Ⅵ LABORATORY INVESTIGATIONS

Anesthesiology 2006; 104:718–23 © 2006 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Reversal of Profound Rocuronium Neuromuscular Blockade by in Anesthetized Rhesus Monkeys Hans D. de Boer, M.D.,* Jan van Egmond, Ph.D.,† Francien van de Pol, Ing.,‡ Anton Bom, Ph.D.,§ Leo H. D. J. Booij, M.D., Ph.D.࿣

Background: Reversal of neuromuscular blockade can be ac- lar blockade and subsequent respiratory insufficiency complished by chemical encapsulation of rocuronium by sug-

have been reported as severe morbidity and even mor- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/104/4/718/361318/0000542-200604000-00016.pdf by guest on 26 September 2021 ␥ ammadex, a synthetic -cyclodextrin derivative. The current tality.1–5 Reversal of neuromuscular blockade can be study determined the feasibility of reversal of rocuronium-in- duced profound neuromuscular blockade with sugammadex in achieved with inhibitors such as 6–8 the anesthetized rhesus monkey using train-of-four stimulation. , edrophonium, or pyridostigmine. In Methods: Four female rhesus monkeys each underwent three clinical practice, cholinesterase inhibitors are used in experiments. In each experiment, first, a 100-␮g/kg dose of combination with muscarinic receptor an- rocuronium was injected and spontaneous recovery was mon- tagonists such as or glycopyrrolate. Both itored. After full recovery, a 500-␮g/kg dose of rocuronium was injected. Up to this point, all three experiments in a single agents, acetylcholinesterase inhibitors as well as musca- monkey were identical. One minute after this rocuronium in- rinic antagonists, have a number jection, either one of the two tested dosages of sugammadex of well-known undesirable side effects.9–12 Moreover, (1.0 or 2.5 mg/kg) was injected or saline was injected. cholinesterase inhibitors, as a consequence of their Results: Injection of 100 ␮g/kg rocuronium resulted in a mechanism of action, are not able to reverse profound ؍ mean neuromuscular blockade of 93.0% (SD 4%), and pro- 13,14 found blockade was achieved by injection of 500 ␮g/kg. In all neuromuscular blockade. experiments, a 100% neuromuscular blockade was achieved at Pharmacologic reversal of neuromuscular blockade by this dose. After injection of the high rocuronium dose, the 90% cholinesterase inhibitors is only effective when the first min) twitch of the train-of-four (TOF) stimulation has already 7 ؍ recovery of the train-of-four ratio took 28 min (SD ,min) after 1 mg/kg sugammadex 9.5 ؍ after saline, 26 min (SD recovered spontaneously to at least 10% of the control ؍ and 8 min (SD 3.6 min) after 2.5 mg/kg sugammadex. Signs of 15,16 residual blockade or recurarization were not observed. Injec- twitch height. There is a need for a new reversal tion of sugammadex had no significant effects on pres- agent with minimal side effects and the capability to sure or heart rate. efficiently reverse neuromuscular blockade, indepen- Conclusions: Chemical encapsulation of rocuronium by sug- dent of its depth. One of the possibilities is chemical ammadex is a new therapeutic mechanism allowing effective encapsulation or chelation of the neuromuscular block- and rapid reversal of profound neuromuscular blockade in- ␥ duced by rocuronium in anesthetized rhesus monkeys. ing agents. Sugammadex, a synthetic -cyclodextrin, has been designed to selectively bind the steroidal neuro- 17 REVERSAL of neuromuscular blockade induced by neu- muscular blocking drug rocuronium. The encapsula- romuscular blocking agents is important for a safe post- tion of the rocuronium molecule results in a rapid de- operative recovery of the patient. Residual neuromuscu- crease 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 This article is accompanied by an Editorial View. Please see: reverse neuromuscular blockade induced by steroidal ᭜ Kopman AF: Sugammadex: A revolutionary approach to neu- neuromuscular blocking agents in in vitro experiments romuscular antagonism. ANESTHESIOLOGY 2006; 104:631–3. 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 * Staff Anesthesiologist and Research Scientist, Department of Anesthesiology, profound neuromuscular blockade with sugammadex in a Radboud University Medical Center Nijmegen. Staff Anesthesiologist, Depart- ment of Anesthesiology, Martini Hospital Groningen, Groningen, The Nether- rocuronium-induced profound neuromuscular blockade in lands. † Research Scientist and Clinical Physicist, ‡ Technical Research Asso- anesthetized rhesus monkeys, using TOF stimulation. ciate, Department of Anesthesiology, Radboud University Medical Center Nijmegen. § Research Scientist, Department of Pharmacology, Organon New- house, Scotland, United Kingdom. ࿣ Professor, Department of Anesthesiology, Radboud University Medical Center Nijmegen. Member of the Scientific Advisory Board, Organon NV, Oss, The Netherlands. Materials and Methods Received from the Department of Anesthesiology, Radboud University Nijme- gen Medical Center Nijmegen, Nijmegen, The Netherlands. Submitted for publi- In vivo experiments were performed in the experi- cation April 13, 2005. Accepted for publication November 8, 2005. Supported by a grant from Organon NV, Oss, The Netherlands. mental laboratories of the Department of Anesthesiology Address correspondence to Dr. de Boer: Department of Anesthesiology, Rad- at the Radboud University Medical Centre in Nijmegen, boud University Medical Center Nijmegen, P. O. Box 9101, 6500 HB Nijmegen, The Netherlands. [email protected]. Individual article reprints may be pur- The Netherlands. The experiments were approved by chased through the Journal Web site, www.anesthesiology.org. the regional ethical committee on animal experiments

