Aims To determine the effects of hepatic cirrhosis on the pharmacodynamics and pharmacokinetics of rocuronium bromide. Methods We studied 21 healthy patients and 17 patients with mild or moderate cirrhosis (Child-Pugh Class A and B). Patients were premedicated with diazepam orally; anaesthesia was induced with fentanyl and thiopentone, and maintained with isoflurane 0.6% (end-tidal) and nitrous oxide 66% in oxygen. The compound action potential of the adductor pollicis muscle in response to supramaximal stimulation of the ulnar nerve was recorded using the train-of-four (TOF) twitch technique. A bolus dose of rocuronium 0.6 mg kg −1 was then given. Venous blood samples were taken for up to 8 h, and plasma rocuronium concentrations determined by h.p. Keywords: hepatic cirrhosis, neuromuscular block, rocuronium (Child's class B), and eight healthy patients, Khalil and Introduction colleagues [6] found that the onset of neuromuscular block was slower in cirrhotic than in healthy patients (158 s vs Rocuronium bromide is an aminosteroid non-depolarizing neuromuscular blocking agent with a more rapid onset of 108 s), and that recovery of twitch height (T 1 5T 0 ) to 75% and 90% was prolonged. The plasma concentrations of action than other currently available non-depolarizing drugs, but a duration of action comparable with vecuronium [1].rocuronium were more variable in the cirrhotic patients, and pharmacokinetic analysis showed that the central volume The other aminosteroid non-depolarizing neuromuscular blocking drugs, pancuronium and vecuronium, have been of distribution and mean residence time were greater in the cirrhotic. Although the mean clearance was lower in the shown to have a prolonged effect and an increased elimination half-life in hepatic cirrhosis [2,3]. Rocuronium, cirrhotic group (2.41 vs 2.79 ml kg −1 min −1 ), this did not achieve statistical significance. More recently, Magorian and like vecuronium, is a monoquaternary cation and might be expected to undergo considerable biliary excretion [4], and colleagues studied a group of 10 patients with liver dysfunction of diverse aetiology and compared them with this has been directly suggested by work in the cat [5].There have been two previous studies of the pharmaco-10 healthy patients studied previously [7]. They found no difference in either time to onset of block or recovery of dynamics and pharmacokinetics of rocuronium in cirrhosis, with conflicting findings. In a study of 10 cirrhotic patients twitch height (T 1 5T 0 ) to 25% (clinical duration). They applied a population approach to pharmacokinetic analysis, and found an increase in initial volume of distribution (V 1 ), and also an increase in the peripheral compartments (V 2 and

The pharmacokinetics of a bolus dose of atracurium 0.6 mg kg-1 and its metabolite laudanosine were studied in 11 elderly (mean age 80.9 yr) and 10 young patients (mean age 23.8 yr) undergoing elective surgery. The elimination half-life (T1/2 beta) of atracurium was significantly longer in the elderly group (23.1 v. 20.1 min), but there was no significant difference between the two groups in clearance (Cl), the volume of distribution (V beta) or the mean residence time (MRT) of atracurium. Laudanosine T1/2 beta was also significantly longer (229.1 v. 173.1 min) and the clearance significantly slower (4.85 v. 7.29 ml min-1 kg-1) in the elderly. There was, however, no significant difference in V beta for laudanosine between the two groups. These data suggest that atracurium depends to a small extent on the liver or the kidney for its metabolism and excretion, and that, as these routes of excretion are less efficient in the elderly, T1/2 beta is prolonged in this age group. The deteriorating function of these organs with increasing age may also explain the altered pharmacokinetics of laudanosine.

We have studied the pharmacodynamics of the 1R cis-1'R cis isomer of atracurium (51W89) in 15 healthy subjects and in 17 patients with chronic renal failure using a bolus dose of 51W89 0.1 mg kg-1 (2 x ED95). Fifteen patients with normal renal function were investigated also using an approximately equipotent dose of atracurium (0.4 mg kg-1). The compound surface action potential of the adductor pollicis muscle, in response to train-of-four stimulation of the ulnar nerve at the wrist, was recorded until recovery of the height of the first response of the train-of-four compared with baseline (T1:T0) had reached at least 85% and the train-of-four ratio (T4:T1) at least 80%. In the healthy and renal failure patients who received 51W89, there were no significant differences in any of the onset or recovery variables except for the time to 90% depression of T1:T0, which was longer in patients with renal failure (mean 3.7 min vs 2.4 min; P < 0.05). Of the healthy patients who were given either 51W89 or atracurium, there were no significant differences in the onset data, except for time to maximum block, which was longer in the 51W89 group (mean 7.7 min vs 6.2 min; P < 0.01). The mean times to 10%, 25%, 50% and 75% recovery of T1:T0 and the time for T4:T1 > 70% were significantly longer in patients receiving 51W89.(ABSTRACT TRUNCATED AT 250 WORDS)

To ascertain the effects of chronic renal failure on the pharmacokinetics of 1R-cis 1'R-cis atracurium besylate (a stereoisomer, designated 51W89), we gave a bolus dose of 0.1 mg kg-1 (2 x ED95) to 17 patients with end-stage renal failure and to 15 patients with normal renal function undergoing elective surgery. All patients received thiopentone, fentanyl and midazolam i.v. and 70% nitrous oxide in oxygen. Blood samples were obtained over 8 h and plasma analysed for 51W89 and laudanosine concentration, using high pressure liquid chromatography. A two-compartment model was fitted to the 51W89 plasma concentration data using the NONMEM program, to estimate pharmacokinetic variables and to determine the influence of renal failure, age, weight and sex. Clearance of 51W89 was found to be reduced by 13% in renal failure. The typical value of T1/2 beta was 4.2 min longer in renal failure than in the healthy patients (34.2 vs 30.0 min, P < 0.005). In the healthy patients, clearance of 51W89 was greater in males, but it decreased with increasing age by approximately 1.5 ml min-1 yr-1. Mean plasma laudanosine concentrations were significantly higher in the renal failure group; nevertheless, they were approximately one-tenth of those reported after atracurium.

