ABSTRACT
BACKGROUND: Previous studies reported a slow neuromuscular response with the currently recommended dose of cisatracurium in critically ill patients. Pharmacokinetic and pharmacodynamic studies of cisatracurium in critically ill patients are still limited. To our knowledge, this is the first study performed to better understand the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a loading dose of cisatracurium and to identify factors that affect PK and PD changes in critically ill patients. METHODS: A prospective PKs and PDs study was designed. Arterial blood samples of 10 critically ill patients with respiratory failure were collected after administering a loading dose of 0.2 mg/kg of cisatracurium. Plasma cisatracurium and laudanosine concentrations were determined using liquid chromatography-tandem mass spectrometry. The achievement of the desired pharmacodynamic response was evaluated by both 1) clinical assessment and 2) train-of-four monitoring. The PK/PD indices were analyzed for their correlation with patient'characteristics and other factors. RESULTS: The one-compartment model best described the plasma pharmacokinetic parameters of cisatracurium. The volume of distribution at steady state and total clearance were 0.11 ± 0.04 L/kg and 2.74 ± 0.87 ml/minute/kg, respectively. The mean time to train-of-four 0/4 was 6 ± 3.86 minutes. A time to the desired pharmacodynamic response of less than 5 minutes was found in 10% of the patients. A positive correlation was found between cisatracurium concentration and albumin levels and between pharmacokinetics data and patient factors [partial pressure of carbon dioxide and respiratory alkalosis]. CONCLUSION: The currently recommended loading dose of cisatracurium might not lead to the desired pharmacodynamic response in critically ill patients with respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03337373. Registered on 9 November 2017.
Subject(s)
Atracurium/analogs & derivatives , Critical Care/methods , Neuromuscular Blocking Agents/pharmacology , Respiration, Artificial/methods , Respiratory Insufficiency/blood , Respiratory Insufficiency/therapy , Adult , Aged , Aged, 80 and over , Atracurium/blood , Atracurium/pharmacokinetics , Atracurium/pharmacology , Critical Illness , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Neuromuscular Blocking Agents/blood , Neuromuscular Blocking Agents/pharmacokinetics , Prospective StudiesABSTRACT
Many adverse reactions to therapeutic drugs appear to be allergic in nature, and are thought to be triggered by patient-specific Immunoglobulin E (IgE) antibodies that recognize the drug molecules and form complexes with them that activate mast cells. However, in recent years another mechanism has been proposed, in which some drugs closely associated with allergic-type events can bypass the antibody-mediated pathway and trigger mast cell degranulation directly by activating a mast cell-specific receptor called Mas-related G protein-coupled receptor X2 (MRGPRX2). This would result in symptoms similar to IgE-mediated events, but would not require immune priming. This review will cover the frequency, severity, and dose-responsiveness of allergic-type events for several drugs shown to have MRGPRX2 agonist activity. Surprisingly, the analysis shows that mild-to-moderate events are far more common than currently appreciated. A comparison with plasma drug levels suggests that MRGPRX2 mediates many of these mild-to-moderate events. For some of these drugs, then, MRGPRX2 activation may be considered a regular and predictable feature after administration of high doses.
