the effect of sugammadex at a dose of 2.5 mg/kg on the recovery of profound neuromuscular blockade. Here, the twitch heights of the first and fourth twitches of the TOF are depicted. The first dip is related to the initial low dose of rocuronium, and the second is the result of 5 times this dose. This particular experiment shows the reversal effect of 2.5 mg/kg sugammadex administered 1 min after 500 μg/kg rocuronium (approximately 5 × ED90). Note that at this dosage of sugammadex, recovery after this high dose of rocuronium with the reversal agent is faster than spontaneous recovery after rocuronium, one fifth of this dose. This figure also demonstrates how a very profound blockade by rocuronium may be reversed by a high dose of sugammadex.
Table 1
Table 1
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Fig. 2
Fig. 2
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The neuromuscular recovery times of the profound blockade experiments are presented in table 1 as well as the defined recovery ratios. In figure 2, all recoveries after the high dose of rocuronium after saline or after sugammadex are depicted in four subsets corresponding to the four different monkeys involved in this study.
Fig. 3
Fig. 3
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Heart rate and arterial pressure were measured during all the experiments, and all of the animals recovered completely without complications. In figure 3, a typical example is displayed of changes in heart rate and mean arterial pressure due to the injection of the high dose of rocuronium and sugammadex. Although there are clear responses in heart rate and mean arterial pressure due to this high dose of rocuronium, there are no visible effects due to the highest dose of sugammadex as compared with saline.
Train-of-four monitoring for an extra hour after twitch height had fully recovered indicated that neither residual blockade nor recurarization occurred in any of the animals tested after injection of sugammadex.
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Discussion

Sugammadex, per-6-(2-carboxyethylthio)-per-6-deoxy-γ-cyclodextrin sodium salt, belongs structurally to the family of cyclodextrins. Cyclodextrins, a group of oligosaccharides, are cylindrical capsules with a lipophilic internal cavity and a hydrophilic exterior. With this lipophilic internal cavity, cyclodextrins are able to encapsulate guest molecules such as rocuronium and form a host-guest inclusion complex. This is also known as chemical encapsulation or chelation.18 Cyclodextrins are highly water soluble and biologically well tolerated, and therefore, it is unlikely that side effects will occur.17,18 Sugammadex is a synthetic γ-cyclodextrin derivative that has been especially designed to selectively bind rocuronium. The current study shows that profound neuromuscular blockade can also be effectively and rapidly reversed by sugammadex without signs of residual blockade or recurarization. Although recovery times are significantly shortened by the reversal with 1.0 mg/kg sugammadex, as compared with saline, it is obvious that clinically reversal requires higher dosages, such as 2.5 mg/kg. Injection of sugammadex did not cause significant cardiovascular changes.
The chemical encapsulation or chelation of rocuronium by sugammadex is the mechanism behind this effective and rapid reversal of profound neuromuscular blockade induced by rocuronium in anesthetized rhesus monkeys. In contrast, the administration of cholinesterase inhibitors only has a reliable result in reversing neuromuscular blockade when the first twitch of TOF stimulation (or the single twitch) has recovered spontaneously to at least 10% of the control twitch height.14,17 Currently, cholinesterase inhibitors are used to reverse neuromuscular blockade. The recovery from neuromuscular blockade after the administration of cholinesterase inhibitors is the sum of the increased acetylcholine in the synapse as a result of the enzyme inhibition and the spontaneous recovery by distribution and elimination of the relaxant.20 Administration of cholinesterase inhibitors increases the half-life of the acetylcholine and therefore its concentration at the neuromuscular junction on the surface of the muscle fibers, but does not have direct effects on the concentration of the relaxant at the neuromuscular junction. However, in contrast with the effects of cholinesterase inhibitors, encapsulation of the rocuronium molecule by sugammadex results in a decrease of the concentration of free rocuronium in plasma and subsequently at the motor endplate. Rocuronium is therefore less available to bind nicotinic receptors in the neuromuscular junction.18 This will promote the liberation of acetylcholine receptors, and muscle activity will reappear. As a result of its lack of direct or indirect action on cholinergic transmission, it is unlikely that muscarinic side effects will occur.16 Sugammadex-rocuronium complexes are highly hydrophilic, and it has been demonstrated that sugammadex is excreted rapidly and dose dependently in urine of anesthetized guinea pigs.21
Previous in vitro studies in the mouse hemidiaphragm have shown that sugammadex results in an effective reversal of neuromuscular blockade induced by rocuronium.18 Thereafter, in vivo experiments in cats, guinea pigs, and rhesus monkeys confirmed the ability of sugammadex to reverse neuromuscular blockade induced by rocuronium without significant cardiovascular side effects. The current results extend these findings by showing that sugammadex can also reverse profound neuromuscular blockade without apparent cardiovascular side effects in rhesus monkeys. The mechanism of reversal by encapsulation allows only immediate (i.e., very fast) reversal if the concentration of the reversal agent is such that complex formation binds so much of the blocking agent that its concentration is reduced to values below the threshold value necessary to induce any blockade. Our data show a significant response to a dose of 2.5 mg/kg and a minimal although significant response to a dose of 1 mg/kg. Studies with additional doses larger than 1 mg/kg (and possibly larger than 2.5 mg/kg) are necessary to determine the optimal dose. However, because the safety of this compound has been demonstrated in humans, it is likely that additional dose determination studies will be conducted in humans rather than in monkeys.22,23 In the current study, only four monkeys were studied. Although the conclusion about the reversing power of sugammadex is very significant, conclusions about cardiovascular side effects cannot be decisive in such a small group.
In conclusion, this study has shown that sugammadex at a dose of 2.5 mg/kg can rapidly reverse profound neuromuscular blockade induced by rocuronium in anesthetized rhesus monkeys.
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