The Clinical Use of Rocuronium. Eric N

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THE CLINICAL USE OF ROCURONIUM E.N. Robertson

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

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 neuromuscular blocking agents have been introduced into clinical practice over the last 60 years (Table 2).

2 Both depolarizing (acetylcholine agonist) and non-depolarizing (acetylcholine antagonist) neuromuscular blocking agents have been produced. Many of the compounds that have been synthesized and investigated were never used clinically. The neuromuscular blocking agents that we now have, viz., rocuronium, vecuronium, pancuronium, atracurium, mivacurium, cisatracurium and suxamethonium, are likely to be used for years to come since they all come close to some of the ideals defined in Table 1. However, what is still missing is a non-depolarizing relaxant that has a rapid onset time (<1 min) and a short duration of action (<10 min).

Table 2

Depolarizing neuromuscular blocking drug

Suxamethonium Decamethomum

Non depolarizing neuromuscular blocking drug

Tubocuranne Pancuronium Fazadmium

Metocurme Vecuronium Gallamme

Alcuromum Pipecuromum

Atracurium Rocuronium

Doxacunum Rapacuromum

Mivacurium

Cisatracurium

Although suxamethonium (Fig. 2) has been known to chemists since 1906, it was introduced into clinical anaesthetic practice in Europe and the U.S.A. around 1950 and is the only depolarizing relaxant still in use. Suxamethonium has an excellent time-course profile (rapid onset/short duration), and is used to allow rapid endotracheal intubation in the rapid sequence induction of anaesthesia technique and for the relief of laryngospasm. It can also be used for short periods of muscle relaxation under light general anaesthesia.

3 Unfortunately, suxamethonium has many unwanted side effects, such as life-threatening hyperkalaemia, cardiac arrhythmias, fasciculations, increased intracranial, intragastric and intraocular pressures and muscle pains. Many of these side effects occur because suxamethonium is chemically made up of two acetylcholine molecules attached to each other (Fig. 2). This means that suxamethonium has some intrinsic action at the neuromuscular junction, and thus can sometimes cause massive potassium release from the muscle cells of the patient.

Figure 2 + Suxamethonium CH2-COO-CH2-CH2-N (CH3)3 CH2-COO-CH2-CH2-N+(CH3)3

There was uproar [5,6] in the anaesthetic community after December, 1993, when the manufacturer of suxamethonium (Burroughs Wellcome) stated that the use of suxamethonium is contraindicated in children and adolescents "except when used for emergency tracheal intubation or instances where immediate securing of the airway is necessary". This statement was based on 36 cases that had been reported worldwide between 1990 and 1993 where life-threatening arrhythmias and even death had occurred after the use of suxamethonium. These problems appeared to have occurred mainly in children and infants with undiagnosed muscular dystrophies who had also received halothane anaesthesia. Following this statement, the FDA issued a warning regarding the use of suxamethonium in children. After much heated debate, a committee of learned anaesthetists advised the FDA to allow the use of suxamethonium but to insert a "strong warning" in the package insert stating the potential major complication of cardiac arrhythmias, especially in infants and children with undiagnosed muscular dystrophies. Since then there have been a number of case reports that describe the use of suxamethonium in the way suggested by the FDA where life- threatening arrhythmias have still occurred. The authors of these reports have suggested that teaching the prevention and treatment of these major side effects (seen mainly in boys under the age of eight years with undiagnosed Duchenne or Becker's muscular dystrophy) might be of more benefit and more important than an outright ban, since there is not yet any satisfactory substitute for suxamethonium.

4 The syndrome is not frequently seen and the Toronto Sick Children's Hospital group of anaesthetists have stated that they "have established neuromuscular block in hundreds of thousands of infants, children and adolescents without a single death attributable to succinylcholine"[7]. They state that careful preoperative assessment of all patients appears to help in the avoidance of this problem. Many, if not all of the side effects of suxamethonium could be avoided if a non-depolarizing neuromuscular blocking agent were to be used as a substitute for suxamethonium. Much research has gone into the search for a non-depolarizing neuromuscular blocking drug with a similar time-course profile as suxamethonium, but until the introduction of rocuronium, there did not seem to be an alternative to suxamethonium with regard to onset time. There are several non-depolarizing neuromuscular blocking agents still in use. Two main structural groups of non-depolarizing neuromuscular blocking drugs are found in modern clinical practice, namely the bis-benzylisoquinolinium compounds, atracunum, mivacurium and cisatracurium, as shown in Fig.3,

Figure 3

Atracurium Besylate H 0 Ι ί .], u ll ,[· 1 Ì

Cisatracurium H y „ [ ( -i J // U* 1 I V • H' ^ 1 l[ C f ' l Mivacurium and the amino steroidal compounds pancuronium, vecuronium and rocuronium as shown in Fig.4.

Figure 4 Pancuronium Bromide

O-^ CHj

Vecuronium Bromide

Rocuronium Bromide

I J

NV 1

These two groups of non-depolarizing neuromuscular blocking agents appear to be completely dissimilar. However, they do have features that are common to both groups of drugs. Two quaternary or tertiary nitrogens are present in all these compounds and these nitrogens are all between 1-1.4 nM apart. This is necessary to allow the neuromuscular blocker to interact with the acetylcholine receptor in the postsynaptic neuromuscular junction. The non-depolarizing

6 neuromuscular blocker itself has no intrinsic activity and does not cause depolarization of the postsynaptic membrane. In this way, neuromuscular block is produced, since the acetylcholine released from the presynaptic nerve ending is competitively prevented from having its normal effect (i.e. depolarization, leading to action potential, then muscle contraction) at the neuromuscular junction. The amino steroidal compound, rocuronium, is the subject of this thesis. The brilliant work of the late Dr.C.Hewitt and the late Dr.D.Savage and their team of chemists of Organon Scotland in Glasgow, in the 1960's led to the clinical introduction of the steroid- based neuromuscular blocking agents. (Strangely enough, the benzylisoquinolinium compounds were, around the same time, in the same city, being investigated by a different team led by Prof. J.B.Stenlake). Pancuronium was one of the first completely synthetic non-depolarizing neuromuscular blocking drugs. It was a potent relaxant that had fewer side effects than the existing relaxants at that time, but it did have a long duration of action. When it was introduced it was the most potent of all neuromuscular blocking drugs, and is still in use today. Dr. Leslie Baird and Dr. Alec Reid, both consultant anaesthetists at Glasgow Royal Infirmary, Scotland, performed the first clinical studies into the properties of pancuronium [8]. Although an improvement on existing relaxants at the time (less histamine release), pancuronium still does not meet many of the requirements suggested by Saverese and Kitz [4] in 1975, viz., it has a slow onset time, a long duration of action and a number of cardiovascular side effects. The duration of action of pancuronium is such that in some anaesthetic circles it is now suggested that pancuronium should only be used when the patient will require artificial ventilation postoperatively [9,10].

In the early 1980's vecuronium and atracurium were introduced to clinical practice. Both these relaxants were revolutionary in that they had an intermediate duration of action and few cardiovascular side effects. Unfortunately, both these new relaxants had a fairly slow onset time and could not replace suxamethonium. Vecuronium could be given in large doses without any cardiovascular effects and this could produce a rapid onset time, however, this also led to a prolonged, and initially non-reversible, neuromuscular block that might last much longer than the surgical procedure. Despite this, the introduction of these compounds to anaesthesia did lead to a

7 decrease in the number of patients arriving in the recovery area with residual neuromuscular block [9]. Bowman et al. [11] demonstrated in the cat that a rapid onset of action is produced by steroid-based neuromuscular blocking agents of low potency, and this was confirmed in man [12]. Rocuronium was the next relaxant produced by the team of Organon, and was registered in the U.K., the U.S.A. and The Netherlands in 1994 as a non-depolarizing neuromuscular blocking agent for use in clinical anaesthesia. This was a neuromuscular blocking agent that was less potent than vecuronium but had a similar duration of action and few cardiovascular side effects. The great advantage that rocuronium had over vecuronium (and atracurium) was that it had a more rapid onset time. Over the last few years rocuronium has become the most frequently used neuromuscular blocking drug in the Western world. When given in a dose greater that 0.6 mg kg"1, intubating conditions with rocuronium are as acceptable as suxamethonium [13] although excellent intubating conditions one minute after injection are found more frequently with suxamethonium [14]. Annually, more that 20 million ampoules of rocuronium are sold worldwide and in the Netherlands it is the most frequently used muscle relaxant, accounting for more than 70% of market share. With the increasing popularity and use of rocuronium, there have been a number of reports of anaphylactic reactions after rocuronium [15]. Neuromuscular blocking agents are associated with around 60% of all anaphylactic reactions occurring during anaesthesia. Rocuronium, like most neuromuscular blocking agents in use, is a compound that contains a quaternary nitrogen (Fig. 4), and so it will have the propensity to release histamine and, rarely, anaphylactic reactions. An assessment by Rose and Fisher in Australia [16] suggests that the increased incidence of such reactions is purely a reflection of the increasing use of rocuronium.

Millions of patients have safely received rocuronium, and its popularity among anaesthetists is evidence to its flexibility, safety and usefulness. Reports regarding its use and properties are frequently seen in the anaesthetic literature. This thesis presents some of the work that has been performed on rocuronium in the University Medical Centre Nijmegen, The Netherlands.

8 REFERENCES 1 Griffith HR, Johnson GE. The use of curare in general anaesthesia Anesthesiol 1942;3:418-420 2. Beecher HK, Todd DS. A study of the deaths associated with anaesthesia and surgery, based on a study of 599,548 anaesthesias in ten institutions 1948-1952 inclusive Ann Surg 1954; 140. 2-35 3 Caldwell JE. The problem with long acting muscle relaxants? They cost more1 Anesth Analg 1997,85.476-482 4. Savarese JJ, Kitz RJ Does clinical anesthesia need new neuromuscular blocking agents7 Anesthesiol 1975; 42. 236-239 5. Morell RC, Hall SC, Royster C et al Revised label regarding use of succmylcholme in children and adolescents· I Anesthesiol 1994; 80' 242 6 Badgewell JM, Hall SC, Lockhart C Revised label regarding use of succmylcholme in children and adolescents· II Anesthesiol 1994,80.243 7. Bevan DR. Succmylcholme. Can J Anaesth 1994; 41:465-468 8. Baird WLM, Reid AM The neuromuscular blocking properties of a new steroid compound, pancuronium bromide (a pilot study in man). Br J Anaesth 1967,39. 775- 780 9. Bevan DR, Donati F, Kopman AF. Reversal of neuromuscular blockade. Anesthesiol 1992;77.785-805 10. Berg H, Viby-Mogensen J, Roed J et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications: a prospective, randomised, and blinded study of postoperative complications after atracunum, vecuronium and pancuronium. Acta Anesthesiol Scand 1997; 41.1095-1103 11. Bowman WC, Rodger IW, Houston J et al. Structure· action relationships among some desacetoxy analogues of pancuronium and vecuronium in the anaesthetized cat Anesthesiol 1988, 69. 57-62 12. Kopman AF. Pancuronium, gallamme, and d-tubocuranne compared, is speed of onset inversely related to drug potency9 Anesthesiol 1989, 70: 915-920 13 Perry JJ, Lee J, Wells G Are intubating conditions using rocuromum equivalent to those using succmylcholme9 Acad Emerg Med 2002, 9:813-823 14 Perry J, Lee J, Wells G. Rocuromum versus succmylcholme for rapid sequence induction intubation Cochrane Database Syst Rev 2003,1.CD002788 15 Mertes PM, Laxenaire MC, Alla F Anaphylactic and anaphylacoid reactions during anesthesia in France in 1999-2000 Anesthesiol 2003; 99: 521-523 16 Rose M, Fisher M Rocuromum. high risk for anaphylaxis9 Br J Anaesth 2001 ; 86. 678-682

9 10 CHAPTER II

A COMPARISON OF ROCURONIUM AND VECURONIUM: THE PHARMACODYNAMIC, CARDIOVASCULAR AND INTRA-OCULAR EFFECTS

EN Robertson, MB, ChB, FRCA, JM Hull, MB, ChB, FRCA, LHDJ Booij, MD, PhD, AM Verbeek, MD, PhD.

First published in the European Journal of Anaesthesiology 1994; Suppl 9:116-121. Reproduced with the kind permission of the European Academy of Anaesthesiology.

SUMMARY Background and aim: To achieve a rapid onset time vecuronium must be given in large doses that lead to a long duration of action. Rocuronium is a related relaxant that has a rapid onset time and may replace vecuronium for rapid intubation in patients with penetrating eye injuries. Methods: Anaesthesia was induced iv using propofol 2.5 mg kg1 and fentanyl 2 μg kg1, and maintained with iv propofol 6-12 mg kg'1 h 1. The response of the thumb to supramaximal TOF ulnar nerve stimulation at the wrist was measured using a mechanomyograph. Patients were randomly allocated to receive initially either 0.9 mg kg 1 rocuronium or 0.15 mg kg'1 vecuronium iv. Before administration of relaxant, baseline readings of heart rate, arterial pressure and intraocular pressure were measured until stable, then the appropriate relaxant administered. Thereafter, all readings were repeated at 30, 90, 150, 210 and 270 s. After 300 s tracheal intubation was performed and all recordings repeated 30, 120 and 240 s later. Mechanomyographic monitoring was continued until 70% train-of-four recovery.

11 Results: Rocuronium had a more rapid onset than vecuronium (66 vs 124 s) Other pharmacodynamic parameters were similar for rocuronium and vecuronium. Both relaxants produced similar reductions in intraocular pressure. Rocuronium produced a 10-15% increase in arterial pressure and a slight rise in heart rate while vecuronium had no effect on either Conclusion: With its rapid onset time and lack of intraocular pressure effects rocuronium is perhaps the relaxant of choice in patients with penetrating eye injuries requiring emergency endotracheal anaesthesia where a longer acting relaxant is not contramdicated

INTRODUCTION Vecuronium has been shown to reduce intraocular pressure (IOP) and it has been used in the rapid sequence induction of anaesthesia technique. It has been suggested that it might be the relaxant of choice in patients with penetrating eye injuries requiring emergency endotracheal anaesthesia [1] To achieve a fast enough onset time with vecuronium to allow this technique, however, large doses must be used This produces long and, sometimes, unpredictable paralysis [2] and makes it less useful for surgery that is likely to last only one or two hours. Rocuronium has a more rapid onset time than vecuronium but without the prolonged paralysis If rocuronium has little or no effect on IOP, it might be a better choice of relaxant for such patients.

The aim of this study was to compare the pharmacodynamics of equipotent (3 χ ED95) doses of vecuronium and rocuronium, and to compare their effects on IOP, heart rate (HR), and mean arterial pressure (MAP) during steady state propofol anaesthesia The dose of vecuronium used (0 15 mg kg 1) is the dose that might be used for the rapid sequence induction of anaesthesia technique [2] The dose of rocuronium is also a 3 χ ED95 dose [3], and although higher than the dose expected for the rapid sequence induction of anaesthesia technique, has been used to allow comparison with an equipotent dose of vecuronium

12 PATIENTS AND METHODS

Thirty patients (ASA physical status 1 or 2) aged 18-65 years, about to undergo elective ophthalmic surgery were studied after ethical committee approval of the study, and written informed consent to participate had been obtained. None of the patients was pregnant or had clinical or biochemical evidence of hepatic or renal disease. All were free from neuromuscular disease and drugs that might interfere with neuromuscular function. Patients with extremes of weight (more than 25% or less than 15% expected body weight) were excluded from the study. Each patient had at least one eye where the IOP was normal (<20 mm Hg)

All patients were premedicated with 20-30 mg oxazepam orally 60-90 minutes before anaesthesia, which was induced with 2 5 mg kg 1 propofol and fentanyl 0 002 mg kg 1 intravenously (iv) and maintained with a propofol infusion of 6-12 mg kg 1 h 1 as required Initially, IPPV was started with 100% oxygen by facemask. During the first 10-15 mm after induction of anaesthesia, baseline readings of BP and HR (using a Dmamap 845 and ECG), and IOP using a Tonopen XL (a single touch tonometer) were recorded until stable All IOP readings were performed by the same ophthalmologist who was familiar with the instrument End tidal C02 was constantly measured using a Datex Multicap analyser and maintained between 4.5 and 5 kPa The left ulnar nerve was stimulated supramaximally (duration 0 2 ms and frequency 2 Hz) every 12 s using the tram-of-four (TOF) mode at the wrist via skin electrodes using a Fischer and Paykel constant current peripheral nerve stimulator. The resultant isometric twitch tension of the thumb (with a preload of 200-300G) produced by this stimulation, as quantified by a Gould Statham force displacement transducer, was recorded on a polygraph throughout the study period. The temperature of the left forearm was monitored using a Digimed ETW H10 thermometer and the arm kept warm throughout the study period with loose padding.

After stabilisation of HR, BP, IOP and mechanomyographic (MMG) recordings, either rocuromum 0 9 mg kg 1 (Group 1) or vecuronium 0 15 mg kg 1 (Group 2) was given iv according to a randomization table, and repeat measurements of HR, BP and IOP recorded at 30, 90, 150, 210, 270 s after the NMBA. At 300 s the trachea was

13 intubated and the lungs ventilated artificially using an Engstrom ER 311 ventilator and all recordings repeated at 30, 120, and 240 s after intubation. At 240 s, 60% nitrous oxide was started and all recordings repeated 60 s later. Anaesthesia was continued until the TOF had reached 70%. If at 25% T1 recovery (the first twitch of the TOF) the surgery appeared to be almost finished, neuromuscular blockade was antagonized using iv neostigmine 0.04 mg kg'1 combined with atropine 0.02 mg kg'1, otherwise the block was allowed to recover spontaneously.

The following measurements were made from the MMG traces, all times being measured from the end of injection of NMBA; onset time - time to 100% T1 block; duration 25 - time to 25% T1 recovery; and duration TOF70 - time to 70% TOF recovery. The lag time - time to the first depression of T1 was measured. The recovery index - time from 25-75% T1 recovery was noted.

Between group statistical analysis was performed using the Wilcoxon rank-sum test, which was also used for within group IOP and haemodynamic comparisons. In addition, for haemodynamic parameters, a repeated analysis of variance on the rank transformed data was performed to see if the percentage change from baseline (1) differed between groups, (2) averaged over the two groups, varied with time, and (3) was parallel for the two groups in the course of time. At each assessment, correlation coefficients between the percentage from baseline of IOP and each of the haemodynamic parameters were calculated and statistically tested. Statistical testing was done two-sided, at a significance level of 0.05.

RESULTS No statistically significant differences were seen between groups with respect to age, sex, weight, or height (Table 1). The onset time in patients receiving rocuronium was almost two times faster than in patients receiving vecuronium (66 vs 124 s) (Table 2). The lag time in the rocuronium group (group 1) was 34(6.9) s and in the vecuronium group (group 2) 47(10.2) s. The lag time is significantly (P<0.001) shorter in group 1 compared to group 2

14 Table 1 Characteristics of patients. Values are means with standard deviation in parentheses. Group 1, rocuronium. Group 2, vecuronium. 15 patients in each group l/R time - time from induction to injection of NMBA.

Group age weight height sex l/R time

(yrs) (kg) (cm) (M/F) (mm)

1 39(15) 75(13) 177(9) (10/5) 10

2 43(13) 72(11) 176(10) (10/5) 11

No significant differences between groups.

Table 2 Comparison of the pharmacodynamics of group 1, rocuronium 0.9 mg kg1, and group 2, vecuronium 0.15 mg kg '. Values are mean with SD in parentheses.

Onset time Dur25 DURTOF70 Recovery index

(s) (mm) (min) (mm)

Group 1 65.5(12)* 46.1(11) 61.6(19) 27.6(7)/4.8(1)

Ν 15 15 10s/4a

Group 2 124.1(20) 48.6(15) 64.3(15) 39.4(13)/3 8(2)

Ν 15 15 5s/10a

* Significant difference between groups, P<0.001 ; Ν = number of patients, s = spontaneous recovery; a = antagonized recovery

There were no other significant differences between groups in dur25, durTOF 70 or the induced or spontaneous recovery rate although there were only four patients in group 1 antagonized with neostigmine and 10 patients in group 2. Within group analysis of operating times showed a longer operating time in the non-antagonized patients compared to the antagonized viz., 41.3 vs 80.2 min in group 1, and 40.6 vs 82.0 min in group 2. Between group analysis of operating times showed no significant difference.

15 Figure 1 Percentage changes in intraocular pressure with time for both groups under propofol anaesthesia Zero time is the time of administration of rocuromum 0 9 mg kg ' or vecuronium 0 15 mg kg ' The baseline value of time zero is the last measurement made before the relaxant was given Fifteen patients in each group INTUB = tracheal intubation Statistical comparisons are within group, compared to baseline SEM = Standard Error of the Mean

0- o

ι Γ 120 240 Time (s) Ύ SEM —·- Rocuromum Vecuronium

Figure 2 Percentage changes mean arterial pressure with time Zero time is the time of administration of rocuromum 0 9 mg kg ' or vecuronium 0 15 mg kg ' The baseline value of time zero is the last measurement made before the relaxant was given Fifteen patients in each group INTUB = tracheal intubation Statistical comparisons are within group, compared to baseline SEM = Standard Error of the Mean

— ·— Rocuromum Vecuronium

16 Figure 1 shows the percentage change with time of IOP. No statistically significant differences were seen between groups for both actual value and the percentage change from baseline IOP (13 vs 15 mmHg, roc. and vec. resp). There were statistically significant increases in IOP in both groups after intubation. There was no statistical difference between groups in the maximal increase of IOP. Before intubation, one patient in the rocuronium group and two patients in the vecuronium group had increases in IOP of more than 5 mmHg (approx 30%). After intubation, seven patients in the rocuronium group and three patients in the vecuronium group had increases of more than 5 mmHg in IOP.

