A. G. HEAD-RAPSON, J. C. DEVLIN, C. J. R. PARKER AND J. M. HUNTER. Summary. British Journal of Anaesthesia 1995; 75: 31 36

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1 British Journal of Anaesthesia 1995; 75: Pharmacokinetics and pharmacodynamics of the three isomers of mivacurium in health, in end-stage renal failure and in patients with impaired renal function A. G. HEAD-RAPSON, J. C. DEVLIN, C. J. R. PARKER AND J. M. HUNTER Summary We have studied the pharmacokinetics of cis-trans, trans-trans and cis-cis mivacurium in nine healthy patients (creatinine clearance ml min 1 ), in seven patients with end-stage renal failure requiring dialysis (creatinine clearance 4 11 ml min 1 ) and in seven patients with impaired renal function (creatinine clearance ml min 1 ), during thiopentone fentanyl midazolam nitrous oxide oxygen anaesthesia. Mivacurium chloride was infused at a rate of 15 g kg 1 min 1 for 10 min, 7.5 g kg 1 min 1 for a further 10 min, and then at a rate adjusted to maintain T1/ T0 at 5 %. The minimum duration of infusion was 60 min (range min). The plasma concentration of the three isomers was measured at regular intervals throughout the infusion, and for up to 300 min after the infusion was stopped. Compartmental analysis of the resulting isomer profiles was undertaken: one- and two-compartment models were fitted to derive clearance, volume of distribution and terminal elimination half-life. Clearance of the cis-cis isomer was reduced significantly in the renal failure (median 2.4 (range ) ml kg 1 min 1 ) and intermediate renal function groups (2.1 ( ) ml kg 1 min 1 ), compared with healthy patients (3.8 ( ) ml kg 1 min 1 ) (P 0.01 in each case). There was no significant difference, within the sample size studied, between the clearance of the cis-trans isomer, in health (106 (26 147) ml kg 1 min 1 ), in renal failure (80 (22 135) ml kg 1 min 1 ) or with impaired renal function (87 (58 101) ml kg 1 min 1 ); or of the trans-trans isomer (57 (18 79) ml kg 1 min 1 ), (47 (16 88) ml kg 1 min 1 ) and (44 (40 55) ml kg 1 min 1 ), respectively). Clearance of each isomer correlated significantly with plasma cholinesterase activity (cis-trans, r 0.55, P 0.01; trans-trans, r 0.62, P 0.01), although this could be demonstrated only in healthy patients for the cis-cis isomer (r 0.67, P 0.05). There was no significant difference in the terminal half-lives of any isomer between the groups: cis-cis, healthy (68 (41 204) min), renal failure (80 (55 153) min), impaired renal function (101 (66 157) min); cis-trans, healthy (2.0 ( ) min), renal failure (4.3 ( ) min), impaired renal function (3.5 ( ) min; trans- trans, healthy (2.3 ( ) min), renal failure (4.2 ( ) min), impaired renal function (13.4 (2.1 50) min). Volume of distribution was similar for each isomer in all three groups. The median infusion rate required to maintain T1/ T0 at 5 % was significantly increased in the impaired renal function group, at 10.0 g kg 1 min 1, compared with both healthy patients (5.9 g kg 1 min 1 ) and renal failure patients (5.0 g kg 1 min 1 ) (P 0.05 in each case). (Br. J. Anaesth. 1995; 75: 31 36) Key words Neuromuscular block, mivacurium. Pharmacokinetics, mivacurium. Pharmacokinetics, stereoisomers. Kidney, failure. Pharmacodynamics. The stereospecific pharmacokinetics of the three isomers of mivacurium, the cis-trans (37 %) and trans-trans (57 %), and the much less active cis-cis isomer (6 %), have been described in healthy patients [1] and in those with hepatic cirrhosis [2]. The pharmacodynamics of mivacurium given by infusion have been studied in renal failure patients [3]; a slower mean infusion rate was needed to maintain neuromuscular block of T1/ T0 at 5 % (6.3 g kg 1 min 1 compared with 10.4 g kg 1 min 1 in healthy patients). Recovery from block at the end of the infusion was also prolonged in the anephric group; mean recovery index (25 75 % recovery T1/ T0) was 12.2 min, compared with 7.7 min in the healthy group. These findings may have been accounted for by the lower plasma cholinesterase activity in the renal failure patients, but further clarification requires pharmacokinetic analysis. The pharmacokinetics of mivacurium were studied by Cook and colleagues in a group of patients with end-stage renal failure [4]. They derived pharmacokinetic variables for the active component of mivacurium, and could demonstrate no difference in clearance, volume of distribution or mean residence time between healthy and renal failure patients. A. G. HEAD-RAPSON, BSC, MB, FRCA, J. C. DEVLIN, MB, FRCA, C. J. R. PARKER, MA, MD, FRCA, J. M. HUNTER, MB, FRCA, University Department of Anaesthesia, Royal Liverpool University Hospital, PO Box 147, Prescot Street, Liverpool L69 3BX. Accepted for publication: February 9, 1995.

