Relationship between normalized adductor pollicis train-of-four ratio and manifestations of residual neuromuscular block: a study using acceleromyography during near steady-state concentrations of mivacurium.

BACKGROUND: Baseline acceleromyographic adductor pollicis train-of-four (TOF) ratio varies significantly between individuals and is often greater than unity. Thus, normalization of acceleromyography data is necessary. The relationship between normalized acceleromyographic TOF ratio, lung volumes, and clinical signs of residual neuromuscular block was studied. METHODS: In 12 healthy volunteers, three steady-state levels of neuromuscular block were achieved with mivacurium infusions. TOF ratio was measured acceleromyographically at the adductor pollicis using a preload. Lung volume measurements and a series of clinical tests were made at each stable block and reconciled to the normalized TOF measures. RESULTS: None experienced airway obstruction or arterial oxygen desaturation, even at normalized TOF ratio less than 0.4. Functional residual capacity remained unchanged whereas vital capacity decreased linearly with decreasing TOF ratio. The ability to protrude the tongue was preserved at all times. The ability to clench the teeth was lost in one volunteer at normalized TOF ratio of 0.84 but retained in four at normalized TOF ratio less than 0.4. Four volunteers lost the ability both to raise the head more than 5 s and to swallow, with the most sensitive individual demonstrating these effects at normalized TOF ratio of 0.60. At mean normalized TOF ratio of 0.42, the mean handgrip strength was approximately 20% of baseline value. CONCLUSION: Lung vital capacity decreased linearly with decreasing TOF ratio. Responses to clinical tests of muscle function varied to a large extent among individuals at comparable TOF ratios. None of the volunteers had significant clinical effects of neuromuscular block at normalized acceleromyographic TOF ratio greater than 0.90.

Influence of chronic phenytoin administration on the pharmacokinetics and pharmacodynamics of vecuronium.

BACKGROUND: The duration of action of vecuronium is reduced in patients receiving phenytoin. In this study, the authors examined, simultaneously, the influence of phenytoin on both the pharmacokinetics and the pharmacodynamics of vecuronium. METHODS: This study was approved by the institutional review board of the University of California, San Francisco, and patients gave written informed consent. Twenty-two patients, 11 taking phenytoin and all scheduled to undergo prolonged neurosurgical procedures with general anesthesia, participated in the study. In 12 patients (6 phenytoin, 6 control), vecuronium was infused at 7.5 microg x kg(-1) x min(-1) until the first response (T1) of each train-of-four decreased by 50%; in the remaining 10 patients (5 phenytoin, 5 control), 200 microg/kg vecuronium was infused over 10 min. Arterial blood samples were drawn at intervals over the next 5-7 h. Plasma concentrations of vecuronium and 3-desacetylvecuronium were measured by capillary gas chromatography. Pharmacokinetic and pharmacodynamic modeling was used to characterize the disposition of vecuronium and patient responses to it in the two groups. RESULTS: Clearance was typically increased by 138% (95% confidence interval, 93-183%) in patients taking phenytoin. The effect of vecuronium was well described using a sigmoid Emax model. The concentration of vecuronium giving 50% twitch depression was increased 124% (45-202%) in patients taking phenytoin. CONCLUSIONS: Chronic phenytoin therapy reduces the effect of vecuronium by mechanisms that include both increased vecuronium metabolism and reduced sensitivity of the patient to circulating concentrations of vecuronium.

Pharmacokinetic analysis of rapacuronium and its metabolite during liver transplantation: an assessment of its potential as a pharmacodynamic probe.

The liver extracts aminosteroidal neuromuscular blocking drugs. We hypothesized that the duration of action of these drugs might provide a pharmacodynamic probe for assessing graft function during orthotopic liver transplantation. The pharmacokinetics of rapacuronium and its active metabolite, ORG 9488, were prospectively studied in 11 patients. Rapacuronium (1.5 mg/kg) was administered at induction of anesthesia, 2 minutes after clamping the portal vein, and 5 minutes after reperfusion of the new graft. Blood samples were drawn at intervals, and an independent laboratory analyzed plasma for both rapacuronium and ORG 9488. Rapacuronium's pharmacokinetics were characterized for 3 stages of the transplant using NONMEM software to construct mixed-effects compartmental models. Rapacuronium plasma clearance during the first stage of orthotopic liver transplantation was 7.25 mL/kg/min. Clearance decreased by only 44% during the anhepatic stage, to 3.91 mL/kg/min, and remained decreased after reperfusion. This effect suggests that an alternate clearance pathway exists. The clearance for ORG 9488 was 13.5 mL/kg/min during the paleohepatic and anhepatic stages, but it decreased 83% on reperfusion, suggesting accumulation after reperfusion. This pharmacokinetic analysis suggests that rapacuronium may not be suitable for use as a pharmacodynamic probe.

Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit.

BACKGROUND: Propofol is a commonly used anesthetic induction agent in pediatric anesthesia that, until recently, was used with caution as an intravenous infusion agent for sedation in pediatric intensive care. Few data have described propofol kinetics in critically ill children. METHODS: Twenty-one critically ill ventilated children aged 1 week to 12 yr were sedated with 4-6 mg. kg(-1).h(-1) of 2% propofol for up to 28 h, combined with a constant morphine infusion. Whole blood concentration of propofol was measured at steady state and for 24 h after infusion using high-performance liquid chromatography. RESULTS: A propofol infusion rate of 4 mg. kg(-1).h(-1) achieved adequate sedation scores in 17 of 20 patients. In 2 patients the dose was reduced because of hypotension, and 1 patient was withdrawn from the study because of a increasing metabolic acidosis. Mixed-effects population models were fitted to the blood propofol concentration data. The pharmacokinetics were best described by a three-compartment model. Weight was a significant covariate for all structural model parameters; Cl, Q2, Q3, V1, and V2 were proportional to weight. Estimates for these parameters were 30.2, 16.0, and 13.3 ml. kg(-1).min(-1) and 0.584 and 1.36 l/kg, respectively. The volume of the remaining peripheral compartment, V3, had a constant component (103 l) plus an additional weight-related component (5.67 l/kg). Values for Cl were reduced (typically by 26%) in children who had undergone cardiac surgery. CONCLUSIONS: Propofol kinetics are altered in very small babies and in children recovering from cardiac surgery. Increased peripheral distribution volume and reduced metabolic clearance following surgery causes prolonged elimination.

