RESUMEN
A method for simultaneous pharmacokinetic-pharmacodynamic (PK-PD) population analysis using an Iterative Two-Stage Bayesian (ITSB) algorithm was developed. The method was evaluated using clinical data and Monte Carlo simulations. Data from a clinical study with rocuronium in nine anesthetized patients and data generated by Monte Carlo simulation using a similar study design were analysed by sequential PK-PD analysis, PD analysis with nonparametric PK data and simultaneous PK-PD analysis. Both PK and PD data sets were 'rich' with respect to the number of measurements per individual. The accuracy and precision of the estimated population parameters were evaluated by comparing their mean error (ME) and root mean squared error (RMSE), respectively. The influence of PD model misspecification on the results was also investigated. The simultaneous PK-PD analysis resulted in slightly more precise population parameter estimates than the sequential PK-PD analysis and the nonparametric PK method. In the presence of PD model misspecification, however, simultaneous analysis resulted in poor PK parameter estimates, while sequential PK-PD analysis performed well. In conclusion, ITSB is a valuable technique for PK-PD population analysis of rich data sets. The sequential PK-PD method is better suited for the analysis of rich data than the simultaneous analysis.
Asunto(s)
Teorema de Bayes , Farmacocinética , Adolescente , Adulto , Anciano , Algoritmos , Androstanoles/farmacocinética , Anestesia General , Sesgo , Simulación por Computador , Interpretación Estadística de Datos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Método de Montecarlo , Relajación Muscular/efectos de los fármacos , Fármacos Neuromusculares no Despolarizantes/farmacocinética , Población , Reproducibilidad de los Resultados , RocuronioRESUMEN
BACKGROUND: Sugammadex reverses the neuromuscular blocking effects of rocuronium by chemical encapsulation. The efficacy, safety, and pharmacokinetics of sugammadex for reversal of profound rocuronium-induced neuromuscular blockade were evaluated. METHODS: Ninety-eight male adult patients were randomly assigned to receive sugammadex (1, 2, 4, 6, or 8 mg/kg) or placebo at 3, 5, or 15 min after 0.6 mg/kg rocuronium. Patients were anesthetized with propofol and fentanyl. The primary endpoint of the study was the time to achieve a recovery of train-of-four ratio to 0.9. Neuromuscular blockade was measured using acceleromyography. Concentrations of rocuronium and sugammadex were determined in venous blood and urine samples. A population pharmacokinetic model using NONMEM (GloboMax LLC, Hanover, MD) was applied. RESULTS: The mean time to recovery of the train-of-four ratio to 0.9 after dosing at 3, 5, and 15 min decreased from 52.1, 51.7, and 35.6 min, respectively, after administration of placebo to 1.8, 1.5, and 1.4 min, respectively, after 8 mg/kg sugammadex. Sugammadex was safe and well tolerated. However, 20.4% of patients showed signs of inadequate anesthesia after its administration. The median cumulative excretion of rocuronium in the urine over 24 h was 26% in the placebo group and increased to 58-74% after 4-8 mg/kg sugammadex. The mean plasma clearances of sugammadex and rocuronium were 0.084 and 0.26 l/min, respectively. CONCLUSIONS: In male subjects, sugammadex safely reversed profound neuromuscular blockade induced by 0.6 mg/kg rocuronium in a dose-dependent manner. Sugammadex enhanced the renal excretion of rocuronium, and its clearance is approximately one third that of rocuronium.
Asunto(s)
Androstanoles/farmacología , Bloqueo Neuromuscular , Fármacos Neuromusculares no Despolarizantes/farmacología , gamma-Ciclodextrinas/farmacología , Adulto , Androstanoles/farmacocinética , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Persona de Mediana Edad , Rocuronio , Seguridad , Sugammadex , gamma-Ciclodextrinas/efectos adversos , gamma-Ciclodextrinas/farmacocinéticaRESUMEN
BACKGROUND: We present a case in which a temporary decrease in train-of-four (TOF) response was observed after reversal of muscle relaxation with a small dose (0.5 mg/kg) of sugammadex administered 42 min after 0.9 mg/kg of rocuronium. At the end of the operation, the TOF ratio was >0.9, and the patient woke normally, without signs of muscle weakness. We describe this temporary decrease in muscle response during muscle relaxation reversal as muscle relaxation rebound and hypothesize that it occurs when the dose of sugammadex is sufficient for complex formation with rocuronium in the central compartment, but insufficient for redistribution of rocuronium from peripheral to central compartments. METHODS: To investigate our hypothesis, we developed and fit a simple pharmacokinetic- pharmacodynamic model of rocuronium, sugammadex, and their interaction to the patient TOF response data. RESULTS: Simulations using the fitted model indicate that muscle relaxation rebound can occur for doses of sugammadex in a limited critical range. CONCLUSIONS: Sufficiently large doses of sugammadex eliminate the possibility for muscle relaxation rebound, which does not require dissociation of the sugammadex/ rocuronium complex.
