Effect of age on cis-atracurium besylate pharmacokinetics following a single 1 mg kg-1 intravenous bolus in young pigs.

OBJECTIVE: To determine the cis-atracurium pharmacokinetic data and laudanosine production of a single 1 mg kg-1 cis-atracurium dose in the pig and to compare the pharmacokinetics between two groups of different ages. STUDY DESIGN: Prospective experimental study. ANIMALS: Sixteen female pigs in two groups. Group A included eight animals aged 2.0-2.5 months and weighed 26.6 ± 3.6 kg. Group B included eight animals aged 4.0-5.0 months and weighed 57.4 ± 8.3 kg. METHODS: The pigs were anaesthetized and monitored throughout the procedure. Arterial blood samples collected at 0, 0.5, 1, 2, 5, 10, 20, 30, 45, 60, 90, 120 and 180 minutes after cis-atracurium injection were cooled and centrifuged. Plasma was acidified and stored at -20 °C for subsequent cis-atracurium and laudanosine analyses. RESULTS: Anaesthetic parameters were within normal ranges throughout the procedure. Plasma cis-atracurium and laudanosine concentrations were measured for the 16 pigs. Elimination rate constant, elimination half-life, area under the curve, mean residence time, distribution volume and total clearance were calculated for each pig. Statistical differences (p < 0.05) in the elimination rate constant, elimination half-life, mean residence time and distribution volume values were observed between the two groups. Elimination half-life, mean residence time and distribution volume values were higher and elimination rate constant lower in younger pigs than in older pigs. No plasma laudanosine concentrations were detected in any pig. CONCLUSION AND CLINICAL RELEVANCE: Longer duration of plasma cis-atracurium concentrations were observed in younger pigs. Distribution volume was also higher in younger pigs. Conversely, total clearance and area under the curve were similar between the two age groups. No laudanosine production was detected, suggesting a different cis-atracurium metabolism in the pig compared with other species.

The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries.

PURPOSE: Rocuronium (ROC) is a neuromuscular blocker mainly eliminated by biliary excretion dependent on organic anion transporting polypeptide 1A2 (OATP1A2) hepatocellular uptake. However, the influence of SLCO1A2 (gene encoding OATP1A2) genetic polymorphism on ROC pharmacokinetics was never described before. The objective of this work was to evaluate the influence of genetic polymorphisms of SLCO1A2 on the pharmacokinetics of rocuronium (ROC). METHODS: Patients undergoing elective surgeries under general anesthesia using rocuronium as a neuromuscular blocker were genotyped for SLCO1A2 polymorphisms in the coding region (41A>G, 382A>T, 404A>T, 502C>T, 516A>C, 559G>A, 830C>A, and 833delA) and in the promoter region (-1105G>A, -1032G>A, -715T>C, -361G>A, and -189_-188insA). Rocuronium pharmacokinetic parameters were estimated by non-compartmental analysis. RESULTS: None of the patients had heterozygous or homozygous variant of 404A>T, 382A>T, 502C>T, 833delA, 830C>A, 41A>G, and -715T>C. A linkage disequilibrium was found between -1105G>A and -1032G>A genotypes. Patients genotyped as -A or AA (n = 17) for SLCO1A2 -189_-188InsA showed reduced total clearance of ROC compared to patients genotyped as -/- (n = 13) (151.6 vs 207.1 mL/min, p ≤ 0.05). The pharmacokinetics parameters of ROC were not significantly different between other SLCO1A2 genotypes. CONCLUSION: SLCO1A2 -189_-188InsA polymorphism is related to the reduced clearance of rocuronium in patients submitted to elective surgeries under general anesthesia. TRIAL REGISTRATION: NCT 02399397 ( ClinicalTrials.gov ).

Influence of preoperative oral rehydration on arterial plasma rocuronium concentrations and neuromuscular blocking effects: A randomised controlled trial.