SummaryWe have compared the pharmacokinetics of cisatracurium with atracurium when given by bolus dose followed by continuous infusion. Twenty healthy patients were anaesthetised with thiopentone, midazolam, fentanyl and 70% nitrous oxide in oxygen. Ten patients (Group C) were randomly allocated to receive cisatracurium 0.1 mg.kg ¹1 and 10 patients (Group A) were given atracurium 0.5 mg.kg ¹1. Neuromuscular block was monitored using a mechanomyograph. When the first twitch of the train-of-four had recovered to 5% of control, an infusion of cisatracurium 3 mg.kg ¹1 .min ¹1 was started in Group C and an infusion of atracurium 10 mg.kg ¹1.min ¹1 was started in Group A. The infusion rates were adjusted to maintain the first twitch of the train-offour at 5% of control. The times to 90% and maximum depression of the first twitch of the trainof-four were significantly longer after cisatracurium than atracurium (2.2 and 3.4 min compared with 1.3 and 1.8 min, respectively; p < 0.01 in each instance). No significant differences were found in recovery parameters between the two groups. Blood samples were taken at regular intervals following the bolus, during the infusion and for 8 h thereafter. The plasma samples were analysed using high-performance liquid chromatography for cisatracurium and atracurium (using a method which distinguishes between the three geometric isomer groups), laudanosine and monoquaternary alcohol. The results were analysed using the Non-linear Mixed Effects Model program. A two-compartment model was fitted to the data. The different isomer groups of atracurium have different pharmacokinetics, the trans-trans group having the highest clearance (1440 ml.min ¹1 ) and the cis-cis group the lowest (499 ml.min ¹1). The clearance of cisatracurium (425 ml.min ¹1 ) is less than that of cis-cis atracurium and its elimination half-life is longer (34.9 min and 21.9 min, respectively). The plasma concentration of laudanosine after cisatracurium was onefifth of that after atracurium. The neuromuscular blocking agent atracurium besylate consists of three groups of geometric isomers: three cis-cis, four cis-trans and three trans-trans [1]. The properties of each of the isomers have been studied to determine whether any possess fewer side-effects than the parent drug. One of the cis-cis isomers, cisatracurium (51W89: 1R-cis 1 0 R-cis atracurium) makes up 15% of atracurium

Prolonged low intraoperative BIS TM levels predict increased risk of post-operative mortality: two-year follow-up report.

Maternal venous (MV), umbilical venous (UV) and umbilical arterial (UA) blood samples were obtained for assay of atracurium, laudanosine and monoquaternary alcohol concentrations in 22 healthy patients undergoing elective Caesarean section under general anaesthesia. At delivery (at a mean time of 8.2 min after atracurium 0.3 mg kg-1), the mean UV concentrations were 103 ng ml-1 (range 44-189 ng ml-1) for atracurium, 26 ng ml-1 (range 6-60 ng ml-1) for laudanosine and 59 ng ml-1 (range 21-148 ng ml-1) for monoquaternary alcohol. The ratios of UV:MV, UA:MV and UA:UV blood concentrations were related positively to time since injection of atracurium for all three substances (P less than 0.01 in each instance). The UV:MV ratio at delivery was greatest for laudanosine: mean 19.4% (range 1-35%), compared with 7% (range 2-21%) for atracurium and 10% (range 0-15%) for monoquaternary alcohol. These low values confirm that, although atracurium crosses the placental barrier and its metabolites may be found in the fetus, the drug is safe to use during Caesarean section.

We have measured the steady state urinary clearances of atracurium, given by constant infusion, and laudanosine in eight patients undergoing artificial ventilation; all had normal renal function (mean creatinine clearance 81 ml min-1). Mean (SD) urinary clearance of atracurium was 0.55 (0.5) ml kg-1 min-1; that of laudanosine was 0.33 (0.2) ml kg-1 min-1. Simultaneous plasma clearances were 7.1 (1.4) ml kg-1 min-1 and 3.8 (1.5) ml kg-1 min-1, respectively. Notional haemofiltration clearances of the two substances were measured also in seven critically ill patients with renal and respiratory failure undergoing continuous venovenous haemofiltration. Mean (SD) clearances of atracurium and laudanosine in the haemofiltrate fluid were 0.11 (0.06) ml kg-1 min-1 and 0.09 (0.02) ml kg-1 min-1, respectively whilst plasma clearances were atracurium 6.7 (1.8) ml kg-1 min-1 and laudanosine 4.5 (1.8) ml kg-1 min-1. There were no significant differences between the plasma clearances of the drugs in the two groups, despite the difference in severity of sickness. Urinary clearance rates of atracurium and laudanosine were approximately 8 and 9% of that in the plasma, but the haemofiltration clearance of both substances was only 2%.