2 32 British Journal of Anaesthesia The aim of this study was to compare the pharmacokinetics of each isomer during an infusion of mivacurium in healthy patients, in patients in end-stage renal failure and in a group of patients with impaired renal function not requiring dialysis. Patients and methods The study was approved by the Committee of Safety of Medicines and the Hospital Ethics Committee. All patients gave written, informed consent. We studied nine healthy subjects (creatinine clearance 65 ml min 1 ), seven patients in end-stage renal failure (creatinine clearance 15 ml min 1 ) and seven patients with impaired renal function (creatinine clearance ml min 1 ). The patients in the latter group were renal transplant recipients receiving immunosuppressant therapy, and they had a variable degree of renal function. All patients were undergoing procedures expected to last at least 1 h; in the healthy and impaired renal function groups, these were general surgical procedures such as laparoscopic cholecystectomy, in the renal failure group, they were mainly vascular access procedures. We did not study patients undergoing renal transplantation. Patients were excluded if they had a history of neuromuscular disorder, asthma, hepatic impairment, difficult tracheal intubation or if they were receiving drugs known to interfere with neuromuscular transmission, plasma cholinesterase activity or the HPLC assay. Patients in the renal failure group were receiving sodium bicarbonate, aluminium hydroxide, ferrous sulphate and erythropoietin. Impaired renal function patients were receiving either cyclosporin mg day 1 (two patients), cyclosporin and prednisolone 5 20 mg day 1 (three patients) or cyclosporin, prednisolone and azathioprine mg day 1 (two patients). All patients had preoperative measurements of haemoglobin concentration, platelet count, urea, and serum electrolyte and albumin concentrations; liver function tests were also performed. Before surgery, plasma cholinesterase activity was meaured using a spectrophotometric method [5] and the dibucaine and fluoride numbers were determined [6]. ASA II and III patients had a chest x-ray and electrocardiogram before operation. Creatinine clearance was measured before surgery in the renal failure and intermediate groups. In the healthy patients, creatinine clearance was calculated from plasma creatinine concentration using standard formulae [7]: (140 age ) weight (kg) males: creatinine ( µ mol litre ) (140 age ) weight (kg) females: creatinine ( µ mol litre ) Patients were premedicated with oral diazepam 10 mg, 2 h before operation. Anaesthesia was induced with midazolam 0.05 mg kg 1, fentanyl 1 2 g kg 1 and thiopentone 3 5 mg kg 1, and maintained with 70 % nitrous oxide in oxygen, together with bolus doses of fentanyl, midazolam and thiopentone as clinically indicated. After induction of anaesthesia, train-of-four (TOF) stimuli were applied to the ulnar nerve at the wrist at 12-s intervals and the surface compound action potential over the adductor pollicis was recorded using a Medelec MS6 [8]. An i.v. cannula for infusion of mivacurium was inserted in one limb and a 14-gauge cannula for blood sampling was placed in the arm used to monitor the electromyographic response. This arm was wrapped in cotton wool padding, but skin temperature was not measured. After a baseline blood sample had been obtained, mivacurium was infused using an Ohmeda 9000 pump at a rate of 15 g kg 1 min 1 for 10 min, 7.5 g kg 1 min 1 for a further 10 min, and then the rate was adjusted to keep the first twitch of the TOF (T1/ T0) at 5 % for the remainder of the procedure. Blood samples (7 ml) were obtained from the opposite