BACKGROUND: The influence of preoperative rehydration on the action of rocuronium has not yet been investigated. OBJECTIVE: The objective is to evaluate the hypothesis that preoperative rehydration lowers arterial rocuronium plasma concentrations and changes its associated neuromuscular blocking effects during induction of anaesthesia. DESIGN: Randomised, single-blinded study. SETTING: A secondary hospital from October 2013 to July 2014. PATIENTS: In total, 46 men undergoing elective surgery were eligible to participate and were randomly allocated into two groups. Exclusion criteria were severe hepatic, renal or cardiovascular disorder; neuromuscular disease; history of allergy to rocuronium; BMI more than 30 kg m; receiving medication known to influence neuromuscular function. INTERVENTION: Participants received 1500 ml of oral rehydration solution (rehydration group) or none (control group) until 2 hours before anaesthesia. Arterial blood samples were obtained 60, 90 and 120 s and 30 min after rocuronium (0.6 mg kg) administration during total intravenous anaesthesia. Responses to 0.1-Hz twitch stimuli were measured at the adductor pollicis muscle using acceleromyography. MAIN OUTCOME MEASURES: Arterial plasma rocuronium concentrations. RESULTS: Arterial plasma rocuronium concentrations at 60, 90 and 120 s in the rehydration and control groups were 9.9 and 13.7, 6.8 and 9.5 and 6.2 and 8.1 µg ml, respectively (P = 0.02, 0.003 and 0.02, respectively); the onset times in the rehydration and control groups were 92.0 and 69.5 s (P = 0.01), and the times to twitch re-appearance were 25.3 and 30.4 min (P = 0.004), respectively. CONCLUSION: Preoperative rehydration significantly reduces arterial plasma rocuronium concentrations in the first 2 minutes after administration, prolonging the onset time and shortening the duration of effect. A higher dose or earlier administration should be considered for patients who receive preoperative rehydration. TRIAL REGISTRATION: Umin identifier: UMIN000011981.

Pharmacokinetics and pharmacodynamics of rocuronium in young adult and elderly patients undergoing elective surgery.

OBJECTIVE: To evaluate the impact of advanced age on rocuronium kinetic disposition in ASA I-III patients undergoing elective surgeries. METHODS: Young adult (20-50 years, n = 15) and elderly patients (65-85 years, n = 14) submitted to surgery under general anaesthesia were investigated. All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol. Rocuronium-induced neuromuscular block was monitored by train of four stimulations of the adductor muscle of the thumb on the ulnar nerve. The pharmacokinetic parameters were calculated by non-compartmental analysis. The relationship between rocuronium plasma concentration and the neuromuscular blockade was described by a sigmoidal Emax model. KEY-FINDINGS: Elderly patients presented decreased Cl (2.1 ml/kg per min vs 2.8 ml/kg per min; P = 0.0123); increased AUC/dose (507.8 µg min/ml (mg/kg) vs 392.2 µg min/ml/(mg/kg); P = 0.0168) and reduced volume of distribution (285.4 ml/kg vs 435.6 ml/kg, P = 0.0434) compared to young adults. The concentrations required to achieve 50% of maximum neuromuscular block (EC50) were similar for young adult (338.8 ng/ml) and elderly (462.7 ng/ml) patients (P > 0.05). CONCLUSIONS: Elderly patients showed increased AUC/D and reduced total Cl compared to young adult patients due to the age-related reduced renal function. Differences in the PK-PD properties of rocuronium in elderly population are due to changes in drug disposition rather than to alterations in the sensitivity to the drug.

Comparison of distributed and compartmental models of drug disposition: assessment of tissue uptake kinetics.

The utility of a circulatory three-compartment model for the assessment of tissue uptake kinetics is tested by comparison with the respective distributed models using pharmacokinetic data of rocuronium in patients These minimal physiologically based models have a common structure consisting of two subsystems representing the lung and the lumped systemic circulation, with two regions, the vascular and tissue space. The distributed models are based on either diffusion-limited tissue distribution, permeability-limited tissue uptake or the assumption of an empirical transit time density function. With a deviation in the estimate of the permeability-surface area product (PS) of about 18 %, the compartmental approach appears as a useful alternative on condition that a priori knowledge of cardiac output is included. It is also shown that the distribution clearance calculated from the parameters of a mammillary compartment model changes proportional to PS and can be used as an indirect measure of permeability-limited tissue uptake of drugs.

The concept behind sugammadex.