Subject(s)
Anaphylaxis/blood , Atracurium/adverse effects , Drug Hypersensitivity/blood , Morphine/adverse effects , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/metabolism , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/agonists , Receptors, Neuropeptide/metabolism , Rocuronium/adverse effects , Vancomycin/adverse effects , Animals , Atracurium/blood , Cell Degranulation/drug effects , Drug Hypersensitivity/immunology , Humans , Immunoglobulin E/metabolism , Mast Cells/immunology , Morphine/blood , Rocuronium/blood , Vancomycin/bloodABSTRACT
BACKGROUND: This study was designed to examine whether severe aortic regurgitation will affect the pharmacodynamics (PD) and pharmacokinetics (PK) of cisatracurium during anesthetic induction. METHODS: A total of 32 patients were divided into two groups: the AR group (n = 16) and the control group (n = 16). Arterial blood samples were drawn before and at 1, 2, 4, 6, 8, 10, 16 and 20 min after intravenous injection of 0.15 mg/kg cisatracurium. TOF tests were applied to determine the onset time of maximal muscle relaxation. The concentration of cisatracurium in plasma was determined by high-performance liquid chromatography. RESULTS: The onset time to maximal neuromuscular block was prolonged from 2.07 ± 0.08 min to 4.03 ± 0.14 min, which indicated that the PD responses to cisatracurium were significantly delayed in the AR group (P < 0.05) compared to the control group. A conventional two-compartment PK model showed a higher plasma concentration of cisatracurium among the AR group with markedly reduced intercompartment transfer rate (K12 = 0.19 ± 0.02 and K21 = 0.11 ± 0.01 in the AR group vs. K12=0.26 ± 0.01 and K21 = 0.19 ± 0.01 in the control group, P < 0.01) compared to the control group. CONCLUSION: Backward blood flow during diastole in severe AR impaired distribution of cisatracurium from the central compartment to the peripheral compartment, which accounted for the lagged PD responses. Findings in this study underlie the importance of muscular blockade monitoring among patients with severe aortic regurgitation during anesthetic induction. REGISTRATION: Name of the registry: Abnormal Cisatracurium Pharmacodynamics and Pharmacokinetics among Patients with Severe Aortic Regurgitation during Anesthetic Induction. TRIAL REGISTRATION NUMBER: ChiCTR1800019654. Date of registration: November 20th 2018.
Subject(s)
Aortic Valve Insufficiency/physiopathology , Atracurium/analogs & derivatives , Neuromuscular Blocking Agents/pharmacology , Aortic Valve Insufficiency/blood , Atracurium/blood , Atracurium/pharmacokinetics , Atracurium/pharmacology , Female , Humans , Male , Middle Aged , Neuromuscular Blocking Agents/blood , Neuromuscular Blocking Agents/pharmacokineticsABSTRACT
Cisatracurium besylate has been determined by fast and highly sensitive spectrofluorimetric method based on measuring the fluorescence intensity of its methanolic solution at 312 nm after excitation at 230 nm (Method I). The linearity occurred over the concentration range of 10.0-130.0 ng/mL with detection limit of 1.07 ng/mL. The method was further extended for the determination of the studied drug in spiked human plasma with good percentage recoveries (97.43-103.50%). Cisatracurium is co-administered with nalbuphine during surgery. The simultaneous determination of both drugs was based on synchronous spectrofluorimetric technique. First derivative synchronous spectrofluorimetric amplitude was measured in methanol at Δ λ = 60 nm and each drug could be estimated at the zero crossing point of the other. Hence, cisatracurium could be measured at 284.6 nm while nalbuphine at 276.3 nm (Method II). The method was linear over the ranges of 50.0-750.0 ng/mL and 0.5-7.0 µg/mL with the detection limits of 2.16 ng/mL and 0.04 µg/mL for cisatracurium and nalbuphine, respectively. The method was further extended for the simultaneous determination of both drugs in spiked human urine with mean percentage recoveries of 99.99 ± 2.06 and 99.53 ± 6.17 for cisatracurium and nalbuphine, respectively. Both methods were validated in agreement with Guidelines adopted by International Council of Harmonization (ICH).
Subject(s)
Atracurium/analogs & derivatives , Nalbuphine/blood , Nalbuphine/urine , Spectrometry, Fluorescence/methods , Urinalysis/methods , Atracurium/blood , Atracurium/urine , Calibration , Dosage Forms , Humans , Limit of Detection , Reproducibility of Results , SolventsABSTRACT
Propofol and cisatracurium besylate have been simultaneously determined using a highly sensitive first derivative synchronous spectrofluorometric method. The method is based on measuring first derivative synchronous spectrofluorimetric amplitude at Δλ = 40 nm with a scanning rate of 600 nm/min. The different experimental parameters affecting the fluorescence intensity of the two drugs were carefully studied and optimized. The amplitude-concentration plots were rectilinear over the range 40.0-400.0 ng/mL and 20.0-280.0 ng/mL for propofol and cisatracurium, respectively with lower detection limits of 4.0 and 2.35 ng/mL and quantification limits of 12.1 and 7.1 ng/mL for propofol and cisatracurium, respectively. The proposed method was successfully applied for the determination of the two compounds in synthetic mixtures and in commercial ampoules. The high sensitivity attained using the proposed method allowed the simultaneous determination of both drugs in spiked plasma samples. The mean % recoveries in spiked human plasma (n = 3) were 96.53 ± 0.90 and 96.20 ± 1.64 for each of propofol and cisatracurium, respectively. The method was validated in compliance with International Council of Harmonization (ICH) Guidelines.
