Plasma Concentrations Of Vecuronium Research Articles

Pharmacokinetic-Pharmacodynamic Model for the Reversal of Neuromuscular Blockade by Sugammadex

Sugammadex selectively binds steroidal neuromuscular blocking drugs, leading to reversal of neuromuscular blockade. The authors developed a pharmacokinetic-pharmacodynamic model for reversal of neuromuscular blockade by sugammadex, assuming that reversal results from a decrease of free drug in plasma and/or neuromuscular junction. The model was applied for predicting the interaction between sugammadex and rocuronium or vecuronium. Noninstantaneous equilibrium of rocuronium-sugammadex complex formation was assumed in the pharmacokinetic-pharmacodynamic interaction model. The pharmacokinetic parameters for the complex and sugammadex alone were assumed to be identical. After development of a pharmacokinetic-pharmacodynamic model for rocuronium alone, the interaction model was optimized using rocuronium and sugammadex concentration data after administration of 0.1-8 mg/kg sugammadex 3 min after administration of 0.6 mg/kg rocuronium. Subsequently, the predicted reversal of neuromuscular blockade by sugammadex was compared with data after administration of up to 8 mg/kg sugammadex at reappearance of second twitch of the train-of-four; or 3, 5, or 15 min after administration of 0.6 mg/kg rocuronium. Finally, the model was applied to predict reversal of vecuronium-induced neuromuscular blockade. Using the in vitro dissociation constants for the binding of rocuronium and vecuronium to sugammadex, the pharmacokinetic-pharmacodynamic interaction model adequately predicted the increase in total rocuronium and vecuronium plasma concentrations and the time-course of reversal of neuromuscular blockade. Model-based evaluation supports the hypothesis that reversal of rocuronium- and vecuronium-induced neuromuscular blockade by sugammadex results from a decrease in the free rocuronium and vecuronium concentration in plasma and neuromuscular junction. The model is useful for prediction of reversal of rocuronium and vecuronium-induced neuromuscular blockade with sugammadex.

Safety and tolerability of single intravenous doses of sugammadex administered simultaneously with rocuronium or vecuronium in healthy volunteers

Sugammadex rapidly reverses rocuronium- and vecuronium-induced neuromuscular block. To investigate the effect of combination of sugammadex and rocuronium or vecuronium on QT interval, it would be preferable to avoid the interference of anaesthesia. Therefore, this pilot study was performed to investigate the safety, tolerability, and plasma pharmacokinetics of single i.v. doses of sugammadex administered simultaneously with rocuronium or vecuronium to anaesthetized and non-anaesthetized healthy volunteers. In this phase I study, 12 subjects were anaesthetized with propofol/remifentanil and received sugammadex 16, 20, or 32 mg kg(-1) combined with rocuronium 1.2 mg kg(-1) or vecuronium 0.1 mg kg(-1); four subjects were not anaesthetized and received sugammadex 32 mg kg(-1) with rocuronium 1.2 mg kg(-1) or vecuronium 0.1 mg kg(-1) (n=2 per treatment). Neuromuscular function was assessed by TOF-Watch SX monitoring in anaesthetized subjects and by clinical tests in non-anaesthetized volunteers. Sugammadex, rocuronium, and vecuronium plasma concentrations were measured at several time points. No serious adverse events (AEs) were reported. Fourteen subjects reported 23 AEs after study drug administration. Episodes of mild headache, tiredness, cold feeling (application site), dry mouth, oral discomfort, nausea, increased aspartate aminotransferase and gamma-glutamyltransferase levels, and moderate injection site irritation were considered as possibly related to the study drug. The ECG and vital signs showed no clinically relevant changes. Rocuronium/vecuronium plasma concentrations declined faster than those of sugammadex. Single-dose administration of sugammadex 16, 20, or 32 mg kg(-1) in combination with rocuronium 1.2 mg kg(-1) or vecuronium 0.1 mg kg(-1) was well tolerated with no clinical evidence of residual neuromuscular block, confirming that these combinations can safely be administered simultaneously to non-anaesthetized subjects. Rocuronium and vecuronium plasma concentrations decreased faster than those of sugammadex, reducing the theoretical risk of neuromuscular block developing over time.

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

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. 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. 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. 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.