Figure 3 Percentage changes in heart rate with time Zero time is the time of administration of rocuronium 0.9 mg kg1 or vecuronium 0.15 mg kg '. The baseline value of time zero is the last measurement made before the relaxant was given. Fifteen patients in each group. INTUB = tracheal intubation Statistical comparisons are within group, compared to baseline SEM = Standard Error of the Mean

Œ I

τ 1 Γ τ r 150 210 270 120 240 60 Time (s) Τ SEM — ·- Rocuronium -••-· Vecuronium

Figures 2 and 3 show the percentage change of MAP and HR with time. Almost every reading of MAP for group 1 shows an increase compared to baseline, and also compared to group 2. Group 2 demonstrates only a small decrease in MAP with time and a rise with intubation. Baseline HR and BP were similar in both groups viz., 55 b min 1 vs 58 b min1 and 72 mmHg vs 80 mmHg MAP after rocuronium and vecuronium resp. Before intubation, MAP increased by more than 10mmHg (approx 10-15%) in seven patients in the rocuronium group

17 and no patient in the vecuronium group No patient in the rocuronium group had a decrease in MAP of more than 10 mmHg before intubation while two patients in the vecuronium group did Group 1 shows an increase in HR at 210 and 270s after rocuronium administration, and after intubation, whereas group 2 shows an increase in HR only after intubation. Before intubation, heart rate increased by more than 10 b mm1 (approx 20%) in one patient in the rocuronium group and two patients in the vecuronium group. Three patients in group 1, and four patients in group 2 had decreases in HR of more than 5 b mm 1 before intubation In group 1, a statistically significant correlation between percentage change in IOP and the haemodynamic parameters was found at 30 and 120 s after intubation No such correlation was seen in group 2

DISCUSSION The pharmacodynamic values (onset time, duration 25, and duration TOF70) of vecuronium are in agreement with those given by other authors [4]. The rapid onset time of rocuronium (65 s) is confirmed in this study [5,6] The lag time is significantly shorter in the rocuronium group compared to the vecuronium group. This short lag time has also been reported previously [7] Meistelman and colleagues [8], showed that the ED90 for rocuronium at the larynx is 0 684 mg kg1 and that the onset time at the larynx was faster than at the thumb Although intubating conditions were not studied in the present study, it would seem likely that good to excellent intubating conditions are likely to be present about one minute after injection of 0 9 mg kg1 rocuronium. This has been confirmed in clinical practice [9] After using this dose of relaxant, however, a clinical duration of action of about 45 minutes can be expected and more than an hour will elapse before the TOF is 70%. At 25% T1 recovery, however, both NMBAs were easily and rapidly (within around five minutes) antagonized with neostigmine

The lack of cardiovascular effects of vecuronium is confirmed in this study [10,11]. The rise in HR following rocuronium has also been seen in man and in animals [6,12] Few studies have demonstrated the rise in MAP that was seen in this study In one study [12], a biphasic effect, initially a rise followed by a fall in BP in pigs, after rocuronium, was seen, but this was not thought to be significant. In the present study, at each of the nine points of assessment of HR and BP (SBP, DBP and MAP), group 1 (rocuronium) showed statistically significant

18 increases from baseline in one or more of the haemodynamic parameters measured. Also, compared to group 2, group 1 had significantly different changes in DBP and MAP. In this study, the NMBA was administered at the same time (10-11 min) after induction of anaesthesia and at a similar depth of anaesthesia in both groups since baseline BP and HR were the same, and the infusion rates of propofol were similar in each group. The rise in BP after rocuronium was immediate (within 60 s) and sustained for 3-4 min during which time there was no surgical stimulation. Seven patients in the rocuronium group had an increase of 10 mmHg or more in BP in the first 5 min after NMBA, while no patient in the vecuronium group had such a rise in BP in the first 5 min after NMBA. If this rise in BP had been due to a light level of anaesthesia, a rise in BP in the vecuronium group should also have occurred. This was not the case. The cause of these cardiovascular changes was not studied but it is likely to be a vagolytic and perhaps a sympathomimetic effect although the latter was thought to be unlikely by Muir and colleagues [12]. Some evidence for a mild sympathomimetic effect has emerged from a recent study [13]. In the average healthy patient these changes are not likely to be clinically important. However, it does seem that rocuronium is not as 'clean' as vecuronium in terms of cardiovascular side effects although vecuronium is an exacting "gold standard". Although not seen in this study, bradycardias are sometimes seen when vecuronium is used intraoperatively. The slight vagolytic, and perhaps sympathomimetic, effect of rocuronium may reduce the incidence of these bradycardias. Further studies are needed to see if this is the case.

Propofol is known to reduce lOP [1] from awake levels. The rise in lOP seen in this study with intubation shows that the propofol had not obtunded the mechanisms responsible for changes in lOP. The lOP measurements in this study were performed during steady state propofol anaesthesia and at similar times for both groups by an experienced ophthalmologist. In the conditions of this study, lOP slowly decreased before intubation after administration of either NMBA. Small falls in lOP have been reported after vecuronium [14,15] and this is also seen in this study. Rocuronium also appears to have no great effect on lOP. The increase in lOP after intubation is well documented [15]. Intubation had a greater, but not significantly different, effect in both groups on lOP, HR and BP than either NMBA.

19 In group 1 but not in group 2, there was a significant correlation between percentage change in IOP and MAP after intubation The significance of this is difficult to assess, but it does seem that rocuronium has no direct effect on IOP Further studies are needed to examine this new NMBA and its effects on IOP at induction of anaesthesia during a rapid sequence technique In conclusion, rocuronium has a similar pharmacodynamic profile to vecuronium except for onset time, which is much shorter for rocuronium at around one minute Good to excellent intubating conditions can be expected one minute after a 0 9 mg kg 1 iv dose of rocuronium Rocuronium has some cardiovascular side effects but these appear to be fairly minimal although statistically significant in this study Neither NMBA had any significant clinical effect on IOP With its rapid onset time, minimal cardiovascular side effects, and lack of IOP effects, rocuronium is perhaps the NMBA of choice in patients with perforating eye injuries needing urgent endotracheal anaesthesia where a longer acting NMBA is not contramdicated

20 REFERENCES 1 Mirakhur RK, Shepherd WFI, Elliot Ρ Intraocular pressure changes during rapid sequence induction of anaesthesia comparison of propofol and thiopentone in combination with vecuronium Br J Anaesth 1988, 60 379-383 2 Ginsberg B, Glass PS, Quill T, Shafron D, Ossey KD Onset and duration of neuromuscular blockade following high-dose vecuronium administration Anesthesiol 1989,71 201-205 3 Foldes FF, Nagashima H, Nguyen HD, Schiller WS, Mason MM, Ohta Y The neuromuscular effects of ORG 9426 in patients receiving balanced anesthesia Anesthesiol 1991,75 191-196 4 Feldman SA, Liban JB Vecuronium - A variable dose technique Anaesthesia 1987, 42 199-201 5 Cooper RA, Mirakhur RK, Maddmem VR Neuromuscular effects of rocuronium bromide (Org 9426) during fentanyl and halothane anaesthesia Anaesthesia 1993, 48 103-105 6 Booth MG, Marsh B, Bryden FM, Robertson EN, Baird WLM A comparison of the pharmacodynamics of rocuronium and vecuronium during halothane anaesthesia Anaesthesia 1992,47 832-834 7 Wierda JMKH, De Wit APM, Kuizenga K, Agoston S Clinical observations on the neuromuscular blocking action of ORG 9426, a new steroidal non-depolarizing agent Br J Anaesth 1990,64 521 523 8 Meistelman C, Plaud B, Donati F Rocuronium (Org 9426) neuromuscular blockade at the adductor muscles of the larynx and adductor polhcis in humans Can J Anaesth 1992,39 665-669 9 Magonan C, Flannery KB, Miller RD Comparison of rocuronium, succmylcholme, and vecuronium for rapid sequence induction of anesthesia in adult patients Anesthesiol 1993, 79 913-918 10 Robertson EN, Booij LHDJ, Fragen RJ, Crul JF Clinical comparison of atracunum and vecuronium (Org 45) Br J Anaesth 1983,55 125-129 11 Tulloch WC, Diana P, Cook DR, Wilks DH, Brandom BW, Stiller RL, Beach CA Neuromuscular and cardiovascular effects of high dose vecuronium Anesth Analg 1990,70 86-90 12 Muir AW, Houston J, Green KL, Marshall RJ, Bowman WC, Marshall IG Effects of a new neuromuscular blocking agent (Org9426) in anaesthetized cats and pigs and in isolated nerve muscle preparations Br J Anaesth 1989,63 400-410 13 McCoy EP, Maddemm VR, Elliot P, Mirakhur RK, Carson IW, Cooper RA Haemodynamic effects of rocuronium during fentanyl anaesthesia comparison with vecuronium Can J Anaesth 1993,40 703-708 14 Mirakhur RK, Shepherd WFI, Elliot Ρ Intraocular pressure changes during rapid sequence induction of anaesthesia comparison of propofol and thiopentone in combination with vecuronium Br J Anaesth 1988,60 379-383 ACKNOWLEDGEMENTS: Thanks are extended to Dr. Tom Vree for help with the figures. This study was supported financially by Organon Teknika, Belgium

21 POSTSCRIPT After the introduction of rocuronium into clinical practice, it soon became clear that the injection of rocuronium itself could be quite painful We noted in 105 consecutive patients the incidence of pain after sub paralysing doses of rocuronium [I] The site of injection, age and sex of the patients and severity of the pain (mild, moderate, severe) were all noted No relation was found between the site of injection, the age or sex of the patient and the pain Of the 105 patients, 52 had pain on injection and of these, 13 stated that the pain was severe We concluded that these results suggested that rocuronium should not be given to patients who were awake Even when patients are asleep, and rocuronium is given, withdrawal of the hand sometimes occurs [II] Before the general introduction of rocuronium there was no mention of this pain on injection since patients were always under anaesthesia when it was injected This pain on injection of rocuronium might explain the rise in arterial pressure and heart rate seen in the study presented here References I Steegers MAH Robertson EN Pain on injection of rocuronium bromide Anesth Analg1996 83 203 II Robertson EN Pain on administration of rocuronium Anaesthesia 1996 51 93

22 CHAPTER III

SUXAMETHONIUM ADMINISTRATION PROLONGS THE DURATION OF ACTION OF SUBSEQUENT ROCURONIUM

EN Robertson, MB, ChB, FRCA, JJ Onessen, MD, PhD, LHDJ Booij, MD, PhD

Accepted for publication by the European Journal of Anaesthesiology, Feb 2004 Reproduced with kind permission of the European Academy of Anaesthesiologists

SUMMARY Background and aim: Rocuromum is sometimes given to patients after they have received suxamethonium In this study, either rocuromum (Group 1) or suxamethonium (Group 2a) was given to 15 patients in each group In Group 2a, after the suxamethonium had recovered, rocuromum was also given The neuromuscular pharmacodynamics of suxamethonium and rocuromum, and their effects on the intraocular pressure, heart rate and arterial pressure were noted The neuromuscular effect of the rocuromum (Group 2b) given after suxamethonium was also noted and compared to the rocuromum (Group 1) given alone Methods: Anaesthesia was induced iv using propofol 2 5 mg kg1 and fentanyl 2 pg kg \ and maintained with iv propofol 6-12 mg kg 1 h 1 The response of the thumb to supramaximal TOF ulnar nerve stimulation at the wrist was measured using a mechanomyograph Patients were randomly allocated to receive initially either 0 6 mg kg 1 rocuromum or 1 mg kg1 suxamethonium iv When T1 had recovered to 90% after suxamethonium, rocuromum 0 6 mg kg 1 was administered Before administration of relaxant, baseline readings of heart rate, arterial pressure and intraocular pressure were measured until stable, then the appropriate relaxant administered Thereafter, all

23 readings were repeated at 30, 90, 150, 210 and 270 s. After 300 s tracheal intubation was performed and all recordings repeated 30 s later. Mechanomyographic monitoring was continued until 70% train- of-four recovery. Results: Suxamethonium had a more rapid onset time than rocuronium (49 vs 74 s resp. P<0.0001). The onset time of rocuronium after suxamethonium was significantly reduced (56 s) and the time to a TOF of 70% of rocuronium was increased by previous suxamethonium administration (47 vs 58 min, P<0.05). Suxamethonium caused marked rises in intraocular pressure (>30%) and heart rate (>10%) while rocuronium had little effect on either. Conclusion: Previous suxamethonium administration decreases the onset time and increases the duration of action of rocuronium. Unlike suxamethonium, rocuronium has few cardiovascular effects and causes little change in intraocular pressure.

INTRODUCTION The choice between suxamethonium and a rapid onset non depolarizing agent like rocuronium for rapid sequence induction and intubation can be difficult in patients with penetrating eye injuries. Suxamethonium is known to cause an increase in intraocular pressure (IOP) but it may still be the relaxant of choice for rapid sequence induction of anaesthesia even in these patients [1,2]. The unexpected difficult intubation or airway may also suggest that suxamethonium might be preferred to rocuronium in the rapid sequence induction of anaesthesia [3] even though rocuronium can provide good intubating conditions for a rapid tracheal intubation [4,5]. Intraocular pressure is little affected by rocuronium administration [6,7] and can be used in the rapid sequence induction technique thus avoiding all the unwanted effects of suxamethonium [4,8]. Rocuronium, however, may be given after suxamethonium in acute situations where a rapid sequence induction technique using suxamethonium has been used. Using dose response curves, Cooper et al [8] did not see any alteration in the potency of rocuronium after prior suxamethonium use, however, no assessment of the duration of neuromuscular block of rocuronium after suxamethonium administration was performed. Dubois and colleagues [9] demonstrated that the onset time of rocuronium is reduced by prior suxamethonium administration. They were unable to demonstrate a statistically significant increase in the clinical duration of action of

24 rocuronium after suxamethonium although there was a tendency to an increase after suxamethonium The aim of this study is, therefore, to compare the neuromuscular effects of rocuronium 0 6 mg kg1 alone, and after suxamethonium 1 mg kg1, and to compare the effects of these neuromuscular blocking agents on IOP, HR, and BP during steady state propofol anaesthesia

PATIENTS AND METHODS After ethical committee approval was obtained, 30 adult patients (ASA physical status 1 or 2) aged 18-65 years and scheduled for elective ophthalmic surgery, were studied after written informed consent from the patient had been obtained None of the patients were pregnant or had clinical or biochemical evidence of hepatic or renal disease All were free from neuromuscular disease and drugs that might interfere with neuromuscular function Patients who could not tolerate an increase in IOP or at the extremes of weight (25% above or 15% below ideal body weight) were excluded from the study Each patient had at least one eye where the IOP was normal (<20 mm Hg) All patients were premedicated with 20-30 mg oxazepam orally 60-90 minutes before anaesthesia which was induced with 2 5 mg kg1 propofol and fentanyl 2 pg kg 1 intravenously (iv), and maintained with a propofol infusion of 6-12 mg kg1 h1 as required Fentanyl 1-2 μg kg1 was given as required Initially, IPPV was started with 100% oxygen by facemask During the first 10-15 mm after induction of anaesthesia, baseline readings of BP and HR (using a Dmamap 845 and ECG), and IOP using a Tonopen XL (a single touch tonometer) were recorded until stable All IOP readings were performed by an ophthalmologist who was experienced with the instrument End-tidal CO2 was constantly measured using a Datex Multicap analyser and maintained between 4 5-5 kPa The ulnar nerve was stimulated supramaximally every 12 s using the tram-of-four (TOF) mode at the wrist via skin electrodes using a constant current peripheral nerve stimulator (Fischer and Paykel) The resultant isometric twitch tension of the thumb (with a preload of 200-300G) produced by this stimulation, as quantified by a force displacement transducer (Gould Statham), was recorded on a polygraph throughout the study period

After stabilisation of HR, BP, IOP and mechanomyographic (MMG) recordings for at least 10 minutes, either rocuronium 0 6 mg kg 1

25 (Group 1) or suxamethonium 1 mg kg'1 (Group 2a) was given iv according to a randomization table. Measurements of HR, BP and lOP were recorded at 0, 30, 90, 150, 210, 270 s were after the NMBA. At 300 s all patients were intubated and ventilated artificially using an Engstrom ER 311 ventilator and all recordings repeated 30 s after intubation. When lOP, HR and BP recordings for the study were stopped, 60% nitrous oxide was started. While these measurements were made, the propofol infusion was altered as little as possible, and no extra fentanyl given. Anaesthesia was continued until the TOF had spontaneously reached 70%. After the suxamethonium-induced block had recovered to 90% T1 (the first twitch of the TOF) recovery, rocuronium 0.6 mg kg'1 (Group 2b) was given. The block was then allowed to recover spontaneously to a TOF of 70%. The following measurements were made from the MMG traces, all times being measured from the end of injection of NMBA; onset time - time to 100% TI block; duration 25 - time to 25% T1 recovery; duration 90 - time to 90% T1 recovery and duration TOF70 - time to 70% TOF recovery. The lag time - time till the first depression of TI and the recovery rate - time from 25-75% T1 recovery was also recorded. All patients were visited the day after surgery to see if there were any side effects that could be attributable to the NMBA. Statistical analysis was performed using paired or unpaired t-tests as required. P< 0.05 was considered significant.

RESULTS No statistically significant differences were seen between groups with respect to age, sex, weight, or height (Table 1). The dose of propofol administered during the period of lOP, HR and BP measurements was the same in both groups and baseline mean lOP, HR and BP were not different between groups. The pharmacodynamic values of neuromuscular block after rocuronium alone (Groupl), and suxamethonium (Group 2a) are presented in Table 2. These values are also given for rocuronium after suxamethonium (Group 2b). The onset time of rocuronium was reduced, and the time to a TOF of 70% increased (P<0.05) by previous suxamethonium administration.

26 Table 1 Demography of Patients Baseline IOP, MAP and HR values No differences between groups Values are mean (SEM) Ν = number of patients

Relaxant/Patients Age Weight Height IOP MAP HR years kg cm mmHg mmHg b mm '

Rocuronium 39(3 Θ) 71(3) 174(2 4) 15(0 7) 71(2 7) 59(3 4) Group! Ν =15

Suxamethonium 39(3 7) 76(2 7) 177(2 6) 16(0 6) 72(2 2) 62(3 2) Group 2 Ν =15

Table 2 Pharmacodynamics of rocuronium 0 6 mg kg ', suxamethonium 1 mg kg1 and rocuronium 0 6 mg kg ' after suxamethonium administration Ν = number of patients Ν = 15 unless otherwise stated Values are mean (SEM) [range] Student s t test was used for statistical analysis N/A = Not applicable

Relaxant Onset time Lag Duration Duration Dur Recovery Sec lime 25, 90, TOF70 rate s mm mm mm mm

Group 1 74(2 7)" 33(2 1)' 30(1 8) 45(2 7)" 47(3 4)· 10(1) Rocuronium [60 90] [25 55] [20 42 5] [30 65] [28 72 5] [5 5 19] alone

Group 2a 49(1 4) 26(1 5) N/A 12(0 9)" [40 60] [15 35] [8 20] Suxamethonium N=13

Group 2b 56(3 2) 26(1 θ) 34(1 Θ) 58(3 5) 11(1) Rocuronium [40-75] [15-36] [21 5 42] [37 87] [6 5 17 5] after N=13 N=13 suxamethonium

** = significant difference between group 1 and 2a, and 1 and 2b P<0 001 * = significant difference between group 1 and 2a, and 1 and 2b P<0 05 Fourteen of the 15 patients in the suxamethonium group had increases in IOP after suxamethonium administration, while 12 of the 15 either had no change or had a decrease in IOP after rocuronium. After suxamethonium, three patients had IOP pressures of >25 mmHg (26, 30, and 35 mmHg) with these high IOP levels sustained for several minutes. Seven of the 15 patients given suxamethonium had increases in HR of >10 b mm1 (range -10 to +35 b min1). Of the patients given rocuronium, only two patients had an increase in HR of >10 b min1 (range -7 to +35 b m1). The HR increases after 27 suxamethonium occurred within 30 s while any HR increases after rocuronium took 2-3 min to appear. There were no significant changes in MAP after either NMBA with time. Four patients complained of muscle pains postoperatively viz., three in the group who had received suxamethonium and one in the group who received rocuronium alone. Nausea occurred in three patients in each group.

DISCUSSION The rapid (mean) onset times of rocuronium 0.6 mg kg'1 and suxamethonium 1 mg kg'1 are confirmed in this study (74 s vs 49 s resp) with suxamethonium having a significantly faster onset time than rocuronium. The longer clinical duration of action of rocuronium compared to suxamethonium is also confirmed (30 min vs 12 min resp) [8,9,10]. Prior administration of suxamethonium significantly reduced the onset time of rocuronium (56 s) compared to the patients who received rocuronium alone (74 s). This confirms the finding of Dubois et al [9] and has been seen with other neuromuscular blocking agents [11]. The time to recovery of rocuronium to a TOF of 70% was significantly increased after prior suxamethonium administration (58 vs 47 min resp) although the clinical duration (duration 25) and recovery rate of rocuronium were not significantly altered. These latter two findings were also seen by Dubois and colleagues [9]. This group only observed the recovery of rocuronium until T1 was 25% at which point more rocuronium was given. The end point in this study, a TOF ratio of 70% is significantly prolonged by previous suxamethonium administration thus confirming what Dubois and colleagues suggested in their study but were unable to demonstrate. In the study of Cooper and colleagues [8] no alteration in the potency of rocuronium was seen when administered after suxamethonium. This study was, however, a dose response study and did not assess the duration of action of a bolus dose of rocuronium after suxamethonium.