Sugammadex is the first selective relaxant binding agent. It allows rapid reversal of any degree of neuromuscular blockade induced by steroidal neuromuscular blocking agents. Sugammadex acts by encapsulation of the neuromuscular blocking agent. This prevents the drug from acting on prejunctional and postjunctional nicotinic receptors, allowing acetylcholine to activate these receptors, and resulting in reversal of the neuromuscular blockade. Objective monitoring of the degree of neuromuscular blockade is strongly recommended to determine the optimal dose of sugammadex. A good understanding of the concept behind sugammadex is essential in order to use this reversal agent in clinical practice.

Automatic control of the NMB level in general anaesthesia with a switching total system mass control strategy.

This paper presents a model based switching control strategy to drive the neuromuscular blockade (NMB) level of patients undergoing general anesthesia to a predefined reference. A single-input single-output Wiener system with only two parameters is used to model the effect of two different muscle relaxants, atracurium and rocuronium, and a switching controller is designed based on a bank of total system mass control laws. Each of such laws is tuned for an individual model from a bank chosen to represent the behavior of the whole population. The control law to be applied at each instant corresponds to the model whose NMB response is closer to the patient's response. Moreover a scheme to improve the reference tracking quality based on the analysis of the patient's response, as well as, a comparison between the switching strategy and the Extended Kalman Kilter (EKF) technique are presented. The results are illustrated by means of several simulations, where switching shows to provide good results, both in theory and in practice, with a desirable reference tracking. The reference tracking improvement technique is able to produce a better reference tracking. Also, this technique showed a better performance than the (EKF). Based on these results, the switching control strategy with a bank of total system mass control laws proved to be robust enough to be used as an automatic control system for the NMB level.

[Increase in serum vecuronium concentration following sugammadex administration in a pediatric patient after prolonged sedation].

It is known that blood concentration of rocuronium increases after administration of sugammadex, but this is not clear in the case of vecuronium. We report a pediatric case in which serum vecuronium concentration increased following sugammadex administration after prolonged sedation using vecuronium. A 19-month-old girl weighing 7.8 kg had a history of aortic valvuloplasty at 4 months of age due to truncus arteriosus. She presented again to our hospital due to aortic regurgitation. She underwent aortic valvuloplasty and then aortic valve replacement. The postoperative course was complicated with severe heart failure and acute kidney injury requiring peritoneal dialysis. For that reason she required long-term sedation including administration of a large amount of muscle relaxant due to severe low cardiac output syndrome after aortic valvuloplasty. A total of 615 mg (79 mg x kg(-1)) of vecuronium was administered over a period of 24 days. On weaning from mechanical ventilation, 125 mg (16 mg x kg(-1)) of sugammadex was given. Vecuronium concentration measured by high-performance liquid chromatography (HPLC) was 5.03 ng x ml(-1) before sugammadex administration and increase to 13.98 ng x ml(-1) after that. However, blood concentration of metabolic products of vecuronium did not exceed the lower limits of measurement in each sample. She was successfully weaned from mechanical ventilation without recurarizarion. Serum concentration of vecuronium increased after administration of sugammadex because extravascular vecuronium was redistributed to intravascular space according to the concentration gradient induced by binding and clathration of vecuronium. The measured values of vecuronium after sugammadex administration on HPLC represented the total amount of free vecuronium and vecuronium combined with sugammadex. Recurarization might occur after sugammadex reversal in patients after long-term administration of vecuronium, especially if relatively smaller doses of sugammadex were given. We experienced a pediatric case in which serum vecuronium concentration increased following sugammadex administration after prolonged sedation using vecuronium. There is a risk of recurarization after sugammadex reversal in patients after long-term administration of vecuronium.

Cisatracurium pharmacokinetics and pharmacodynamics during hypothermic cardiopulmonary bypass in infants and children.