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Pharmacokinetics and pharmacodynamics of vecuronium in children receiving phenytoin or carbamazepine for chronic anticonvulsant therapy

The pharmacokinetics and time course of action of vecuronium in normal children and children receiving anticonvulsant drugs for prolonged periods were characterized. A bolus dose of vecuronium 0.15 mg kg(-1) was administered i.v. to 10 non-epileptic children and to 10 children on phenytoin and 10 children on carbamazepine, who were matched for age and weight. Plasma concentrations of vecuronium, 3-OH desacetylvecuronium (the primary metabolite of vecuronium) and alpha1-acid glycoprotein (AAG) were determined. Pharmacokinetic variables were derived from plasma samples collected before and after administration of vecuronium. Neuromuscular transmission was monitored by evoked compound electromyography. Recovery of the first twitch of the train-of-four (T1/T0) and the recovery index (RI), the time for 25-75% recovery of T1/T0, were determined. The elimination half-life of vecuronium was significantly reduced in both anticonvulsant groups compared with control [control 48.2 (SD 40.3), phenytoin 23.5 (13.1), carbamazepine 18.4 (16.6) min, P<0.05]. Vecuronium clearance was increased in both anticonvulsant groups [control 9.0 (3.6), phenytoin 15.1 (8.9), carbamazepine 18.8 (13.1) ml kg(-1) min(-1), 0.05<P<0.1]. Children on chronic anticonvulsant therapy had a significantly shorter RI than control [control 21.8 (11), phenytoin 12.5 (8.3), carbamazepine 10.6 (5.9) min, P<0.05]. Concentrations of vecuronium at different degrees of recovery of T1, volumes of distribution and AAG concentrations were not different between groups. Our data confirm anticonvulsant-induced resistance to vecuronium in children and support a pharmacokinetic component contributing to the resistance.

The Pharmacokinetics of Vecuronium in Male and Female Patients

To evaluate the effect of gender on the pharmacokinetics of vecuronium, we studied 30 patients (15 male and 15 female) undergoing elective plastic surgery with anticipated surgical blood loss of <300 mL under general anesthesia.General anesthesia was induced with thiopental 4-6 mg/kg and fentanyl 2-4 [micro sign]g/kg and was maintained with 60% nitrous oxide in oxygen and an end-tidal concentration of 1.5%-2% enflurane. After a 2-min infusion of vecuronium 100 [micro sign]g/kg, a modified fluorometric assay was used to determine the plasma concentrations of vecuronium for 5 h. The results showed that, compared with women, the plasma concentrations of vecuronium in men were significantly lower during the first 20 min and that the disposition kinetics of vecuronium can be best described mathematically by a three-compartment open model in the two groups. The volume of the central compartment and the volume of distribution at steady state were 39.6 +/- 8.6 and 164.8 +/- 29.3 mL/kg, respectively, in women. These values increased significantly to 54.4 +/- 14.4 and 201.4 +/- 75.8 mL/kg in men (P < 0.05). When the data were calculated on the basis of ideal body weight, the volume of distribution of vecuronium was also different between men and women (P < 0.05. The half-lives of fast distribution and distribution, the elimination half-life, mean residual time, area under the plasma-concentration curve, and plasma clearance were not different between the two groups. We conclude that the pharmacokinetics of vecuronium are significantly different between genders and that and men have the greater volume of distribution of vecuronium. Implications: The authors found that, compared with women, men had lower plasma concentrations of vecuronium after the IV administration of vecuronium and a larger volume of distribution of vecuronium. The pharmacokinetic differences may be related to the differences in the sensitivity to vecuronium between genders. (Anesth Analg 1998;86:1322-7)

Vecuronium-induced neuromuscular block during xenon or sevoflurane anaesthesia in humans

Twitch response using accelerometry and plasma concentrations, of vecuronium and its metabolite were studied in 27 surgical patients during xenon or sevoflurance anaesthesia after administration of vecuronium 0.05 mg kg-1. Anaesthesia was maintained using oxygen-xenon (MAC = 71%) or oxygen-sevoflurane (MAC = 2%) at an end-tidal concentration equal to 0.8 MAC (i.e. 57% xenon and 1.6% sevoflurane). Mean time from administration of vecuronium to 25% recovery of the first twitch of the train-of-four response was significantly shorter in the xenon group than in the sevoflurane group (12.9 (SD 2.5) min vs 19.4 (6.0) min, respectively). Plasma concentrations of vecuronium at 25% recovery were significantly higher during xenon than during sevoflurane anaesthesia (187 (49) ng ml-1 vs 136 (40) ng ml-1, respectively), while those of 3-desacetylvecuronium were similar in both groups.