Distinguishing animal subsets in toxicokinetic studies: comparison of non-linear mixed effects modelling with non-compartmental methods.

The purpose of this study was to compare the ability of non-compartmental analysis and compartmental mixed effects modelling (MEM) to determine the existence and magnitude of exposure differences (i.e. exposure ratio estimates) between subsets of animals during destructive toxicokinetic studies. Data from five toxicokinetic studies of an experimental compound were analysed using a linear trapezoidal calculation of the area under the curve (non-compartmental analysis) or modelled using MEM. With the non-compartmental method the Bailer-Satterthwaite approximation was used to construct confidence intervals around the exposure estimates of each subset of animals and these were used to determine if exposure differed between the subsets. The MEM analyses were performed on the full datasets and on datasets with arbitrary reductions in the number of animal replicates. With MEM, additional model parameters were used to differentiate between subsets of animals, and were incorporated only if they were justified statistically. Estimates of the existence and magnitude of exposure differences between animal subsets were similar with the two techniques. The MEM analyses were influenced only marginally by substantial reductions in the number of animals studied and were less compromised by extremely limited or unbalanced data. These analyses show that MEM and non-compartmental methods are similarly effective at detecting exposure differences between animal subsets in toxicokinetic studies. Estimates provided by both methods were influenced by the degree of variance in the data. These results support the proposition that it may be possible to reduce the number of animals employed in toxicokinetic studies if MEM is used.

Pharmacokinetics and pharmacodynamics of rapacuronium bromide.

Rapacuronium is an aminosteroidal nondepolarising neuromuscular blocking agent (NMBA). Its neuromuscular blocking effects have a different time course to those of most currently available agents. It also has lower potency than many of the other NMBAs. In doses consistent with short to medium duration of action, rapacuronium has rapid and complete onset. In some doses it gives tracheal intubating conditions that compare favourably with those produced by suxamethonium (succinylcholine) during rapid sequence induction of anaesthesia. Tracheal intubating conditions improve as dose increases, but adverse effects (including potentially severe bronchospasm) become more prominent. Rapacuronium has an active metabolite that is at least as potent as the parent compound and is eliminated much less efficiently. Consequently, the time course of action of rapacuronium is prolonged after multiple doses or an infusion. Its potency is similar across age ranges and its time course after single doses is little altered in patients with hepatic or renal insufficiency. At least in part because of its active metabolite, rapacuronium is highly cumulative in renal failure. In keeping with its rapid onset and short to medium duration of action, rapacuronium has a more rapid clearance than most other NMBAs. Values for clearance are in the range 0.26-0.67 L/h/kg, with most studies giving a value of approximately 0.45 L/h/kg. There is some evidence that clearance declines marginally with advanced age, and it is also reduced in children. A typical value for steady-state volume of distribution is 0.3 L/kg. This is similar to that of many other NMBAs, but is small compared with many other drugs, as expected with a highly polar compound. Pharmacokinetic parameters do not appear to differ markedly in hepatic insufficiency, but clearance is reduced by approximately 30% in renal failure. Rapacuronium equilibrates very rapidly between the plasma and the site of effect. This is the principal explanation behind its unusually rapid onset. It also appears to have a similar potency at the larynx compared with the adductor pollicis; most other NMBAs are less effective at the larynx. Because it gives rapid onset in a dose consistent with brief duration of action, it was hoped that rapacuronium might be a suitable alternative to suxamethonium. It does not have the problems associated with suxamethonium, but its use is associated with bronchospasm, the incidence of which is dose-related. Rapacuronium has been withdrawn from sale because of this adverse effect, and its future availability is uncertain.

The influence of mild hypothermia on the pharmacokinetics and time course of action of neostigmine in anesthetized volunteers.

BACKGROUND: The pharmacokinetics, maximum effect, and time course of action of neostigmine were studied in seven human volunteers. METHODS: Each volunteer was studied twice, during both normothermia and hypothermia. Anesthesia was induced with 30 microg/kg alfentanil and 3 mg/kg propofol, and was maintained with 60-70% nitrous oxide and 0.7-0.9% isoflurane. The mechanical response of the adductor pollicis to train-of-four stimulation of the ulnar nerve was recorded, and central body temperature maintained stable at either less than 34.5 degrees C or greater than 36.5 degrees C by surface cooling or warming. Before neostigmine administration, a stable 5% twitch height was obtained by an infusion of vecuronium, and the infusion rate remained unchanged thereafter. Neostigmine, 70 microg/kg, was then infused over 2 min, and blood samples for estimation of neostigmine concentrations were collected at intervals for 240 min. RESULTS: With hypothermia, the central volume of distribution of neostigmine decreased by 38%, and onset time of maximum effect increased (4.6 vs. 5.6 min). Hypothermia did not change the clearance (696 ml/min), maximum effect, or duration of action of neostigmine. CONCLUSIONS: The efficacy of neostigmine as an antagonist of vecuronium-induced neuromuscular block is not altered by mild hypothermia.