Reversal of rocuronium-induced neuromuscular block by sugammadex is independent of renal perfusion in anesthetized cats

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pharmacokinetics and pharmacodynamics of rocuronium are well known.• A mechanistical pharmacokineticpharmacodynamic model based on limited data describing rocuronium and sugammadex pharmacokinetics has been published.• However, the available pharmacokineticpharmacodynamic model for the effects of sugammadex on rocuronium-induced neuromuscular blockade has limited predictive power. WHAT THIS STUDY ADDS• A pharmacokinetic-pharmacodynamic model is described for rocuronium and sugammadex, based on physiological principles and on data covering a wide range of ages and renal function. From this model, more accurate predictions can be made about sugammadex-mediated reversal of rocuronium-induced neuromuscular blockade, in unexplored regimens or populations. AIMSAn integrated population pharmacokinetic-pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic-pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time. METHODSData (n = 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects. RESULTSSugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg -1 3 min after rocuronium, sugammadex 4 mg kg -1 during deep neuromuscular blockade and sugammadex 2 mg kg -1 during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time. CONCLUSIONSSimulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min.

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“…Experiments performed in anaesthetized cats, in which both renal arteries were completely occluded, support these findings [42].…”

Section: Discussionsupporting

confidence: 76%

Population pharmacokinetic–pharmacodynamic analysis for sugammadex‐mediated reversal of rocuronium‐induced neuromuscular blockade

Kleijn¹,

Zollinger

Heuvel

et al. 2011

Brit J Clinical Pharma

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“…It has been shown that sugammadex is mainly eliminated by excretion through the kidneys. 7,8 Staals and colleagues 16 reported that reversal of a rocuronium-induced neuromuscular blockade is independent of renal perfusion by ligating renal pedicles in anesthetized and paralyzed cats 002; values represent mean ± SEM, n = 6. GV, glomerular vacuolation; TD, tubular dilatation; VVH, vascular vacuolation and hypertrophy; TCDN, tubular cell degeneration and necrosis; DBS, dilatation in Bowman's space; THC, tubular hyaline casts; LI, lymphocyte infiltration; TCS, tubular cell sloughing.…”

Section: Resultsmentioning

confidence: 99%

Reversal of Rocuronium-Induced Neuromuscular Block with Sugammadex and Resulting Histopathological Effects in Rat Kidneys

et al. 2011

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Background: This study investigated the effect of injection of rocuronium or sugammadex alone and rocuronium + sugammadex on urea, creatinine, electrolyte levels, and histopathological findings in rats. Methods: Thirty-six SpragueDawley male rats were divided to receive intravenously 16 or 96 mg/kg sugammadex, 1 mg/kg rocuronium, 1 mg/kg rocuronium + 16 mg/kg sugammadex, or 1 mg/kg rocuronium + 96 mg/kg sugammadex. The control group received an equal volume of physiological serum. Rats receiving rocuronium were ventilated until resumption of spontaneous ventilation and followed for 72 h. Blood samples were withdrawn from the tail vein to measure urea, creatinine, and electrolyte values; then both kidneys were excised, and the tissues were used for histopathological examination. Results: Rats receiving rocuronium and high doses of sugammadex (96 mg/kg) showed increased glomerular vacuolation, tubular dilatation, vascular vacuolation and hypertrophy, lymphocyte infiltration, and tubular cell sloughing compared to the control group (p = 0.002). Biochemical markers of renal function were not significantly altered after treatment with high doses of sugammadex. Conclusion: The elimination half-life of the rocuronium-sugammadex complex was found to be greater than that of free rocuronium or sugammadex, which led to marginal histopathological changes in the kidney without affecting any renal functions.

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“…Acetylcholinesterase inhibitors, used to reverse the effects of nondepolarizing neuromuscular blockers, have important disadvantages such as residual block and hemodynamic side effects [1,2]. The most important reasons for choosing sugammadex, a gamma cyclodextrin derivative which has entered use in recent years, are its superior properties during extubation and recovery stages and low risk of residual block [3].…”

Section: Introductionmentioning

confidence: 99%

Effect of Low and High Dose Sugammadex on the Coagulation and Fibrinolytic System in Rats

Taş

Yağan

Noyan

et al. 2015

Advances in Anesthesiology

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Background. Sugammadex is a new reversal agent that has entered use recently. It is known that with sugammadex some changes in coagulation parameters occur without documented clinical results. Aim of the Work. The objective of this study was to identify effects of sugammadex on liver functions, coagulation, and fibrinolytic systems. Methods. Thirty-six rats were randomized into six groups: Group I, control; Group II, rocuronium group; Group III, sugammadex administered in 16 mg kg −1 dose; Group IV, sugammadex administered in 96 mg kg −1 dose; Group V, rocuronium and sugammadex administered in 16 mg kg −1 dose; and Group VI, rocuronium and sugammadex administered in 96 mg kg −1 dose. After 120 minutes, blood samples were obtained for prothrombin time, activated partial thromboplastin time, D-dimer, fibrinogen, aspartate aminotransferase, alanine aminotransferase, albumin, platelet, and mean platelet volume analyses. Results. Compared to the control group, in all groups measured parameters did not show any effect from a statistical viewpoint either due to the administered drugs alone or due to interaction effects. Conclusion. The conclusion was reached that administration of sugammadex in rats did not have any significant effect on the fibrinolytic system, coagulation parameters, and liver function.

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Reversal of rocuronium-induced neuromuscular block by sugammadex is independent of renal perfusion in anesthetized cats

Abstract: Sugammadex rapidly and effectively reversed rocuronium-induced neuromuscular block in anesthetized cats, even when both renal pedicles were ligated and renal elimination of the drugs was no longer possible.

Cited by 20 publications

References 19 publications

Population pharmacokinetic–pharmacodynamic analysis for sugammadex‐mediated reversal of rocuronium‐induced neuromuscular blockade

Population pharmacokinetic–pharmacodynamic analysis for sugammadex‐mediated reversal of rocuronium‐induced neuromuscular blockade

Reversal of Rocuronium-Induced Neuromuscular Block with Sugammadex and Resulting Histopathological Effects in Rat Kidneys

Effect of Low and High Dose Sugammadex on the Coagulation and Fibrinolytic System in Rats

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