Pharmacokinetics of vecuronium during acute isovolaemic haemodilution

To evaluate the effect of acute isovolaemic haemodilution on the pharmacokinetics of vecuronium, we studied 13 patients undergoing haemodilution during surgery and 13 control patients. General anaesthesia was induced with thiopentone 4-6 mg kg-1 and fentanyl 2-4 micrograms kg-1, and maintained with enflurane and 60% nitrous oxide in oxygen. The haemodilution patients underwent major elective plastic surgery with an anticipated surgical loss of more than 600 ml. Haemodilution was achieved by drainage of venous blood and i.v. infusion of lactated Ringer's solution and 6% dextran, during which the packed cell volume and haemoglobin concentration decreased from 45% to 28.1% and from 14.7 g dl-1 to 9.1 g dl-1, respectively. After administration of a bolus of vecuronium 100 micrograms kg-1, an improved fluorimetric assay was used to measure the plasma concentrations of vecuronium for 5 h. The results showed that the disposition kinetics of vecuronium were best described mathematically by a three-compartment open model in the two groups. The mean volume of the central compartment and volume of distribution at steady state were 42.3 (SD 11.8) ml kg-1 and 168.4 (31.5) ml kg-1, respectively, in control patients, and significantly greater (55.2 (13.4) ml kg-1 and 225.9 (53.3) ml kg-1) in the haemodilution patients (P < 0.05). The elimination half-life was 50.3 (11.5) min in control patients and significantly greater (68.2 (15.1) min) in the haemodilution patients (P < 0.05). The half-lives of fast distribution and distribution, mean residual time, area under the plasma concentration curve and plasma clearance were unchanged in patients who underwent haemodilution compared with the control group.

The Effect of Sevoflurane and Isoflurane on the Neuromuscular Block Produced by Vecuronium Continuous Infusion

Volatile anesthetics enhance the action of neuromuscular blockade to various degrees, although the influence of sevoflurane on the neuromuscular block has not yet been characterized.The purpose of this investigation is to determine the vecuronium infusion rate requirement under sevoflurane anesthesia and to compare it to that of isoflurane anesthesia. Twenty patients scheduled for otorhinolaryngologic surgery were randomly assigned to receive either sevoflurane (SEV) or isoflurane (ISO) at 1 minimum alveolar anesthetic concentration (MAC) (1.7% and 1.2%, respectively) in combination with 67% nitrous oxide. Anesthesia was induced with 5 mg/kg thiopental and muscle relaxation was obtained by a bolus of vecuronium 0.1 mg/kg followed by a continuous vecuronium infusion to achieve 90% muscle relaxation. The plasma concentrations of vecuronium (CVEC) and 3-desacetylvecuronium (CDES) at steady state were measured with a gas chromatographic assay. There was no difference between SEV and ISO in the following variables: the vecuronium infusion rate requirement to achieve 90% muscle relaxation (0.42 +/- 0.11 [SEV] vs 0.40 +/- 0.10 [ISO] micro gram centered dot kg-1 centered dot min-1), CVEC (144.4 +/- 38.1 [SEV] vs 149.7 +/- 69.2 [ISO] ng/mL), CDES (57.2 +/- 20.3 [SEV] vs 65.3 +/- 26.1 [ISO], ng/mL), and plasma vecuronium clearance (2.85 +/- 0.86 [SEV] vs 3.19 +/- 1.24 [ISO] mL centered dot kg-1 centered dot min-1). This study indicates that SEV at 1 MAC requires a vecuronium infusion rate similar to that of ISO at 1 MAC to achieve 90% muscle relaxation. (Anesth Analg 1996;82:942-7)

Mild intraoperative hypothermia does not change the pharmacodynamics (concentration-effect relationship) of vecuronium in humans.

