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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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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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-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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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 (6065 bpm, systolic blood pressure 102138 mm Hg, diastolic blood pressure 6086 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.
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| DISCUSSION |
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To investigate our hypothesis, we developed and fitted a simple pharmacokineticpharmacodynamic (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.
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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 |
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| REFERENCES |
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