Whether this increase in the duration TOF70 of rocuronium seen in this study is of clinical significance is difficult to determine since the recovery rate is not different between the two groups who received rocuronium. Both this study and the study by Dubois and colleagues [9] were performed without inhalational agents, which are known to

28 increase the duration of action of neuromuscular blocking agents. Perhaps the increase in the time to a TOF of 70% seen in this study would be even more pronounced if inhalational agents had been used. The suggestion [12] that a TOF ratio of 80 or even 90% is required to ensure adequate recovery of neuromuscular function at the end of surgery might make this alteration in the duration of action of rocuronium even more pronounced. Careful monitoring of the neuromuscular block intraoperatively should be able to avoid any postoperative problems with this increase in the duration of action of rocuronium. The small rise in HR following rocuronium has also been reported in man [6]. The positive chronotropic effect of suxamethonium has also been previously recorded [13] although bradycardia is the most expected effect. This was not seen in either group in this study. Rocuronium is not as "clean" as vecuronium but compared to the effects that suxamethonium had on HR it would appear to be a more acceptable alternative to suxamethonium. The IOP measurements in this study were performed during steady state propofol anaesthesia and at similar times for both groups by an experienced ophthalmologist. In the conditions of this study, in the rocuronium group, IOP slowly decreased before intubation. Suxamethonium caused a sustained and marked increase in IOP. Although Libonati et al [1] has suggested that suxamethonium can be safely used in patients with penetrating eye injuries, a limited retrospective study of such patients may not be enough for such claims. The study presented here was performed in patients who were premedicated and prepared for surgery, hardly comparable to a patient with a penetrating eye injury. A study on such patients, however, would be ethically impossible. The study presented here confirms that suxamethonium consistently causes a marked increase in IOP (and sometimes HR) while rocuronium does not. This study demonstrates that rocuronium is less likely than suxamethonium to adversely affect the eye and cardiovascular system. Indeed suxamethonium is also known to have many other disadvantages that the use of rocuronium will avoid.

In conclusion, if suxamethonium is used for a rapid sequence induction of anaesthesia and intubation then followed by rocuronium, a longer duration of neuromuscular block produced by rocuronium may be expected.

29 REFERENCES 1 Libonati MM, Leahy JJ, Ellison N. The use of succinylcholine in open eye surgery. Anesthesiol 1985; 62. 637-640 2. Sparr HJ. Choice of muscle relaxant for rapid-sequence induction. Eur J Anaesthesiol 2001 ; 18 (Suppl 23): 71-76 3. Cadamy AJ, Booth MG. Effect of rocuronium compared with succinylcholine on IOP Br J Anaesth 1999; 83: 824-825 4. McCourt KC, Salmela L, Mirakhur RK, et al. Comparison of rocuronium and suxamethonium for use during rapid sequence induction of anaesthesia. Anaesthesia 1998;53.867-871 5. Huizmga ACT, Vandenbrom RHG, Wierda JMKH, Hommes FDM, Hennis PJ. Intubating conditions and onset of neuromuscular block of rocuronium (Org 9426), a comparison with suxamethonium. Acta Anaesthesiol Scand 1992; 36:463-468 6. Robertson EN, Hull JM, Verbeek AM, Booij LHDJ. A comparison of rocuronium and vecuronium: the pharmacodynamic, cardiovascular and mtra-ocular effects. Eur J Anaesthesiol 1994; 11 (Suppl 9): 116-121 7. Mitra S, Gombar KK, Gombar S. The effect of rocuronium on intraocular pressure1 a comparison with succinylcholine. Eur J Anaesthesiol 2001 ; 18: 833-838 8 Cooper R, Mirakhur RK, Clarke RSJ, Boules Ζ. Comparison of intubating conditions after administration of ORG 9426 (Rocuronium) and suxamethonium. Br J Anaesth 1992;69:269-273 9. Dubois MY, Lea DE, Katana B, Gadde PL, Tran DO, Shearrow T. Pharmacodynamics of rocuronium with and without prior administration of succinylcholine. Journal of Clinical Anesthesia 1995; 7:44-48 10 Puhrmger FK, Khuenl-Brady KS, Koller J, Mitterschiffaler G. Evaluation of the endotracheal intubating conditions of rocuronium (ORG 9426) and succinylcholine in outpatient surgery. Anesth Analg 1992; 75:37-40 11. Dubois MY, Fleming NW, Lea DE. Effects of succinylcholine on the pharmacodynamics of pipecuronium and pancuronium Anesth Analg 1992,72: 364-368 12 Caldwell JE. The problem with long acting muscle relaxants9 They cost more' Anesth Analg 1997; 85' 476-482 13,Yasuda I, Hirano T, Amaha K, Fudeta H, Obara S. Chronotropic effects of succinylcholine and succinylmonocholme on the sinoatrial node Anesthesiol 1982; 57. 289-292 ACKNOWLEDGEMENTS This study was supported financially by Organon Teknika, Turnhout, Belgium.

30 CHAPTER IV

THE TIME-COURSE OF ACTION AND RECOVERY OF ROCURONIUM 0.3 MG KG 1 IN INFANTS AND CHILDREN DURING HALOTHANE ANAESTHESIA MEASURED WITH ACCELEROMYOGRAPHY

JJ Dnessen, MD, PhD, EN Robertson MB.ChB, FRCA, J van Egmond, PhD, LHDJ Booij, MD, PhD.

This study has been presented in part at the annual meeting of the American Society of Anesthesiology, Orlando, USA, October 17-21, 1998. Published in Pediatric Anesthesia 2000. 10. 493-497. Reproduced with kind permission of Blackwell Publishing Ltd.

SUMMARY This study compares the time-course of action of neuromuscular paralysis after 0 3 mg kg 1 of rocuronium during nitrous oxide- halothane anaesthesia in children of three different age groups With appropriate approval and informed consent from the parents, 51 children, ASA l-ll, scheduled for elective surgery requiring muscle relaxation, were studied. The children were assigned to three groups according to age group 1: 0-6 months, group 2: 6-24 months, and group 3 >24 months of age. Induction of anaesthesia and endotracheal intubation were performed under halothane anaesthesia Acceleromyography of the thumb was recorded after supramaximal transcutaneous ulnar nerve stimulation using tram-of-four (TOF) stimulation

Rocuronium 0 3 mg kg 1 was given as a rapid intravenous bolus prior to surgical incision The onset time (time to max effect) and the maximal depth of the block, the time to recovery of the first twitch (T1 ) to 25% and 75% of its baseline, the recovery index (RI), and the

31 time to recovery of the TOF ratio to 70% after the end of injection ofrocuromum were all measured The mean (SD) age of the children in groups 1, 2, and 3 was 3 1 (1 6), 12 6 (3 7), and 63 (46) months, respectively The onset time of rocuromum was 47 (12), 83 (42) and 94 (12) s, respectively, in group 1, 2, and 3 (P <0 05 group 1 vs 2 and 3) One hundred percent block was achieved in 18/19 patients in group 1, 12/14 in group 2, and 6/18 in group 3 The times to 25% and 75% recovery of T1 and the time for recovery of the TOF ratio to 70% were all significantly longer in groups 1 and 2 compared to group 3 Group 1 and 2 showed no significant differences m recovery times The RI was significantly prolonged in group 1 versus 3 The authors conclude that rocuromum 0 3 mg kg1 during halothane anaesthesia causes more neuromuscular depression and has a longer duration of action in infants than in children older than 2 years

INTRODUCTION Rocuromum is a steroid non-depolarizing muscle relaxant with a fast onset and an intermediate duration of action Using evoked electromyographic recording of neuromuscular transmission it has been found that in infants the duration of action of rocuromum after a rapid sequence intubation dose of 0 6 mg kg 1 is significantly prolonged compared with older children [1] The aim of the present study was to evaluate acceleromyographically the time-course and duration of action of a single dose of 0 3 mg kg 1 of rocuromum in children of three age groups (< 6 months, 6-24 months, >24 months) during 0 8% halothane anaesthesia

MATERIALS AND METHODS The study was approved by the hospital Ethical Committee on Human studies and informed consent was obtained from the parents Fifty-one children, ASA physical status l-ll, requiring neuromuscular relaxation for elective surgical procedures with minimal blood loss were included No patient had any hepatic, renal or cardiac dysfunction or received any drugs known to alter neuromuscular function Exposure to antibiotics for prophylaxis was limited to cephalosporins, penicillins and metronidazole Children less than 2 yrs of age received no premedication while older children received oral midazolam 0 5 mg kg 1 Paracetamol 20 mg kg 1 was given rectally 30 mm before anaesthesia to all children The children were assigned to

32 three groups according to age group 1, < 6 months, group 2,6-24 months, group 3, 2 - 8 years Anaesthesia was induced in all patients with halothane and nitrous oxide 60% in oxygen and tracheal intubation was achieved without muscle relaxants After intubation anaesthesia was maintained with 60% nitrous oxide in oxygen at an end-tidal halothane concentration of 0 8% as measured by a Hewlett-Packard M1026A airway gases monitor Ventilation was controlled to maintain the end tidal COg concentration between 4 5 and 5 5 kPa (35-42 mmHg) For peroperative analgesia intravenous meperidine 0 5-2 mg kg1 was given Surface stimulation electrodes (Neotrode®, Conmed, Utica, NY, USA) were placed over the ulnar nerve at the wrist after induction of anaesthesia and an acceleration transducer (TOF- Guard", Organon Teknika, Turnhout, Belgium) was attached to the flexor aspect of the freely mobile thumb with surgical tape while the movement of the other fingers was restricted in the extension position The accelerograph was used in the TOF mode delivering supramaximal tram-of-four stimuli with square wave pulses of 0 2 ms at a frequency of 2 Hz every 15 s The response to the first stimulus of the tram-of- four (TOF) prior to injection of rocuromum was considered as the baseline T1

Rocuromum 0 3 mg kg1 was given prior to surgical incision as a rapid bolus into a T-connector of a rapidly running intravenous infusion The variables of neuromuscular blockade were measured onset time (time between the end of rocuromum injection and the occurrence of maximal block), time to recovery of TI to 25% and 75 % of its baseline values, time to recovery of the TOF ratio to 0 7, and the recovery index (RI = time from 25 to 75% recovery of the T1) All data obtained with the TOF- Guarcf were stored electronically and read out in a Windows computer program for further analysis (Card reader 1 0 for Windows, supplied by Organon Teknika, Turnhout, Belgium)

The electrocardiogram, NIBP, Sp02, hand and rectal temperature, and end-tidal carbon dioxide and halothane were monitored throughout The rectal temperature was maintained between 35 5 and 370C and the palmer skin temperature greater than 330C using a circulating water mattress and isolating body covers Analysis of variance followed by the Scheffe test was used for statistical comparison of the onset and recovery times in the three

33 study groups. Pearson correlation analysis was used to assess the effect of age on recovery times. Ρ <0.05 was considered significant. Data are presented as mean +/- SD.

RESULTS Table 1 shows the demographic data in the three groups of patients. The mean palmar skin temperature at the end of neuromuscular monitoring was 34.4 (1.1 ), 34.3 (1.4) and 34.4 (1.2) 0C in groups 1, 2, and 3.

TABLE 1 Patient and perioperative characteristics

Group 1 Group 2 Group 3

(n=19) (n=14) (η=1β)

Age (months) 3 1(1 6) 12 6(3 7) 63 (46)

Weight (kg) 4 3(17) 8 1 (2 1 ) 18 4(8)

Duration of anaesthesia (mm) 131 (47) 97 (40) 114(88)

Duration of surgery (mm) 103(44) 72(41) 88 (48)

Data are represented as mean and SD

Table 2 shows the neuromuscular patient data after iv administration of 0.3 mg kg1 rocuronium. The maximal depth of block was 100% in 18/19 patients in group 1, 12/14 in group 2, but only in 6/18 in group 3. In group 3 the maximal block was between 90 and 99% in 10 patients, between 80 and 90% in eight patients, and 52% in one patient. The mean onset time to maximal block was significantly shorter in group 1 than in group 2 and 3. The mean time to recovery of T1 to 25% and to 75% of baseline and the time to recovery of the TOF ratio to 70% were significantly longer in group 1 and 2 than in group 3. The RI in group 1 was longer than in group 3.

34 Table 2 Onset and recovery times and incidence of 100% block after 0 3 mg kg 1 rocuronium

Group 1 Group 2 Group 3 (0-6 mo) (6-24 mo) (> 24 mo)

Onset (s) 47(12)" 83 (42) 94(12)

100% block (n) 18/19 12/14 6/18

TI Recovery 25% (mm) 26.1 (11 1) 22.3 (7.9) 13 7(4 4)*

T1 Recovery 75% (mm) 41.9(14.7) 34 6(10 7) 20.7 (8 2)*

TOF Recovery 0.7 (mm) 46.9(15 9) 37.7(12.3) 23 0 (8 8)*

RI (mm) 16.8(9.0) 12.3(7 5) 7.8 (3 9)#

Onset and recovery times represented as mean and SD * Ρ <0.05 for difference between group 3 versus both 1 and 2 ** Ρ <0.05 for difference between group 1 versus 2 and 3. # Ρ < 0.05 for difference between group 1 versus 3.

Figure 1a The time to recovery of the TOF ratio to 70% is plotted against age The solid line is obtained by analysis of linear regression The Pearson correlation coefficient between age and recovery of the TOF to 70% was -0 52 (P = 0.001 ).

Time to 70% recovery of TOF vs age

100 E 90 80 S« t- 70 o ΐ 60 E ~ 3D $ 40 ο S SD Ο 2° —ι 10 0 20 40 60 80 100 120 Age (months)

35 There was a significant correlation between age and recovery times and index. The calculated regression lines for age against recovery times were as follows: T1 recovery 25% (min) = 23.5 - 0.126 χ age in months T1 recovery 75% (min) = 37.96 - 0.21 χ age in months TOF 0.7 recovery (min) = 42.29 - 0.243 χ age in months (fig 1a) RI (min) = 14.66 - 0.086 χ age in months (fig 1b) The mean baseline TOF ratio was 109 (6) % for the whole group of patients. The mean final T1 and TOF ratio for all patients at the end of the measurement period were 102 (27) and 98 (9) % of the control values. The only significant difference between the three age groups was a lower mean final T1 in group 1 (89%, SD 20) compared to group 3 (115%, SD 22).

Figure 1b The recovery index (RI = time from 25 to 75% recovery of T1 ) is plotted against age The solid line is obtained by analysis of linear regression The Pearson correlation coefficient between age and recovery index was -0 38 (P = 0 0092)

Recovery index vs age

40 60 80 120 Age (months)

DISCUSSION Our study shows that in infants up to 2 years of age, an initial bolus dose of rocuronium 0.3 mg kg1 during halothane anaesthesia causes a more profound neuromuscular block and has a longer duration of action than in older children.

36 The faster onset in small infants and the more frequent occurrence of 100% block after rocuromum 0 3 mg kg1 in infants suggest a greater potency than in children older than two years This has already been shown for the (rapid sequence induction) dose of 0 6 mg kg 1 of rocuromum [1] Our data show a significantly longer duration of action after 0 3 mg kg1 rocuromum during halothane anaesthesia in children younger than 2 years compared to older children This is in agreement with data shown for rocuromum 0 6 mg kg1 [1] Such a prolonged duration of action in infants compared to children has also been reported for vecuronium, from which rocuromum is a structural derivative [2]

After an equipotent 1 χ ED95 dose, which was about 40 % lower in infants 1-12 months compared to children older than 2 years, an approximately similar duration of action of rocuromum m infants, children and adults was found by Taivamen and colleagues [3], although the recovery index was significantly longer in infants than in children Similarly, Wierda and colleagues [4] found no significant difference in recovery times between five infants and five children after an ED90 dose of rocuromum, despite a higher volume of distribution and a lower plasma clearance in infants However, in these two studies, the dose used in infants was approximately 40% lower than m children 2-10 years and the recovery index was still 30% longer This would predict that after repeated administration the duration of action of rocuromum during volatile anaesthesia would be prolonged m children younger than 2 years These two studies [3,4] on rocuromum in infants did not use volatile anaesthetics, which are known to potentiate the effect of non depolarizing relaxants Due to the long equilibration time of halothane between the muscle and alveolar compartments, the potentiation by halothane in our study was probably not fully established at the time of administration of rocuromum, but definitely during its recovery This potentiation might have accentuated the difference in duration of action of rocuromum between infants and children over 2 years Although mechanomyography is often considered the 'gold standard' in neuromuscular transmission monitoring, it is time-consuming and difficult to set up in neonates and infants Most of the pharmacodynamic studies of rocuromum (and other muscle relaxants) in infants have been done using electromyographic

37 analysis of the responses to nerve stimulation [1 -3]. The electromyographic twitch response often does not return to the baseline value and may further be disturbed by electrical interference and direct muscle stimulation [5]. The acceleromyographic method, compared with mechanomyography, underestimates a rocuronium neuromuscular block during onset in children [6]. During recovery, however, both methods are fairly comparable with the accelerographic TOF ratio slightly higher than the mechanomyographic TOF [5,7]. This may be related to the common finding that the baseline TOF obtained with acceleromyography is also consistently greater than unity [5], as was also found in our study groups. Despite considerable variability, the final TI and TOF ratios in our study were near to the baseline value, indicating the validity of the acceleromyographic measurement method in small children since it improves the precision of the calculation of recovery times.

Neonates and infants have a higher sensitivity (lower ED50 and EDgs) for most non-depolarizing muscle relaxants than older children [8,9]. In addition, the longer duration of the rocuronium-induced neuromuscular block in neonates and infants is consistent with data on several other non-depolarizing drugs [2,8,9]. The maturation of neuromuscular transmission (transition from foetal to adult type ACh receptors, transition from slow to fast muscle fibres) occurs in the first 2-3 months of age [10,11], and may explain the greater sensitivity and increased duration of action of non-depolarizing neuromuscular blockers in small infants. However, other factors must also be considered to explain the different sensitivity and duration of action in infants up to 2 years of age. Fisher showed in 1982 that both infants and neonates require lower plasma concentrations of d-tubocurarine for the same level of neuromuscular block than both children and adults, and that there was no difference between neonates and infants [12]. Pharmacokinetically, neonates and infants have a higher volume of distribution and a delayed elimination of several neuromuscular blocking drugs, both tending to increase the duration of action. These mechanisms are reviewed elsewhere [8-9].

In conclusion, an initial bolus dose of 0.3 mg kg ' rocuronium during 0.8% halothane anaesthesia causes more neuromuscular depression and has a longer duration of action in infants compared to children older than 2 years.

38 REFERENCES 1. Oelfel SK, Brandom BW, McGowan FX et al Neuromuscular effects of 600 pg.kg ' of rocuronium m infants during nitrous oxide-halothane anaesthesia. Ped Anesth 1994; 4.173-177 2. Meretoja OA Is vecuronium a long-acting neuromuscular blocking agent in neonates and infants9 Br J Anaesth 1989; 62:184-187 3 Taivainen T, Meretoja OA, Erkola O et al Rocuronium in infants, children and adults during balanced anaesthesia Paed Anaesth 1996; 6.271-275 4. Wierda JMKH, Meretoja OA, Taivanen Τ et al. Pharmacokinetics and pharmacokmetic-dynamic modelling of rocuronium in infants and children. Br J Anaesth 1997; 78.690-695 5 Viby-Mogensen J. Neuromuscular monitoring In Miller RD, ed Anesthesia. New York Churchill Livingstone, 1994:1345-1361 6 McCluskey A, Meakm G, Hopkmson JM et al A comparison of acceleromyography and mechanomyography for determination of the dose-response curve of rocuronium in children. Anaesthesia 1997, 52· 345-349 7. Saitoh Y, Fujn Y, Ueki M et al Accelographic and mechanical post-tetanic count and train-of-four ratio assessed at the great toe Eur J Anaesthesiol 1998; 15. 649-655 8 Meretoja OA, Taivanen T. Recent developments in muscle relaxation in children Curr Anaesth Cnt Care 1994, 5: 202-208 9. McLoughin CC, Mirakhur RK Muscle relaxants in paediatric anaesthesia. In. Harper NJN, Pollard BJ, ed Muscle Relaxants in Anaesthesia London· Edward Arnold, 1995,198-220 10 Crumrme RS, Yodlowski EH Assessment of neuromuscular function in infants Anesthesiol 1981,54-29-32 11. Goudsouzian NG, Standaert FG. The infant and the myoneural junction. Anesth Analg 1986; 65:1208-1217 12 Fisher DM, O'Keeffe C, Stanski DR et al Pharmacokinetics and pharmacodynamics of d-tubocuranne in infants, children and adults Anesthesiol 1982, 82. 203-208

39 40 CHAPTER V

TIME-COURSE OF ACTION OF ROCURONIUM 0.3 MG KG 1 IN CHILDREN WITH AND WITHOUT ENDSTAGE RENAL FAILURE

JJ Driessen, MD, PhD, EN Robertson MB, ChB, FRCA, J van Egmond, PhD, LHDJ Booij, MD, PhD.

This study has been presented in part at the Annual Meeting of the American Society of Anesthesiology, San Francisco (USA), October 16,2000. Published in Pediatric Anesthesia 2002; 12: 507-510. Reproduced with kind permission of Blackwell Publishing Ltd.