To investigate the effect of mild hypothermia on the neuromuscular junction sensitivity to vecuronium, we determined the pharmacodynamics (concentration-effect relationship) of vecuronium in 10 patients (ASA physical class I or II; age range, 21-46 yr; weight range, 54-104 kg), during isoflurane-nitrous oxide-fentanyl anesthesia. Five were cooled to a mean temperature of 34.4 degrees C and five were maintained normothermic at a mean temperature of 36.8 degrees C. Neuromuscular function was monitored by measuring the evoked mechanical response of the adductor pollicis muscle after supramaximal train-of-four stimulation of the ulnar nerve at the wrist. Vecuronium, 3 micrograms.kg-1.min-1, was infused for 10 min, venous blood sampled for 60 min, and twitch tension and plasma concentration data were used to determine pharmacodynamic variables in each patient. Results for the hypothermic and normothermic groups were compared by Mann-Whitney U-test. There were no differences in any pharmacodynamic variable between the hypothermic and normothermic patients. For the hypothermic and normothermic patients, respectively, steady-state plasma concentrations of vecuronium producing 50% neuromuscular block (Css50) were 73 +/- 13 ng/mL (mean +/- SD) and 79 +/- 31 ng/mL; the rate constants for equilibration of vecuronium between the plasma and the neuromuscular junction (Keo) were 0.27 +/- 0.14 per min-1 and 0.26 +/- 0.11 per min, and the power functions representing the slope of the concentration-effect relationship (gamma) were 5.7 +/- 1.9 and 4.4 +/- 1.8.(ABSTRACT TRUNCATED AT 250 WORDS)

Persistent Paralysis in Critically Ill Patients After Long-Term Administration of Vecuronium

SEGREDO, V.; CALDWELL, J. E.; MATTHAY, M. A.; SHARMA, M. L.; GRUENKE, L. D.; MILLER, R. D. Author Information

Persistent paralysis in critically ill patients after long-term administration of vecuronium.

The muscle relaxant vecuronium is sometimes administered to facilitate mechanical ventilation. Neuromuscular paralysis lasting up to seven days may occur after the termination of long-term administration (i.e., more than two days) of vecuronium in critically ill patients. We investigated the role of clinical factors and plasma concentrations of vecuronium and its metabolite in causing this prolonged neuromuscular blockade. We studied 16 critically ill adult patients (8 women and 8 men) who had received vecuronium to facilitate mechanical ventilation for at least two consecutive days. Clinical factors and plasma concentrations of vecuronium and 3-desacetylvecuronium, the active metabolite of vecuronium, were compared in patients with and without prolonged neuromuscular blockade. In addition, we performed detailed pharmacokinetic studies in the patients without prolonged neuromuscular blockade. Seven of the 16 patients had prolonged neuromuscular blockade, lasting from six hours to more than seven days, after the termination of vecuronium therapy. These seven patients, six of whom were women, had higher plasma magnesium concentrations and lower arterial blood pH values than the nine patients without prolonged neuromuscular blockade. They also had higher plasma concentrations of 3-desacetylvecuronium and a higher frequency of renal failure (seven of seven patients vs. four of nine patients, P less than 0.03). In the patients without prolonged neuromuscular blockade, the mean (+/- SD) plasma clearance, elimination half-life, and volume of distribution of vecuronium were 2.5 +/- 1.0 ml per kilogram of body weight per minute, 299 +/- 154 minutes, and 1.1 +/- 0.6 liters per kilogram, respectively. Prolonged neuromuscular blockade after the termination of long-term treatment with vecuronium is associated with metabolic acidosis, elevated plasma magnesium concentrations, female sex, and probably more important, the presence of renal failure and high plasma concentrations of 3-desacetylvecuronium.

DOES A SUBPARALYSING DOSE OF VECURONIUM ENHANCE DIAPHRAGM FATIGUE?

We have examined, in six healthy volunteers, the effect of a subparalysing dose of vecuronium on the development of diaphragm fatigue. Vecuronium was given as a 0.5-mg bolus i.v. followed by 0.5 mg infused over 30 min; as a control, saline was given in random order. Diaphragm strength was assessed by measuring transdiaphragm pressure and by electromyography. Diaphragm fatigue was induced by breathing against an inspiratory resistance. The plasma concentration of vecuronium varied between 15 and 30 ng ml-1 15 min after administration of vecuronium was started. Peripheral neuromuscular block was not detected in any subject. Diaphragm fatigue developed within the same period in both groups: mean 334 (SD 166) s after saline and 345 (190) s after vecuronium. The electromyographic pattern of diaphragm fatigue and the time constant of relaxation of transdiaphragm pressure after fatigue were similar in both groups. We conclude that, at low plasma concentrations of vecuronium, similar to those present in the postoperative period, there was no predisposition to diaphragm fatigue.