Subject(s)
Atracurium/analogs & derivatives , Propofol/blood , Spectrometry, Fluorescence , Atracurium/blood , Atracurium/chemistry , Humans , Molecular Structure , Propofol/chemistryABSTRACT
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.
Subject(s)
Anesthesia/veterinary , Atracurium/pharmacokinetics , Neuromuscular Nondepolarizing Agents/pharmacokinetics , Swine/physiology , Animals , Animals, Newborn/physiology , Atracurium/administration & dosage , Atracurium/blood , Female , Injections, Intravenous/veterinary , Isoquinolines/blood , Neuromuscular Nondepolarizing Agents/administration & dosage , Neuromuscular Nondepolarizing Agents/blood , Prospective Studies , Swine/metabolismABSTRACT
The proposed method describes a high performance liquid chromatographic method with fluoremetric detection for the determination of cisatracurium (CIS) and propofol (PRP) simultaneously, which are co-administered as a pre-operative injection mixture. The separation of the two drugs was achieved using monolithic column (100 mm and 4.6 mm internal diameter) and mixture of methanol and 0.1 M phosphate buffer in the ratio of 80:20 (v/v) at pH 4.5 as a mobile phase. The fluorescence detection was carried out at 230/324 nm. The procedure showed good linearity through the concentration ranges of 0.01-1.00 µg/mL and 0.1-3.0 µg/mL with limits of detection of 0.002, 0.030 µg/mL and limits of quantification of 0.006, 0.100 µg/mL for CIS and PRP, respectively. Simultaneous determination of CIS and PRP in spiked human plasma samples was additionally executed and the results were satisfactory precise and accurate.
Subject(s)
Atracurium/analogs & derivatives , Chromatography, High Pressure Liquid/methods , Propofol/blood , Atracurium/blood , Atracurium/chemistry , Humans , Limit of Detection , Linear Models , Propofol/chemistry , Reproducibility of ResultsABSTRACT
The neuromuscular blocking agent cisatracurium is frequently used adjunctively in anesthesia to facilitate endotracheal intubation and to provide muscle relaxation during surgery. We aimed to determine the pharmacokinetics (PK)/pharmacodynamics (PD) of cisatracurium in patients with congenital heart defects (CHDs), such as ventricular septal defects and atrial septal defects, and to assess the effects of CHDs on the PK/PD profiles of cisatracurium. A modified two-compartment model with drug clearance from both compartments was best fitted to the PK data to determine the PK parameters. The model suggested that septal defects significantly lowered the rate of cisatracurium distribution from the central to peripheral compartment. The intercompartment rate constants k12 and k21 were significantly reduced (35%-60%, P < 0.05) in patients with ventricular septal defects and in patients with atrial septal defects compared with control patients. Consistently, septal defects caused a marked increase (160%-175%, P < 0.001) in the distribution half-life. Furthermore, significantly delayed pharmacodynamic responses to cisatracurium were observed in patients with septal defects. The onset time (i.e., the time to maximal neuromuscular block) was prolonged from 2.2 minutes to 5.0 minutes. PK/PD modeling suggested that reduced concentrations of cisatracurium in the effect compartment due to poorer distribution were the main cause of lagged pharmacodynamic responses. In conclusion, cisatracurium PK/PD were significantly altered in patients with septal defects. Our study should be of use in clinical practice for the administration of cisatracurium to patients with CHDs.