limb to that used to infuse mivacurium at 1, 2, 5, 10, 11, 12, 15, 20, 30, 45 and 60 min after the start of the infusion, then at 30-min intervals until the infusion was stopped, and at 0, 1, 2, 5, 10, 15, 30, 45, 60, 120, 180, 240 and 300 min after termination of the infusion. All samples were placed immediately into lithium heparin bottles containing phospholine iodide 5 mg to inhibit plasma cholinesterase. After separation, the plasma samples were frozen until analysis. Tracheal intubation was attempted at 8 min after the start of the infusion. This slow initial infusion, rath er th an a bolus injection of mivacurium 0.15 mg kg 1, was used to facilitate determination of the kinetics of the two more potent and short-acting isomers. Normocapnia was maintained throughout using a Datex Capnomac. Electromyographic monitoring was continued throughout surgery and until T1/ T0 had recovered to at least 85 % and the TOF ratio (T4/ T1) had reached at least 80 %. No anticholinesterase was given. After completion of surgery, and when T4/ T1 was greater than 80 %, anaesthesia was discontinued and, when ventilation was considered adequate, the trachea was extubated. The isomeric content of any batch of mivacurium may vary slightly. The drug used in this study was supplied by the Wellcome Foundation plc. Before use, th e solution was known to h ave a total mivacurium content of % of that stated on the label, and the relative proportions of the three isomers were: cis-trans 36.4 %, trans-trans 57.5 % and cis-cis 6.1 %. Mivacurium isomer concentrations were measured using a stereospecific HPLC assay. The drug assay was automated ( ASPEC, Gilson). The isomers of mivacurium were extracted from plasma by a solid phase technique (Phenyl Bond-Elut cartridges), separated chromatographically on a strong cation exchange ( Spherisorb SCX5 ) column and detected fluorimetrically. The lower limit of detection of the assay was 2.5 ng ml 1, its calibration was linear over the range ng ml 1 and the coefficient of variation for the three isomers was %. Compartmental analysis of the resulting isomer profiles was carried out using the NONMEM

3 Pharmacokinetics and pharmacodynamics of mivacurium 33 Table 1 Patient characteristics, cholinesterase activity and creatinine clearance in the three groups (mean (SD) [range]). **P 0.01 Healthy (n 9) Renal failure (n 7) Impaired renal function (n 7) Age (yr) 40 [20 61] 46 [28 64] 30 [17 54]** Weight (kg) 71 [48 84] 67 [40 80] 62 [43 72] Sex (M : F) 5 : 4 3 : 4 5 : 2 Cholinesterase activity ( i.u. litre 1 ) 932 (214) 837 (232) 799 (250) (normal range i.u. litre 1 ) [ ] [ ] [ ] Creatinine clearance 99 (24) 8.6 (2.5) 46 (6.3) (ml min 1) [66 133] [4 11] [32 49] Figure 1 Plasma profiles of the three isomers in a healthy patient, with mivacurium infused at 15 g kg 1 min 1 for 10 min, 7.5 g kg 1 min 1 for a further 10 min and then 5 g kg 1 min 1 for the remaining 70 min (cis-trans ("), trans trans ( ), cis-cis (!)). Table 2 Steady state infusion rate and duration of infusion in the three groups (median (SD) [range]). *P 0.05 compared with both healthy and renal failure groups Health y (n 9) Renal failure (n 7) Impaired renal function (n 7) Infusion rate 5.9(2.4) 5.0(3.4) 10.0(3.0)* ( g kg 1 min 1 ) [ ] [ ] [ ] Duration (min) 100 (55) 115 (33) 60 (45) [60 235] [60 150] [60 180] program in single patient mode [9]; one- and twocompartment models were fitted. Elimination was assumed to be from the central compartment only. A two-compartment model was preferred if it resulted in a significant decrease in the NONMEM objective function (more than 7.6; P 0.05). Values for clearance and total (steady state) volume of distribution were