The Clinical Use of Rocuronium. Eric N

PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/58694 Please be advised that this information was generated on 2021-09-27 and may be subject to change. Β :&*•**&* •JK* WAV//////////////////////^ fL Bfll '4(1 •IE ^clinical use of Rocuronium R f ^^ ^ r If,- 'E.N. Robertson THE CLINICAL USE OF ROCURONIUM E.N. Robertson Nijmegen, August 2004. All rights reserved. No part of this book may be reproduced or transmitted, in any form or by any means, without permission of the author Financial support for the publication of this thesis was received from Organon, Oss, The Netherlands ISBN-90-9018343-4 Printed by MacDonald/SSN Nijmegen Cover Ancient Hunting Robertson Tartan with aminosteroids on the front cover and chelated Rocuromum by Org 25969 on the back cover. Designer- C.H.W. Jansen, Layout: F.J G.M Schaap, Organon bv, Oss, The Netherlands Molecular Design: Dr. M.L.C E Kouwijzer NV Organon, Oss, The Netherlands II HET KLINISCH GEBRUIK VAN ROCURONIUM THE CLINICAL USE OF ROCURONIUM Een wetenschappelijke proeve op het gebied van de Medische Wetenschappen PROEFSCHRIFT Ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen, op gezag van de Rector Magnificus Prof. Dr. C.W.P.M. Blom, volgens besluit van het College van Decanen in het openbaar te verdedigen op vrijdag 17 december 2004 des namiddags om 1.30 uur precies door Eric Nelson Robertson Geboren op 10 Augustus 1950 te Glasgow, Schotland. Ill PROMOTORES Prof. dr. G.J. Scheffer Prof. dr. LH.D.J. Booij CO-PROMOTOR Dr. J.J. Driessen MANUSCRIPTCOMMISSIE Prof. dr. P. Smits, Voorzitter Prof. dr. R.J. Fragen Northwestern University, Chicago Prof. dr. J.R.M. Cruysberg Dr. K. Kuizinga, Universiteit van Groningen Dr. O. Wilder Smith IV TABLE OF CONTENTS FOREWORD VI CHAPTER 1 1 NEUROMUSCULAR BLOCKING AGENTS 1 REFERENCES 9| CHAPTER II 11 A COMPARISON OF ROCURONIUM AND VECURONIUM: THE PHARMACODYNAMIC, CARDIOVASCULAR AND INTRAOCULAR EFFECTS 11 SUMMARY 11 INTRODUCTION 12 PATIENTS AND METHODS 13 RESULTS 14 DISCUSSION 18 REFERENCES 21 POSTSCRIPT 22 CHAPTER III 23 SUXAMETHONIUM ADMINISTRATION PROLONGS THE DURATION OF ACTION OF SUBSEQUENT ROCURONIUM 23 SUMMARY 23 INTRODUCTION 24 PATIENTSAND METHODS 25 RESULTS 26 DISCUSSION 28 REFERENCES 30 CHAPTER IV 31 THE TIME-COURSE OF ACTION AND RECOVERY OF ROCURONIUM 0.3 MG KG ' IN INFANTS AND CHILDREN DURING HALOTHANE ANAESTHESIA MEASURED WITH ACCELEROMYOGRAPHY 31 SUMMARY 31 INTRODUCTION 32 MATERIALS AND METHODS 32 RESULTS 34 DISCUSSION 36 REFERENCES 39 CHAPTER V 41 TIME-COURSE OF ACTION OF ROCURONIUM 0 3 MG KG 'IN CHILDREN WITH AND WITHOUT ENDSTAGE RENAL FAILURE 41 SUMMARY 41 INTRODUCTION 42 PATIENTS AND METHODS 42 RESULTS 44 DISCUSSION 45 REFERENCES 48 CHAPTER VI 49 PHARMACOKINETICS AND PHARMACODYNAMICS OF ROCURONIUM IN PATIENTS WITH AND WITHOUT RENAL FAILURE 49 SUMMARY 49 INTRODUCTION 50 V METHOD 51 PHARMACOKINETICS AND STATISTICS 53 RESULTS .53 DISCUSSION 58 REFERENCES 61 CHAPTER VII 63 PHARMACODYNAMICS OF ROCURONIUM 0.3 MG KG ' IN ADULT PATIENTS WITH AND WITHOUT RENAL FAILURE 63 SUMMARY 63 INTRODUCTION 64 PATIENTS AND METHODS 65 RESULTS 66 DISCUSSION 69 REFERENCES 71 ACKNOWLEDGEMENTS 71 CHAPTER VIII 73 ACCELERATED RECOVERY AND DISPOSITION FROM ROCURONIUM IN AN END-STAGE RENAL FAILURE PATIENT ON CHRONIC ANTICONVULSANT THERAPY WITH SODIUM VALPROATE AND PRIMIDONE 73 INTRODUCTION 73 CASE REPORT 73 DISCUSSION 77 REFERENCES 80 ACKNOWLEDGEMENTS 80 CHAPTER IX 81 GENERAL DISCUSSION AND CONCLUSIONS 81 REFERENCES 86 HOOFDSTUK IX 87 SAMENVATTING en CONCLUSIES 87 LITERATUUR 92 PUBLICATIONS NOT INCLUDED IN THE THESIS ..93 ACKNOWLEDGEMENTS 95 CURRICULUM VITAE 97 VI FOREWORD Rocuronium was introduced into clinical anaesthetic practice in early 1994 in the Netherlands, the United States of America and Great Britain As with all new medicines, comparative studies of established medicines are necessary to see what advantages or disadvantages are present in the new drug A clinical assessment of the beneficial effects and possible side effects is also necessary for such drugs after they have been approved for general use since pre-clinical studies are carried out in animals, volunteers and selected groups of patients. The University Medical Centre, Nijmegen, has an almost 30-year tradition of the study of neuromuscular blocking agents, both in the animal laboratory and in the clinical setting; firstly under Prof J.F. Crul, then Prof L.H.D.J. Booij, and presently Prof. G.J. Scheffer. This Medical Centre is also the largest hospital for renal transplantation in the Netherlands. The clinical investigation of muscle relaxants and the presence of a large renal transplant centre, where some of the clinical effects of rocuronium have been studied, are the background to the development