Asunto(s)
Androstanoles/antagonistas & inhibidores , Bloqueo Neuromuscular , Fármacos Neuromusculares no Despolarizantes/farmacología , gamma-Ciclodextrinas/farmacología , gamma-Ciclodextrinas/farmacocinética , Femenino , Humanos , Persona de Mediana Edad , Modelos Químicos , Hipotonía Muscular , Relajación Muscular/efectos de los fármacos , Rocuronio , Sugammadex , Tecnología Farmacéutica , Factores de TiempoRESUMEN
OBJECTIVES: The aim of this study is to investigate whether quantitative sensory testing with Von Frey monofilaments (VFMs) can be used for the quantification of allodynia in patients with chronic neuropathic pain, and how the pain threshold of affected skin differs from healthy skin. METHODS: Using VFMs, we aimed to determine the pain threshold in 22 patients suffering from allodynia as a consequence of a chronic unilateral neuropathic pain syndrome. We performed quantitative sensory testing according to the Method of Limits protocol. We used the patient's own contralateral side and 5 healthy control participants to obtain reference values. RESULTS: On the affected side, we found in 20 out of 22 patients that the pain threshold could be determined with the monofilaments. On average, these 20 patients indicated pain upon the application of monofilament with logarithmic nr. 4.56, whereas no pain threshold could be determined on the contralateral, unaffected side, and in the healthy control participants for any monofilament. DISCUSSION: We showed that although etiology and pathophysiology of allodynia vary individually, with VFMs the clinical symptom allodynia can be quantified in a simple and practical fashion in almost all patients.
Asunto(s)
Hiperestesia/etiología , Hiperestesia/fisiopatología , Neuralgia/complicaciones , Umbral del Dolor , Adulto , Anciano , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estimulación FísicaRESUMEN
The time course of twitch depression following neuromuscular blocking agent (NMBA) administration is influenced by the duration of control neuromuscular monitoring (twitch stabilization). The physiological mechanism for this interaction is not known. During twitch stabilization twitch response often increases to a plateau, this is known as twitch potentiation or the staircase phenomenon. Since twitch potentiation contributes to the observed twitch response it may also influence the time course of twitch depression following NMBA administration. Our objective was to estimate the degree that twitch potentiation influences the time course of twitch depression following NMBA administration under conditions typical for muscle relaxation studies. We used previousy described pharmacokinetic-pharmacodynamic (PK-PD) and twitch potentiation models to simulate twitch data. Simulations consisted of twitch stabilization followed by a NMBA bolus dose and subsequent onset and recovery from muscle relaxation. Twitch data were analyzed for onset and recovery characteristics and the results compared to clinical muscle relaxation studies in existing literature. We found that twitch potentiation likely plays a minor role in shortened onset time and increased duration of twitch depression observed with long periods of twitch stabilization.
Asunto(s)
Bloqueantes Neuromusculares/farmacología , Bloqueantes Neuromusculares/envenenamiento , Unión Neuromuscular/efectos de los fármacos , Simulación por Computador , Humanos , Modelos Biológicos , Unión Neuromuscular/fisiologíaRESUMEN
Repeated motor nerve stimulation performed during neuromuscular monitoring enhances the evoked mechanical response of the corresponding muscle resulting in an increased twitch response. This is known as twitch potentiation or the staircase phenomenon. For neuromuscular modelling research twitch stabilisation techniques are often used to reduce the visible effect of potentiation, but such techniques are not always effective. Our objective was to model pharmacokinetic-pharmacodynamic (PK-PD) and twitch potentiation and to estimate neuromuscular block (NMB) in the presence of twitch potentiation. We combined a standard PK-PD model with a model describing the degree of twitch potentiation. The combined model was used to predict mechanomyographic twitch measurements and estimate NMB and twitch potentiation during muscle relaxation monitoring. Model parameters and prediction accuracy were compared to the standard PK-PD model with and without linear baseline correction. The PK-PD-potentiation model allows NMB to be estimated in the presence of twitch potentiation. It also accurately predicts data from twitch stabilisation, which is ignored with the standard PK-PD model. Compared to the standard PK-PD model, estimated PD parameters ec50 and gamma were found to be higher using the PK-PD-potentiation model. Compared to linear baseline correction, estimated PD parameters ke0 and ec50 were found to be higher. A PK-PD-potentiation model can estimate the degree of twitch potentiation and the degree of NMB during neuromuscular monitoring. This model leads to different PD parameter estimations than the standard PK-PD model however the differences are small enough to be unlikely to cause great concern among researchers.