obtained from the compartmental analysis, and the terminal half-life was calculated using standard formulae [10]. The electromyographic recording from each patient was analysed to determine the times to 95 % and maximum depression of T1/ T0, and the maximum depression of T1/ T0 (%) achieved during the mivacurium infusion. The times to recovery of T1/ T0 to 10 %, 25 % and 75 %, the recovery index (time for T1/ T0 to recover from 25 % to 75 %), and the time for T4/ T1 to return to 70 % were also noted. Physical characteristics and cholinesterase activity Figure 2 Plasma profiles of each of the three isomers, cis-trans (A), trans-trans (B) and cis-cis (C) (mean (SEM)) in healthy patients (!), renal failure patients (") and in the impaired renal function group ( ) on cessation of mivacurium infusion. of the three groups were compared with ANOVA and Student s unpaired t test. Pharmacokinetic variables of the three groups, and the pharmaco-

4 34 British Journal of Anaesthesia dynamic and infusion rate data were compared using Kruskal Wallis, non-parametric, one-way analysis of variance. Where differences between the groups were detected, the Mann Whitney U test was used to determine which groups differed significantly. Plasma clearance, infusion rates and cholinesterase activity were tested for correlation with Pearson s correlation coefficient. Results Plasma cholinesterase activity did not differ significantly in the three groups, and the median value in each group was within the normal range (table 1). One patient in the renal failure group and one in the impaired renal function group was heterozygous for both the dibucaine and fluoride genes (renal failure: cholinesterase activity 848 i.u. litre 1 (normal i.u. litre 1 ), dibucaine number 57 (normal 77 83), fluoride number 42 (normal 55 67); impaired renal function: cholinesterase activity 418 i.u. litre 1, dibucaine number 67, fluoride number 48). Plasma profiles of the three isomers in a typical healthy subject are shown in figure 1. In this patient the duration of infusion was 90 min. The cis-trans and trans-trans isomers appeared to reach a steady state plasma concentration during the infusion, and the plasma concentration declined rapidly when the infusion was stopped. For the cis-cis isomer, at 90 min the plasma concentration was still increasing and the decrease in plasma concentration on cessation of the infusion was much more prolonged. Median steady state infusion rates and total duration of infusion are shown in table 2. In all three groups a wide variation in steady state infusion rate was apparent. The infusion rate required to maintain T1/ T0 at 5 % was significantly higher for the impaired renal function group than for both the healthy and renal failure patients. The infusion rate correlated significantly with plasma cholinesterase activity (r 0.54, P 0.01). The decline in plasma concentration of each of the three isomers on cessation of the infusion is shown for each of the three groups in figure 2. There was little difference in these terminal plasma profiles between the groups for the cis-trans and the transtrans isomers (fig. 2A, B). The elimination of the ciscis isomer, however, was prolonged, particularly in the impaired renal function group (fig. 2C). A two-compartment model was a significantly better fit than a one-compartment model in all 23 data sets for the cis-cis isomer and for five of the 23 data sets for the trans-trans isomer; for the data sets for the cis-trans isomer there was no improvement on the one-compartment model. Values for clearance, terminal half-life and volume of distribution are shown in table 3. Clearance of the cis-cis isomer was reduced