BACKGROUND: Hypothermia potentiates neuromuscular blockade in adults during cardiopulmonary bypass (CPB) but the pediatric literature is sparse. Temperature-dependent Hoffman degradation of cisatracurium may allow reduction in infusion rate (IR) during hypothermia. The effect of hypothermic CPB on the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium has not been described in children. METHODS AND MATERIALS: Using neuromuscular monitoring with a Datex Relaxograph, cisatracurium IR was adjusted to obtain a pseudo-steady state during each phase of surgery (pre-CPB, CPB, post-CPB). Paired samples were taken at each phase. Cisatracurium plasma concentrations (Cpss) were determined by HPLC. Core and skin temperatures were recorded. RESULTS: Data from ten infants were analyzed: Group 1: mean 33.6°C; Group 2: mean 21.9°C. To maintain T1% between 5% and 10% in Group 2, the IR was decreased by a mean of 89% (P < 0.001). IR was not significantly different in Group 1. Post-CPB IR approximated pre-CPB rates in both groups. During CPB, Cpss fell by 27% in Group 1 and by 50% in Group 2 (P = 0.039). Post-CPB Cpss was not significantly different to pre-CPB in either group. Clearance did not change significantly in Group 1 but fell significantly in Group 2 during CPB (P = 0.002). Clearance post-CPB was unchanged from pre-CPB. CONCLUSIONS: Cisatracurium IR may be decreased by around 60% during CPB with moderate hypothermia but can be maintained at baseline during mild hypothermia.

Circulatory model of vascular and interstitial distribution kinetics of rocuronium: a population analysis in patients.

The time-course of the neuromuscular blocking effect of rocuronium depends on circulatory mixing and the rate of distribution into the interstitial space. In order to quantitatively evaluate these processes, a physiologically meaningful model of distribution kinetics based on circulatory transport and interstitial diffusion, was fitted to rocuronium disposition data in 10 patients using a population approach. Information on cardiac output and circulatory mixing was obtained from the kinetics of indocyanine green (ICG), which was injected simultaneously with rocuronium. As a compromise between physiological reality and parameter identifiability, the organs of the systemic circulation were lumped into a heterogeneous subsystem, described by an axially distributed model of extravascular diffusion. Diffusion into the interstitial space determines the rate of rocuronium distribution in the body (diffusional time constant 89 min). The resulting whole body distribution kinetics depends both on cardiac output and on the apparent permeability surface area product (0.16 l/min). The analysis of the ICG data revealed that heterogeneity of blood transit time through the systemic circulation decreased and that cardiopulmonary volume increased, respectively, with cardiac output. The approach should be useful for studying the effect of disease states on distribution kinetics of drugs.

Rocuronium profile during orthotopic liver transplantation: effect of changing the order of vascular clamp release at reperfusion of the hepatic graft.

BACKGROUND: Clearance of rocuronium in the neohepatic period may be a criterion for graft function during orthotopic liver transplantation (OLT). Our goal was to demonstrate that changes in rocuronium elimination are caused mainly by variations in blood volume at reperfusion. We have explored the influence on rocuronium plasma concentrations of changing the order of vascular unclamping at graft reperfusion. METHODS: Thirty patients were randomized at graft reperfusion: initial arterial revascularization (IAR; n = 14) wherein the hepatic artery was released first, and initial portal revascularization (IPR; n = 16) wherein the portal vein was released first. Tracheal intubation was facilitated by rocuronium (1 mg/kg) with an infusion initiated at 0.25 mg kg(-1) h(-1) to maintain a response to the first stimulus of the train of four <25% of controls. Rocuronium plasma concentrations (RPC) were measured throughout the transplantation. RESULTS: No differences were observed in rocuronium consumption at different stages. RPCs decreased after reperfusion, with primarily portal unclamping responsible. In 6 patients of the IAR group and 5 patients of the IPR group, RPC at 60 minutes after reperfusion was higher than previous values. Indicators of graft dysfunction among those 11 did not differ from the other patients. Two patients in the IPR group required retransplantation without any relation to changes in RPCs. CONCLUSION: The increase of blood flow produced by portal vein unclamping influenced RPCs; no relation was observed between RPCs and graft outcomes.

[Sugammadex, a novel drug for neuromuscular blockade reversal]. / Sugammadex. Nuevo fármaco reversor del bloqueo neuromuscular.

Significant progress in the management of aminosteroid nondepolarizing neuromuscular blockers will follow the introduction of sugammadex (Org 25969). Safety and rapid recovery of muscle force will improve and the adverse effects of acetylcholinesterase inhibitors will be avoided. Sugammadex is a modified gamma-cyclodextrin agent developed for the specific reversal of rocuronium and, to a lesser extent, vecuronium. This novel drug functions by means of encapsulation (chelation). Sugammadex was recently approved by the European Medicines Evaluation Agency and became available in Spain in 2009, leading to a series of changes related to patient safety and surgical conditions. We review the literature on sugammadex published to date.