Anesthesiology, V 104, No 4, Apr 2006 718 REVERSAL OF PROFOUND BLOCKADE BY SUGAMMADEX 719

Fig. 1. Tracings of twitch and train-of- four (TOF) ratio. (A) The twitch height of the first (T1) and fourth twitch (T4)ofthe TOF of one experiment is depicted. The first dip is related to the initial low dose of 100 mg/kg rocuronium (close to ED90 in the monkey population), the second is the result of 5 times this dose. After re- covery to full twitch height from the first Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/104/4/718/361318/0000542-200604000-00016.pdf by guest on 26 September 2021 dose, the preparation is left for full elim- ination and distribution of rocuronium for at least 1 more hour before the high dose of rocuronium is administered. This particular experiment shows the reversal effect of the 2.5 mg/kg sugammadex ad- ministered 1 min after high dose of rocu- ronium, 500 mg/kg. (B) The value of the initial low dose, given before the actual reversal experiment. Here, the onset and recovery of the TOF ratio after the low dose of rocuronium is shown of the same monkey in three different sessions (each separated at least 6 weeks from the next), corresponding to the three tested dos- ages of sugammadex: 0.0 (vehicle, sa- line), 1.0, and 2.5 mg/kg. It is obvious, although responses are similar, that in one instance, recovery is faster than in another. And it is expected that if the low dose is eliminated/distributed faster, the same will be the case for the high dose, later administered in the same experi- ment. The ratio R of the recovery times, as defined in the text, is expected to elim- inate much of this variability.

