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ANESTHETIC PHARMACOLOGY

A Temporary Decrease in Twitch Response During Reversal of Rocuronium-Induced Muscle Relaxation with a Small Dose of Sugammadex

From Research Group for Experimental Anesthesiology and Clinical Pharmacology, University Medical Center, University of Groningen, Groningen, The Netherlands.

Address correspondence and reprint requests to Douglas Eleveld, Research Group for Experimental Anesthesiology and Clinical Pharmacology, University Medical Center, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. Address e-mail to d.j.eleveld{at}anest.umcg.nl.

	Abstract

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BACKGROUND: We present a case in which a temporary decrease in train-of-four (TOF) response was observed after reversal of muscle relaxation with a small dose (0.5 mg/kg) of sugammadex administered 42 min after 0.9 mg/kg of rocuronium. At the end of the operation, the TOF ratio was >0.9, and the patient woke normally, without signs of muscle weakness. We describe this temporary decrease in muscle response during muscle relaxation reversal as muscle relaxation rebound and hypothesize that it occurs when the dose of sugammadex is sufficient for complex formation with rocuronium in the central compartment, but insufficient for redistribution of rocuronium from peripheral to central compartments.

METHODS: To investigate our hypothesis, we developed and fit a simple pharmacokinetic– pharmacodynamic model of rocuronium, sugammadex, and their interaction to the patient TOF response data.

RESULTS: Simulations using the fitted model indicate that muscle relaxation rebound can occur for doses of sugammadex in a limited critical range.

CONCLUSIONS: Sufficiently large doses of sugammadex eliminate the possibility for muscle relaxation rebound, which does not require dissociation of the sugammadex/ rocuronium complex.

	Introduction

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Sugammadex, a modified -cyclodextrin, is in clinical development as a reversal drug for rocuronium- and vecuronium-induced muscle relaxation. It achieves reversal of muscle relaxation by complex formation with free muscle relaxant molecules. The dissociation constant of the sugammadex/rocuronium complex is very low (1), leading to very strong binding. Because dissociation of the sugammadex/rocuronium complex is likely to be negligible, the potential for muscle weakness after reversal of rocuronium-induced muscle relaxation with sugammadex is also considered to be negligible (2). We present a case in which a temporary decrease in train-of-four (3) (TOF) response was observed after reversal of rocuronium-induced muscle relaxation with a small dose of sugammadex.

	CASE REPORT

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A 48-yr-old woman (108 kg, 180 cm, ASA Class II) presented for correction of her nasal septum. After informed consent, the patient agreed to take part in Phase II dose-finding clinical trial of sugammadex approved by a medical ethics committee and supported by NV Organon (Oss, The Netherlands). Anesthesia was induced with propofol and maintained with sevoflurane and remifentanil. Muscle relaxation was monitored at the left adductor pollicis muscle using the continuous TOF mode of a TOF-Watch SX accelerometric muscle relaxation monitor (NV Organon, Oss, The Netherlands) attached to data recording hardware. After twitch stabilization was complete, rocuronium 0.9 mg/kg was administered, and after onset of muscle relaxation, the patient's trachea was intubated. Every 5 min, a posttetanic-count (4) (PTC) stimulation was performed.

After 42 min, the PTC value was 1 and muscle relaxation was reversed with 0.5 mg/kg sugammadex. The return of twitch response after reversal (Fig. 1) showed a temporary decrease in TOF response and in the first TOF twitch (T1). During twitch recovery, no drugs that might interfere with muscle relaxation were administered. Sevoflurane end-tidal concentrations varied between 1.3% and 1.5%. Her heart rate and arterial blood pressure were stable (60–65 bpm, systolic blood pressure 102–138 mm Hg, diastolic blood pressure 60–86 mm Hg), and the skin temperature at the adductor pollicis was above 32°C. At the end of the operation, the TOF ratio was >0.9. The patient woke normally and was tracheally extubated (107 min after rocuronium administration) without signs of muscle weakness and was able to self-ventilate and successfully perform a head-lift test.

View larger version (33K): [in this window] [in a new window]   Figure 1. Temporary decrease in train-of-four (TOF) ratio and T1 during reversal of rocuronium-induced muscle relaxation (0.9 mg/kg) with sugammadex (0.5 mg/kg administered 42 min after rocuronium). At the time of sugammadex administration the posttetanic-count (PTC) value was 1.