[Estimated blood concentration of rocuronium administrated by continuous infusion to maintain an appropriate neuromuscular blockade under propofol anesthesia].

We managed 10 cases of propofol anesthesia with rocuronium, and recorded the time course of the neuromuscular blockade evaluated through accelerometry, as well as the estimated blood concentrations of rocuronium calculated from the administration history with a pharmacokinetic simulation analysis. Rocuronium was injected at 0.6 mg x kg(-1) initially, and the infusion rates were managed in order to maintain a twitch height at 3-10% of the control. The mean estimated rocuronium concentration (1.6 microg x ml(-1)) in our study was similar to the measured blood concentrations at the appropriate neuromuscular blockade that was previously reported. The estimated rocuronium concentrations at the appropriate neuromuscular blockade showed twice the inter-individual difference, and the time from the initial bolus of rocuronium to the spontaneous recovery with a twitch height of 5% showed a good relationship with the estimated rocuronium concentrations at the appropriate neuromuscular blockade. The time to spontaneous recovery with a twitch height of 25% and a reappearance of the fourth response in train-of-four ratio (TOF ratio) nerve stimulation was twenty minutes, even after a five-hour infusion, and was not affected by the length of the infusion. Thus, continuous infusion of rocuronium might be an effective and safe way to maintain appropriate neuromuscular blockade.

Reduced clearance of rocuronium and sugammadex in patients with severe to end-stage renal failure: a pharmacokinetic study.

BACKGROUND: Sugammadex is a selective relaxant binding agent designed to encapsulate the neuromuscular blocking agent, rocuronium. The sugammadex-rocuronium complex is eliminated by the kidneys. This trial investigated the pharmacokinetics (PKs) of sugammadex and rocuronium in patients with renal failure and healthy controls. METHODS: Fifteen ASA class II-III renal patients [creatinine clearance (CL(CR)) <30 ml min(-1)] and 15 ASA I-II controls (CL(CR) > or =80 ml min(-1)) were included. After induction of anaesthesia, a single i.v. dose of rocuronium 0.6 mg kg(-1) was given, followed by a single i.v. dose of sugammadex 2.0 mg kg(-1) at reappearance of the second twitch of the train-of-four response. Plasma concentrations of rocuronium and sugammadex were estimated and PK variables determined using non-compartmental analyses. Percentages of sugammadex and rocuronium excreted in the urine were measured. RESULTS: PK data were obtained from 26 patients. Mean total plasma clearance (CL) of sugammadex was 5.5 ml min(-1) in renal patients and 95.2 ml min(-1) in controls (P<0.05). Rocuronium CL was 41.8 ml min(-1) in renal patients and 167 ml min(-1) in controls (P<0.05). The median amount of sugammadex and rocuronium excreted in the urine over 72 h in renal patients was 29% and 4%, respectively, and 73% and 42% over 24 h in controls. CONCLUSIONS: Large differences in the PKs of sugammadex and rocuronium between patients with renal failure and healthy controls were observed. The effect of renal impairment on the PK variables of rocuronium was less than with sugammadex. Urinary excretion of both drugs was reduced in renal patients.

Dose-dependency of pharmacokinetic/pharmacodynamic parameters after intravenous bolus doses of cisatracurium.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) parameters of neuromuscular blocking agents (NMBAs) are generally assumed to be dose-independent. To our knowledge, there are very few clinical reports where the PK/PD parameters of a NMBA were derived separately for each dose group during a formal dose-ranging study. The primary objective of this study was to challenge a potential dose-dependency of cisatracurium PK/PD parameters by conducting a well-controlled experimental study. METHODS: Eight dogs were anaesthetized with pentobarbital and mechanically ventilated. Two doses of cisatracurium (1.5xED(95) and 6xED(95)) were administered in a randomized cross-over design after an appropriate washout period. Neuromuscular function was monitored using train-of-four (TOF) stimulation. Arterial blood was sampled continuously for the first minute after cisatracurium injection and at frequent intervals thereafter. Cisatracurium plasma concentrations were determined by high performance liquid chromatography analysis. PK/PD modelling of individual data sets was performed with NONMEM using a non-parametric approach and a descriptive sigmoid E(max) model. RESULTS: Cisatracurium PKs were linear over the dose range studied. Using non-parametric PK/PD analysis, mean values for plasma-effect compartment equilibration delay (k(e0)) were 0.0600 vs 0.1278 min(-1) (P<0.05) and sensitivity (EC(50)) were 323 vs 235 ng ml(-1) (P<0.05) for the high and low doses, respectively. CONCLUSIONS: A dose-dependent effect on the PK/PD parameters of cisatracurium has important clinical implications as an accurate estimate of the EC(50) is desirable. PK/PD parameters derived after intubating bolus doses of cisatracurium would be more reliable.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Estimation of the plasma effect-site equilibration rate constant (ke0) of rocuronium by the time of maximum effect: a comparison with non-parametric and parametric approaches.