Vecuronium in alcoholic liver disease: a pharmacokinetic and pharmacodynamic analysis.

To determine the effect of alcoholic liver disease on the pharmacokinetics and pharmacodynamics of vecuronium, the authors administered vecuronium 0.1 mg.kg-1 iv to ten surgical patients with alcoholic liver disease and ten healthy surgical patients. All patients were anesthetized with nitrous oxide and isoflurane. We recorded and quantitated the force of thumb adduction in response to supramaximal ulnar nerve stimulation. Plasma concentrations of vecuronium and its 3-desacetyl metabolite were determined by a capillary gas chromatography assay. Only the time to attain 100% twitch depression (onset time) was prolonged in liver disease patients (2.8 +/- 0.7 min; mean +/- SD) as compared to control patients (1.9 +/- 0.4 min). The time from vecuronium administration to recovery of twitch tension was unaffected by alcoholic liver disease. The time to the reappearance of twitch response was 32.7 +/- 9.7 min in patients with liver disease and 36.8 +/- 15.5 min in controls. Plasma concentration-time data were fit to a two-compartment model. Vecuronium clearance, steady-state volume of distribution, and elimination half-time were unchanged by alcoholic liver disease. The authors conclude that alcoholic liver disease does not affect the pharmacokinetics or duration of action of vecuronium when an intravenous bolus dose of 0.1 mg.kg-1 is administered.

Pharmacokinetics and Pharmacodynamics of Vecuronium and Pancuronium in Anesthetized Children

The pharmacokinetics and pharmacodynamics of vecuronium and pancuronium were determined in 12 children (3-6 yr) undergoing minor surgery under 60% nitrous oxide, 1 MAC halothane anesthesia. When the level of anesthesia and the electromyograph (EMG) recording of the adductor pollicis were stable, an intravenous bolus of vecuronium (100 micrograms/kg) or pancuronium (100 micrograms/kg) was administered. Plasma concentrations of the two muscle relaxants were determined for 6 hr after the administration by means of a fluorimetric assay followed by a thin layer chromatography. Plasma concentrations of vecuronium and pancuronium declined biexponentially in children and no metabolites could be detected in plasma. The elimination half-lives of vecuronium and pancuronium did not differ significantly. The volume of distribution at steady state (Vdss) was greater (P less than 0.05) after vecuronium (320 +/- 181 ml/kg; mean +/- SD) than after pancuronium (203 +/- 36 ml/kg). Plasma clearance of vecuronium (2.8 +/- 0.9 ml X min-1 X kg-1) was greater than that of pancuronium (1.7 +/- 0.2 ml X min-1 X kg-1; P less than 0.05). Plasma concentrations measured at 10%, 50%, or 90% recovery of the EMG response did not differ significantly for vecuronium and pancuronium. Thus the shorter duration of action of vecuronium is probably due to its greater apparent volume of distribution, as well as to its higher plasma clearance. Thus although the elimination half-lives are comparable, the plasma disappearance of vecuronium is more rapid than that of pancuronium.

Vecuronium in patients with and without renal failure.

Fifteen patients with and ten patients without renal failure (RF) were given vecuronium as the sole muscle relaxant during anaesthesia. RF patients were divided into two subgroups according to the daily diuresis (RF I, below 0.5 l/d; RF II, over 0.5 l/d). Vecuronium was given in small doses until the electromyographic twitch response showed 90% relaxation. The results showed great individual variations, and there were no statistically significant differences between the study groups in the parameters studied (ED90 dose, total consumption of the drug in mg kg-1 min-1, vecuronium plasma concentrations, twitch response) during induction and anaesthesia. After reversal of relaxation, the twitch response recovered more slowly in the RF I group than in the others (P less than 0.05). No complications occurred and it is confirmed that it is safe to use vecuronium as a muscle relaxant in patients with RF.