	DISCUSSION

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We describe this phenomenon as "muscle relaxation rebound" and hypothesize that it may be due to redistribution of unbound muscle relaxant molecules from peripheral compartments back into central and effect compartments. After sugammadex administration, the concentration of unbound rocuronium molecules in the central compartment decreases rapidly, leading to a rapid decrease in muscle relaxation intensity. The decreased unbound rocuronium concentration in the central compartment leads to a redistribution of unbound rocuronium from peripheral compartments back into the central compartment. If insufficient sugammadex is present for additional complex formation, then this redistribution process will lead to a temporary increase in unbound rocuronium concentration in the central compartment and in the effect compartment. Thereafter, the unbound rocuronium concentration decreases because of clearance of the drug.

To investigate our hypothesis, we developed and fitted a simple pharmacokinetic–pharmacodynamic (PK-PD) model of rocuronium, sugammadex and their interaction to the patient data shown in Figure 1. We used a three-compartment PK model and a sigmoidal Emax PD model. The muscle relaxation effect compartment was linked to the central compartment and the effect parameter was TOF ratio. For sugammadex, we assumed the same PK variables as for rocuronium. In the primary and effect compartments, sugammadex was assumed to bind immediately and irreversibly with rocuronium. We fitted the PK-PD model to the patient data using a Bayesian approach with prior values obtained from unpublished research in our department. The resulting PK-PD model parameters are shown in Table 1. On the basis of these PK-PD parameters, we performed simulations of various doses of sugammadex (Fig. 2). For this patient, doses about 1 mg/kg or larger achieved rapid stable muscle relaxation reversal, whereas doses smaller than about 0.25 mg/kg lead to negligible initial change in twitch response. We conclude that muscle relaxation rebound can occur for doses of sugammadex in a limited critical range. These observations support our hypothesis that rebound may occur because of redistribution of unbound muscle relaxant molecules from peripheral compartments back into central and effect compartments. Muscle relaxation rebound can therefore occur without dissociation of the sugammadex/ rocuronium complex. This implies that for a reliable reversal of neuromuscular blockade without muscle relaxation rebound, a sufficiently large dose of sugammadex is necessary. Presumably, the recommended doses of sugammadex under these conditions (PTC 1) will be larger than 0.5 mg/kg, and will thus prevent muscle relaxation rebound. This is likely given that 0.5 mg/kg was the smallest dose in the dose-finding study.

View larger version (37K): [in this window] [in a new window]   Figure 2. Observed train-of-four (TOF) data (+) and the results of simulations (solid lines) of various sugammadex dosing amounts. Muscle relaxation rebound only occurs for sugammadex doses in a limited range. The simulations indicate that for this patient, doses larger than about 1 mg/kg are sufficient to achieve rapid muscle relaxation reversal and avoid muscle relaxation rebound.

Muscle relaxation rebound has not been reported in previous clinical studies of sugammadex. There may be several reasons for this. First, the majority of published studies used rocuronium bolus doses of 0.6 mg/kg, whereas in our patient 0.9 mg/kg was given. According to our hypothesis, smaller bolus doses are less likely to produce muscle relaxation rebound because there is less of the drug distributed to peripheral compartments, thereby reducing drug redistribution. Second, most of the sugammadex doses administered in existing studies were outside the limited range that we found to be associated with muscle relaxation rebound. Third, muscle relaxation rebound depends on drug redistribution, and patients vary in their redistributive properties. It is not clear whether all patients, or only a subset of patients, have the potential to exhibit muscle relaxation rebound. One other patient taking part in the dose-finding study received the same rocuronium and sugammadex doses as our patient, but did not exhibit muscle relaxation rebound. Two patients from the study received the same sugammadex dose for reversal of vecuronium-induced muscle relaxation and did not exhibit muscle relaxation rebound.

Muscle relaxation rebound can occur under specific conditions and can be explained by redistribution of unbound rocuronium from peripheral to central and effect compartments. Doses of sugammadex should be sufficient for complex formation with rocuronium present in the central compartment as well as for rocuronium to return to central from peripheral compartments. If there is a chance of muscle relaxation rebound, neuromuscular monitoring should be continued after sugammadex administration to detect it.

	Footnotes

 
Accepted for publication October 3, 2006.

	REFERENCES

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1. Bom A, Bradley M, Cameron K, et al. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew Chem Int Ed Engl 2002;41:266–70.
2. Gijsenbergh F, Ramael S, Houwing N, van Iersel T. First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology 2005;103:695–703.[Web of Science][Medline]
3. Ali HH, Savarese JJ. Monitoring of neuromuscular function. Anesthesiology 1976;45:216–49.[Web of Science][Medline]
4. Saitoh Y, Fujii Y, Toyooka H, Amaha K. Post-tetanic burst count: a stimulating pattern for profound neuromuscular blockade. Can J Anaesth 1995;42:1096–100.[Web of Science][Medline]

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