BACKGROUND: The first order plasma-effect-site equilibration rate constant (k(e0)) links the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. For the calculation of the k(e0), one method uses a single point of the response curve corresponding to the time to peak effect of a drug (t(peak)); however, it has not been validated. This study compares the k(e0) calculated with the method of t(peak) and the k(e0) calculated with traditional non-parametric and parametric methods. METHODS: Fifteen adult patients receiving total intravenous anaesthesia (TIVA) were studied. All patients were monitored with an NMT Monitor 221 (GE Healthcare, Helsinki, Finland) to obtain the evoked compound EMG of the adductor pollicis to a train-of-four stimuli at 10 s intervals. During TIVA, rocuronium 0.15 mg kg(-1) was given i.v. as a bolus, and the neuromuscular response was recorded until recovery from block. Using the t(peak) and the complete response curve, k(e0) of rocuronium was calculated with the three methods using the predicted plasma concentrations of rocuronium from a PK model. Values of k(e0) are median (range). RESULTS: The k(e0)s obtained were 0.19 min(-1) (0.09-0.72) with the 't(peak)' method, 0.20 min(-1) (0.14-0.44) with the non-parametric method, and 0.19 min(-1) (0.11-0.38) [typical value (range)] with the parametric method (NS). CONCLUSIONS: If the t(peak) can be adequately estimated from the data, the 't(peak) method' is a valid alternative to traditional methods to calculate the k(e0).

Long-term effects of botulinum toxin on neuromuscular function.

BACKGROUND: Recent reports indicate increased incidence of Clostridium botulinum infections, particularly among drug abusers and tissue allograft recipients. Botulinum toxin also has potential application in biochemical warfare. The neurotoxin-induced paralysis often requires mechanical ventilation with and without muscle relaxants. The authors investigated the long-term effects of botulinum toxin on muscle function, expression of nicotinic acetylcholine receptors (nAChRs), and their interaction with muscle relaxant, atracurium. METHODS: Rats (n=30) were injected with varying doses (0.625, 2.5, and 10 U) of botulinum toxin into the tibialis muscle. Control animals (n=9) received an equivalent volume of saline. At 128 days after injection, neuromuscular function, pharmacodynamics of atracurium, and nAChRs were evaluated. RESULTS: Nerve-evoked tensions, including tetanic tension and muscle mass, were decreased on the toxin-injected side in a dose-dependent manner relative to saline-injected controls as well as the contralateral side. Specific muscle tension and specific tetanic muscle tension (tensions/muscle mass) were not reduced. The ED10 of atracurium was reduced, the ED50 was unchanged, and the ED90 was increased in the highest (10-U) dose of toxin group. The atracurium plasma concentration to maintain a steady state 50% paralysis was significantly reduced in the 10-U toxin group. The nAChR concentrations in the tibialis muscle were significantly increased in a dose-dependent manner in all experimental groups. CONCLUSION: Botulinum toxin causes dose-dependent long-term neuromuscular changes. The loss of tension generating capacity is almost exclusively related to muscle atrophy, because the specific tension did not change. The decreased ED10, unaltered ED50, and increased ED90 to atracurium suggest its interactions with different isoforms of receptors having varying sensitivity to atracurium. The absence of fade, despite the persistent botulinum toxin-induced denervation (increased nAChRs), suggests that the up-regulated nAChRs may have compensated for the prejunctional effects of botulinum toxin.