significantly in both the renal failure and intermediate renal function groups compared with the healthy patients. There was no significant difference in the clearance of the cis-trans or trans-trans isomers with the sample size studied. Clearance of the cis-trans and trans-trans isomers correlated significantly with plasma cholinesterase activity (fig. 3); cis-trans, r 0.55, P 0.01 (n 23), trans-trans, r 0.62, P 0.01 (n 23). For the cis-cis isomer, there was a significant correlation in healthy patients only; cis-cis, r 0.67, P 0.05 (n 9). There was no significant difference between the groups in the volume of distribution of any isomer. There was no significant difference in the terminal half-lives of any isomer between the groups (table 3), although the range of values was consistently greater in the impaired renal function group. Time to maximum block was reduced significantly in the intermediate renal function group compared with Table 3 Pharmacokinetic variables during infusion of mivacurium chloride in healthy patients, renal failure patients and patients with an intermediate degree of renal function (median (SD) [range]). **P 0.01 compared with the healthy group Clearance (ml kg 1 min 1 ) V ss (ml kg 1 ) T β ½ (min) Cis-cis mivacurium Healthy 3.8 (0.7) 227 (54) 68 (49) [ ] [ ] [41 204] Renal failure 2.4 (0.2)** 244 (106) 80 (33) [ ] [ ] [55 153] Impaired renal function 2.1 (0.3)** 265 (48) 101 (30) [ ] [ ] [66 157] Cis-trans mivacurium Healthy 106 (36) 278 (145) 2.0 (1.1) [26 147] [ ] [ ] Renal failure 80 (40) 475 (245) 4.3 (1.8) [22 135] [72 883] [ ] Impaired renal function 87 (16) 443 (209) 3.5 (2.9) [58 101] [ ] [ ] Trans-trans mivacurium Healthy 57 (18) 211 (81) 2.3 (2.3) [18 79] [ ] [ ] Renal failure 47 (23) 270 (140) 4.2 (1.6) [16 88] [55 533] [ ] Impaired renal function 44 (6) 244 (149) 13.4 (17) [40 55] [ ] [2.1 50]

5 Pharmacokinetics and pharmacodynamics of mivacurium 35 both healthy and renal failure patients. All other pharmacodynamic onset and recovery variables were similar (table 4). There was no significant correlation between plasma cholinesterase activity and recovery from neuromuscular block after the infusion had been stopped, in any of the three groups. Figure 3 Correlation of clearance of the three isomers, cistrans (A) (r 0.55, P 0.01), tranf-trans (B) (r 0.62, P 0.01) and cis-cis (C) (healthy, r 0.67, P 0.05; renal failure, r 0.37, ns; impaired renal function, r 0.09, ns) with plasma cholinesterase activity in healthy patients (!), renal failure patients (") and in the impaired renal function group ( ). Discussion The short-lived cis-trans and trans-trans isomers of mivacurium are metabolized predominantly by plasma cholinesterase and have very high rates of clearance (106 and 57 ml kg 1 min 1, respectively). The values derived here are consistent with those from previous stereospecific studies [1, 2]. There appeared to be little difference in the pharmacokinetics of these active isomers between renally compromised and healthy patients, which is the conclusion Cook and colleagues reached in their non-stereospecific study [4]. The strong positive correlation between plasma cholinesterase activity and clearance of these two isomers suggests that recovery from neuromuscular block is largely enzyme-dependent. A further finding of this study was the significantly reduced rate of clearance of the cis-cis isomer of mivacurium in patients with end-stage renal failure, and in those with impaired renal function. The reduced clearance of this isomer is comparable with a neuromuscular blocking agent which is excreted in part through the kidney, such as vecuronium [11]. In addition, cis-cis mivacurium is metabolized