Asunto(s)
Relajantes Musculares Centrales/farmacología , Relajantes Musculares Centrales/farmacocinética , Algoritmos , Sinergismo Farmacológico , Estimulación Eléctrica , Humanos , Modelos Lineales , Modelos Biológicos , Modelos Estadísticos , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Estándares de ReferenciaRESUMEN
Automatic muscle relaxation control may reduce anesthesiologists' workload freeing them for other patient care requirements. In this report we describe a muscle relaxation controller designed for routine clinical application using rocuronium and the train-of-four count. A muscle relaxation monitor (TOF Watch SX) was connected to a laptop computer running a controller algorithm program that communicates with a syringe pump to form a closed-loop muscle relaxation system. The control algorithm uses proportional-integral and lookup table components and is designed to avoid the usability restrictions of existing controllers. The controller is optimized using an objective method to avoid the uncertainties of ''hand-crafted'' controller algorithms. Controller target was train-of-four count 1 or 2 and controller performance was evaluated in 15 patients. During 39 hours of closed-loop control, 96.1% of all twitches recorded were in the target range. Average rocuronium infusion rate was 0.36 mg.kg(-1).h(-1) (sd 0.18 mg.kg(-1).h(-1)). We show that the controller remains useful even in the presence of disturbances that can arise in routine clinical conditions. The muscle relaxation controller maintained the target train-of-four count values and may serve as a basis for the design of hardware and user interfaces for closed-loop muscle relaxation control in clinical conditions.
Asunto(s)
Anestesia , Anestesiología/instrumentación , Relajación Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Anciano , Algoritmos , Androstanoles/administración & dosificación , Automatización , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio , Fármacos Neuromusculares no Despolarizantes/administración & dosificación , RocuronioRESUMEN
BACKGROUND: In myasthenic patients, the sensitivity for nondepolarizing relaxants is increased and the time course of effect is prolonged due to a reduced number of functional acetylcholine receptors at the neuromuscular junction. The authors investigated both the performance of the link model proposed by Sheiner and a pharmacodynamic-pharmacokinetic model taking into account the number of unbound acetylcholine receptors in myasthenic pigs. METHODS: After obtaining the approval of the Animal Experiments Committee of their institution, the authors studied eight myasthenic pigs and eight control pigs. Myasthenia gravis was induced by injecting Torpedo acetylcholine receptors in weeks 1 and 4. On the day of the experiments, the pigs were anesthetized and intubated, and the appropriate muscles and nerves were prepared for the measurements. Rocuronium was administered by infusion to reach 90% twitch height block. Arterial blood was sampled during onset and offset of effect, and the plasma concentration of rocuronium was measured with high-performance liquid chromatography. Plasma concentration-time effect data were analyzed using two different pharmacokinetic-pharmacodynamic models, the link model according to Sheiner and a pharmacokinetic-pharmacodynamic model taking into account the unbound receptor concentration. Muscles were removed after the experiment for laboratory analysis of the acetylcholine receptor concentration. RESULTS: All eight pigs of the myasthenic group developed clinical signs of myasthenia gravis (muscle weakness) and showed increased sensitivity toward rocuronium. Pharmacokinetic modeling revealed no significant differences between myasthenic and control pigs. In pharmacokinetic-pharmacodynamic analysis, visual inspection as well as the Akaike Information Criterion (3,605 3,769) and the residual SD (3.2 3.6%) revealed a better fit for the unbound receptor model in myasthenic animals compared to the Sheiner model. Pharmacokinetic-pharmacodynamic analysis with the unbound receptor model demonstrated a decreased EC50 of 0.27 micro m (ranging from 0.17 to 0.59 micro m) compared to 2.71 micro m (ranging from 2.42 to 4.43 micro m) in control animals. The results of the Sheiner pharmacokinetic-pharmacodynamic analysis were in the same range. Both the laboratory analysis and pharmacokinetic-pharmacodynamic modeling showed a decrease in receptor concentration of more than 75%. CONCLUSION: Both the Sheiner model and the unbound receptor model may be used to fit plasma concentration-effect data of rocuronium in pigs. The unbound receptor concentration model, however, can explain the observed differences in the time course of effect, based on receptor concentration.