Subject(s)
Atracurium/analogs & derivatives , Heart Septal Defects, Atrial/metabolism , Heart Septal Defects, Ventricular/metabolism , Neuromuscular Blocking Agents/pharmacokinetics , Neuromuscular Junction/drug effects , Adult , Atracurium/administration & dosage , Atracurium/blood , Atracurium/pharmacokinetics , Female , Heart Septal Defects, Atrial/blood , Heart Septal Defects, Ventricular/blood , Humans , Injections, Intravenous , Male , Metabolic Clearance Rate , Middle Aged , Models, Biological , Neuromuscular Blocking Agents/administration & dosage , Neuromuscular Blocking Agents/blood , Neuromuscular Monitoring , Tissue Distribution , Young AdultABSTRACT
A high-performance liquid chromatography (HPLC) assay with fluorescence detection (FLD) for quantification of cisatracurium in human plasma was developed and fully validated. Liquid-liquid extraction was employed for sample preparation. The separation was carried out on a C18 column with ternary mobile phase composed of 30mmolL(-1) phosphate buffer (pH 3.0), acetonitrile and methanol (60:35:5, v/v/v). Verapamil was used as the internal standard. The isocratic elution with programmed flow rate was employed by setting at 0.8mLmin(-1) from 0 to 3.5min, 0.5mLmin(-1) from 3.5 to 6min, and 1.0mLmin(-1) from 6 to 10min. The fluorescence detection was performed at 236nm for excitation and 324nm for emission. The assay was linear from 50 to 2800ngmL(-1), with a detection limit of 12ngmL(-1). The correlation coefficient (r) for linear regression was 0.9997. The intra-day coefficients of variation (CVs) were less than 2.0%, and the inter-day CVs were less than 4.0%. The mean recoveries were in the range of 92.1-100.4%. The total HPLC run time was less than 10min. The developed HPLC method was fast, simple, sensitive, accurate and suitable for studying the pharmacokinetics of cisatracurium in infants and children after intravenous administration.
Subject(s)
Atracurium/analogs & derivatives , Chromatography, High Pressure Liquid/methods , Atracurium/blood , Atracurium/chemistry , Atracurium/pharmacokinetics , Child, Preschool , Drug Stability , Humans , Infant , Limit of Detection , Linear Models , Liquid-Liquid Extraction , Reproducibility of ResultsABSTRACT
A high performance liquid chromatographic method coupled with fluorometric detection has been developed for the determination of atracurium and its major metabolite laudanosine in dog plasma. The separation of atracurium and laudanosine was performed on an Agilent Eclipse Plus C18 column, and the mobile phase consisted of 0.03 mol/L dipotassium hydrogen phosphate and acetonitrile (72: 28, v/v) at a flow rate of 1.0 mL/min. Verapamil was used as the internal standard. The sample was extracted by dichloromethane, concentrated and dissolved in the mobile phase. The detection is performed at 240 nm for excitation and 320 nm for emission. The results showed that the linear concentration ranges of the calibration curve were 25 - 5 000 microg/L for atracurium (r = 0.999 0), and 25 - 6 000 microg/L for laudanosine (r = 0.9984). The recoveries were 92.1% - 109.5%. The limits of detection were 3 microg/L for atracurium and 1 microg/L for laudanosine. The RSDs of intra-day and inter-day were less than 10%. The stability tests under various conditions have been performed. The method is specific, sensitive and accurate in the determination of atracurium and laudanosine, and also can be used for the pharmacokinetic investigations of atracurium and laudanosine in plasma.
Subject(s)
Atracurium/blood , Chromatography, High Pressure Liquid , Fluorometry , Isoquinolines/blood , Animals , Calibration , Cardiopulmonary Bypass , Dogs , VerapamilABSTRACT
The suicide of a 43-year-old male by intravenous injection of cisatracurium, a non-depolarizing neuromuscular blocking agent, and thiopental, an ultra-short-acting barbiturate, is presented. Systematic toxicological screening by gas chromatography-mass spectrometry (GC-MS), liquid chromatography (LC)-diode-array detection, and LC-MS-MS confirmed the presence of thiopental. A large peak in the GC-MS chromatogram was matched by the Pfleger-Maurer library as corlumine, but neither atracurium neither its metabolite, laudanosine, were detected. To confirm the absence or the presence of laudanosine in the blood sample, an ultra-performance liquid chromatography-MS-MS method for cisatracurium and laudanosine quantification was developed. The calibration range was 2.5-500 ng/mL for laudanosine and 10-500 ng/mL for cisatracurium. The biases were lower than 12.3%. Intraday and interday precisions, expressed as coefficient of variation, were lower than 13.3%. This method allowed to confirm the presence of laudanosine and measurement of laudanosine in all samples. The femoral blood concentration was therapeutic (0.46 µg/mL). This case report documents a possible analytical pitfall and describes a simple and fast method for cisatracurium determination. Moreover, the purpose of this case report was to document the postmortem redistribution of cisatracurium and laudanosine, which could help make it possible to interpret tissue or cardiac blood concentrations in forensic cases where femoral blood is not available.
