The pharmacokinetics and pharmacodynamics of rocuronium in patients with hepatic cirrhosis.

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.l.c. RESULTS: The time to onset of neuromuscular block and maximal block achieved did not differ between the two groups. The mean (s.d.) recovery times were prolonged in the cirrhotic compared with the healthy group: 25% recovery T1:T0, 53.7 (18.1) vs 42.3 (14.2) min; 50% recovery T1:T0, 73.9 (33.9) vs 52.6 (19.8) min; 75% recovery T1:T0, 84.2 (24.5) vs 66.8 (27.2) min (all P<0.05); recovery of T4:T1 to 70%, 114.9 (31.7) vs 76.1 (28.8) min (P<0.01). A pharmacokinetic and pharmacodynamic model was fitted to the data for each patient. Three compartments were used to model the pharmacokinetic data; an effect compartment was added to model the pharmacodynamic data. Plasma clearance was significantly reduced in the cirrhotic group (2.66 (0.60) vs 3.70 (1.03) ml kg(-1) min (-1); P<0.005). The central (V1) and steady state volumes of distribution (V(ss)) did not differ significantly between the groups. The slow redistribution (t1/2,lambda1) and elimination (t1/2,z) half-lives were both significantly prolonged in cirrhosis (28.3 (12.1) vs 16.8 (4.6) min, P < 0.005; and 143 (80) vs 92 (40) min, P < 0.05 respectively). The exit rate constant for the effect compartment k(eo) was significantly increased in the cirrhotic group (0.25 (0.18) vs 0.16 (0.06) min(-1); P < 0.05), but cirrhosis had no significant effect on the parameters of the concentration-effect relationship Cp(ss)(50) and gamma. CONCLUSIONS: Hepatic elimination is an important pathway in the clearance of rocuronium, and delayed disposition causes the effect to be prolonged.

A comparison of cisatracurium (51W89) and atracurium by infusion in critically ill patients.

OBJECTIVE: To evaluate and compare the safety and efficacy of cisatracurium (51W89) and atracurium administered by continuous infusion to critically ill patients requiring neuromuscular blocking agents to facilitate mechanical ventilation. DESIGN: Open, randomized, multicenter study of patients receiving cisatracurium or atracurium infusion to facilitate mechanical ventilation. SETTING: Five university teaching hospital intensive care units in the United Kingdom. PATIENTS: Sixty-one adult patients requiring neuromuscular blocking agents to facilitate mechanical ventilation. INTERVENTIONS: Bolus doses followed by continuous infusions of cisatracurium or atracurium were administered. Onset, maintenance, and recovery of neuromuscular blockade were measured, using transcutaneous ulnar nerve stimulation and an accelerometer. MEASUREMENTS AND MAIN RESULTS: Forty patients received cisatracurium (mean duration 48.1 +/- 4.2 [SEM] hrs), and 21 patients received atracurium (mean duration 46.1 +/- 5.8 hrs). The infusion rate for patients receiving cisatracurium was 3.1 +/- 0.2 microg/kg/min, and for patients receiving atracurium 10.4 +/- 0.9 microg/kg/min. There were no significant differences in mean times to 70% recovery of Train-of-Four ratio (cisatracurium 60 mins, atracurium 57 mins), although there was considerable interpatient variation (20 to 175 mins with cisatracurium vs. 35 to 85 mins with atracurium). One patient who received cisatracurium exhibited intermittent bronchospasm during and after the study period. CONCLUSIONS: Cisatracurium, an isomer of atracurium, appears to be a suitable agent for providing muscle relaxation in critically ill patients.

Pharmacokinetics and pharmacodynamics of cisatracurium in young and elderly adult patients.

BACKGROUND: The effects of a muscle relaxant may differ in elderly compared with young adult patients for a variety of reasons. The authors compared the effects of a new muscle relaxant (cisatracurium) in young and elderly adults and used pharmacokinetic/pharmacodynamic modeling to identify factors explaining differences in time course of effect. METHODS: Thirty-one young (18-50 yr) and 33 elderly ( > 65 yr) patients anesthetized with nitrous oxide, isoflurane, and fetanyl were studied. Cisatracurium (0.1 mg/kg) was given after induction of anesthesia and later additional boluses of 0.025 mg/kg or an infusion of cisatracurium was given. Neuromuscular transmission was measured using the first twitch of the train-of-four response at the adductor pollicis after supramaximal stimulation of the ulnar nerve at 2 Hz every 15 s. Five venous blood samples were obtained for plasma drug concentration at intervals ranging from 2 to 120 min from every patient. Three additional samples were obtained from those who received an infusion. A population pharmacokinetic/pharmacodynamic model was fitted to the plasma concentration and effect data. The parameters of the model were permitted to vary with age to identify where differences existed between young and elderly adults. RESULTS: Onset of block was delayed in the elderly; values being mean 3.0 (95% confidence interval 1.75-11.4) min and 4.0 (2.4-6.5) min in the young and elderly, respectively (P < 0.01). Duration of action was similar in the two groups. Plasma clearance was 319 (293-345) ml/min in the study population and did not differ between young and elderly patients. Apparent volume of distribution was 13.28 (9.9-16.7) 1 and 9.6 (7.6-11.7) 1 in the elderly and young adults, respectively (P < 0.05). There also were differences in pharmacodynamic parameters between the young and elderly; the predominant change being a slower rate of biophase equilibration (ke0) in the elderly (0.060 [0.052-0.068])/min compared with the young (0.071 [0.065-0.077]/min; P < 0.05). CONCLUSIONS: The pharmacokinetics of cisatracurium differ only marginally between young and elderly adults. Onset is delayed in the elderly because of slower biophase equilibration.