Asunto(s)
Androstanoles/farmacología , Androstanoles/farmacocinética , Fármacos Neuromusculares no Despolarizantes/farmacología , Fármacos Neuromusculares no Despolarizantes/farmacocinética , Receptores Colinérgicos/efectos de los fármacos , Algoritmos , Androstanoles/sangre , Animales , Femenino , Inmunohistoquímica , Modelos Biológicos , Miastenia Gravis Autoinmune Experimental/metabolismo , Unión Neuromuscular/efectos de los fármacos , Unión Neuromuscular/metabolismo , Fármacos Neuromusculares no Despolarizantes/sangre , Receptores Colinérgicos/inmunología , Rocuronio , Porcinos , TorpedoRESUMEN
UNLABELLED: Patients with myasthenia gravis are more sensitive than healthy patients to nondepolarizing neuromuscular blocking drugs. We performed a pharmacokinetic/pharmacodynamic modeling study of rocuronium in eight myasthenic patients and eight matched control patients. Patients were anesthetized with propofol and sufentanil and a mixture of nitrous oxide/oxygen. Mechanomyographical monitoring of the adductor pollicis was applied. Rocuronium was infused at a rate of 25 micro g. kg(-1). min(-1) in myasthenic patients and 116.7 micro g. kg(-1). min(-1) in control patients and was terminated at 70% neuromuscular block. Arterial blood samples were drawn during onset and offset of the block and for 4 h after the administration of rocuronium. Plasma concentrations were determined by high-performance liquid chromatography. Pharmacokinetic/pharmacodynamic modeling was performed by using the Sheiner model and the unbound receptor model (URM), which takes into account the number of unbound acetylcholine receptors. The effective concentration at 50% effect and the steepness of the concentration-effect relationship were significantly decreased in myasthenic patients. Both the URM and the Sheiner model provided an adequate fit in myasthenic patients. The acetylcholine receptor concentration was significantly decreased in myasthenic patients. The URM explains the observed differences in time course and potency, whereas the Sheiner model does not. IMPLICATIONS: We performed a pharmacokinetic/pharmacodynamic modeling study in myasthenic patients and control patients. The unbound receptor model, which takes into account the number of unbound acetylcholine receptors in the biophase, was introduced and compared with the model proposed by Sheiner.
Asunto(s)
Androstanoles/farmacología , Androstanoles/farmacocinética , Miastenia Gravis/metabolismo , Fármacos Neuromusculares no Despolarizantes/farmacología , Fármacos Neuromusculares no Despolarizantes/farmacocinética , Receptores Colinérgicos/efectos de los fármacos , Adolescente , Adulto , Teorema de Bayes , Inhibidores de la Colinesterasa/farmacología , Estimulación Eléctrica , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Bromuro de Piridostigmina/farmacología , RocuronioRESUMEN
BACKGROUND: A model of an antegrade, perfused, isolated rat peroneal nerve anterior tibial muscle was developed to study potentially important factors governing the time course of action of (nondepolarizing) neuromuscular blocking agents such as concentration, blood flow, and temperature. The model allows observation of the effects of selective changes in these factors. METHODS: The authors isolated the anterior tibial muscle and cannulated the anterior tibial artery and vein, providing a way for single-pass perfusion with blood from a donor rat. A force transducer was connected to the tibialis anterior muscle and a stimulator was connected to the tibial nerve. The influence of intrinsic potency (EC90) and muscle blood flow rate on the time course of pancuronium and rocuronium was investigated. RESULTS: The model remained stable for at least 4 h with respect to twitch height, muscle structure and function, and blood chemistry. Doubling the muscle-blood flow resulted in a significantly faster onset and offset for both pancuronium and rocuronium. Trebling the intrinsic potency (EC90) was not associated with significant changes in the time course of action of the relaxants. CONCLUSION: The authors developed and validated a model that allows us to study biophase kinetics of neuromuscular blocking agents in the anterior tibial muscle of the rat. In this model, muscle-blood flow rather than EC90 appears to predominantly determine the onset and offset time of nondepolarizing muscle relaxants.