by plasma cholinesterase in healthy patients (fig. 3C). It is fortunate that this isomer has little neuromuscular blocking potency (ED 95 in anaesthetized cats: cis-cis 592 g kg 1 compared with cis-trans 45 g kg 1 and trans-trans 42 g kg 1 [12]), as it may accumulate in renal failure patients receiving prolonged infusions of mivacurium. We found no difference in recovery from neuromuscular block between healthy patients and those with renal dysfunction in this study (table 4) and this Table 4 Pharmacodynamic onset and recovery data during and after infusion for the three groups (median (SD) [range]). *P Healthy ( n 9 ) Renal failure ( n 7 ) Impaired renal Function ( n 7 ) Onset 95 % T1/ T0 8.4 (7.7) 8.8 (4.5) 8.1 (0.8) depression (min) [ ] [ ] [ ] (n 4) Maximum T1/ T (8.0) 12.2 (3.5) 11.3 (0.7)* depression (min) [ ] [ ] [ ] Maximum block (%) 99 (1.0) 99.1 (1.7) 97.4 (3.1) [ ] [96 100] [ ] Recovery 10 % T1/ T0 8.0 (2.8) 6.4 (1.9) 7.0 (5.4) recovery [ ] [ ] [ ] 75 % T1/ T (7.7) 23.8 (6.5) 17.7 (10.0) recovery [ ] [ ] [ ] Recovery index 9.9 (3.6) 10.8 (3.4) 7.6 (3.5) (25 75 % T1/ T0) [ ] [ ] [ ] 70 %T4/T (9.2) 25.5 (9.1) 24.2 (11.7) recovery [ ] [ ] [ ]

6 36 British Journal of Anaesthesia probably reflects the similar plasma cholinesterase activities in each group. Patients with renal failure may have reduced cholinesterase activity [13, 14]. In a study of a larger number of patients, prolongation of neuromuscular block was demonstrated in 20 anephric patients with a plasma cholinesterase activity significantly lower than healthy controls [3]. Neuromuscular monitoring should certainly be used routinely when mivacurium is given to patients with abnormal renal function, as they may have reduced plasma cholinesterase activity (of which the anaesthetist would be unaware) and thus prolonged recovery. The significantly higher infusion rate required by the impaired renal function group was notable. There are many causes of resistance to nondepolarizing neuromuscular blocking agents, with changes in volume of distribution, plasma protein binding and receptor sites being implicated [15]. All patients in this group had a functioning renal transplant, and these effects may have been caused by the intercurrent immunosuppressive therapy. Two patients were receiving azathioprine which may antagonize neuromuscular block; this has been shown to be caused by phosphodiesterase inhibition [16]. In clinical practice, however, such antagonism is thought to be slight and transient [17]. In contrast, the potentiation of neuromuscular block by cyclosporin has been clearly demonstrated, both in the cat, where it has been shown to increase the neuromuscular block produced by both atracurium and vecuronium [18] and, anecdotally, in a patient given pancuronium [19]. The mechanism for this is unknown, but when aminosteroids are used, may be caused by hepatic enzyme inhibition. It contrasts with the present study, where a relative resistance to neuromuscular block occurred in patients taking cyclosporin who received a benzylisoquinolinium neuromuscular blocking agent. Acute glucocorticoid therapy may also potentiate non-depolarizing neuromuscular blocking agents, although the effects of long-term therapy are less clear [20]. Renal failure has been shown to affect not only hepatic drug metabolism, but also metabolism by extrahepatic routes [21]. Preliminary analysis of the population pharmacokinetics of the cis-cis isomer found evidence for its elimination by plasma cholinesterase, by renal function, and by a third, unspecified, mechanism in the impaired renal function group [22]. This isomer may undergo hepatic or extrahepatic metabolism which may become significant