Effects of remifentanil on brain responses to noxious stimuli during deep propofol sedation.

BACKGROUND: The safety of anaesthesia has improved as a result of better control of anaesthetic depth. However, conventional monitoring does not inform on the nature of nociceptive processes during unconsciousness. A means of inferring the quality of potentially painful experiences could derive from analysis of brain activity using neuroimaging. We have evaluated the dose effects of remifentanil on brain response to noxious stimuli during deep sedation and spontaneous breathing. METHODS: Optimal data were obtained in 26 healthy subjects. Pressure stimulation that proved to be moderately painful before the experiment was applied to the thumbnail. Functional MRI was acquired in 4-min periods at low (0.5 ng ml-1), medium (1 ng ml-1), and high (1.5 ng ml-1) target plasma concentrations of remifentanil at a stable background infusion of propofol adjusted to induce a state of light unconsciousness. RESULTS: At low remifentanil doses, we observed partial activation in brain areas processing sensory-discriminative and emotional-affective aspects of pain. At medium doses, relevant changes were identified in structures highly sensitive to general brain arousal, including the brainstem, cerebellum, thalamus, auditory and visual cortices, and the frontal lobe. At high doses, no significant activation was observed. CONCLUSIONS: The response to moderately intense focal pressure in pain-related brain networks is effectively eliminated with safe remifentanil doses. However, the safety margin in deep sedation-analgesia would be narrowed in minimising not only nociceptive responses, but also arousal-related biological stress.

Mapping the neural systems driving breathing at the transition to unconsciousness.

After falling asleep, the brain needs to detach from waking activity and reorganize into a functionally distinct state. A functional MRI (fMRI) study has recently revealed that the transition to unconsciousness induced by propofol involves a global decline of brain activity followed by a transient reduction in cortico-subcortical coupling. We have analyzed the relationships between transitional brain activity and breathing changes as one example of a vital function that needs the brain to readapt. Thirty healthy participants were originally examined. The analysis involved the correlation between breathing and fMRI signal upon loss of consciousness. We proposed that a decrease in ventilation would be coupled to the initial decline in fMRI signal in brain areas relevant for modulating breathing in the awake state, and that the subsequent recovery would be coupled to fMRI signal in structures relevant for controlling breathing during the unconscious state. Results showed that a slight reduction in breathing from wakefulness to unconsciousness was distinctively associated with decreased activity in brain systems underlying different aspects of consciousness including the prefrontal cortex, the default mode network and somatosensory areas. Breathing recovery was distinctively coupled to activity in deep brain structures controlling basic behaviors such as the hypothalamus and amygdala. Activity in the brainstem, cerebellum and hippocampus was associated with breathing variations in both states. Therefore, our brain maps illustrate potential drives to breathe, unique to wakefulness, in the form of brain systems underlying cognitive awareness, self-awareness and sensory awareness, and to unconsciousness involving structures controlling instinctive and homeostatic behaviors.

Evaluation of the density spectral array in the Wada test: report of six cases.

Wada test is an invasive procedure used in the preoperative evaluation for epilepsy surgery to determine language lateralization, postoperative risk of amnesia syndrome, and to assess the risk of memory deficits. It involves injection of amobarbital into internal carotid artery of the affected hemisphere followed by the healthy hemisphere to shut down brain function. We performed an observational study evaluating the density spectral array (DSA) of the bilateral bispectral index VISTA™ Monitoring System (BVMS) in 6 patients with drug-resistant epilepsy undergoing Wada test. DSA revealed the presence of bifrontal alpha waves in absence of loss of consciousness in all patients.

Effect of dexmedetomidine on evoked-potential monitoring in patients undergoing brain stem and supratentorial cranial surgery.

BACKGROUND: Dexmedetomidine is used as adjuvant in total intravenous anaesthesia (TIVA), but there have been few studies concerning its effect on intraoperative neurophysiological monitoring (IONM) during cranial surgery. Our aim was to study the effect of dexmedetomidine on IONM in patients undergoing brain stem and supratentorial cranial surgery. METHODS: Two prospective, randomized, double-blind substudies were conducted. In substudy 1, during TIVA with an infusion of propofol and remifentanil, 10 patients received saline solution (SS) (PR group) and another 10 (PRD group) received dexmedetomidine (0.5 mcg/kg/h). Total dosage of propofol and remifentanil, intensity, latency and amplitude of motor-evoked potentials following transcranial electrical stimulation (tcMEPs) as well as somatosensory-evoked potentials (SSEP) were recorded at baseline, 15, 30, 45 minutes, and at the end of surgery. In order to identify differences in the same patient after dexmedetomidine administration, we designed substudy 2 with 20 new patients randomized to two groups. After 30 minutes with TIVA, 10 patients received dexmedetomidine (0.5 mcg/kg/h) and 10 patients SS. The same variables were recorded. RESULTS: In substudy 1, propofol requirements were significantly lower (P = .004) and tcMEP intensity at the end of surgery was significantly higher in PRD group, but no statistically significant differences were observed for remifentanil requirements, SSEP and tcMEP latency or amplitude. In substudy 2, no differences in any of the variables were identified. CONCLUSIONS: The administration of dexmedetomidine at a dosage of 0.5 mg/kg/h may reduce propofol requirements and adversely affect some neuromonitoring variables. However, it can be an alternative on IONM during cranial surgeries. REDEX EudraCT: 2014-000962-23.