(Radboud University Medical Centre in Nijmegen, The pressure was determined with a cuff placed around the Netherlands). Female rhesus monkeys (CSIMS, Beijing, tail (Finapres; Ohmeda). Body temperature was mea- China) with a body weight of 5.2–7.1 kg were sedated sured by a rectal probe and kept at 37°–38°C. with 10 mg/kg (Nimatek Eurovet, Bladel, The For monitoring purposes, the median nerve of the Netherlands) intramuscularly. Two intravenous lines right arm was stimulated supramaximally near the wrist were placed: one for administration, includ- using needle electrodes. Stimulation was performed ing rocuronium, the other for test drug administration. with 2-ms square wave pulses in a TOF of 2 Hz with an This was followed by intravenous injection of 25 mg/kg interval of 15 s delivered by a Grass S88 Stimulator (Grass pentobarbitone sodium (Ceva Sante Animale, Libourne Medical Instruments, Quincy, MA). The resulting con- Cedex, France) and a subsequent continuous infusion of tractions of the thumb muscles were quantified with a 5–10 mg · kgϪ1 ·hϪ1. The monkeys were intubated force displacement transducer and recorded on a poly- endotracheally, and the lungs were ventilated with a graph. The sequence of events during an actual experi- mixture of and (volume ratio of ment can be read from figure 1A. Before the profound 2:3). Four animals were each studied on three different blockade experiments were started, an initial dose of occasions. The occasions differed by the administration of 100 ␮g/kg (further named initial of either saline or a low (1.0 mg/kg) or high (2.5 mg/kg) or “low dose”) was given as a rapid bolus to determine dose of sugammadex. Between the experiments, the the degree of neuromuscular blockade it produced. This monkeys recovered for at least 6 weeks. Heart rate and dose of rocuronium was chosen because it is close to the oxygen saturation were determined at the ear with a ED90 in our monkey population. Blockade was allowed pulse oximeter (Biox; Ohmeda, Madison, WI). Blood to recover to full twitch spontaneously. After this, recov-

Anesthesiology, V 104, No 4, Apr 2006 720 DE BOER ET AL.

ery was allowed for at least another hour. Then, a rapid romuscular blockade of 93% (4%), with a mean onset bolus injection equal to 500 ␮g/kg (approximately 5 ϫ time of 1.2 (0.12) min. After full recovery, profound

ED90, further named “high dose”) rocuronium bromide neuromuscular blockade was achieved by a bolus injec- was administered, producing profound neuromuscular tion of 500 ␮g/kg rocuronium bromide, which always block (100% blockade in all 12 instances), but at 1 min resulted in a 100% neuromuscular blockade, with a mean after this bolus injection, either vehicle (saline) or one of onset time of 0.51 (0.08) min. two dosages of sugammadex was intravenously adminis- tered as a rapid bolus. For each monkey, in three differ- Reversal of Profound Blockade ent experiments (at three dates, separated by at least 6 Figure 1A shows typical tracings of the effect of sug- weeks), reversal was induced by either 0.9% saline, su- ammadex at a dose of 2.5 mg/kg on the recovery of