SUMMARY Background and aim: The time-course of the neuromuscular effects of rocuronium 0.3 mg kg1 during nitrous oxide-halothane anaesthesia in children with and without renal failure is unknown. This study compares the neuromuscular blocking effects in these groups. Methods: The study was approved by the Hospital Ethical Committee. In the control group, 14 healthy children without renal disease were scheduled for various elective surgical procedures. Sixteen children with endstage renal failure, 14 of whom were already on renal dialysis, were scheduled for (re)placement of dialysis catheters (n = 14) or for renal transplantation (n = 2). Anaesthesia was induced and maintained with halothane and nitrous oxide in oxygen. Acceleromyographic thumb adduction after supramaximal ulnar nerve stimulation was recorded using train-of-four stimulation every 15 s. The onset time, the time to recovery of the first twitch 25 or 75% and to recovery of a train-of-four ratio of 0.7 after rocuronium 0.3 mg kg 1 were measured. Statistical analysis was performed with Student's t - test. P<0.05 was considered statistically significant.

41 Results: The onset time was longer in children with renal failure (139 s, SD = 71 ) than in control children (87 s, SD = 43) (Ρ = 0 02) There were no significant differences in the duration of action of rocuromum between children without renal failure and in 15 out of 16 children with renal failure Conclusions: In children with renal failure, aged over 1 year, a single bolus dose of rocuromum 0 3 mg kg1 does not cause a prolonged block, but has a slower onset than in healthy children

INTRODUCTION In children and adults with chronic renal failure the use of suxamethonium should be restricted due to hyperkalaemia Rocuromum may be an alternative In adults, the effect of chronic endstage renal failure on the clearance and the duration of action of rocuromum are still not fully clear While a prolonged effect was reported after rocuromum 0 6 mg kg 1 in one study [1], others found no statistically significant difference compared with healthy controls [2,3] In children, there are no reported data on the effect of endstage renal failure on rocuromum pharmacodynamics In a previous study, we showed that 0 3 mg kg 1 rocuromum is a suitable first dose during halothane anaesthesia in infants and children [4] The aim of this study was to compare the onset and duration of action of rocuromum 0 3 mg kg1 during nitrous oxide-halothane anaesthesia in children with and without renal failure

PATIENTS AND METHODS The study was approved by the Hospital Ethical Committee on Human studies and informed consent was obtained from the parents of the patients Two groups of children were studied In the non renal failure group 14 ASA class I and II children with no history or evidence of renal disease were scheduled for various elective surgical procedures Sixteen children with endstage renal failure (creatinine clearance <5-10 ml"1 mm-11 73 m2) were scheduled for placement or replacement of peritoneal (n = 10) or central venous (n = 4) dialysis catheters or for renal transplantation (n = 2) Fourteen patients were dialysed the day before surgery Only two children were not being dialysed at the time of the study Medication for essential therapy of the renal failure

42 patients (vitamins, calcium and iron) was continued. Exposure to antibiotics for prophylaxis was limited to cephalosporins, penicillins and metronidazole. Children less than 2 years received no premedicat ion while older children received oral midazolam 0.5 mg kg 1. Anaesthesia was induced in all patients with halothane and nitrous oxide 60% in oxygen and maintained with halothane at an end tidal concentration of 0.8% as measured by an airway gas monitor. Tracheal intubation was performed under deep halothane anaesthesia without muscle relaxants Ventilation was controlled to maintain the end tidal CO2 concentration between 4 5 and 5 5 kPa (35-42 mmHg) For peroperative analgesia intravenous pethidine 0.5-2 mg kg1 was given Surface stimulation electrodes (Neotroder\ Conmed, Utica, NY, USA) were placed over the ulnar nerve at the wrist after induction of anaesthesia and an acceleration transducer (TOF-Guard®, Organon, Boxtel, The Netherlands) was attached to the flexor aspect of the freely mobile thumb while the movement of the other fingers was restricted m the extension position. The accelerograph was used in the tram-of-four (TOF) mode delivering supramaximal TOF stimuli (square wave pulses of 0.2 ms at a frequency of 2 Hz) every 15 s The response to the first twitch response (T1) in the TOF after 3-5 mm of stabilization was manually calibrated at 100% and considered as the baseline T1 prior to the administration of rocuromum.

Rocuromum 0.3 mg kg1 was given prior to surgical incision as a rapid bolus via a T-connector in a rapidly running intravenous infusion The following variables of neuromuscular blockade were measured onset time (time between the end of rocuromum injection and the occurrence of maximal block), time to recovery of T1 to 25% and 75 % of its baseline values, time to recovery of the TOF ratio to 0 7 The recovery index was calculated as the time from 25 to 75% recovery of T1 All times were measured from the end of injection of rocuromum All data obtained with the TOF-Guard^ were stored digitally and read out in a computer program for further analysis (Card reader 1 0 for Windows, Organon, Boxtel, The Netherlands) The electrocardiogram, automatic oscillometric blood pressure, pulse oximetry, end tidal carbon dioxide and halothane, and the temperature of the rectum and the skin of the hand were monitored throughout. The rectal temperature was maintained between 35.5 and 37 0C and the palmer skin temperature was kept above 33 0C using a circulating water mattress and isolating body covers.

43 Statistical analysis was performed using Student's t- test. P<0.05 was considered statistically significant.

RESULTS There were no significant differences in mean age, weight, and duration of anaesthesia and surgery between either group (Table 1). All children with renal failure received supplements of vitamins, iron and calcium; seven out of 16 children with renal failure received calcium antagonists, five of 16 angiotensin-converting-enzyme- inhibitors, and three of 16 received beta-blocking agents. The main preoperative laboratory data of the children with renal failure are given in table 2.

TABLE 1 Patient characteristics.

Non-RF group RF group

(n = 14) (n-16)

Age (months) 54(40) [9-156] 55 (56) [9-172]

Weight (kg) 15.5 (8) [6 9-29 8] 144(9) [5 1-32 3]

Duration of anaesthesia (mm) 94 (48) [38-218] 91 (52) [46-240]

Duration of surgery (mm) 70 (50) [20-194] 70 (51) [37-213]

Data are mean (SD) [range]

TABLE 2 Laboratory data (and normal values) of children with renal failure.

Normal values preoperative values

Serum creatinine (30-90 pmol L ') 496 (204) [230-906]

Serum urea (3 0-7 0 mmol L ') 19.6 (7.9) [9.9-31 6]

Serum potassium (3 4-4.8 mmol L ') 4 7 (0.7) [3 5-5 8]

Haemoglobin (6 0-9.0 mmol L ') 6.8 (1 4) [4.4-8 9]

Albumin (37-53 g L ') 36 1 (6 1) [24-46]

Data are mean (SD) [range]

44 Table 3 summarizes the neuromuscular responses to 0.3 mg kg1 of rocuronium. The onset time was longer in children with renal failure (139 s, SD = 71) than in control children (87 s, SD = 43) (Ρ = 0.02). A 100 % block was achieved in five of 16 children with renal failure versus seven of 14 children without renal failure. In one patient in each group the maximum block was less than 75%. There were no significant differences in the mean recovery times and the recovery index between children without renal failure and 15 out of 16 children with renal failure. However, in one 9-month infant with renal failure, weighing 5.1 kg, the time to recovery of T1 to 25% of baseline was more than 45 min and, since surgery was ended, neostigmine 20 μg kg1 was given with recovery to a TOF ratio of 0.7 in 4 min

TABLE 3 Responses to rocuronium 0 3 mg kg1 in patients with and without renal failure

Non- RF group RF group

(n=14) (n=15)

Onset time (s) 87 3 (43) [30-150] 139 (71) [30-260]*

Maximum depression of T1 (%) 95 5 (13) [52-100] 91 9 (8) [71-100]

Time to 25% recovery of T1 (mm) 16 θ (4 4) [9-23] 15 1 (6 2) [9-31]

Time to 75% recovery of T1 (mm) 27 0(10 2) [10-52] 26 3 (9 2) [9 5-40]

Time to TOF ratio 0 7 29 4 (12 7) [11 5-54] 28 9(11 0) [10 5-48]

Recovery index (mm) 11 5 (6 1) [5-29 5] 12 2 (5 6) [4-24]

* P<0 05 Data are mean (SD) [range]

The interpatient variability in duration parameters was equally high in both groups. The mean final T1 response at the end of the study period was 109.5 (SD = 19.3) in the control group and 108.6 (SD = 11.3) in the renal failure group

DISCUSSION In the present study the onset time of rocuronium 0.3 mg kg1 was slower in the children with renal failure compared with the control. This may be related to a greater volume of distribution of rocuronium, possibly due to a decreased serum albumin. However, renal dialysis

45 was performed in 14 of 16 children the day before surgery and no overt signs of fluid overload were present in any child with renal failure Another possibility is that the cardiac medication, which many renal failure patients were taking, reduced the cardiac output leading to a prolongation of the onset times of neuromuscular blocking agents Although no difference in onset after a bolus of 0 6 mg kg 1 rocuronium in adults was observed between healthy and renal failure patients [1, 2], a delayed onset and a slight resistance to vecuronium and tubocuranne has been reported in renal failure patients [5] This slowing of the onset time of rocuronium in renal failure children may have clinical consequences It has been proposed that rocuronium may be used in the rapid sequence induction of anaesthesia technique [6] If rocuronium is likely to have a slower onset time in renal failure children, then a higher dose of relaxant might be needed to produce a rapid onset time This will then lead to an increase in the duration of the neuromuscular block produced by the higher dose of rocuronium

There was no difference m the duration of action of rocuronium 0 3 mg kg1 between the two groups This lack of difference in duration of action between children with and without renal failure is not completely unexpected since, after a single bolus injection, the duration of action of most non-depolarizing muscle relaxants is related more to redistribution than elimination Furthermore, biliary elimination of rocuronium is more important than renal elimination In adults some controversy remains in the literature regarding the effect of chronic renal failure on the clearance and duration of action of rocuronium One study reported that the clearance of rocuronium Is not affected by renal failure in adults [3], but this study was performed in patients receiving kidney transplants where the elimination of rocuronium by the newly transplanted kidney may have confounded the responses Another study [2] showed an important decrease in rocuronium clearance after a dose of 0 6 mg kg1 in patients with renal failure and concluded that the effects of a bolus dose of rocuronium 0 6 mg kg1 may be prolonged in patients with renal failure This prolongation in the duration of action of rocuronium in renal failure patients was seen in another study [1] Therefore, we cannot conclude from our study that a higher or repeat dose of rocuronium in children with renal failure will not have a prolonged effect The contribution of renal elimination of rocuronium apparently increases with dosage In adult patients, up to 33% of the

46 administered dose of 1 mg kg1 rocuronium is excreted in the urine within 12-24 hours [7] and the renal excretion of rocuronium may be dose-dependent since the fraction of the rocuronium dose excreted in the urine was greater after 1 mg kg1 [7] than after 0.6 mg kg 1 [8]. We found a markedly profound prolongation of action of rocuronium in one small-for-dates 9-month old, 5 1 kg infant This was the youngest and smallest-for-date infant in both groups. This finding may just be the confirmation of an almost doubling of the duration of action after rocuronium 0 3 mg kg 1 during halothane anaesthesia in children younger than 2 years compared to older children [4]. What was noticeable in this infant was that when TOF ratio had recovered to 30%, the block was rapidly and completely reversed with neostigmine Despite considerable variability, the final twitch response in our study was near the baseline value indicating the validity of the acceleromyographic measurement method m children. We conclude that in children older than one year with endstage renal failure, the duration of action of a single bolus dose of rocuronium 0.3 mg kg 1 during halothane anaesthesia is not consistently prolonged, but the onset is slower than in healthy children.

47 REFERENCES. 1. Robertson EN, Onessen JJ, Bunschoten Ρ et al. Comparison of the pharmacodynamics of rocuronium in patients with and without renal failure Anesthesiol 1998, 89, A987 2. Cooper RA, Maddmeni VR, Mirakhur RK et al. Time course of neuromuscular effects and pharmacokinetics of rocuronium (ORG 9426) during isoflurane anaesthesia in patients with and without renal failure. Br J Anaesth 1993; 71: 222-226 3. Szenohradszky J, Fisher DM, Segredo V et al. Pharmacokinetics of rocuronium bromide (ORG 9426) in patients with normal renal function or patients undergoing cadaver renal transplantation Anesthesiol 1992; 77' 899-904 4 Dnessen JJ, Robertson EN, van Egmond J et al. The time-course of action and recovery of rocuronium 0.3 mg.kg 1 in infants and children during halothane anaesthesia measured with acceleromyometry. Ped Anesth 2000; 10.493-497 5. Hunter JM, Jones RS, Uttmg JE Companson of vecuronium, atracunum and tubocurarine in normal patients and in patients with no renal function Br J Anaesth 1984;56:941-950 6. Magorian T, Flannery KB, Miller RD. Comparison of rocuronium, succinylcholine, and vecuronium for rapid-sequence induction of anesthesia. Anesthesiol 1993; 79: 913-918 7. Wierda JMHK, Kleef UW, Lambalk LM et al. The pharmacodynamics and pharmacokinetics of ORG 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl. Can J Anaesth 1991;38:430-435 8. Van den Broek L, Wierda JMKH, Smeulers NJ et al. Clinical pharmacology of rocuronium. study of the time course of action, dose requirement, reversibility and pharmacokinetics J Clin Anesth 1994; 6: 288-296

48 CHAPTER VI

PHARMACOKINETICS AND PHARMACODYNAMICS OF ROCURONIUM IN PATIENTS WITH AND WITHOUT RENAL FAILURE

EN Robertson MB, ChB, FRCA, JJ Driessen, MD, PhD, LHDJ Booij, MD, PhD.

Part of this study was presented in Orlando, USA, at the ASA meeting on 21 st October 1998. In Press (European Journal of Anaesthesiology); Reproduced with kind permission of the European Academy of Anaesthesiology.

SUMMARY Background and aim: This study clarifies the relationship between the neuromuscular blocking effects of rocuronium 0.6 mg kg 1 and its pharmacokinetics in patients with renal failure. Methods: Seventeen healthy and 17 patients with renal failure were studied under propofol anaesthesia in this prospective open label study. Rocuronium 0.6 mg kg'1 was given after induction of anaesthesia. The train-of-four mechanomyographic response of the thumb after supramaximal stimulation of the ulnar nerve at 2 Hz every 12 s was measured. Venous blood samples (4mL) were obtained 0, 2, 4, 7, 10, 15, 20, 30, 60, 120, 180, 240 and 360 min after relaxant administration. Samples were centrifuged, separated, and stored at - 20oC until plasma levels of rocuronium and its metabolites were measured. Two and three-exponential equations were used to describe the pharmacokinetic data in each group and these were compared to each other using the Wilcoxon rank-sum test, as was the pharmacodynamic data. P<0.05 was significant. Results: Onset of block was similar in both groups. Clinical duration and the time to recovery of the train-of-four to 70% were prolonged in the renal failure group compared to control; 49 vs. 32 min

49 (P<0.004, 95% ci of 17 min, difference 5-28) and 88 vs. 55 min (P<0.001, ci of 33 min, difference 17-50) respectively. Clearance of rocuronium was reduced by 39% in the renal failure patients compared to control, with an 84% increase in the mean residence time. The volume of distribution was unaffected by renal failure. Conclusion: The duration of action of a bolus dose of 0.6 mg kg1 rocuronium is increased significantly in patients with end-stage renal failure compared to healthy controls. This increase may be due to a decreased clearance of rocuronium, the disease process causing the renal failure and/or the medication, which patients with renal failure need in their treatment.

INTRODUCTION Rocuronium is commonly used during anaesthesia [1-3]. Although up to 33% of the administered dose of rocuronium is excreted in urine within 12-24 h [4], it is not dependent on renal blood flow for its major route of excretion but is taken up in the liver and excreted in the bile. Rocuronium should be used with caution and with neuromuscular monitoring in patients with advanced renal and/or hepatic disease [5,6]. The putative metabolite of rocuronium, 17-desacetylrocuronium, is not as active as the metabolite of vecuronium and has approximately 5% of the neuromuscular blocking potency of rocuronium [2]. Previous studies of rocuronium in patients with renal failure have not consistently demonstrated an effect of renal failure on the pharmacokinetics and pharmacodynamics of rocuronium [7,8] although Cooper [6] did demonstrate a decrease in the clearance of rocuronium in renal failure. A prolongation in the duration of action of rocuronium was not found. This may be due to the small number of patients in the study (nine patients). No other study [5,7] has demonstrated either an increase in the duration of action of rocuronium or an alteration in the clearance of rocuronium in patients with renal failure compared to control patients. All of these studies [5- 7] were performed with isoflurane as the main anaesthetic agent. This might have made their results more difficult to interpret since isoflurane is known to potentiate non-depolarizing neuromuscular blockade.

The aim of this study is to compare the pharmacokinetics and pharmacodynamics of a bolus dose of rocuronium under standardized

50 conditions, without inhalation anaesthesia, in patients with and without renal failure.

METHOD Subjects: After ethical committee approval and written informed consent, 34 patients aged 18-65 yr were included in this open label, non-randomized, parallel group Phase 3 study. Sixteen patients had a creatinine clearance of <10 mL min"1, one patient had a creatinine clearance of <15 mL min"1. They were scheduled for nephrectomy, arteriovenous shunt surgery or removal/implantation of a peritoneal dialysis catheter. All these patients were dialyzed the day before surgery. A control group consisted of 17 healthy patients who were scheduled for general surgery and had normal renal function. Exclusion criteria included pregnancy, neuromuscular disease, weight <85% or >130% of ideal body weight or allergy to any anaesthetic agents. Table 1 Medicines taken by renal failure group * Pt 21 was removed from further analysis because of the effect of valproate on the pharmacokinetic and pharmacodynamic values

Piricnr Number Mediations 2 Insulin, I crrous Sulplnte, C aptopril, ( .ilciuni, I ruscmitlc

1 Xmitrvpulim., rriisuiudc, ( apropnl, Vmlodipnu, Insulin 4 Vrcnolol, ( .iluum, I crrous Sulphaic, Multiurimms 5 Prednisolone, ( \closponnc, \tcnolol, ( .ipropnl, 1 ruscmidc, ( iltium, I ruhiopoutin 6 Prednisolone, Xrenolol, Nifedipine, ( .ileium, I nihropoeinn 9 raisemiele, ( ilcmm, I enrous Sulphate, I η tliropoeitin, /eiolit, 1 jsinopnl 11) Sotilol, 1 ruscmidc, Minoxidil 19 1 ruscmidc, ( .tlcium, \lenolol, Snllmumo], Sodium Bie.irhomic 20 \renolol, Multninmins, 1 crrous Sulphate, I nalnpnl 21 Sodium Yalpmarc, Primidone*, Metoprolol, ( alcium, 1 crrous Sulphate 22 Insulin, Nitedipine, Mcloprolol, ( aptopnl, I crrous Sulphate, ( ilcium 21 tenolol, I crrous Sulphate, ( alcium 24 I ruse miele, ( alcium. Insulin, ( aptopnl, ( alcium, \tcnolol, I crrous Sulph lie M \rro\cni, Mulmitamins, I ruscmidc, (alcium, I nthropocmn, Thcoplnllinc, Gaxiscon 34 I nalapnl, \tcnolol. Prednisolone, C \elosporinc, I ruscmidc, 1 nthropocmn, I eirous Sulphate, ( allium IS Vtcnolol, 1 η throp()eitin, Sim\astatine', ( alcium V) MultiMiamins, Nitedipine, I ruscmidc, I nthropocmn, Mucol, lolbutamidc Medication: Medication drugs needed in the treatment of the renal failure patients (Table 1 ) were continued. Sixty minutes after oral premedication with 10-20 mg oxazepam, anaesthesia was induced

51 using 1 5-2 5 mg kg 1 propofol and 2-4 μg kg1 fentanyl intravenously (IV) Anaesthesia was maintained using propofol 6-12mg kg1 h1, nitrous oxide 60% in oxygen and supplemental fentanyl 50 μg as required Ventilation was with facemask, then via endotracheal tube that was inserted after relaxant administration, to maintain an end-tidal carbon dioxide concentration of 4 5-5 5 kPa Heart rate, non-invasive arterial pressure, oxygen saturation and temperature were monitored routinely Skin temperature over the adductor polhcis was kept above 320C by wrapping the arm in cotton wool Neuromuscular Monitoring: Neuromuscular monitoring was commenced after induction of anaesthesia using transcutaneous electrodes with supramaximal stimuli of 0 2 ms duration to the ulnar nerve at the wrist in a tram-of-four (TOF) mode every 12 s (Fischer and Paykel) The resultant force of contraction of the thumb was measured with a Statham force transducer (Gould, Ine , OH, Cleveland) and recorded on a polygraph A resting tension of 150- 300G was applied to the thumb After anaesthetic conditions and TOF were stable, usually around 10 mm, the single twitch (T1) mode of stimulation every 10 s was started and allowed to stabilise for 5-10 mm The duration of stabilization period was the same in both groups Rocuronium 0 6 mg kg 1 was then given as a bolus iv Neuromuscular transmission was recorded until T1 had returned to 25% then TOF mode started until recovery of the TOF was at least 70% If possible, recovery was allowed to occur spontaneously The following times were recorded from the end of injection of the relaxant onset time - time to maximum block, clinical duration - time to recovery of T1 to 25% (Dur 25), total duration - time to a TOF of 70% (Dur TOF70) The time from 25 to 75% twitch height recovery was also recorded (recovery time) Sampling: Venous blood samples (4 mL) were drawn from the patients before and at 2, 4, 7, 10, 15, 20, 30, 60, 120, 180, 240, and 360 minutes after rocuronium administration Samples were hepanmzed and stored in ice, then centnfuged within 4 h of sampling Each resultant millilitre of plasma was mixed with 0 2 mL 1 M 0 NaH2P04, and then stored at -20 C until analysis Analysis: Analysis of rocuronium and its putative metabolites, 17- desacetyl rocuronium and 16 N-desallyl-rocuromum was carried out

52 using high pressure liquid chromatography (HPLC) by a method described previously for vecuronium and validated for rocuromum and using 3,17-didesacetyl vecuronium as the internal standard After extraction of rocuromum and its metabolites from the sample, the compounds were separated by HPLC and the concentrations determined using fluorimetrie detection after post-column ion-pair extraction The assay accuracy, expressed as a percentage recovered of the added amount, over the range of 25-100 ng varied from -14 to +14% (depending on concentration, matrix and amount). The mean precision as indicated by the coefficients of variation from the intra-day variability and the recovery data was 6.8%, 6.8%, and 5.9% for rocuromum, 17-desacetyl-rocuronium and desallyl-rocuromum, respectively. The limit of quantification with a precision better than 15% was 10 ng mL1 for rocuromum and 20 ng mL1 for 17-desacetyl- rocuromum and desallyl-rocuromum [9]

PHARMACOKINETICS AND STATISTICS Plasma concentration vs time data were plotted for individual patients to both two- and three-exponential equations using a computer program for non-linear curve fitting (Multifit, JH Proost, University of Groningen, The Netherlands) allowing estimation of parameters of various compartimentai models using minimizing algorithms [10] These procedures and pharmacokinetic formulae have been derived from a previous study [11] The method has been validated using results from other programs. The appropriate model was determined for each patient using the F-test. The initial and elimination half-lives, plasma clearance Vc, Vdss and mean residence time (MRT) were summarized and the two groups compared with respect to the mam parameters using the Wilcoxon rank-sum test. Pharmacodynamic parameters were also analyzed. P<0.05 was considered significant.