Subject(s)
Atracurium/analogs & derivatives , Hypnotics and Sedatives/poisoning , Neuromuscular Blocking Agents/poisoning , Suicide , Thiopental/poisoning , Adult , Atracurium/administration & dosage , Atracurium/blood , Atracurium/poisoning , Drug Overdose , Fatal Outcome , Humans , Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/blood , Injections, Intravenous , Male , Neuromuscular Blocking Agents/administration & dosage , Neuromuscular Blocking Agents/blood , Thiopental/administration & dosage , Thiopental/bloodABSTRACT
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.
Subject(s)
Atracurium/analogs & derivatives , Cardiopulmonary Bypass , Hypothermia, Induced , Neuromuscular Nondepolarizing Agents/pharmacology , Neuromuscular Nondepolarizing Agents/pharmacokinetics , Atracurium/blood , Atracurium/pharmacokinetics , Atracurium/pharmacology , Body Temperature , Calibration , Child, Preschool , Chromatography, High Pressure Liquid , Electromyography , Female , Heart Defects, Congenital/surgery , Humans , Infant , Male , Monitoring, Intraoperative , Neuromuscular Nondepolarizing Agents/blood , Skin TemperatureABSTRACT
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.
Subject(s)
Atracurium/analogs & derivatives , Neuromuscular Nondepolarizing Agents/administration & dosage , Anesthesia, General/methods , Animals , Atracurium/administration & dosage , Atracurium/blood , Atracurium/pharmacology , Chromatography, High Pressure Liquid/methods , Cross-Over Studies , Dogs , Dose-Response Relationship, Drug , Electric Stimulation/methods , Infusions, Intravenous , Male , Neuromuscular Blockade , Neuromuscular Junction/drug effects , Neuromuscular Nondepolarizing Agents/blood , Neuromuscular Nondepolarizing Agents/pharmacologyABSTRACT
The paper presents a new method for target control infusion (TCI) for neuromuscular blockade (NMB) level control of patients subject to general anaesthesia. The method combines an inversion of the pharmacokinetic/pharmacodynamic (PK/PD) model with a hybrid parameter estimation method that uses on-line data from the initial bolus response to estimate the model parameters. Although atracurium is considered as relaxant, the newly proposed method may be applied to other drugs for which the PK/PD model is available. Simulation results on a bank of 100 patient models are presented to demonstrate the achievable performance.
Subject(s)
Atracurium/administration & dosage , Atracurium/pharmacokinetics , Drug Therapy, Computer-Assisted/methods , Models, Biological , Neuromuscular Blockade/methods , Neuromuscular Blocking Agents/administration & dosage , Neuromuscular Blocking Agents/pharmacokinetics , Atracurium/blood , Computer Simulation , Humans , Infusions, Intravenous/methods , Neuromuscular Blocking Agents/bloodABSTRACT
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.
Subject(s)
Botulinum Toxins/toxicity , Muscle Contraction/drug effects , Neuromuscular Junction/drug effects , Receptors, Nicotinic/drug effects , Animals , Atracurium/blood , Atracurium/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Male , Neuromuscular Nondepolarizing Agents/blood , Neuromuscular Nondepolarizing Agents/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
Quaternary ammonium drugs (atracurium, bretylium, edrophonium, ipratropium, mivacurium, neostigmine, pancuronium and rocuronium) and herbicides (difenzoquat, diquat and paraquat) in human whole blood were analysed by LC/MS/MS with positive electrospray ionisation (ESI), following extraction with Bond Elut LRC-CBA cartridges. Internal standards were benzyldimethylphenylammonium chloride monohydrate and ethyl viologen for drug and herbicide analysis, respectively. Ion-pair chromatography used heptafluorobutyric acid (15 mM)-ammonium formate (20 mM) buffer adjusted to pH 3.30 with formic acid and a linear gradient from 5 to 90% methanol run over 18 min. Recoveries ranged from 79.7 to 105.1%, detection limits were between 3.6 and 20.4 ng/ml and the intra- and inter-day precisions were less than 18.6% at a concentration of 10 ng/ml. The method was applied to a case of accidental paraquat poisoning in which the concentration of paraquat in blood was 0.64 mg/l, which is within the range associated with fatal paraquat poisoning.