gammadex at a dose of 1.0 mg/kg, or sugammadex at a profound neuromuscular blockade. Here, the twitch Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/104/4/718/361318/0000542-200604000-00016.pdf by guest on 26 September 2021 dose of 2.5 mg/kg. heights of the first and fourth twitches of the TOF are At the end of each experiment, the animals were depicted. The first dip is related to the initial low dose of allowed to recover from . rocuronium, and the second is the result of 5 times this dose. This particular experiment shows the reversal ef- Statistical Analysis fect of 2.5 mg/kg sugammadex administered 1 min after ␮ ϫ Figure 1B depicts the tracings of recovery after the 500 g/kg rocuronium (approximately 5 ED90). Note initial low dose of rocuronium in one particular monkey that at this dosage of sugammadex, recovery after this in the three experiments performed in this animal. Al- high dose of rocuronium with the reversal agent is faster though the tracings are very similar, recovery times dif- than spontaneous recovery after rocuronium, one fifth of fer between the three experiments. This variance is to this dose. This figure also demonstrates how a very be expected on the basis of variation in pharmacokinet- profound blockade by rocuronium may be reversed by a ics and pharmacodynamics over such a long period of high dose of sugammadex. time (from 6 to 12 weeks between the experiments). The neuromuscular recovery times of the profound These differences are taken into account by taking the blockade experiments are presented in table 1 as well as ratio of the recovery after the high dose of rocuronium the defined recovery ratios. In figure 2, all recoveries and those after the low dose. The rationale behind this after the high dose of rocuronium after saline or after ratio is that if the response to the first dose is faster on sugammadex are depicted in four subsets corresponding one occasion compared with another, the response to to the four different monkeys involved in this study. the second dose is likely to also be faster; we do not Heart rate and arterial pressure were measured during know whether this is explained by time-related changes all the experiments, and all of the animals recovered in pharmacokinetics or pharmacodynamics. completely without complications. In figure 3, a typical From the experimental traces at 50%, 75%, and 90%, example is displayed of changes in heart rate and mean TOF ratio recovery times from low-dose rocuronium arterial pressure due to the injection of the high dose of ␮ block, 100 g/kg (t50,low,t75,low, and T90,low), as well as rocuronium and sugammadex. Although there are clear from the high dose (t50,high,t75,high, and t90,high) with responses in heart rate and mean arterial pressure due to saline or sugammadex at both dosages were calculated at this high dose of rocuronium, there are no visible effects recovery. Then, the ratios were calculated of recovery due to the highest dose of sugammadex as compared times after high and low doses: with saline. Train-of-four monitoring for an extra hour after twitch t t t ϭ 50,high ϭ 75,high ϭ 90,high height had fully recovered indicated that neither residual R50 ,R75 ,R90 . (1) t50,low t75,low t90,low blockade nor recurarization occurred in any of the ani- The significance of the effect of both dosages of sugam- mals tested after injection of sugammadex. madex on these variables’ R was tested in an analysis of variance procedure. P values less than 0.05 were con- sidered statistically significant. Measurements regarding Discussion the recovery times, maximal blockade, and onset times Sugammadex, per-6-(2-carboxyethylthio)-per-6-deoxy- are presented as mean (SD). ␥-cyclodextrin sodium salt, belongs structurally to the family of cyclodextrins. Cyclodextrins, a group of oligo- saccharides, are cylindrical capsules with a lipophilic Results internal cavity and a hydrophilic exterior. With this li- Neuromuscular Blockade pophilic internal cavity, cyclodextrins are able to encap- In all experiments, a bolus injection of 100 ␮g/kg sulate guest molecules such as rocuronium and form a

rocuronium bromide (ED90 value for our rhesus monkey host–guest inclusion complex. This is also known as population) was administered, resulting in a mean neu- chemical encapsulation or chelation.18 Cyclodextrins are

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Table 1. The Neuromuscular Recovery Times and Recovery Ratios of Profound Rocuronium Neuromuscular Blockade

Series I: 0.9% Series II: 1.0 mg/kg Series III: 2.5 mg/kg Saline (n ϭ 4) Sugammadex (n ϭ 4) Sugammadex (n ϭ 4)

TOF ratio

Recovery times from rocuronium ED90 50% 5.8 (1.3) 7.1 (1.9) 6.7 (2.4) 75% 7.2 (1.5) 8.7 (2.8) 8.4 (3.0) 90% 8.4 (1.8) 9.9 (3.5) 9.6 (3.3) ϫ Recovery times from rocuronium 5 ED90 50% 21.4 (5.2) 18.1 (6.0) 3.9 (1.8) 75% 24.5 (5.9) 21.5 (7.4) 5.9 (3.0) 90% 28.3 (7.0) 25.9 (9.5) 7.9 (3.6) Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/104/4/718/361318/0000542-200604000-00016.pdf by guest on 26 September 2021 Recovery time ratios

R50 3.67 (0.35) 2.53 (0.27)* 0.56 (0.06)† R75 3.42 (0.23) 2.46 (0.24)* 0.68 (0.09)† R90 3.37 (0.19) 2.60 (0.35)* 0.80 (0.10)†

Mean vales of times for recovery of train-of-four (TOF) ratio (in minutes) after 100 ␮g/kg rocuronium and after profound neuromuscular blockade induced by 500 ␮g/kg rocuronium combined with the administration of either 0.9% saline or sugammadex in a bolus dose of 1.0 or 2.5 mg/kg. Recovery time ratios, as defined in the text, are also provided. Three columns provide the data of three series of experiments, characterized by the dose of the reversal agent. SD for all variables is provided in parentheses. * P Ͻ 0.01 compared with saline. † P Ͻ 0.001 compared with saline. highly water soluble and biologically well tolerated, and cular blockade can also be effectively and rapidly re- therefore, it is unlikely that side effects will occur.17,18 versed by sugammadex without signs of residual Sugammadex is a synthetic ␥-cyclodextrin derivative that blockade or recurarization. Although recovery times are has been especially designed to selectively bind rocuro- significantly shortened by the reversal with 1.0 mg/kg nium. The current study shows that profound neuromus- sugammadex, as compared with saline, it is obvious