RESULTS Patients: The patients in the two groups were similar in age, weight, height and sex distribution (Table 2) Seventeen patients were studied in each group Patients in the renal failure group frequently had quite severe pathology related to their renal disease, viz , hypertension, blindness, anaemia, diabetes mellitus, left ventricular hypertrophy, etc

53 Table 2 Physical and biochemical characteristics (mean (SD) [range]) of the two groups

Renal failure Normal renal function (n = 17) (n = 17)

Age, (yr) (13) [27-65] (11) [18-58] Weight, (kg) (1Θ) [60-124] (13) [59-102] Height, (cm) 174 (10) [155-195] 180 (10) [161-196] Sex, (M: F) 13:4 13 4

Urea, mmol L ' 29 1 [12 5-43 4] 4.8 [3 0-5 9]* Great, mmol L1 773 [505-1227] 84(65-100]*

Hb, mmol. L1 6.2 [4.9-7.5] 88[7.1-101]- Haematocrit 30 [20-34] 42 [34-49]*

Albumin, mmol L1 38 [28-43] 43 [35-52]

'Significant difference between groups They also tended to be on medication for their renal failure. This did not occur in the control group. Plasma electrolyte values were similar in both groups although three patients in the renal failure group had potassium levels above 5 mmol L'1 (range 5.1-5.8 mmol L1) Table 3 Characteristics of neuromuscular block. Mean (SD) [range] η = number of patients Onset time = time to maximum block, Dur 25 = time to recovery of twitch (T1 ) to 25% of control value, Dur75 = time to recovery of T1 to 75% of control value; DurTOF70 = Time to recovery of TOF to 70%. Times measured from the end of injection of rocuronium. Recovery rate = Time of recovery of T1 from 25-75%

Parameter η Renal failure Patients η Control Patients

Onset time (s) 16 137(130)[50-288] 17 116(64)[60-600]

Dur25 (mm) 16 49(21 )[23-109] 17 32(8)[20-46]*

DurTOF70 (mm) 13 88(26)[45-150] 16 54(14)[35-78]**

Recovery rate (mm) 16 19(7) 17 12(4)**

Plasma cone (ug L ') 13 770(191)[413-1031] 15 497(111 )[268-660]" at TOF of 70%

'Significant difference between groups; P< 0 004 ''Significant difference between groups; P<0.001

54 while no patient in the control group had such a level of potassium. Urea and creatinine plasma concentrations were higher in the renal patients compared to control, while haemoglobin and haematocrit were lower in the renal failure group compared to control.

Pharmacodynamics and pharmacokinetics: The onset time and duration of action of rocuronium are given in Table 3. One hundred percent block was achieved in all but one control patient who had 97% block. The clinical duration, total duration and recovery rate of rocuronium were all increased significantly in the renal failure group compared to the control group. No difference was seen in the onset time between groups or the depth of block. One patient (number 21) in the renal failure group had received sodium valproate for epilepsy. This caused a dramatic reduction of the depth and duration on the block produced by rocuronium and has been reported earlier [12]. This patient was therefore excluded from the pharmacodynamic and pharmacokinetic parts of this study. The analysis of the blood samples was for technical reasons impossible in one control patient and the pharmacokinetic analysis of this patient has been omitted. Figure 1 Individual plasma rocuronium concentration vs time in control patients

15000- _ 10000 - '_l E 5000 - σι c 2500 - υ e 8 loco - to 57 min ε 500- XìV^sUr^ t-w? (/) TO CL E .2 100 - f 50- --^W- ο ο CU 10- 100 200 300 400 Time (min)

55 One renal failure patient was later found to have a protocol violation but is included m the present analysis since no difference in the final conclusions is present if the intention-to-treat group is compared to the per-protocol group (181 cm tall, body weight 58 kg, limits >69<105 kg)

Figure 2 Individual plasma concentration vs time in renal failure patients

15000 η, _ 10000-1;

0 100 200 300 400 Time (mini

Due to the exceptionally long duration of action (>120 minutes) with respect to surgery time available, three patients in the renal failure group and one in the control group did not spontaneously reach a TOF of 70% and were antagonised with neostigmine and atropine.

Figures 1 and 2 show the individual plasma concentrations of rocuronium in the control and the renal failure group. Figure 3 shows the mean plasma concentrations of rocuronium in the same groups. The plasma concentrations of rocuronium in the renal failure group start to deviate from those of the control group 20 mm after relaxant administration

56 Figure 3 Mean (±SE) plasma rocuronium concentrations vs time curves m control (n=16) and renal failure patients (n=16) Curves significantly different after 20 minutes

10000

Renal failure

Control 10 -1 100 200 300 400 Time (min)

Table 4 shows the main pharmacokinetic variables of rocuronium calculated with a two-compartment model. The clearance of rocuronium in the renal failure group is lower than in the control group (P<0.0001), There is also a slightly prolonged elimination half-life of 70 ± 23 min vs. 57 ± 17 min, and a significantly increased MRT of 83 ± 26 min vs. 45 ± 11 min, respectively (P<0.0001 ) in the renal failure group compared to the control group. In patients with renal failure, the following differences were seen compared to the control group using the 2-compartment model (16 patients in each group): Clearance decreased by 39% (P<0.0001); distribution clearance increased by 123% (P<0.007); and MRT increased by 84% (P<0.0001). Renal failure did not appear to influence the volume of distribution. The individual curves were fitted by a two- and a three-compartment model. In both groups, for 7 out of 16 patients, the three-compartment model fitted better than the two-compartment model. If the differences between the two- and three-compartment models are large, then a clear difference in the plasma concentration-time profiles must be observed.

57 Table 4 Main pharmacokinetic variables found in the two-compartment model (mean (SD) [range]) V, = volume of the central compartment, Vss= Volume of distribution at steady state, t, ^,, t, 2(21 = half lives of the first and second exponential phases, CI = plasma clearance, CL,2= Distribution clearance to the 2nd compartment, MRT = mean residence time N=16

Parameter Renal Failure patients Control patients

CI ml kg 'mm ' 2 7(0 7)[1 6-4 3] 4 5(1 2)[31-6 7]"

CL12ml kg 'mm ' 5 4(3 4)[1 2-13 7] 2 4(1)[1-5]*

V, ml kg' 88(30)[41-153] 84(14)[58-108]

V5S ml kg ' 220(77)[113-380] 194(45)[121-297]

t, 2(1| mm 6 5(3)[2 2-12] 7 8(1 8)[4 8-10 8]

t, 2I2) mm 70(23)[43-122] 57(17)[38-89]

MRT mm 83(26)[50-142] 45(11)[30-68]**

"Significant difference between groups, P<0 0001 * Significant difference between groups, P<0 007

This was not seen and so the analysis of the two-compartment model only is presented. Metabolite kinetics: In most patients, low concentrations (1% of rocuronium) of the 17-desacetyl metabolite of rocuronium were found in the early samples. These concentrations fell within 20 min to below the limit of quantification. It was not possible to conclude that the metabolite was formed by metabolism or was simply due to the presence of small amounts of the metabolite in the ampoules.

DISCUSSION This is the first study that clearly shows both an alteration in the pharmacokinetics of rocuronium in renal failure patients and an increase in the duration of action of a bolus dose of rocuronium 0.6 mg kg1. The pharmacodynamic values for the control group are similar to previously reported values, so this increase in the duration of action in renal failure patients is likely to be due to the renal failure, its treatment and/or its altered pharmacokinetics.

58 It was notable that three patients in the renal failure group did not recover spontaneously to a TOF of 70% Indeed, two patients had still not recovered sufficiently even after 140 mm at which time the block was antagonised with neostigmine, when recovery was rapid and complete This study was performed under propofol anaesthesia that does not tend to potentiate neuromuscular blocking agents If one of the inhalation agents had been used it would be expected that this prolonged effect of rocuromum might be seen more often

Although the volume of distribution (Vss) and the volume of the central compartment (V,) are unaltered between the two groups, there is a 39% decrease in clearance (CI) in the renal failure group Distribution clearance (Cl12) is increased by 123% and mean residence time (MRT) increased by 84% in the renal group compared to control The pharmacokinetic results obtained in the present study agree well with the data reported by Cooper and colleagues [6] The present study shows a somewhat higher clearance and a shorter MRT and terminal half-life in both control and renal failure groups When comparing the renal failure patients to controls, however, similar differences are seen in both studies Cooper and colleagues were unable to demonstrate an increase in the duration of action of rocuromum despite finding the decreased clearance This was probably due to the small number of patients or the fact that isoflurane was used as the anaesthetic Szenohradszky and colleagues [7] failed to demonstrate any alteration in the clearance of rocuromum between patients with renal failure and healthy controls but did show an increase in the volume of distribution at steady state, which led to an increase in the elimination half-life in renal failure patients The renal patients in the study by Szenohradszky and colleagues, however, were undergoing renal transplantation This may have altered the elimination characteristics of rocuromum The study by McCoy and colleagues [13] has similar pharmacokinetic values as the present study for the control group

Wierda and colleagues [3] reported that 33% of a rocuromum dose of 1 mg kg1 is excreted into urine of normal patients At a dose of 0 6 mg kg1, Van den Broek and colleagues [14] found 12-22% of the dose excreted in urine, suggesting a dose-dependent renal excretion of rocuromum Although hepatic uptake and biliary elimination are thought to be the mam routes of elimination for rocuromum [15], it does appear that renal failure does have a marked effect on rocuromum pharmacokinetics and pharmacodynamics The hepatic route of excretion is both variable and rate limited and may be less

59 important at the higher doses of rocuronium. Whether these two factors are directly related is not within the remit of this study. Many medicines that the renal failure patients are taking may have some effect on the neuromuscular block. Indeed, patient 21 was removed from the analysis because the alteration in the rocuronium-induced block was so abnormal that they were reported elsewhere [12]. In children with renal failure, the duration of action of a bolus dose of 0.3 mg kg1 rocuronium is not prolonged compared to healthy children [16]. This may also suggest that renal excretion of rocuronium is dose dependent. Perhaps if a lower dose of rocuronium is used in adult renal failure patients there may be little or no increase in the duration of action of rocuronium compared to healthy adults. On the other hand, the disease process in children is less well established as in the adults of the present study. Perhaps years of dialysis, drug therapy, disease and age will convert these children to adults where the duration of action of rocuronium will be prolonged compared to control. The higher concentration of rocuronium present in the renal failure group at a TOF of 70% has also been reported earlier [6]. This may be due to an altered sensitivity of the receptors in the renal failure patients. Another possibility is that non-specific rocuronium sites are saturated with endogenous compounds thus causing an increase in the plasma concentration and limiting redistribution. This effect could be caused by the high urea, concurrent medication, electrolyte imbalance or the original disease process itself e.g., diabetes, hypertension etc. In conclusion the duration of action of rocuronium is markedly increased in patients with reduced renal function. The clearance of rocuronium is also reduced in renal failure. The cause of these changes is not clear.

60 REFERENCES 1 Mirakhur RK, Cooper R, McCarthy G, Elliot Ρ Comparison of the intubating conditions and some neuromuscular effects following administration ol Org 9426 and succmylcholme Anesth Analg 1992,74 S210 2 Mirakhur RK Safety aspects on non-depolarizing neuromuscular blocking agents with special reference to rocuronium bromide Eur J Anaesthesiol 1994,11(suppl 9) 133 140 3 Wierda JMHK, Kleef UW, Lambalk LM, Kloppenburg WD, Agoston S The pharmacodynamics and pharmacokinetics of Org 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl Can J Anaesth 1991, 38 430- 435 4 Wierda JMKH, Proost JH, Schiere S, Hommes FDM Pharmacokinetics and pharmacokinetic/dynamic relationship of rocuronium bromide in humans Eur J Anaesthesiol 1994,11 66-74 5 Khuenl-Brady KS, Pomaroli A, Puhrmger F, Mitterschiffthaler G, Koller J The use of rocuronium in patients with chronic renal failure Anaesthesia 1993, 48 873-875 6 Cooper RA, Maddinem VR, Mirakhur RK, Wierda JMHK, Brady M, Fitzpatrick KTJ Time course of neuromuscular effects and pharmacokinetics of rocuronium bromide during isoflurane anaesthesia in patients with and without renal failure Br J Anaesth 1993, 71 222-226 7 Szenohradszky J, Fisher DM, Segredo V, Caldwell JE, Bragg P, Sharma ML, Gruenke LD Miller RD Pharmacokinetics of rocuronium bromide in patients with normal renal function or patients undergoing cadaver renal transplantation Anesthesiol 1992, 77 899-904 8 Cooper AR, Wierda JMKH, Mirakhur RK, Maddinem VR Pharmacodynamics and pharmacokinetics ot rocuronium bromide in patients with and without renal failure Eur J Anaesthesiol 1994,11(suppl 9) 82 84 9 Kleef UW, Proost JH, Roggeveld J, Wierda JMKH Determination of rocuronium and its putative metabolites in body fluids and tissue homogenates J Chromatogr 1993, 621, 65-76 10 Press WH, Flannery BP, Teukolsky SA, Vetterlmg WT Eds, Numerical Recipes Cambridge Cambridge University Press, 1986 11 Wagner JG Fundamentals of Clinical Pharmacokinetics Hamilton Drug Intelligence Publications, 1975 12 Dnessen JJ, Robertson EN, BOOIJ LHDJ, Vree TB Accelerated recovery and disposition from rocuronium in an end stage renal failure patient on chronic anticonvulsant therapy with sodium valproate and primidone Br J Anaesth 1998, 80 386-388 13 McCoy EP, Mirakhur RK, Maddinem VR, Wierda JMKH, Proost JH Pharmacokinetics of rocuronium after bolus and continuous infusion during halothane anaesthesia Br J Anaesth 1996, 76 29-33 14 Van den Broek L, Wierda JMKH, Smeulers NJ, Van Santen GJ Ledere MGL, Hennis PJ Clinical pharmacology of rocuronium study of the time course of action, dose requirement, reversibility and pharmacokinetics J Clin Anesth 1994, 6 288-296 15 Kheunl-Brady K, Castagnoli KP, Canfell PC, Caldwell JE, Agoston S, Miller RD The neuromuscular blocking effects and pharmacokinetics of Org 9426 and Org 9616 in the cat Anesthesiol 1990, 72, 669 674 16 Dnessen JJ, Robertson EN, Van Egmond J, Booij LHDJ Time-course of action of rocuronium 0 3 mg kg1 in children with and without endstage renal failure Ped Anesth 2002,12, 507-510

ACKNOWLEDGEMENTS J.H. Proost and J.M.K.H. Wierda are thanked for the rocuronium assays and analysis at the Pharmacology Department of the University of Groningen, The Netherlands. Thanks are also extended to Dr.Tom Vree for help with the figures. This study was supported financially by Organon Teknika, Belgium.

61 62 CHAPTER VII

PHARMACODYNAMICS OF ROCURONIUM 0.3 MG KG 1 IN ADULT PATIENTS WITH AND WITHOUT RENAL FAILURE

EN Robertson MB, ChB, FRCA, JJ Dnessen, MD, PhD, M Vogt, H de Boer MD, GJ Scheffer, PhD

Submitted for publication to the European Journal of Anaesthesiology

SUMMARY Background and aim: The neuromuscular effects of a bolus dose of rocuromum 0 6 mg kg 1 under propofol anaesthesia in renal failure patients are prolonged compared to healthy control patients The present study aims to describe the neuromuscular effects of 0 3 mg kg 1 rocuromum under propofol anaesthesia in patients with renal failure and to compare these effects with healthy control patients Methods: With institutional approval and informed consent, 18 healthy patients and 18 patients with renal failure took part in this prospective open label study All the patients were undergoing surgery where muscle relaxants were needed The renal failure patients were undergoing either renal transplantation or insertion of shunt Rocuromum 0 3 mg kg 1 was given intravenously after induction of anaesthesia with propofol 1-2 mg kg1 and fentanyl 2 μg kg1 Propofol 6-12 mg ' kg1 h1 was used for maintenance of anaesthesia Four acceleromyographic responses of the thumb after supramaximal stimulation of the ulnar nerve using surface electrodes at 2Hz every 15 s were measured and recorded The onset time, the time to recovery of the first twitch to 25% recovery and the time to a tram-of- four ratio of 0 7 were all recorded Wilcoxon rank-sum testing was used to compare the pharmacodynamics and to see if medication, gender or electrolytes influenced duration of the block P<0 05 was considered significant

63 Results: No statistical differences were seen in the neuromuscular blocking effects of rocuromum between the two groups but there was a significant difference in the variability of the total duration of the block. Conclusions: Rocuromum 0 3 mg kg1 is suitable for use in patients with renal failure when endotracheal intubation and neuromuscular block for a short period of time are needed Tracheal intubation is facilitated within four minutes and the block can be antagonized within 20 minutes.

INTRODUCTION During propofol-based anaesthesia, in patients with renal failure, rocuromum 0.6 mg kg1 has an increased duration of action compared to healthy control patients [1] This increase in the duration of action in renal failure patients is thought to be due to the renal failure, its treatment and/or its altered pharmacokinetics Previously published studies [2-4] comparing rocuromum 0.6 mg kg 1 in renal failure and healthy patients did not show any significant difference m the neuromuscular effects between the two groups of the administered rocuromum However, these studies were performed under isoflurane anaesthesia, which is known to potentiate neuromuscular block Another study [5] demonstrated, using acceleromyography, that the duration of action of rocuromum 0.3 kg kg1 in children with renal failure is not increased compared to healthy children There is a reduction in the onset time in the children with renal failure This study was performed under halothane anaesthesia, which has less effect on neuromuscular blocking agents than the other mhalational agents. No studies have been published comparing the pharmacodynamics of rocuromum 0.3 mg kg ' in renal failure and healthy patients under intravenous (iv) anaesthesia. The aim of the present study is to compare the neuromuscular effects, using acceleromyography, under iv anaesthesia, of a bolus dose of 0 3 mg kg 1 of rocuromum in adult patients with and without renal failure. The usefulness of this lower dose of rocuromum for surgery where tracheal intubation and neuromuscular blockade are needed for short periods is assessed.