Predicting unconsciousness after propofol administration: qCON, BIS, and ALPHA band frequency power.

During anesthesia induction with propofol the level of arousal progressively decreases until reaching loss of consciousness (LOC). In addition, there is a shift of alpha activity from parieto-occipital to frontal zones, defined as anteriorization. Whilst monitoring LOC and anteriorization would be useful to improve propofol dosage and patient safety, the current devices for anesthetic depth monitoring are unable to detect these events. The aim of this study was to observe LOC and anteriorization during anesthesia induction with propofol by applying electrodes placed in the frontal and parietal areas. Bispectral index (BIS) and quantium consciousness index (qCON) monitors were simultaneously employed. BIS™ and qCON sensors were placed in the frontal and parieto-occipital regions of 10 alopecic patients who underwent anesthesia with propofol, alfentanil, and remifentanil. The initial biophase target of propofol was 2.5 mcg/mL which was gradually increased until reaching LOC. Wilcoxon signed-rank test was used to study differences in alpha power and qCON/BIS indices along the study; and Pk value to evaluate predictive capability of anteriorization of BIS, qCON, and alpha waves. Parietal BIS and qCON values became significantly higher than frontal values 15 min after loss of eye reflex. Anteriorization was observed with both monitors. Pk values for BIS and qCON were strongly predictive of frontal alpha absolute power. During anesthesia induction with propofol it is possible to identify anteriorization with BIS and qCON in the frontal and parieto-occipital regions. Both indices showed different patterns which need to be further studied.

Largest scale dissociation of brain activity at propofol-induced loss of consciousness.

The brain is a functional unit made up of multilevel connected elements showing a pattern of synchronized activity that varies in different states. The wake-sleep cycle is a major variation of brain functional condition that is ultimately regulated by subcortical arousal- and sleep-promoting cell groups. We analyzed the evolution of functional MRI (fMRI) signal in the whole cortex and in a deep region including most sleep- and wake-regulating subcortical nuclei at loss of consciousness induced by the hypnotic agent propofol. Optimal data were obtained in 21 of the 30 healthy participants examined. A dynamic analysis of fMRI time courses on a time-scale of seconds was conducted to characterize consciousness transition, and functional connectivity maps were generated to detail the anatomy of structures showing different dynamics. Inside the magnet, loss of consciousness was marked by the participants ceasing to move their hands. We observed activity synchronization after loss of consciousness within both the cerebral cortex and subcortical structures. However, the evolution of fMRI signal was dissociated, showing a transient reduction of global cortico-subcortical coupling that was restored during the unconscious state. An exception to cortico-subcortical decoupling was a brain network related to self-awareness (i.e. the default mode network) that remained connected to subcortical brain structures. Propofol-induced unconsciousness is thus characterized by an initial, transitory dissociated synchronization at the largest scale of brain activity. Such cortico-subcortical decoupling and subsequent recoupling may allow the brain to detach from waking activity and reorganize into a functionally distinct state.