of this thesis. The aim of this thesis is to: Elucidate some pharmacodynamic and pharmacokinetic effects of rocuronium in anaesthetic practice and the effect of rocuronium on heart rate, intraocular pressure and arterial pressure, Compare rocuronium with vecuronium and suxamethonium, Describe the use of rocuronium in clinical practice in adults and children with and without renal failure. Chapter I gives a short history of the use of neuromuscular blocking agents in clinical practice with special reference to the origin and development of rocuronium Chapters II and III compare the neuromuscular effects of rocuronium (0 9 mg kg 1) with those of vecuronium (0.15 mg kg 1) and rocuronium (0 6 mg kg1) with suxamethonium (1 mg kg 1) respectively. The effects of these relaxants on intraocular pressure, heart rate and arterial pressure are also described. The effects of suxamethonium on the pharmacodynamics of subsequently administered rocuronium are also presented in Chapter III. Chapters IV and V describe, respectively, the neuromuscular effects of rocuronium 0.3 mg kg1 in healthy infants VII and children under halothane anaesthesia and compare the neuromuscular effects of rocuronium in children with and without renal failure. Chapter VI presents a study of the pharmacodynamics and pharmacokinetics of rocuronium in adults with and without renal failure. The neuromuscular effects and pharmacokinetics of rocuronium 0.6 mg kg1 are compared between the two groups of patients. Chapter VII is a follow-up study to the study in Chapter VI in adult patients with and without renal failure where a smaller dose of rocuronium (0.3 mg kg1) is given. Chapter VIII is a case report in which the neuromuscular effects and pharmacokinetics of rocuronium 0.6 mg kg1 in a patient with renal failure receiving sodium valproate and primidone are described. A summary and general conclusions are presented in both English and Dutch in Chapter IX. VIII CHAPTER I NEUROMUSCULAR BLOCKING AGENTS Scientists have been studying neuromuscular blocking agents (curare alkaloids) since the mid-19'h century after Claude Bernard demonstrated the site of action of curare in the frog. Structure/activity relationship studies have been carried out extensively for the last 150 years to try to understand the physiological process of neuromuscular transmission. Indeed, muscle relaxants were instrumental in the identification of acetylcholine as the neurotransmitter at the neuromuscular junction, and helped in defining these receptors as the nicotinic subtype. Neuromuscular blocking agents have only been used in clinical anaesthetic practice for the last 60 years, after the introduction of d- tubocurarine (Fig. 1) by Griffith and Johnson in 1942 in Montreal [1]. Their introduction led to a revolution in anaesthesia and surgery, and allowed prolonged invasive surgery without having to induce dangerously deep levels of anaesthesia, which at that time was necessary to produce adequate muscle relaxation for procedures in the abdominal and thoracic cavities. Patients were also able to awaken quickly after surgery, and so the complications of long recovery periods after deep surgical general anaesthesia were avoided. Beecher and Todd [2], however, reported in 1954 that the introduction of d-tubocurarine to clinical practice was associated with a six-fold increase in operative mortality. When d-tubocurarine had been used, a mortality rate of 1 in 370 was found, whereas when no relaxant was used, a mortality rate of 1 in 2100 was found. Although the conclusions of Beecher and Todd have been questioned (patients were more ill and not ventilated in the curare group; faulty study design), there is little doubt that residual curarization in the recovery room is still a problem even with the newer intermediate acting neuromuscular blocking agents [3]. In these days of modern anaesthesia, it is hard to believe that a drug such as d-tubocurarine was used without artificial ventilation and not antagonized at the end of surgery. Once assisted ventilation became routine in surgical cases, neuromuscular blocking agents became an integral part of modern ι anaesthesia by the mid 1950's. Dissatisfaction with, and difficulties in the production of d-tubocurarine led to the search for new muscle relaxants. Figure 1 d-tubocurarine chloride Savarese and Kitz [4] described what anaesthetists wanted as an "ideal muscle relaxant" and these properties are summarized in Table 1. Table 1 Ideal properties of a neuromuscular blocking agent Non-depolarizing mechanism of action Rapid onset time Short duration of action Rapid recovery Non cumulative No cardiovascular side effects Reversible Many different

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