64 PATIENTS AND METHODS Subjects: After institutional approval and informed consent from the patient, 36 adults aged 18-65 yr were included in this open label, non randomized, parallel group Phase 4 study. All the renal failure patients had a preoperative creatinine clearance of <10 ml min"1. All but one of the renal failure patients were scheduled for renal transplantation. These patients were dialysed the day before surgery. A control group of 18 healthy patients scheduled for general surgery requiring muscle relaxation and having normal renal function were used to compare the neuromuscular effects of the administered rocuronium. Exclusion criteria included pregnancy, neuromuscular disease, obesity (weight >130% of ideal body weight) or allergy to any anaesthetic agents. Medication: Medication for essential therapy of the renal failure patients was continued and noted. Sixty minutes after oral premedication with 10-20 mg oxazepam, anaesthesia was induced using 1.5-2.5 mg kg'1 propofol and 2-4 μg kg"1 fentanyi iv. Anaesthesia was maintained using propofol 6-12 mg kg1 h 1, nitrous oxide 60% in oxygen and supplemental fentanyi 50 μg as required. Ventilation was with facemask then via endotracheal tube that was inserted at maximum neuromuscular block after relaxant administration. End tidal carbon dioxide was maintained at 4.5-5.5 kPa. Heart rate, NIBP, oxygen saturation and temperature were monitored routinely. Skin temperature over the adductor pollicis was kept above 320C by wrapping the arm in cotton wool and the use of forced air warming. Neuromuscular Monitoring: Neuromuscular monitoring was commenced immediately after induction of anaesthesia and before administration of muscle relaxant, using skin electrodes with supramaximal stimuli of 0.2 ms duration to the ulnar nerve at the wrist in atrain-of-four (TOF) mode every 15 s (TOF-Watch"or TOF-Guard", Organon, Oss, The Netherlands). The resultant movement of the thumb was measured acceleromyographically and recorded. After anaesthetic conditions and TOF were stable, usually around 5-10 min after induction of anaesthesia, rocuronium 0.3 mg kg'1 was given as a bolus iv. If possible, recovery was allowed to occur spontaneously to a TOF of 70%, however if the surgery required more muscle relaxation, additional rocuronium was given as needed. The following times were recorded from the end of injection of the relaxant: onset

65 time - time to maximum block, clinical duration - time to recovery of T1 to 25% (Duration 25), total duration - time to a TOF of 70% The initial TOF ratio and the maximum T1 block achieved were also recorded Statistical analysis The pharmacodynamic variables, initial TOF, onset time, maximum block, time to a T1 recovery of 25% and recovery to a TOF of 70% were compared using the Wilcoxon rank- sum test This was also performed to determine if any individual medication or medication combinations, gender or biochemistry might have led to an alteration in the duration of action of the given rocuronium in the renal failure patients Student's t test was used to see if the variation in the duration of action between the two groups was comparable P<0 05 was considered statistically significant

RESULTS All the patients for renal transplantation received methylpredmsolone 100 mg and Cephtazidim 2000 mg before the administration of rocuronium Table 1 lists the medications that the renal failure patients were receiving before surgery Table 2 lists the mam laboratory values of the renal failure patients and the mean age, weight and height m both groups Blood testing was not routinely performed as part of the study but in some of the control patients biochemical and haematological values were available and these are also shown in Table 2 Table 3 lists the mam neuromuscular responses to rocuronium 0 3 mg kg 1 in both groups There was no statistical difference in any of the parameters Some recovery values were not available in both groups often when more surgical relaxation was needed before the TOF was 70% Two patients m each group did not achieve a 75% block The initial TOF ratio was 108 and 104 in the control and renal failure groups, respectively There was no statistical difference in the duration of action of rocuronium between the two groups The variation in the DurTOF70 was, however, significantly different between the two groups (P<0 00001)

66 Table 1 Medicines taken by renal failure group of patients receiving 0 3 mg kg ' rocuromum

Patient Medications Number

1 Frusemide, Nifedipine, Losartan, Metoprolol, Simvastatine, Calcium, Seveiamer, Sennapod, Lactulose

2 Ferrofumarate, Vitamins, Seveiamer, Calcium, Enalapnl

3 Simvastatine, Nifedipine, Frusemide, Ascal, Multivitamins

4 Ferrofumarate, Fosinopril, Losartan, Folic acid, Amlodipine, Metoprolol, Simvastatine, Frusemide

5 Diltiazem, Frusemide, Zopiclon, Oxazepam, Simvastatine,

6 Vit C, Metoprolol, Simvastatine, Omeprazol, Amlodipine, Hydrokinine, Ferrofumarate, Lisinopril

7 Erythropoeitm, Amlodipine, Metoprolol, Calcium, Loratadine, Vitamins

θ Metoprolol, Amlodipine, Dihydrotachysterol, Calcium, Ferrofumarate, Erythropoeitm, Vit Β

9 Omeprazol, Lisinopril, Erythropoeitm, Multivitamins, Ferrous Sulphate, Etalpha, Calcium

10 Resomum, Metoprolol, Losartan

11 Metoprolol, Simvastatine, Doxazosme, Vitamins

12 Metoprolol, Simvastatine, Doxazosme, Phosphate, Vitamins

13 Bumetamide, Movicolon, Nebivolol, Erythropoeitm, Seveiamer, Vitamins

14 Erythropoeitm, Mirtazapme, Frusemide, Enalapril, Calcium

15 Temazepam, Enalapril, Metoprolol, Ca Carbonate, Omeprazol

16 Vitamins, Calcium, Frusemide

17 Metoprolol, Ascal, Ferrofumarate, Alfacalcidol, Atenolol, Vit D, Seveiamer, Amlodipine

18 Calcium, Doxazosme, Erythropoeitm, Nebivolol, Esomeprazol, Metoclopramide, Lisinopril

67 Table 2 Physical characteristics (mean (SD) [range]) of the two groups. Ν = number of patients = 18 unless otherwise stated. The main biochemical and haematology values are presented. * = Statistical difference between groups, P<0.001

Renal failure patients Control patients

Age, yr 44.8(13.1 )[21 -63] 42.6(12)[20-63] Weight, kg 71.8(11 7)[53-99] 78(12.8)[54-105] Height, cm 171 (9.9)[154-187] 176(12.1 )[156-192] Sex, M/F 10M/8F 10M/8F

Urea, m mol L1 22.9(8.8)[7-48.5] 4.4(0 5)[3 7-5] N=5* Great, m mol L1 793(256)[435-1170] 78(9.3)[66-90] N=7* Κ, mmol L1 4.2(0 5)[3-5.1] 3.8(0.2)[3.6-4.3] N=7 Hb, mmol L' 7.5(0.7)[6.4-9.1] 8.8(0.9)[7.5-9.9] N=9* Ht 37.3(3.6)[31-45] 42.4(3 8)[37-49] N=9* Ca, m mol L1 2.5(0.3)[2 2-3.3] 2 3(0.9) N=2

Table 3 Characteristics of neuromuscular block after rocuronium 0 3 mg kg '. Median [range]. Ν = number of patients. Onset time = time to maximum block; Dur25 = time to recovery of twitch (T1 ) to 25% of control value; DurTOF70 = Time to recovery of TOF to 70%. Times measured from the end of injection of rocuronium There are no differences between the groups.

Parameter Ν Renal failure patients Ν Control patients

Onset time (min) 17 4.25[0.7-7 7] 18 4.5[1-6.3]

Dur25 (min) 14 8.6[0-33.5] 15 11.4(0-24.3)

DurTOF70 (mm) 17 26[11.5-94.2] 18 26.1[19-40.1]

Max block (%) 18 85[50-100] 18 91 [49-100]

68 DISCUSSION The most noticeable finding in this study is the wide range of the duration of action of rocuromum in the patients with renal failure The time to recovery of the TOF to 70% ranged in the renal failure group, after 0 3 mg kg 1 rocuromum, from 11 to almost 95 minutes Three patients in the renal failure group had prolonged (87-95 mm) durations of action compared to the other patients in their group (11-49 mm) In the control group there was much less spread in the duration of action within the group (range 17- 40 mm) This difference in spread was highly statistically (and possibly clinically) significant P<0 00001) between the two groups The given rocuromum had, in most patients, a clinical duration of action of 7-15 mm Both groups of patients had median onset times of 4-5 mm and a depth of block of 85-90% after 0 3 mg kg1 rocuromum These are similar to values found in previous studies [6] where mechanomyograph recordings were used Eriksson in an Editorial in Anesthesiology has suggested that it is time that quantitative assessment of neuromuscular block be routine, or even mandatory, when non-depolarizing neuromuscular blocking agents are used [7] Kopman and colleagues have questioned this suggestion [8] and suggest that counting the number of twitches (at least two) after TOF stimulation with a nerve stimulator before antagonism with neostigmine is sufficient to avoid problems in the recovery room In renal failure patients perhaps the suggestion of Eriksson might be more relevant since the variation in the duration of action of rocuromum is so great Both these suggestions are, however, valid since a TOF count of two confirms that reversal is likely to succeed, and quantitative monitoring confirms that reversal has or has not been successful It is still not certain however, which TOF ratio is satisfactory to assume adequate reversal using acceleromyography A TOF of 90% is perhaps needed to assume adequate reversal although it was not an aim of this study to define this Acceleromyographic monitoring was, however, easy to set up in this study in the clinical setting and does appear to provide useful information

Rocuromum 0 3 mg kg 1 provided satisfactory intubating conditions in all 36 patients even though several patients did not achieve 75% block Other studies have demonstrated that 0 3 mg kg1 rocuromum allows satisfactory intubating conditions in both children and adults [9- 11] In the present study, the onset time was around four minutes

69 Thus this dose can be used in elective situations where tracheal intubation is required. Even in the patients with renal failure who had a prolonged neuromuscular block (>85 mm), this study suggests that 20 minutes after rocuromum administration, the block can be easily antagonized with neostigmine since the TOF count was greater than two after 20 mm in all the patients. Many drugs that patients use can alter the neuromuscular block induced by non-depolarizing neuromuscular blocking agents For example, frusemide and manmtol administered mtraoperatively potentiate the effects of d-tubocurarme [12] and verapamil potentiates pancuronium and suxamethonium induced neuromuscular block [13] Many of the renal failure patients m this study were taking combinations of frusemide, beta-blockers and calcium channel blockers. Seventeen of the 18 patients in the present study received methylpredmsolone for the renal transplantation Acute steroid therapy has been shown to potentiate neuromuscular block [14] There was, however, no evidence of potentiation of the neuromuscular block by steroids or any other drug in the present study. A significant prolongation in the mean duration of block is seen in the renal failure group of patients compared to control group after 0 6 mg kg1 rocuromum [1] under iv anaesthesia This was not seen in the present study with 0.3 mg kg1 rocuromum under the same anaesthetic technique. Most of the recovery of this smaller dose of rocuromum is due to distribution of the rocuromum to binding sites, while with the larger dose, elimination plays a greater role This may explain why there is no difference m the duration of action of rocuromum with the smaller dose In conclusion, rocuromum 0.3 mg kg1 is a useful dose of rocuromum in patients with renal failure when short periods of neuromuscular blockade are required. This study highlights the role, under propofol anaesthesia, of this lower dose of rocuromum in achieving elective endotracheal intubation in patients with renal failure With this lower dose of rocuromum, the neuromuscular block produced can be antagonized within 20 minutes

70 REFERENCES 1. Robertson EN, Dnessen JJ, BOOIJ LHDJ Pharmacokinetics and pharmacodynamics of rocuronium m patients with and without renal failure. Eur J Anaesthiol 2004; in press 2. Khuenl-Brady KS, Pomaroli A, Puhringer F, Mitterschiffthaler G, Koller J. The use of rocuronium in patients with chronic renal failure. Anaesthesia 1993; 48:873-875 3. Cooper RA, Maddmeni VR, Mirakhur RK, Wierda JMHK, Brady M, Fitzpatrick KTJ. Time course of neuromuscular effects and pharmacokinetics of rocuronium bromide during isoflurane anaesthesia in patients with and without renal failure. Br J Anaesth 1993;71:222-226 4. Szenohradsazky J, Fisher DM, Segredo V, Caldwell JE, Bragg P, Sharma ML, Gruenke LD, Miller RD. Pharmacokinetics of rocuronium bromide in patients with normal renal function or patients undergoing cadaver renal transplantation Anesthesiol 1992; 77' 899-904 5. Dnessen JJ, Robertson EN, Van Egmond J, Booij LHDJ. Time-course of action of rocuronium 0.3 mg kg"1 in children with and without endstage renal failure Ped Anesth 2002;12:507-510 6. Lambalk LM, de Wit APM, Wierda JMKH, Hennis PJ, Agoston S Dose-response relationship and time course of action of Org 9426 Anaesthesia 1991 ; 46: 907-911 7. Eriksson LI. Evidence-based practice and neuromuscular monitoring and residual curanzation: it's time for routine quantitative assessment. Anesthesiol 2003; 98: 1037-1039 8. Kopman AF, Zank LM, Ng J, Neumann GG. Antagonism of cisatracurium and rocuronium block at a tactile train-of-four count of 2: Should quantitative assessment of neuromuscular function be mandatory? Anesth Analg 2004; 98.102-106 9. Barclay K, Eggers K, Asai T. Low-dose rocuronium improves conditions for tracheal intubation after induction of anaesthesia with propofol and alfentaml. Br J Anaesth 1997,78:92-94 10. Prien T, Zahn Ρ, Menges M, Brussel T. 1 χ ED90 dose of rocuronium bromide, tracheal intubation conditions and time-course of action. Eur J Anaesthesin Suppl 1995,11:85-90 11. Eikermann M, Renzmg-Kohler K, Peters J. Probability of acceptable intubation conditions with low dose rocuronium during light sevoflurane anaesthesia in children Acta Anaesthesiol Scand 2001 ; 45.1036-1041 12. Miller RN, Sohn YJ, Matteo RS. Enhancement of d-tubocuranne neuromuscular blockade by diuretics in man. Anesthesiol 1976; 45:442-445 13. Durant NN, Nguyen Ν, Katz RL. Potentiation of neuromuscular blockade by Verapamil Anesthesiol 1984; 60' 298-303 14. Fischer JR, Baer RK. Acute myopathy associated with combined use of corticosteroids and neuromuscular blocking agents. Ann Pharmacother 1996; 30 1437-1445

ACKNOWLEDGEMENTS Dr.J. van Egmond is thanked for the statistical analysis. Prof. J.E. Caldwell is thanked for his helpful comments on the manuscript.

71 72 CHAPTER VIM

ACCELERATED RECOVERY AND DISPOSITION FROM ROCURONIUM IN AN END-STAGE RENAL FAILURE PATIENT ON CHRONIC ANTICONVULSANT THERAPY WITH SODIUM VALPROATE AND PRIMIDONE

JJ Driessen, MD, PhD, EN Robertson MB, ChB, FRCA, LHDJ Booij, MD, PhD, T. Vree, PhD.

Published in the British Journal of Anaesthesia 1998; 80: 386-388. Reproduced with kind permission of the Oxford University Press and the British Journal of Anaesthesia.

INTRODUCTION It is well documented that patients treated with anticonvulsant drugs such as phenytoin or carbamezapine are resistant to the effects of neuromuscular blocking drugs [1-5]. Larger doses of neuromuscular blocking agents are required to produce a given degree of neuromuscular block and recovery from paralysis is faster. We report the case of an end-stage renal failure patient, receiving chronic treatment with the anticonvulsants, sodium valproate and primidone, who showed marked resistance to neuromuscular block, with enhanced elimination and clearance of rocuronium.

CASE REPORT A 40-year-old male (1.96 m, 69 kg) was undergoing placement of a peritoneal dialysis catheter. The patient suffered from end-stage renal failure caused by chronic glomerulonephritis and had been on haemodialysis for 2 yr. His daily urine output was approximately 100

73 ml and creatinine clearance <5 ml min"1. Because of hypertension, mild left ventricular hypertrophy was present. After meningitis in early childhood, he had developed epileptic seizures. With his present medication, he had experienced no seizures since 1983. The patient had given written consent to participate in a study into the pharmacokinetics and pharmacodynamics of rocuronium 0.6 mg kg'1 in patients with renal failure, but the investigators were unaware of his antiepileptic therapy, which would have excluded him from the study. Haemodialysis was performed 24 h before surgery. Preoperative laboratory investigations included: haemoglobin 5.4 mmol litre'1, serum creatinine 549 mmol litre'1, serum urea 15.7 mmol litre"1, serum albumin 34 g litre'1, total serum protein 63 g litre"1, serum ALAT/GPT 9 iu litre"1, serum ASAT/GOT 15 iu litre"1 and potassium 4.8 mmol litre"1. His routine medication was; metoprolol 200 mg twice daily, minoxidil 10 mg twice daily, primidone 250 mg twice daily, sodium valproate 300 mg four times daily and calcium carbonate 500 mg five times daily. I.v. flucloxacillin 1 g, three times daily was given in the perioperative period as antibiotic prophylaxis. The patient was premedicated with paracetamol 1 g and oxazepam 10 mg orally, 1 h before surgery. Before surgery, systolic arterial pressure was 150/90 mmHg with a heart rate of 72 beats min'1. General anaesthesia was induced with fentanyl 0.1 mg and propofol 2 mg kg"1 via an iv infusion, and was maintained with continuous infusion of propofol 6-10 mg kg"1 h'1, with supplementary bolus doses of fentanyl 0.1 mg as required. When the patient was asleep, neuromuscular function was monitored using transcutaneous supramaximal square wave stimuli of 0.2 ms delivered at 0.1 Hz with surface electrodes over the ulnar nerve at the wrist. Muscle contraction of the adductor pollicis was measured mechanomyographically with a Grass FT-03 force displacement transducer. After stabilization of the control twitch response for 5 min, rocuronium 42 mg (0.6 mg kg1) was administered as a fast iv bolus before tracheal intubation. Thereafter the patient's lungs were ventilated with 40% oxygen in nitrous oxide to achieve an end-tidal carbon dioxide partial pressure of 4-4.7 kPa. After the single twitch response recovered to 25%, train-of-four (TOF) stimuli were used every 12 s. Onset time (time to maximum twitch depression) time to recovery of the TOF ratio to 0.7 were recorded. The time from

74 injection of blocker until the first twitch of the TOF reached 75% recovery was also recorded Venous blood samples (4 ml) for measurement of rocuromum concentrations were obtained from the contralateral arm before and 2, 4, 7, 10, 15, 20, 30, 120, 180, 240 and 360 mm after the bolus dose of rocuromum Blood samples were anticoagulated with heparin, iced and centnfuged within 1 h of collection Plasma was mixed with 0 2 ml of sodium dihydrogen phosphate 0 02 mol litre 1 for every 1 ml of plasma, and stored at - 30°C until analysis by high pressure liquid chromatography (HPLC) Analysis of rocuromum and the metabolites 17-desacetyl-rocuronium and 16-N-desallyl-rocuronium was performed according to the HPLC method of Kleef and colleagues [6] Intra-day variability of rocuromum in plasma was 5 7% (cv) at 10 ng ml1 and 0 82% at 100 ng ml1, mter- day variability was 15 2% and 15 8%, respectively The accuracy of the assay in plasma was 97 9% at 10 ng ml1 and 96 5% at 100 ng ml1 Pharmacokinetic variables were calculated from the fitted plasma concentration-time curve after iv administration (r2 > 0 98) according to a three-compartment model using the MW/Pharm computer package (Mediware, Groningen, The Netherlands)[7]

Elimination half-life (T, 2) values were calculated from In2/ß, where β is calculated by log-linear regression analysis of the terminal log-linear phase AUC00 x (area under the plasma concentration-time curve) was calculated using the linear trapezoidal rule, with ί being extrapolated to infinity Total body clearance (C/) is described as Cl= dose/AUC ο χ Vss, the volume of distribution at steady state, = CI χ MRT Cl= Vss χ Z kei = Vss χ 0 693/TÌ 2 Mean residence time (MRT) = AUMCQ ,/AUC0 X, where AUMC0 x is the area under the moment curve from zero to infinity Table 1 shows the mam pharmacodynamic and pharmacokinetic variables after rocuromum 0 6 mg kg 1 in our patient who was receiving primidone and sodium valproate, compared with published data in control renal failure and healthy patients Onset time in our patient was 150 s and maximal depression 99% Figure 1 shows the plasma concentration-time curve of rocuromum in this patient Total body clearance of rocuromum was 14 4 ml mm1 kg 1 and the terminal plasma elimination half-life was 52 mm The volume of distribution at

75 steady state in our patient approximated the mean values in the reported studies. Table 1 Pharmacodynamics and pharmacokinetics after administration of rocuronium 0.6 mg kg'' in a patient receiving sodium valproate/primidone compared with chronic renal Z failure patients or healthy patients [8,9]. Clpl = plasma clearance; Ti/2 = terminal half- life; l^s = volume of distribution at steady state; MRT = mean residence time. CRF = chronic renal failure.

Study Pt CRF Pts Healthy Pts

Ref8 Ref9 Ref8

Onset (s) 150 61(25) 63(17) 65(16)

25% Recovery of T1 5.5 55(27) 54(22) 42(9.3) (min)

75% Recovery of TI 8.5 84(37) 81(34) (min)

TOF ratio 0.7 (min) 11.3 99(41) 73(24)

EC50 (mg litre'1) 2

1 1 C/pl (ml kg' min' ) 14.4 2.5(1.1) 3.0(1.3) 3.7(1.4)

V„ (mi kg"') 246 212(47) 239(77) 207(49)

Tìaa (min) 1.5 1.6(0.7) 1.8(1.5)

7",e " (min) 8.3 24.3(11.1) 14.8(5.5)

TV (min) 52 104(441) 91(21) 97(26.4)

MRT (min) 17 97(49) 58(9.6)

The estimated plasma concentration of rocuronium in this patient at TOF ratios of 0.7 and 0.9 were 0.85 mg litre"1 and 0.58 mg litre"1, respectively. The EC50 was calculated to be 2 mg litre'1. No metabolites of rocuronium were detectable in the plasma.