Subject(s)
Chromatography, Liquid/methods , Herbicides/blood , Quaternary Ammonium Compounds/blood , Spectrometry, Mass, Electrospray Ionization/methods , Androstanols/blood , Atracurium/blood , Bretylium Compounds/blood , Diquat/blood , Edrophonium/blood , Humans , Ipratropium/blood , Isoquinolines/blood , Mivacurium , Neostigmine/blood , Pancuronium/blood , Paraquat/blood , Pyrazoles/blood , Reproducibility of Results , RocuroniumABSTRACT
We studied the pharmacokinetics and pharmacodynamics of cisatracurium in 9 children (mean weight, 17.1 kg) aged 1-6 yr (mean, 3.75 yr) during propofol-nitrous oxide anesthesia. Neuromuscular monitoring was performed. Venous samples were taken before injection of a 0.1 mg/kg dose of cisatracurium and then at 2, 5, 10, 30, 60, 90, and 120 min. Cisatracurium plasma concentrations were determined by high performance liquid chromatography. Onset time was 2.5 +/- 0.8 min, recovery to 25% of baseline twitch height was 37.6 +/- 10.2 min, and the 25%-75% recovery index was 10.9 +/- 3.7 min. Distribution and elimination half-lives were 3.5 +/- 0.9 min and 22.9 +/- 4.5 min, respectively. Steady-state volume of distribution (0.207 +/- 0.031 L/kg) and total body clearance (6.8 +/- 0.7 mL/min/kg) were significantly larger than those published for adults. Pharmacodynamic results were comparable to those obtained in pediatric studies during halothane or opioid anesthesia with the exception of a longer recovery to 25% baseline. Although the plasma-effect compartment equilibration rate constant was twofold faster (0.115 +/- 0.025 min(-1)) than that published for cisatracurium in adults, the effect compartment concentration corresponding to 50% block was similar (129 +/- 27 ng/mL).
Subject(s)
Anesthesia, Intravenous/methods , Atracurium/analogs & derivatives , Nitrous Oxide/administration & dosage , Propofol/administration & dosage , Anesthesia, Inhalation/methods , Atracurium/administration & dosage , Atracurium/blood , Atracurium/pharmacokinetics , Child , Child, Preschool , Female , Humans , Infant , Male , Oxygen/administration & dosageABSTRACT
BACKGROUND: Neonates and infants often require extended periods of mechanical ventilation facilitated by sedation and neuromuscular blockade. METHODS: Twenty-three patients aged younger than 2 yr were randomly assigned to receive either cisatracurium or vecuronium infusions postoperatively in a double-blinded fashion after undergoing congenital heart surgery. The infusion was titrated to maintain one twitch of a train-of-four. The times to full spontaneous recovery of train-of-four without fade, extubation, intensive care unit discharge, and hospital discharge were documented after drug discontinuation. Sparse sampling after termination of the infusion and a one-compartment model were used for pharmacokinetic analysis. The Mann-Whitney U test and Student t test were used to compare data between groups. RESULTS: There were no significant differences between groups with respect to demographic data or duration of postoperative neuromuscular blockade infusion. The median recovery time for train-of-four for cisatracurium (30 min) was less than that for vecuronium (180 min) (P < 0.05). Three patients in the vecuronium group had prolonged train-of-four recovery: Two had long elimination half-lives for vecuronium, and one had a high concentration of 3-OH vecuronium. There were no differences in extubation times, intensive care unit stays, or hospital stays between groups. CONCLUSIONS: Our results parallel data from adults demonstrating a markedly shorter recovery of neuromuscular transmission after cisatracurium compared with vecuronium. Decreased clearance of vecuronium and the accumulation of 3-OH vecuronium may contribute to prolonged spontaneous recovery times. Cisatracurium is associated with faster spontaneous recovery of neuromuscular function compared with vecuronium but not with any differences in intermediate outcome measures in neonates and infants.