Short- and long-term outcome of patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVE: To describe short-term and 5-year rates of mortality and poor outcome in patients with spontaneous aneurysmal subarachnoid hemorrhage (aSAH) who received repair treatment. METHODS: In this prospective observational study, mortality and poor outcome (modified Rankin Scale score 3-6) were analyzed in 311 patients with aSAH at 3 months, 1 year, and 5 years follow-up. Sensitivity analysis was performed according to treatment modality. In-hospital and 5-year complications were analyzed. RESULTS: Of 476 consecutive patients with spontaneous subarachnoid hemorrhage, 347 patients (72.9%) had aSAH. Of these, 311 (89.6%) were treated (242 endovascular, 69 neurosurgical), with a mean follow-up of 43.4 months (range, 1 to 145). Three-month, 1-year, and 5-year mortality was 18.4%, 22.9%, and 29.0%, and poor outcome was observed in 42.3%, 36.0%, and 36.0%, respectively. Adjusted poor outcome was lower in endovascular than in neurosurgical treatment at 3 months (odds ratio [OR] 0.36 [95% confidence interval [CI] 0.18-0.74]), with an absolute difference of 15.8% (number needed to treat = 6.3), and at 1 year (OR = 0.40 [95% CI 0.20-0.81]), with an absolute difference of 15.9% (number needed to treat = 6.3). Complications did not differ between the 2 procedures. However, mechanical ventilation was less frequent with the endovascular technique (OR 0.67 [95% CI 0.54-0.84]). CONCLUSIONS: Patients with aSAH treated according to current guidelines had a short-term mortality of 18.4% and 5-year mortality of 29%. The majority (64.0%) of patients remained alive without disabilities at 5-year follow-up. Patients prioritized to endovascular treatment had better outcomes than those referred to neurosurgery because endovascular coiling was not feasible.

Anaesthesia in electroconvulsive therapy. Special conditions / Anestesia en terapia electroconvulsiva. Condiciones especiales

OBJECTIVES: Electroconvulsive therapy (ECT) is one of the main techniques available for the treatment of such serious mental illnesses as schizophrenia and drug-resistant depression. The pre-anaesthetic assessment appropriate for patients with various mental disorders or pathologies does not differ substantially from that of any patient prior to undergoing anaesthesia for a surgical procedure. The present review aims to propose guidelines to achieve a higher level of safety and effectiveness during ECT in the most frequent situations, in accordance with the current literature. METHODS: We conducted a search on the role of anaesthesia in ECT in the Ovid MEDLINE, PubMed, and SciELO (Scientific Electronic Library Online) databases, with special attention to the populations undergoing this type of therapy. The search was carried out between 1978 and December 2016. RESULTS: We included the 96 articles that contained the most important recommendations for the preparation of this guide. CONCLUSIONS: We propose these guidelines in order to achieve a higher level of safety and effectiveness during ECT in special conditions. We also summarize the most important attitude to be taken into account by the anaesthesiologist in these cases

OBJETIVOS: La terapia electroconvulsiva (TEC) es una de las principales técnicas disponibles para el tratamiento de enfermedades mentales tan graves como la esquizofrenia y la depresión resistente al tratamiento farmacológico. La evaluación preanestésica adecuada en pacientes con diversos trastornos mentales o enfermedades no difiere sustancialmente de la de otros pacientes antes de recibir anestesia para un procedimiento quirúrgico. La presente revisión tiene como objetivo proponer pautas para lograr mayor nivel de seguridad y efectividad durante la TEC en las situaciones más frecuentes, de acuerdo con la bibliografía actual. MÉTODOS: Se realizó una búsqueda sobre el papel de la anestesia en la TEC en las bases de datos Ovid MEDLINE, PubMed y Scientific Electronic Library Online (SciELO), con especial hincapié en las poblaciones que reciben este tipo de terapia. La búsqueda se realizó entre 1978 y diciembre de 2016. RESULTADOS: Se incluyeron los 96 artículos que contenían las recomendaciones más importantes para la preparación de esta guía. CONCLUSIONES: Proponemos estas pautas para lograr mayor nivel de seguridad y efectividad durante la TEC en condiciones especiales. También resumimos la actitud más importante que debe tener en cuenta el anestesiólogo en estos casos

Anaesthesia in electroconvulsive therapy. Special conditions.

OBJECTIVES: Electroconvulsive therapy (ECT) is one of the main techniques available for the treatment of such serious mental illnesses as schizophrenia and drug-resistant depression. The pre-anaesthetic assessment appropriate for patients with various mental disorders or pathologies does not differ substantially from that of any patient prior to undergoing anaesthesia for a surgical procedure. The present review aims to propose guidelines to achieve a higher level of safety and effectiveness during ECT in the most frequent situations, in accordance with the current literature. METHODS: We conducted a search on the role of anaesthesia in ECT in the Ovid MEDLINE, PubMed, and SciELO (Scientific Electronic Library Online) databases, with special attention to the populations undergoing this type of therapy. The search was carried out between 1978 and December 2016. RESULTS: We included the 96 articles that contained the most important recommendations for the preparation of this guide. CONCLUSIONS: We propose these guidelines in order to achieve a higher level of safety and effectiveness during ECT in special conditions. We also summarize the most important attitude to be taken into account by the anaesthesiologist in these cases.