␮ ؋ Fig. 2. Tracings of recovery from profound neuromuscular blockade induced with 500 g/kg rocuronium (roughly 5 ED90). Four panels show the experiments in the four different monkeys. For each monkey, recovery after the high dose of rocuronium was tested after injection of (1) saline, (2) 1 mg/kg sugammadex, or (3) 2.5 mg/kg sugammadex. The resulting tracings of these three h:min) for injection of rocuronium. Saline or) 0:00 ؍ experiments are projected on top of one another with the reference point t .train-of-four ؍ TOF .0:01 ؍ sugammadex was injected at t

Anesthesiology, V 104, No 4, Apr 2006 722 DE BOER ET AL.

nium 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 rocuro- nium.18 Thereafter, in vivo experiments in cats, guinea pigs, and rhesus monkeys confirmed the ability of sug- ammadex to reverse neuromuscular blockade induced by rocuronium without significant cardiovascular side

effects. The current results extend these findings by Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/104/4/718/361318/0000542-200604000-00016.pdf by guest on 26 September 2021 showing that sugammadex can also reverse profound neuromuscular blockade without apparent cardiovascu- lar side effects in rhesus monkeys. The mechanism of Fig. 3. Cardiovascular effects of rocuronium and sugammadex. reversal by encapsulation allows only immediate (i.e., -approxi ؍ The effect of high-dose rocuronium (500 ␮g/kg ؋ mately 5 ED90) and 2.5 mg/kg sugammadex are shown in the very fast) reversal if the concentration of the reversal tracings of heart rate (HR) and mean arterial pressure (MAP) in agent is such that complex formation binds so much of two experiments in the same monkey. In both experiments, the blocking agent that its concentration is reduced to h:min), the effect of which) 0:00 ؍ rocuronium was injected at t is clear in both cases. One minute later, saline or 2.5 mg/kg values below the threshold value necessary to induce sugammadex was injected. There are no visible effects of these any blockade. Our data show a significant response to injections. a dose of 2.5 mg/kg and a minimal although significant response to a dose of 1 mg/kg. Studies with additional that clinically reversal requires higher dosages, such as doses larger than 1 mg/kg (and possibly larger than 2.5 mg/kg. Injection of sugammadex did not cause sig- 2.5 mg/kg) are necessary to determine the optimal dose. nificant cardiovascular changes. However, because the safety of this compound has been The chemical encapsulation or chelation of rocuro- demonstrated in humans, it is likely that additional dose nium by sugammadex is the mechanism behind this determination studies will be conducted in humans effective and rapid reversal of profound neuromuscular rather than in monkeys.22,23 In the current study, only blockade induced by rocuronium in anesthetized rhesus four monkeys were studied. Although the conclusion monkeys. In contrast, the administration of cholines- about the reversing power of sugammadex is very sig- terase inhibitors only has a reliable result in reversing nificant, conclusions about cardiovascular side effects neuromuscular blockade when the first twitch of TOF cannot be decisive in such a small group. stimulation (or the single twitch) has recovered sponta- In conclusion, this study has shown that sugammadex 14,17 neously to at least 10% of the control twitch height. at a dose of 2.5 mg/kg can rapidly reverse profound Currently, cholinesterase inhibitors are used to reverse neuromuscular blockade induced by rocuronium in neuromuscular blockade. The recovery from neuromus- anesthetized rhesus monkeys. cular blockade after the administration of cholinesterase inhibitors is the sum of the increased acetylcholine in the as a result of the inhibition and the References spontaneous recovery by distribution and elimination of the relaxant.20 Administration of cholinesterase inhibi- 1. 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