if plasma cholinesterase activity or renal elimination is impaired. Acknowledgements We thank the Wellcome Foundation plc for supplying mivacurium, and providing a grant towards this study. We are also grateful to G. G. Lovell, G. A. Ridout and A. Jeffries for performing the assay, and Mrs E. Lawton for measuring plasma cholinesterase activities. References 1. Lien CA, Schmith VD, Embree PB, Belmont MR, Wargin WA, Savarese JJ. The pharmacokinetics and pharmacodynamics of the stereoisomers of mivacurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 1994; 80: Head-Rapson AG, Devlin JC, Parker CJR, Hunter JM. Pharmacokinetics of the three isomers of mivacurium and pharmacodynamics of the chiral mixture in hepatic cirrhosis. British Journal of Anaesthesia 1994; 73: Phillips BJ, Hunter JM. Use of mivacurium chloride by constant infusion in the anephric patient. British Journal of Anaesthesia 1992; 68: Cook DR, Freeman JA, Lai AA, Kang Y, Stiller RL, Aggarwal S, Harrelson JC, Welch RM, Samara B. Pharmacokinetics of mivacurium in normal patients and in those with hepatic or renal failure. British Journal of Anaesthesia 1992; 69: Kalow W, Lindsay HA. A comparison of optical and manometric methods for the assay of human serum cholinesterase. Canadian Journal of Biochemistry and Physiology 1955; 55: Kalow W, Genest K. A method of detection of atypical forms of human pseudocholinesterase. Canadian Journal of Biochemistry and Physiology 1957; 35: Cockcroft DW, Gault MH. Production of creatinine clearance from serum creatinine. Nephron 1976; 16: Kent AP, Hunter JM. The pharmacodynamics of alcuronium in the elderly. Anaesthesia 1991; 46: Boeckmann AJ, Sheiner LB, Beal SL. NONMEM V4.0, User Guide Part V. University of California, San Francisco, CA: NONMEM Project Group, 1992; Gibaldi M, Perrier D. Pharmacokinetics, 2nd Edn. New York: Dekker, 1982; Lynam DP, Cronnelly R, Castagnoli KP, Canfell PC, Caldwell J, Arden J, Miller RD. The pharmacodynamics and pharmacokinetics of vecuronium in patients anesthetized with isofluranc with normal renal function or with renal failure. Anesthesiology 1988; 69: Maehr RB, Belmont MR, Wray DL, Savarese JJ, Wastila WB. Autonomic and neuromuscular effects of mivacurium and isomers in cats. Anesthesiology 1991; 75: A Thomas JL, Holmes JH. Effect of hemodialysis on plasma cholinesterase. Anesthesia and Analgesia 1970; 49: Ryan DW. Preoperative serum cholinesterase concentration in chronic renal failure. British Journal of Anaesthesia 1977; 49: Hunter JM. Resistance to non-depolarizing neuromuscular blocking agents. British Journal of Anaesthesia 1991; 67: Dretchen KL, Morgenroth VH III, Standaert FG, Walts LF. Azathioprine: effects on neuromuscular transmission. Anesthesiology 1976; 45: Gramstad L. Atracurium, vecuronium and pancuronium in end-stage renal failure. Dose response properties and interactions with azathioprine. British Journal of Anaesthesia 1987; 59: Gramstad L, Gjerløw JA, Hysing ES, Rugstad HE. Interaction of cyclosporin and its solvent, cremophor, with atracurium and vecuronium. British Journal of Anaesthesia 1986; 58: Crosby E, Robblee JA. Cyclosporine pancuronium interaction in a patient with a renal allograft. Canadian Journal of Anaesthesia 1988; 35: Durant NN, Briscoe JR, Katz RL. The effects of acute and chronic hydrocortisone treatment on neuromuscular blockade in the anesthetized cat. Anesthesiology 1984; 61: Elston AC, Bayliss MK, Park GR. Effect of renal failure on drug metabolism by the liver. British Journal of Anaesthesia 1993; 71: Parker CJR, Head-Rapson AG, Devlin JC, Hunter JM. Pharmacokinetics of cis-cis mivacurium: a population approach. British Journal of Anaesthesia 1993; 71: P.