Comparison of the pharmacodynamics and pharmacokinetics of an infusion of cis-atracurium (51W89) or atracurium in critically ill patients undergoing mechanical ventilation in an intensive therapy unit.

We have studied 12 critically ill, sedated patients who required a neuromuscular blocking drug to assist mechanical ventilation in an intensive care unit. Patients were randomized to receive an infusion of cis-atracurium 0.18 mg kg-1 h-1 (group 1, n = 6) or atracurium 0.6 mg kg-1 h-1 (group 2, n = 6) preceded, if necessary, by a bolus dose of 2 x ED95 of the same drug (cis-atracurium 0.1 mg kg-1 or atracurium 0.5 mg kg-1). Neuromuscular block was monitored using an accelerograph and the infusion rate adjusted regularly so that it was possible to detect the first response to train-of-four (TOF) stimulation of the ulnar nerve at the wrist. Blood samples were obtained for estimation of plasma cis-atracurium and laudanosine concentrations (group 1) or the three groups of atracurium isomers and laudanosine (group 2). There was no apparent haemodynamic or allergic response to either drug. The mean infusion time in group 1 was 37.6 h and in group 2, 27.5 h. On termination of the infusion, the time for the TOF ratio to reach 0.7 was similar in the two groups (group 1 = 60 min; group 2 = 62 min). The mean infusion rate of cis-atracurium was 0.19 mg kg-1 h-1 and of atracurium 0.47 mg kg-1 h-1 (expressed as mg of bis-cation): cis-atracurium was 2.5 times more potent than atracurium. Using the NONMEM program, a single compartment pharmacokinetic model was fitted to the plasma concentrations of cis-atracurium and the cis-cis, cis-trans and trans-trans isomers of atracurium. The mean population pharmacokinetic values for cis-atracurium were: volume of distribution (V) = 21,900 (SEM 416) ml; clearance (Cl) = 549 (79) ml min-1; half-life (T1/2) = 27.6 (3.6) min; and for the three groups of atracurium isomers were: cis-cis, V = 15,100 (720) ml, Cl = 449 (42) ml min-1, T1/2 = 23.4 (1.2) min; cis-trans, V = 18,000 (667) ml, Cl = 1070 (43) ml min-1, T1/2 = 11.7 (0.1); trans-trans, V = 13,100 (1280) ml, Cl = 1560 (55) ml min-1, T1/2 = 5.8 (0.4) min. Plasma laudanosine concentrations were lower in the cis-atracurium (peak value 1.3 micrograms ml-1) than in the atracurium (maximum 4.4 micrograms ml-1) group.

Delusions in schizophrenia: a phenomenological and psychological exploration.

The psychopathological basis of delusions in schizophrenia is poorly understood. The most enduring of several early theories has suggested a causal link with formal thought disorder, whereas recent approaches have proposed relationships with a variety of cognitive abnormalities. The correlations of delusions with other schizophrenic symptoms and with cognitive functions including semantic memory, executive function, and also probabilistic reasoning bias, were examined in a series of (overlapping) groups of 43-79 schizophrenic patients. Delusions were found to be significantly correlated with formal thought disorder, with evidence for a particular link between bizarreness and fragmentariness of delusions and "loosening of association". Delusions were not significantly correlated with overall intellectual function or memory, although there was some suggestion of a complex interaction between delusions, formal thought disorder, and semantic memory impairment. No association between delusions, formal thought disorder, and any measure of executive function was found. Although, as a group, schizophrenic patients showed evidence of probabilistic reasoning bias, this was unrelated to presence and severity of delusions.

Pharmacokinetics of 1R-cis 1'R-cis atracurium besylate (51W89) and plasma laudanosine concentrations in health and chronic renal failure.

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.

Pharmacodynamics of the 1R cis-1'R cis isomer of atracurium (51W89) in health and chronic renal failure.

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)

Pharmacokinetics of 51W89: preliminary data.

The pharmacokinetics of the 1R cis-1'R cis-isomer of atracurium (51W89) and its metabolite, laudanosine, were studied in 11 healthy patients with normal renal function and in 12 patients with chronic renal failure undergoing regular dialysis. A bolus dose of 51W89 (0.1 mg/kg) was given, and the plasma concentration was measured at regular intervals for 480 min. The elimination half-life of 51W89 was significantly longer in renal failure patients than in healthy controls (38.9 min vs 30.6 min; P < 0.05). The plasma laudanosine levels were lower than those reported after an equipotent dose of atracurium besylate. 51W89 may have a prolonged effect in renal failure patients.

Manipulation for locked knee.

There is a type of locked knee in which the last 10 to 40 degrees of extension are lost. The manipulation used in the treatment of six patients is described. Manipulation in this instance should primarily be regarded as a first aid procedure to restore function and to stop the pain. The condition is usually caused by an abnormality of the lateral meniscus and meniscectomy may be required later.