Subject(s)
Atracurium , Atracurium/analogs & derivatives , Cardiac Surgical Procedures , Heart Defects, Congenital/surgery , Neuromuscular Nondepolarizing Agents , Vecuronium Bromide , Atracurium/administration & dosage , Atracurium/blood , Atracurium/pharmacokinetics , Biotransformation , Chromatography, High Pressure Liquid , Double-Blind Method , Half-Life , Humans , Infant , Infant, Newborn , Intensive Care Units , Length of Stay , Monitoring, Intraoperative , Neuromuscular Nondepolarizing Agents/administration & dosage , Neuromuscular Nondepolarizing Agents/blood , Neuromuscular Nondepolarizing Agents/pharmacokinetics , Synaptic Transmission/drug effects , Vecuronium Bromide/administration & dosage , Vecuronium Bromide/blood , Vecuronium Bromide/pharmacokineticsABSTRACT
BACKGROUND: Systemic inflammation may be associated with resistance to nondepolarizing neuromuscular blocking drugs, the mechanisms of which are, however, uncharacterized. The authors therefore investigated the pharmacodynamics of atracurium and its relation to the expression of nicotinic acetylcholine receptors and alpha1 -acid glycoprotein in a rat model of systemic inflammation. METHODS: To induce a systemic inflammation, male CD rats received 56 mg/kg corynebacterium parvum intravenously. On days 2, 4, 6, 8, 10, 12, 14, or 16 after infection, neuromuscular transmission was measured. The individual effective dose of atracurium was determined, followed by an atracurium infusion at a rate to establish a steady state neuromuscular block of 50%. Total and unbound plasma concentrations of atracurium for 50% paralysis were measured using high-performance liquid chromatography. Acetylcholine receptors were quantitated using 125I-alpha-bungarotoxin. alpha1 -Acid glycoprotein concentrations in the serum were measured using a competitive chemiluminescence immunoassay. RESULTS: The effective dose of atracurium was increased on days 4, 6, and 8. Total atracurium plasma concentrations at 50% neuromuscular paralysis were increased on days 4, 6, 8, and 10, with a peak at day 8 (8.0 +/- 1.3 micro g/ml) compared with control rats (4.23 +/- 0.82 micro g/ml). The alpha1 -acid glycoprotein concentrations were increased between days 2 and 10, with a peak on day 4 (6.52 +/- 1.45 mg/ml), and recovered to control values (0.61 +/- 0.33 mg/ml) on day 12. Unbound plasma concentrations of atracurium to achieve 50% depression, as well as the expression of acetylcholine receptors, did not differ between groups. CONCLUSION: Resistance to atracurium during corynebacterium parvum-induced systemic inflammation is due to increased drug binding to alpha1 -acid glycoprotein and is unrelated to changes in acetylcholine receptor expression.
Subject(s)
Atracurium/pharmacology , Inflammation/pathology , Neuromuscular Nondepolarizing Agents/pharmacology , Receptors, Cholinergic/biosynthesis , Anesthesia , Animals , Atracurium/blood , Drug Resistance , Kidney/drug effects , Kidney/metabolism , Liver/drug effects , Liver/metabolism , Male , Membranes/drug effects , Membranes/metabolism , Models, Biological , Myography , Neuromuscular Nondepolarizing Agents/blood , Nitric Oxide/blood , Orosomucoid/biosynthesis , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Neuromuscular blocking agents may exert central nervous system effects when they reach the brain. This study assessed the concentrations and the time course of passage of vecuronium, atracurium, and its metabolite laudanosine in the cerebrospinal fluid (CSF) of patients undergoing intracranial aneurysm clipping. METHODS: Twenty-five patients with subarachnoid hemorrhage were randomly allocated to receive an intravenous infusion of vecuronium (n=13) or atracurium (n=12). Arterial blood and lumbar CSF were sampled before and 1, 2, 3, 4 and 8 h after the start of the relaxant infusion. The samples were analyzed by liquid chromatography-electrospray ionization mass spectrometry (vecuronium) and high-pressure liquid chromatography (atracurium and laudanosine). RESULTS: The data of 20 patients (10 in both groups) were analyzed. In 11 CSF samples from five patients atracurium was detected in concentrations from 10 to 50 ng/ml. Laudanosine was retrieved in all CSF samples at 1, 2, 3, 4 and 8 h; the highest CSF concentration of laudanosine occurred at 3 h [38 (18-63) ng/ml: median (range)]. Vecuronium was not found in any CSF sample. CONCLUSION: Significant concentrations of atracurium and laudanosine but not of vecuronium were detected in the CSF of patients during and immediately after intracranial aneurysm surgery.