76 Figure 1 Plasma concentration-time curve (semi-log plot) after the administration of rocuronium 0.6 mg kg1 (42 mg) iv to a patient with end-stage renal failure receiving chronic anticonvulsant therapy with primidone and valproate. No metabolites were measurable. Plasma concentrations of rocuronium at 180, 240 and 360 mm were below the limit of quantitation of 10 ng ml ' T,2 = Terminal plasma elimination half-life (52 mm)

10000

c 1000 Ü c O o co E 100 (A ra o. E e o L_ 10 D O O

25 50 75 100 125 150 time (mm) DISCUSSION The clinical duration and recovery of rocuronium 0.6 mg kg 1 in our renal failure patient were markedly shorter than in the renal failure patients reported in two previous studies [8,9] or in healthy patients [8]. Clearance of rocuronium in our patient was faster and elimination half-life was shorter than in healthy patients. A comparable case of decreased duration of action of rocuronium in a renal failure patient receiving chronic therapy with phenytoin has been reported [9]. In that patient, a greatly increased clearance of rocuronium was also found, which could in part be explained by the fact that the patient was still able to produce urine. The authors suggested that hepatic enzyme induction by phenytoin as the likely mechanism of the interaction with rocuronium. Loan and colleagues [10] also found reduced duration of action of rocuronium 0.6 mg kg1

77 in patients receiving carbamezapine alone or in combination with other anticonvulsants. For the observed resistance to non-depolarizing neuromuscular blocking drugs in patients receiving long-term treatment with phenytoin and carbamezapine, three possible mechanisms are reported: (1) increased hepatic metabolism and clearance by enzyme induction [1,9]; metabolites must be included in the overall analysis; (2) increase in protein binding which results in a deceased free fraction of drug to interact with the acetylcholine (ACh) receptor [11,12]; and (3) decreased ACh receptor sensitivity with subsequent up-regulation of the ACh receptor [11, 12]. Our patient was receiving chronic therapy with two other anticonvulsant drugs for which the interaction with neuromuscular blocking drugs is less well studied. Primidone is a prodrug; it is converted to phénobarbital, which produces the antiepileptic effects. Primidone (phénobarbital) strongly induces the activity of drug metabolizing enzymes [13]. This is compatible with the- high clearance and short elimination of rocuronium in our patient. Of the elimination pathways of rocuronium hepatobiliary elimination is thought to be most important; only 10-30% of an injected dose of rocuronium is eliminated via the kidney [1]. The main metabolic pathway of rocuronium is esterase hydrolysis to 17-desacetyl-rocuronium. In this patient, plasma concentrations of metabolites were below the limit of quantitation. Thus it appears that rapid elimination and high clearance are unlikely to be caused by increased esterase or enzyme activity. The metabolites 17-desacetyl-rocuronium or 17-hydroxy-rocuronium could be immediately excreted renally or conjugated with glucuronic acid and then excreted. However, this is also unlikely in our patient, as he had renal failure. A similar line of reasoning can be followed for the vecuronium-carbamezapine interaction because vecuronium shows comparable metabolic pathways to rocuronium (3ΌΗ- and 17-OH- vecuronium); therefore, metabolites must be included in the overall analysis to detect increased metabolic elimination. The actions of atracurium and mivacurium, neuromuscular blocking drugs, which are eliminated mainly by plasma esterase and Hofmann degradation, are not affected by co-medication with phenytoin or carbamezapine [14]. However, recovery after doxacurium was twice as fast in patients receiving carbamezapine and phenytoin compared with a control group [14]. Thus vecuronium-rocuronium metabolism

7Θ must differ from that of atracurium and mivacurium. Enzyme induction is followed by increased liver size and increased liver blood flow. If most of a dose of rocuronium is tightly/covalently bound to this increased number of liver receptor sites, then the apparent increased elimination, without metabolism, may explain the pharmacokinetic variables found in this patient [15]. When these liver binding sites are saturated, for example after long term infusion in the ICD, then renal excretion becomes more important in the elimination of rocuronium in a similar way as that demonstrated for pancuronium [16]. Sodium valproate is not an enzyme inducer but its addition to primidone increases serum concentrations of phénobarbital [13]. In contrast, valproic acid may cause up-regulation of the ACh receptor as acute administration in animals causes partial neuromuscular block and potentiates the effects of neuromuscular blocking drugs [11]. In this patient, however, the EC5U of rocuronium and plasma concentrations at TOF ratios of 0.7 and 0.9 were within the normal range [8]. As the clinical relevance and mechanism of the interaction of sodium valproate and primidone with neuromuscular blocking drugs remains unclear, further clinical and experimental study is necessary.

79 REFERENCES 1 Alloul Κ Whalley DG, Shutway F, Ebrahim Ζ, Varin F Pharmacokinetic origin of carbamezapine-induced resistance to vecuronium neuromuscular blockade in anesthetized patients Anesthesiol 1996, 84 330-339 2 Hickey DR, Sangwan S, Bevan JC Phenytom-mduced resistance to pancuronium Anaesthesia 1988, 43 757-759 3 Omstem E, Matteo RS, Schwartz AE, Silverberg PA, Young WL, Diaz J The effects of Phenytoin on the magnitude and duration of neuromuscular block following atracunum or vecuronium Anesthesiol 1987, 67 191-197 4 Platt PA, Thackray NM Phenytom-mduced resistance to vecuronium Anaesth Intensive Care 1993,21 185-191 5 Whalley DG, Ebrahim Ζ Influence of carbamezapme on the dose response relationship of vecuronium Br J Anaesth 1994, 72 125-126 6 Kleef UW , Proost JH, Roggeveld J, Wierda JMKH Determination of rocuronium and its putative metabolites m body fluids and tissue homogenates Journal of Chromatography 1993, 621 65 76 7 Proost JH, Meyer DKW MW/Pharm, an integrated software package for drug dosage regimen calculation and therapeutic drug monitoring Computers in Biological Medicine 1992, 22 155-163 8 Cooper RA, Maddinem VR, Mirakhur RK, Wierda JMKH, Brady M, Fitzpatrick KTJ Time course of neuromuscular effects and pharmacokinetics of rocuronium bromide (ORG 9426) during isoflurane anaesthesia in patients with and without renal failure Br J of Anaesth 1993, 71 222 226 9 Szenohradszky J, Caldwell JE, Sharma ML, Gruenke LD, Miller RD Interaction of rocuronium (ORG 9426) and phenytom m a patient undergoing cadaver renal transplantation a possible pharmacokinetic mechanism'' Anesthesiol 1994, 80 1167 1170 10 Loan PB, Connolly FM, Mirakhur RK, Kumar N, Farlmg Ρ Neuromuscular effects of rocuronium in patients receiving beta-adrenoceptor blocking, calcium entry blocking and anticonvulsant drugs Br J of Anaesth 1997, 78 90-91 11 Pollard BJ Drug Interactions In Harper NJN, Pollard BJ, eds Muscle Relaxants in Anaesthesia London Edward Arnold, 1995, 177-190 12 Martyn JAJ, White DA, Gronert GA, Jaffe RS, Ward JM Up-and-down regulation of skeletal acetylcholine receptors Effects on neuromuscular blockers Anesthesiol 1992, 76 822-843 13 Levy RH, Koch KM Drug interactions with valproic acid Drugs 1982,24 543 56 14 Ornstein E, Matteo RS, Weinstein JA, Halevy JD, Young WL, Abou-Donia MM Accelerated recovery from doxacunum-induced neuromuscular blockade m patients receiving chrome anticonvulsant therapy Journal of Clin Anesth 1991, 3 108-111 15 Pirttiaho HI, Sotamemi EA, Pelkonen RO, Pitkanen U Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants Eur J of Clin Pharmacol 1982, 22 441 -445 16 Crul JF, Vree TB Neuromuscular blocking agents In Stoeckel H, ed Quantitation, Modelling and Control in Anaesthesia Stuttgart Thieme Verlag, 1985, 219-231

ACKNOWLEDGEMENTS The authors thank Organon Teknika, Clinical Development Department, for their support in the analysis of plasma samples and for giving permission for publication of this patient who was eliminated from the original pharmacokinetic study in renal failure patients.

80 CHAPTER IX

GENERAL DISCUSSION AND CONCLUSIONS

Chapter I introduces the reader to neuromuscular blocking agents in general and gives a brief history of the development of these drugs to clinical practice. As a "descendent" of pancuronium, rocuronium belongs to the aminosteroid group of neuromuscular blocking agents. This group of drugs was developed after the postulated structure of d- tubocurarine was known. D-tubocurarine was originally thought to be a bisquaternary ammonium compound but it is now realised that it is in fact monoquaternary and that one of the nitrogen atoms is tertiary. At body pH this tertiary atom becomes protonated and thus d- tubocurarine has two positively charged centres. The late Dr.David Savage, who helped develop pancuronium from the then supposed structure of d-tubocurarine, told me several years ago that the structure he was given for d-tubocurarine (bisquaternary) was incorrect and that if he had been given the correct structure (monoquaternary) he would have probably found vecuronium as his first usable neuromuscular blocking agent. If that had been the case perhaps this thesis about rocuronium could have been written 20 years ago!

Chapter II of this thesis compares the neuromuscular effects of a large dose of rocuronium (0.9 mg kg1) and compares it to an equipotent dose of vecuronium (0.15 mg kg1). Although a similar duration of action is seen, rocuronium has a more rapid onset time than vecuronium. Neither neuromuscular blocking agent had any great effect on intraocular pressure. Vecuronium had no effect on heart rate or arterial pressure, whereas rocuronium caused a small rise in heart rate and a small increase in arterial pressure. At the time of writing this was thought to be due to a mild vagolytic effect that rocuronium was known to possess. Once rocuronium was introduced into clinical practice, the likely cause of the cardiovascular effects was seen, namely, pain on injection of rocuronium. This pain is not a problem as long as the patient is asleep or sedated adequately. One might even say that the need to use rocuronium as a priming dose or a precurarizing dose for suxamethonium is probably unnecessary since

81 rocuronium provides good intubating conditions within one minute of injection Suxamethonium has many unwanted side effects and the search for a replacement goes on Chapters II and III demonstrate that rocuronium has a rapid onset time but a longer duration of action than suxamethonium No significant cardiovascular or intraocular effects are seen with rocuronium, while suxamethonium can affect both systems with an increase (and sometimes a decrease) in heart rate and a sustained increase in intraocular pressure Another important finding was that suxamethonium appeared to prolong the neuromuscular block produced by rocuronium Propofol anaesthesia was used in this study If one of the mhalational agents had been used, then this prolongation might have been even more significant Careful monitoring of the neuromuscular block should avoid any problems with this change The use of rocuronium 0 3 mg kg 1 in infants and children under halothane anaesthesia is described in Chapter IV Three age groups were compared to each other, viz , 1 -6 months, 6-24 months and >24 months In the youngest group of children, a more rapid onset time was seen than in the other two groups The duration of action and the recovery time of the youngest groups were significantly prolonged compared to the oldest group of children Chapter V presents the time-course of action of a bolus dose of rocuronium 0 3 mg kg 1 in children aged older than nine months under halothane anaesthesia There were two groups of children, viz , one group had endstage renal failure and the other was healthy The most important finding in this study was that in the renal failure children a slower onset time was seen, although the duration of action of the administered rocuronium was not prolonged Thus, if rocuronium were to replace suxamethonium in a rapid sequence induction of anaesthesia technique, a larger dose of rocuronium might be needed, with the possible consequence that a prolonged duration of action might occur Chapter VI presents the pharmacokinetics and neuromuscular effects of rocuronium 0 6 mg kg1 in adult patients with and without endstage renal failure This was the first study published that clearly showed both a decrease in the clearance of rocuronium in renal failure patients and a prolongation in the duration of action of the rocuronium given Whether these two findings are directly related is difficult to

82 determine, since the two groups have such different levels of health The renal failure patients were all being dialysed, and often had concomitant diseases such as diabetes and hypertension. They also had greatly increased urea and creatinine plasma levels, and were often taking various drugs to control the effects of the renal failure and hypertension. The control group of patients were all healthy ASA 1 or 2 patients, were taking no significant medication and had normal haematology and biochemistry. It can be concluded from this study that when using rocuromum in renal failure patients, sufficient neuromuscular monitoring should be used to pick out the occasional patient who develops a prolonged neuromuscular block after rocuromum Three of the 17 renal failure patients had such a prolonged duration of action of rocuromum that neostigmine was necessary to reverse the neuromuscular blockade more than two hours after rocuromum administration. Chapters V and VI compare the effects of 0.3- and 0 6 mg kg 1 rocuromum in renal failure patients and control patients, in children and adults, respectively In Chapter VII, a follow-up study is performed with rocuromum 0 3 mg kg 1 in adults. This is administered to both renal failure and healthy patients, and the resultant neuromuscular block is monitored using acceleromyography This kind of neuromuscular monitoring is becoming more common in routine anaesthetic practice in our institution. Although no statistical difference in the duration and depth of neuromuscular block produced by this lower dose of rocuromum was seen between the two groups, the renal failure group was remarkable for the range of the duration of action of the rocuromum. The time to a recovery of the TOF to 70% ranged from 11 to almost 95 minutes, and this variation was statistically significant compared to the control group There were actually only three patients in the renal failure group who had a prolonged (>85 mm) duration of action after rocuromum Even in the patients with prolonged block, however, the block could be antagonized within 20 minutes of injection of rocuromum since at least two responses to TOF stimulation were present 20 minutes after rocuromum in all 36 patients.

It has been suggested that quantitative monitoring of the block produced by neuromuscular blocking agents should be performed routinely In patients with renal failure this is probably even more applicable because of the spread of the duration of action of

83 rocuronium. Acceleromyography using the TOF-Guard" or more recently the TOF-Watch" appears to be suitable for such monitoring. Chapter VIII is an illustrative case report, which arose from the study reported in Chapter VI. This patient took part in this pharmacokinetic and pharmacodynamic study, but was later found to have taken sodium valproate and primidone as antiepileptic medication. Chronic use of such drugs is known to reduce the response to neuromuscular blocking agents. The case reported here monitored not only the neuromuscular block produced by rocuronium, but also the plasma levels of rocuronium and its metabolites. This study compared the duration of action of rocuronium with the published data at that time. The results reported in Chapter VI also confirm how short acting rocuronium is in this patient. The main pharmacokinetic findings in this case are that no metabolites could be measured in the plasma of the patient and that the plasma concentration at a TOF of 0.7 and 0.9 appeared to be within normal limits. This suggested that metabolism was therefore not likely to be one of the reasons for the short duration of action of rocuronium and that such patients do not appear to be resistant to rocuronium because of up-regulation of acetylcholine receptors. Distribution, possibly to an increased number of binding sites, may be the cause of the short duration of action of rocuronium in patients using this combination of chronic antiepileptic medication.

CONCLUSIONS Rocuronium has found its place as the most commonly used non depolarizing neuromuscular blocking agent in anaesthetic clinical practice with good reason. The studies presented here confirm that rocuronium has several advantages over existing drugs, but the studies in children and patients with renal failure, however, remind practising anaesthetists that every medicine introduced into the clinic must be carefully assessed to find out how the new medicine actually behaves in different groups of patients. Rocuronium is not yet the replacement for suxamethonium in all situations. The real message from these studies, particularly in the renal failure patients, is that it is almost impossible to predict the duration of action of a given dose of rocuronium. Objective monitoring of the depth of neuromuscular block is helpful and perhaps even necessary in renal failure patients.

84 This can be achieved fairly easily in the clinical situation using acceleromyog raphy.

THE RECENT PAST Organon (Oss, The Netherlands) introduced the new neuromuscular blocking agent, rapacuronium, to the anaesthetic world in the late 1990's. This was also an aminosteroid-based neuromuscular blocking agent that was less potent than rocuronium, and fitted the suggestion of Prof. W. Bowman that low potency meant rapid onset time. Rapacuronium did have a rapid onset time equal to that of suxamethonium. It also had a shorter duration of action than the other steroid-based neuromuscular blocking agents, and appeared to be a real substitute for suxamethonium, although the duration of action was longer than that of suxamethonium. After its introduction to the American market in 1999, rapacuronium was widely used. A series of case reports were published in 2001 describing bronchospasm in adults and children given rapacuronium. Although bronchospasm is a possibility with any neuromuscular blocking agent, it appeared to occur more frequently than with rocuronium or vecuronium. Rapacuronium has an affinity for muscarinic receptors in the lung and destabilization of the balance between M2 and M3 receptors is the mechanism of bronchospasm. It is unlike any other relaxant in this regard. The bronchospasm was severe in a number of cases, and led Organon to withdraw rapacuronium from the market in the U.S.A. Thus, this new promising neuromuscular blocking agent cannot be used because of the high incidence of bronchospasm.

THE FUTURE Recently, a non-depolarizing neuromuscular blocking agent, GW280430A, has been described in the literature. (Anesthesiology, April 2004). This compound is an asymmetric mixed- tetrahydroisoquinolinium chlorofumarate, and is structurally similar to mivacurium. The important point about this compound is that in initial trials, it appears to have as short a duration of action (10 min) as suxamethonium and little tendency to cumulate [1]. The onset time is, however, longer than suxamethonium at around 1.5 min. Increasing the dose does not appear to reduce the onset time greatly or increase greatly the duration of action. Thus GW280430A is the closest that a non-depolarizing neuromuscular blocking agent comes to

85 suxamethonium in terms of duration of action. Doses greater than 3 χ ED90 do, however, tend to cause histamine release, which can cause flushing, hypotension and tachycardia. Increasing the dose tends to increase the chance of histamine release. In an Editorial in Anesthesiology in April 2004, Prof. J. Caldwell [2] has suggested that because of this problem with histamine release, "GW280430A may never be released into clinical practice, but it is quite conceivable that a drug closely related will be". Organon, in conjunction with several anaesthetic departments, including UMC Nijmegen, are in the phase II development stage of a specific binding agent for the aminosteroid group of neuromuscular blocking agents, including rocuronium. This agent, known at present as Org 25969, works by chelation of the neuromuscular blocking drug. It is a cyclodextrin from the group of compounds known as cyclic oligosaccharides, which are known to encapsulate lipophilic molecules such as steroids [3] (see back cover). It seems that this new antagonist is able to reverse deep levels of neuromuscular block very rapidly with, until now, few side effects [4]. In the future, larger doses of rocuronium may be given to produce even more rapid onset times, which will allow rapid endotracheal intubation. At present, after such large doses of rocuronium, a long period of neuromuscular block might be expected, but the rocuronium will be chelated by the new drug, which will lead to the abolition of the neuromuscular block. If the present studies into Org 25969 prove to be as good as they appear at the moment, rocuronium may indeed come to replace suxamethonium in most, if not all, situations. As with all new drugs, however, this will be investigated further once it comes into general clinical use.

REFERENCES 1. Belmont MR, Lien CA, Tjan J, Bradley E, Stem B, Patel SS, Savarese JJ. Clinical pharmacology of GW280430A in humans. Anesthesiol 2004; 100, 4 768-73 2 Caldwell JE. The continuing search for a succinylcholme replacement. Editorial views. Anesthesiol 2004; 100' 763 3. Epemolu O, Bom A, Hope F, Mason R Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of the novel reversal agent Org 25969. Anesthesiol 99:632-7, 2003 4 De Boer HD, Onessen JJ, Robertson EN, van Egmond J, Bom A, Booij LHDJ. Org 25969, a new binding agent for profound neuromuscular block induced by rocuronium in the anaesthetized rhesus monkey Presentation ESA congress, Lisbon, June 5-8, 2004

86 HOOFDSTUK IX

SAMENVATTING EN CONCLUSIES

Hoofdstuk I geeft een algemene inleiding over neuromusculair blokkerende farmaca (of spierverslappers) en een historisch overzicht van hun ontwikkeling in het laboratorium tot in de kliniek Als een afstammeling van pancuronium behoort ook rocuronium tot de groep van neuromusculair blokkerende farmaca met ammosteroidstructuur Deze groep werd ontwikkeld na ontrafeling van de chemische structuur van d-tubocuranne Alhoewel oorspronkelijk werd gedacht dat d-tubocurare een bisquaternaire ammomumstructuur bevatte, is het nu duidelijk dat het monoquaternair is en dat een van de N- atomen tertiair is BIJ lichaamstemperatuur wordt dit tertiaire N-atoom geprotoneerd en krijgt d-tubocurare dus twee positief geladen centra Dr David Savage, die meehielp aan de ontwikkeling van pancuronium vanuit de veronderstelde structuur van d-tubocurare, vertelde me enkele jaren geleden dat de bisquaternaire structuur die hij aan d-tubocurare toebedeelde onjuist was Had hij meteen de juiste structuur (monoquaternair) bepaald, dan zou waarschijnlijk met pancuronium, maar vecuronium het eerste bruikbare neuromusculair blokkerende farmacon na d-tubocurare geworden zijn In dat geval zou dit proefschrift over rocuronium misschien twintig jaar eerder geschreven zijn

Hoofdstuk II vergelijkt de neuromusculaire effecten van een hoge dosering van rocuronium (0,9 mg kg1) en een equipotente dosering van vecuronium (0,15 mg kg1) bij patiënten tijdens oogheelkundige ingrepen Hierbij werd een vergelijkbare werkingsduur vastgesteld, terwijl rocuronium een snellere inwerking ("onset") had dan vecuronium Geen van beide spierverslappers had enig effect op de mtraoculaire druk Vecuronium had geen effect op hartfrequentie of bloeddruk, terwijl rocuronium een kleine verhoging van de hartfrequentie en bloeddruk veroorzaakte Aanvankelijk werd dit toegeschreven aan een mild vagolytisch effect van rocuronium Na de introductie van rocuronium bleek dat die polsversnelling eerder veroorzaakt wordt door de pijn na intraveneuze injectie van rocuronium, die bij ongeveer 50% van alle patiënten optreedt

87 Dit is normaal niet belangrijk aangezien de patiënten slapen, maar als rocuronium gebruikt wordt als precurarisatie ("priming") kan het wel degelijk ongemak veroorzaken. Suxamethonium heeft vele ongewenste bijwerkingen, reden waarom nog steeds gezocht wordt naar een vervangend spierrelaxans met vergelijkbare snelheid van werking en korte werkingsduur. Hoofdstuk III vergelijkt de neuromusculaire effecten en de invloed op de oogboldruk van suxamethonium 1mg kg'1 en rocuronium 0,6 mg kg"1 tijdens oogheelkundige ingrepen bij patiënten met normale oogboldruk. Er werd aangetoond dat rocuronium een snelle werking heeft, maar wel een veel langere werkingsduur dan suxamethonium. Er traden geen significante cardiovasculaire veranderingen of stijging in intraoculaire druk op na rocuronium, terwijl suxamethonium zowel een polsversnelling als een aangehouden verhoging van de intraoculaire druk veroorzaakt. Deze studie onderzocht ook het effect van voorafgaande toediening van suxamethonium (voor endotracheale intubatie) op de aansluitende toediening van rocuronium 0,6 mg kg 1 (voor onderhoud van de spierverslapping). Een niet eerder gerapporteerde bevinding was dat voorafgaande toediening van suxamethonium het neuromusculair block veroorzaakt door rocuronium verlengt. Tijdens deze studie werd onderhoud van anesthesie verricht met propofol dat, in tegenstelling tot dampvormige anesthetica, geen potentiatie van rocuronium veroorzaakt. Bij gebruik van dampvormige anesthetica zou de verlenging van werkingsduur van rocuronium na voorafgaand suxamethonium waarschijnlijk nog groter geweest zijn. Zorgvuldig meten van de spierrelaxatie maakt het mogelijk problemen met dit soort interacties te voorkomen.

Hoofdstuk IV beschrijft het gebruik van rocuronium 0,3 mg kg"1 bij zuigelingen en kinderen tijdens halothaananesthesie. Drie leeftijdsgroepen werden vergeleken: 1-6 maanden, >6-24 maanden en >24 maanden. In de jongste groep was de "onset" significant korter dan in de twee groepen van oudere kinderen. De werkingsduur daarentegen was sterk verlengd in de twee jongste groepen, vergeleken met de oudste groep. Hoofdstuk V vergelijkt de neuromusculaire effecten van rocuronium 0,3 mg kg1 tijdens halothaananesthesie bij kinderen (>9 maanden) met terminaal nierfalen en bij gezonde kinderen. De belangrijkste bevindingen waren een tragere inwerkingssnelheid bij kinderen met nierfalen en een vergelijkbare werkingsduur van rocuronium tussen

ΘΘ beide groepen. Dit impliceert dat, wanneer rocuronium suxamethonium zou moeten vervangen in een "rapid sequence" techniek van anesthesie-inleiding, een hogere dosering van rocuronium nodig zou zijn met als waarschijnlijk gevolg een verlengde werkingsduur. Hoofdstuk VI presenteert de farmacokinetische en neuromusculaire effecten van rocuronium 0,6 mg kg1 bij volwassen patiënten met of zonder terminaal nierfalen. Dit was de eerste gepubliceerde studie die aantoonde dat én de klaring van rocuronium kleiner is én zijn werkingsduur verlengd is bij patiënten met nierfalen in vergelijking met gezonde patiënten. Het is moeilijk te bepalen of deze twee bevindingen direct gerelateerd zijn wegens het grote verschil in gezondheid en ASA klasse tussen beide groepen. De patiënten met nierfalen werden alle preoperatief gedialyseerd en hadden vaak andere ziekten zoals hypertensie en diabetes. Zij hadden ook sterk verhoogde plasmaspiegels van ureum en creatinine en namen meestal multipele medicatie om de gevolgen van nierfalen en de hypertensie te controleren. De controlegroep bestond uit ASA klasse 1 en 2-patiënten met normale laboratoriumwaarden en zonder medicatie. Wij concludeerden dat bij gebruik van rocuronium bij nierfalen neuromusculaire bewaking noodzakelijk is om een verlengde neuromusculaire blokkade op te sporen. Drie van de 17 patiënten met nierfalen hadden een dermate sterk verlengde blokkade dat antagonering met neostigmine noodzakelijk was twee uur na toediening van rocuronium.

In hoofdstuk VII wordt een studie met rocuronium 0,3 mg kg"1 tijdens TIVA bij volwassenen met of zonder nierfalen beschreven als vervolg van de studies beschreven in de hoofdstukken V en VI. Het resulterend neuromusculair block werd hier gemeten met acceleromyografie in plaats van mechanomyografie. Acceleromyografie is een nieuwere methode die omwille van haar eenvoudigere en snellere "set-up" meer en meer tot de routinepraktijk in onze afdeling behoort. Alhoewel er geen statistisch significant verschil tussen de twee groepen werd gevonden in de diepte en duur van het block, werd er in de groep met nierfalen een opvallend grotere spreiding in de werkingsduur van rocuronium aangetoond. De tijd tot herstel van de TOF ratio tot 70% varieerde van 11 tot 95 minuten. De uitgebreide co-medicatie gebruikt door patiënten met nierfalen zal ongetwijfeld bijgedragen hebben aan deze grotere variabiliteit.

89 Slechts drie patiënten met nierfalen hadden een significant verlengde (>85 min) werkingsduur van neuromusculaire blokkade na rocuronium. Echter zelfs bij de patiënten met een verlengde werkingsduur kon het block binnen 20 minuten na de injectie met rocuronium geantagoneerd worden, omdat bij alle 36 patiënten 20 minuten na toediening van de rocuronium minimaal twee responses op de TOF stimulatie aanwezig waren. Recente literatuur toont aan dat kwantitatieve meting van spierrelaxatie bij gebruik van spierverslappers routinematig toegepast zou moeten worden om onverwachte residuele spierverslapping in de postoperatieve fase te voorkomen. Deze studie toont aan dat dit bij patiënten met nierfalen nog sterker het geval is gezien de zeer grote spreiding in de werkingsduur. Acceleromyogafie (met de TOF-Guard(i?, en meer recent met de TOF-Watchto) blijkt geschikt voor deze bewaking. Hoofdstuk VIII is een illustratief "case report" dat zich voordeed tijdens het onderzoek beschreven in hoofdstuk VI. Deze patiënt nam deel aan de farmacokinetische en farmacodynamische studie, maar slechts na de inclusie werd opgemerkt dat hij niet in aanmerking kwam wegens preoperatief gebruik van anti-epileptische medicatie (sodium valproate and primidone). Deze farmaca verminderen bij chronisch gebruik de spierverslappende werking van neuromusculair blokkerende farmaca. Vergeleken met de patiënten met nierfalen in hoofdstuk VI had deze patiënt een zeer korte blokkade na rocuronium 0,6 mg kg"1. Er konden geen rocuronium metabolieten gemeten worden in het plasma en de plasmaconcentraties van rocuronium bij een herstel van de TOF ratio tot 0.7 en 0.9 lagen binnen normale grenzen. Dit suggereert dat versneld rocuronium metabolisme niet de waarschijnlijke reden was voor de korte werkingsduur van rocuronium en dat de resistentie aan rocuronium ook niet te wijten was aan "up-regulation" van de acetylcholine receptoren ter hoogte van de neuromusculaire junctie. Redistributie, mogelijk naar hepatische bindingsplaatsen voor rocuronium, is waarschijnlijk belangrijk in de resistentie en kortere werkingsduur van rocuronium bij patiënten die chronisch anti- epileptische medicatie nemen.

CONCLUSIES Rocuronium heeft niet ten onrechte zijn plaats gevonden als het meest gebruikte niet-depolariserend spierrelaxans in de klinische

90 anesthesiepraktijk wereldwijd. De studies gepresenteerd in dit proefschrift bevestigen dat rocuronium verschillende voordelen heeft boven andere aminosteroïde spierverslappers. Toch tonen de studies bij zuigelingen en patiënten met nierfalen aan dat ieder geneesmiddel zorgvuldig bestudeerd moet worden bij verschillende patiënten groepen. Ook blijkt dat rocuronium, in de gebruikelijke dosering, nog niet de perfecte vervanger is voor suxamethonium in alle situaties. De grootste boodschap van onze studies is dat, met name bij patiënten met nierfalen, het bijna onmogelijk is om de werkingsduur van een gegeven dosering rocuronium te voorspellen. Objectieve bewaking van de diepte van een neuromusculaire blokkade is daarom noodzakelijk en dit kan redelijk eenvoudig toegepast worden in de klinische praktijk met de methode van de acceleromyografie.

DE RECENTE ONTWIKKELINGEN Organon (Oss, Nederland) introduceerde in de tweede helft van de vorige eeuw nog een nieuwe niet-depolariserende spierverslapper met aminosteroïde structuur, het rapacuronium. Vergeleken met rocuronium is rapacuronium minder potent en dit bevestigde de hypothese van prof. W. Bowman dat kleinere potentie een snellere "onset" zou betekenen. Rapacuronium heeft inderdaad een snelle "onset" die vergelijkbaar is met die van suxamethonium en leek een reële vervanger voor suxamethonium, al was zijn werkingsduur duidelijk langer dan die van suxamethonium. Na zijn introductie op de Amerikaanse markt in 1999 werd rapacuronium veel gebruikt. Echter, in 2001 werd een serie gevallen gepubliceerd van bronchospasme bij volwassenen en kinderen na toediening van rapacuronium. Alhoewel bronchospasme na iedere spierverslapper mogelijk is, bleek de kans hierop groter na rapacuronium dan na rocuronium en vecuronium. Rapacuronium veroorzaakt namelijk een verstoring van de balans tussen M2 en M3 (muscarine) receptoren in de longen. Sommige gevallen van gerapporteerde bronchospasme waren ernstig en deden Organon besluiten rapacuronium terug te trekken van de markt in de VS.

DE TOEKOMST Onlangs werd een nieuwe niet-depolariserende spierverslapper van de groep van benzylisoquinolines, GW280430A, beschreven.

91 Het is een asymmetrisch gemengd tetrahydro-isoquinolinium chlorofumaraat, structureel gelijkend op mivacurium. In initiële studies [1] blijkt dat deze stof een werkingduur heeft in de buurt van die van suxamethonium (10 min) en weinig cumulatie veroorzaakt. De "onset" tijd is echter langer dan die van suxamethonium (90 vs 30 s) waarbij dosisverhoging slechts weinig effect heeft op de "onset". GW280430A is derhalve een niet-depolariserende spierverslapper die dicht bij suxamethonium komt in termen van werkingsduur. Echter, doseringen van 3 maal de ED90 veroorzaken "flushing", hypotensie en tachycardie; alle symptomen van histaminevrijzetting. Verhoging van de dosering verhoogt de histaminevrijzetting. In een editorial schreef prof. J. Caldwell [2] dat GW280430A misschien wel niet op de markt zal komen, maar wellicht wel een andere spierverslapper met sterk verwante structuur. Organon werkt aan fase II-studies met een specifiek farmacon dat de werking van aminosteroïde spierverslappers, in casu rocuronium kan reverseren. Dit farmacon, ORG 25969, werkt door chelatie van rocuronium. Het is een cyclodextrine van de groep van cyclische Oligosacchariden, waarvan bekend is dat zij lipofiele moleculen als Steroiden omkapselen. Deze nieuwe "antagonist" is in staat een diep neuromuscular block snel te reverseren met ogenschijnlijk weinig bijwerkingen [3]. Dit maakt het mogelijk grotere doseringen rocuronium te geven met nog snellere "onset" voor snelle endotracheale intubatie. De lange duur van spierverslapping daarmee geassocieerd kan vervolgens met ORG 25969 opgeheven worden [4]. Als de lopende studies dit bevestigen zou rocuronium inderdaad suxamethonium kunnen vervangen in de meeste, zoniet alle situaties.

LITERATUUR 1 Belmont MR, Lien CA, Tjan J, Bradley E, Stem B, Patel SS, Savarese JJ. Clinical pharmacology of GW280430A in humans Anesthesiol 2004,100, 4.768-73 2. Caldwell JE. The continuing search for a succmylcholine replacement Editorial views. Anesthesiol 2004; 100 763 3. Epemolu O, Bom A, Hope F, Mason R. Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of the novel reversal agent Org 25969 Anesthesiol 99:632-7, 2003 4. De Boer HD, Onessen JJ, Robertson EN, van Egmond J, Bom A, Booij LHDJ. Org 25969, a new binding agent for profound neuromuscular block induced by rocuronium in the anaesthetized rhesus monkey. Presentation ESA congress, Lisbon, June 5-8, 2004

92 PUBLICATIONS NOT INCLUDED IN THE THESIS

1 Dnessen JJ, Robertson EN, Booij LHDJ Which is better in children edrophonium or neostigmine? Br J Anaesth 2000, 84 293-294 2 Vanlmthout LE, Booij LHDJ, van Egmond J, Robertson EN Effect of isoflurane and sevoflurane on the magnitude and time coourse of neuromuscular block produced by vecuronium, pancuronium and atracunum Br J Anaesth 1996,76 389-395 3 Vanlmthout LE, Robertson EN, BOOIJ LHDJ Response to suxamethonium during propofol-fentanyl-N20/02 anaesthesia in a patient with active myasthenia gravis receiving long-term anticholinesterase therapy Anaesthesia 1994,49 509-511 4 Booth MG, Marsh Β, Bryden FM, Robertson EN, Baird WL, A comparison of the pharmacodynamics of rocuronium and vecuronium during halothane anaesthesia Anaesthesia 1992,47 832-834 5 Caldwell JE, Robertson EN, Baird WL Antagonism of vecuronium and atracunum companson of neostigmine and edrophonium administered at 5% twitch height recovery Br J Anaesth 1987, 59 478-481 6 Caldwell JE, Robertson EN, Baird WL Antagonism of profound neuromuscular blockade induced by vecuronium or atracunum Comparison of neostigmine with edrophonium Br J Anaesth 1986, 58 1285-1289 7 Robertson EN, Fragen RJ, Booij LHDJ, van Egmond J, Crul JF Some effects of dnsopropyl phenol (ICI 35868) on the pharmacodynamics of atracunum and vecuronium in anaesthetized man Br J Anaesth 1983, 55 723-728 8 Robertson EN, Booij LHDJ, Fragen RJ, Crul JF Intradermal histamine release by 3 muscle relaxants Acta Anaesthesiol Scand 1983,27 203-205 9 Fragen RJ, Booij LHDJ, van der Pol F, Robertson EN, Crul JF Interactions of dnsopropyl phenol (ICI 35868) with suxamethonium, vecuronium and pancuronium in vitro Br J Anaesth 1983,55 433-436 10 Robertson EN, Booij LHDJ, Fragen RJ, Crul JF Clinical comparison of atracunum and vecuronium (Org NC 45) Br J Anaesth 1983, 55 125-129 11 Fragen RJ, de Grood PM, Robertson EN, BOOIJ LHDJ, Crul JF Effects of premedication on dipnvan induction Br J Anaesth 1982, 54 913-916 12 Nash CW, Gillespie JS, Robertson EN Noradrenaline uptake properties of the anococcygeus muscle of the rat Can J Physiol Pharmacol 1974, 52 430-440 13 Dnessen JJ, Robertson EN, BOOIJ LHDJ The time-course of action of rocuronium 0 3 mg/kg in children with and without end-stage renal failure Anesthesiol 2000, 93(Suppl) A1008 14 Dnessen JJ, Robertson EN, BOOIJ LHDJ The time course of action and recovery of rocuronium 0 3mg/kg in infants and children during halothane anesthesia Anesthesiol 1998,89(Suppl) A1015 15 Robertson EN, Booij LHDJ Clinical use of non-depolarizing muscle relaxants In BOOIJ LHDJ, ed Neuromuscular transmission London BMJ Publishing Group, 1996 91-123 16 Whitford AM, Godschalkx A, Robertson EN, Booij LHDJ A clinical comparison of some cardiovascular and intraocular effects of ORG9487, vecuronium and succmylcholme, Anesthesiol 1997,87(Suppl) A848

93 17. Bunschoten Ρ, Robertson EN, Booij LHDJ. Antagonism of muscle relaxation with the aid of neostigmine. Ned Tijdschr Geneeskd 1997; 141.1459-1460 18. Robertson EN, Hull JM, Vanlmthout LEH, Booij LHDJ. Pharmacodynamics of rocuromum and succmylcholme and their effects on BP, HR, and IOP. Anesthesiol 1994;81(Suppl):A1071 19. Hull JM, Robertson EN, BOOIJ LHDJ. Comparison of onset times, clinical duration and reversibility of Org 9426 and vecuronium. In: Abstracts of thet 10th World Congress of Anaesthesiologists; 1992 June 12-19; The Hague.Netherlands Congress Centre, 1992:322 20 Hull JM, Robertson EN, Booij LHDJ. Effect of rocuromum and vecuronium on intraocular pressure. Br J Anaesth 1992; 69:534P 21. Gimbrere JSF, Robertson EN. Vecuronium in intensive care. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Symposium, 1983 Apr 21 -22; Geneva. Amsterdam: Exerpta Medica, 1983:189-190. (Current Clinical Practice Series; vol 11) 22. Booij LHDJ, Robertson EN. Clinical comparison between vecuronium bromide and atracunum di-besylate. In: Agoston S, ed. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Workshop; 1982 May 24-25; Corsendonk. Amsterdam: Exerpta Medica, 1983: 38-45 23 Fragen RJ, Robertson EN, BOOIJ LHDJ, Crul JF A comparison of vecuronium and atracunum in man. Anesthesiol 1982; 57(Suppl): A253 24. Dnessen JJ, Robertson EN, Booij LHDJ. Acceleromyography in neonates and small infants: baseline calibration and recovery of the responses after neuromuscular blockade with rocuronium. Eur J Anaesthesiol 2004; in press

94 ACKNOWLEDGEMENTS

I would first like to thank Prof. G.J. Scheffer for giving me the chance to finish off the work that I had done in the Radboud University Nijmegen before his arrival. Gert Jan, without your backing this thesis would never have been completed. In 1990, Prof. L.H.D.J. Booij invited me to return to the Radboudziekenhuis, and in the years thereafter I was able to perform most of the studies included in this thesis. Thank you, Leo, for the opportunity. To Dr.J.J. Driessen, my friend, my copromotor, author and co-author throughout this thesis I say, Jacques, thank you for your encouragement and advice during the creation of the book. Dr.J. van Egmond and Dr.T. Vree, although often not mentioned in the articles, it was always nice to know that Jan and Tom were in the background and willing to help if needed with computers, figures and statistics. Thank you both. To Dr.J. Hull, Dr.A.M. Verbeek, Dr.M. Vogt and Dr.H. de Boer, I say, Julian, Ad, Mark and Hans, thank you for the effort you put into your parts of this thesis. Any clinical study that is performed often depends on several people and you all played your part wholeheartedly. As a native speaker of English myself, it was fine that I could call on the expert advice of Prof. J.E. Caldwell of the University of San Francisco, California, to edit the English text and to add his knowledge to this thesis. Thank you, Jim, for taking the time out of your busy schedule for me. Dr.P. Ponsioen as Chef de Clinique continually helped me to access suitable patients for my studies. Thank you, Philip. Dr.M. Hasenbos and Dr.D. van Diejen took over your role and also helped in rostering me in to the right programmes. Thank you Marcel and Dirk. My anaesthetic colleagues, both assistents and staff members that I have known over the years, I would like to thank for the help and

95 support with the studies. If a suitable patient presented on a list I would be notified and helped as much as possible. The anaesthetic doctors assistants and anaesthetic nurses never complained when I came with my neuromuscular monitoring apparatus or my strange requests for different anaesthetic techniques. Thank you all for your patience and helpfulness. The patience of my surgical colleagues and theatre personnel, especially from the general surgical and eye departments, was remarkable. Some of the studies added time to the lists, but there was never any complaint of time shortage. Luckily, I seldom did more than one study in one day so your coffee level did not have to rise too high. Thank you all for your tolerance. To F.J.G.M. Schaap of Organon, I say, Frans, you have helped in the formatting of the thesis and your computer expertise still amazes me. Thank you for your enthusiasm. My daughters Alexis and Joanna hardly knew I was "doing my proefschrift", but when they heard about it they were surprised and pleased for me. It was nice to tell Joanna when she came back after her travels in New Zealand and Australia (following in the adventurous footsteps of Alexis) that the thesis was finished. Thanks for making it easy for me. I thank especially Carla, my wife, for supporting me in the creation of this thesis. Sometimes I thought it would never happen, but you were sure that it should, and now it has thanks to your encouragement. Thank you also for your expert editing of the English and Dutch texts.

96 CURRICULUM VITAE Eric Nelson Robertson was born on 10th August 1950 in Glasgow, Scotland. After Levern Primary School (1955-1962), he attended Shawlands Academy Secondary School from 1962-1968. In the autumn of 1968 he began his medical studies at Glasgow University. In 1973 he graduated B.Sc, (Honours) in pharmacology and in 1975 he graduated in medicine with M.B., Ch.B. Between 1975 and 1977 he was a junior house officer, for six months in general surgery in the Victoria Infirmary in Glasgow, six months general medicine in Stirling Royal Infirmary, and then moved to Duphar Laboratories in Southampton, England for four months. In January 1977 he started his anaesthetic career as a senior house officer in Kilmarnock Royal Infirmary under Dr. G. McNab. From then until May 1979 he worked in the many hospitals in the Ayrshire area including Ayr County Hospital (three months), Ayrshire Central Hospital (three months), Seafield Children's Hospital (six months) and Ballochmyle Hospital (one year). In May 1979 he moved as a registrar to work for three months in the Neurosurgical unit of the Southern General Hospital, Glasgow, then transferred to Glasgow Royal Infirmary under Prof. D. Campbell. In June 1980, he qualified as a Fellow of the Royal College of Anaesthetists in London (FRCA). In June 1981, he came as a junior staff member to the Radboudziekenhuis in Nijmegen under Prof. J.F. Crul. In March 1983, he returned to Scotland as a senior registrar in the Glasgow area rotational training scheme, after which he became a consultant anaesthetist at Glasgow Royal Infirmary in September 1984. From September 1990 till the present he has worked in the Radboud Medical Centre as a staff member, firstly under Prof. L.H.D.J. Booij and now under Prof. G.J. Scheffer. He has studied neuromuscular blocking agents in the clinical setting since his first visit to the Netherlands. The work presented in this thesis was carried out in the Radboud Medical Centre over the last few years. He is married to Carla Vermeulen and has two daughters, Alexis (1982) and Joanna (1985).

Conclusions related to the Thesis:

The Clinical use of Rocuronium. Eric N. Robertson, 17th December 2004.

1. Monitoring of neuromuscular function intraoperatively is a good idea (This thesis).

2. Als je enige gereedschap een hamer is, ziet elk probleem eruit als een spijker (Abraham Maslow).

3. Why is 'conclusion Γ not followed by many anaesthetists? (ipse dixit)

4. Rocuronium has a rapid onset time (This thesis).

5. Een hamer heeft ook bijwerkingen (Luc Wouters).

6. Renal failure alters the course of action of rocuronium (This thesis).

7. A Committee is a group of people who individually can do nothing, but as a group decide that nothing can be done (Anon).

8. Slapen kan heerlijk zijn, het is alleen jammer dat het zo veel tijd kost (Ruud Krosse).

9. Clinical research would be impossible without altruistic patients (ipse dixit).

10. Ignorance of one's misfortunes is clear gain (Euripides).

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