Is 1 mg/kg of sugammadex sufficient to reverse moderate neuromuscular block? A randomized clinical trial / ¿Es suficiente 1mg/kg de sugammadex para revertir el bloqueo neuromuscular moderado? Ensayo clínico aleatorizado

Abstract Background: Sugammadex has made it possible to reverse any type of rocuronium-induced block quickly and safely. The most frequent neuromuscular blockade is the moderate one where doses smaller than those recommended by the industry could get a full reversal. Objective: We aimed to evaluate the effectiveness of half the industry recommended dose of sugammadex to reverse a moderate neuromuscular block. Methods: Unicenter phase IV clinical trial that included 34 patients undergoing laparoscopic cholecystectomy. Intravenous general anesthesia was induced, with acceleromyographic monitoring of the neuromuscular block. After the intervention, the block was reversed with all or half the dose of sugammadex recommended for moderate blocks, using a blinded syringe. Results: Patient characteristics of the 2 groups were similar. Mean time to recovery was 3.6± 1.7minutes for the study group and 3.1 ± 1.7minutes for the control group (P=0.42). Reversal of the block was complete with a single dose of sugammadex in all patients. There was an important linear correlation between depth of block and time to recovery. Conclusion: Intraoperative monitoring is essential to allow us to individualize the dose of the neuromuscular blocking agent. To reverse a moderate block under neuromuscular monitoring, a dose of 1 mg/kg is sufficient in most cases and is equally safe and effective.

Resumen Introducción: El sugammadex permite revertir cualquier tipo de bloqueo inducido por rocuronio de forma rápida y segura. El bloqueo neuromuscular más frecuente es el moderado, en el cual dosis inferiores a las recomendadas por la industria podrían revertirlo completamente. Objetivo: Evaluar la efectividad de la mitad de la dosis de sugammadex recomendada por la industria para revertir un bloqueo neuromuscular moderado. Métodos: Ensayo clínico de fase IV en un unico centro que incluyó a 34 pacientes intervenidos de colecistectomía laparoscópica. Se realizó anestesia general intravenosa con monitoreo aceleromiográfico del bloqueo neuromuscular. Tras la intervención, el bloqueo se revirtió con la totalidad o con la mitad de la dosis de sugammadex recomendada para bloqueos moderados, utilizando una jeringa ciega. Resultados: Las características de los pacientes de los dos grupos fueron similares. La media de tiempo de recuperación fue de 3,6 ± 1,7 minutos para el grupo de estudio y de 3,1 ± 1,7 minutos para el grupo de control (p = 0,42). La reversión del bloqueo se completó con una dosis única de sugammadex en todos los pacientes. Hubo una correlación lineal importante entre la profundidad del bloqueo y el tiempo de recuperación. Conclusión: El monitoreo transquirúrgico es esencial para individualizar la dosis del agente de bloqueo neuromuscular. Para revertir un bloqueo moderado bajo monitoreo neuromuscular, una dosis de 1mg/kg es suficiente e igualmente segura y efectiva.

Misdiagnosis Worsens Prognosis in Subarachnoid Hemorrhage With Good Hunt and Hess Score.

Background and Purpose- Our aim was to describe variables associated with initial misdiagnosis of subarachnoid hemorrhage (SAH). We also analyzed the relationship of misdiagnosis with poor outcome and complications in good Hunt and Hess (HH) cases. Methods- In a prospective cohort of 401 patients with SAH, misdiagnosis was defined as failure to correctly identify, at first physician contact, a subsequently documented SAH; this meant no urgent radiological study and lumbar puncture was performed. Poor outcome was defined as modified Rankin Scale score 3 to 6 at 3-month follow-up. We recorded age, sex, hypertension, diabetes mellitus, current smoking, previous antithrombotic treatment, initial HH and radiological severity, presence of aneurysm, first therapeutic procedure, hydrocephalus, delayed cerebral ischemia (DCI), rebleeding, and procedure-related complications. Results- Misdiagnosis was confirmed in 104/401 (25.9%) patients, who also had a longer time-to-admission to hospital. Misdiagnosis was associated with less clinical and radiological severity, compared with a correct diagnosis; the 2 groups did not differ in age or cardiovascular risk factor profile. Poor outcome was registered in 167/401 patients (41.6%). Age, misdiagnosis, and greater clinical and radiological initial severity were independent predictors of poor outcome. In the 236 patients (58.8% of cohort) with HH 1-2, misdiagnosis was associated with poor outcome in univariate and multivariate analysis, respectively (odds ratio=3.89; 95% CI, 1.89-8.01). Delayed cerebral ischemia (odds ratio=2.47; 95% CI, 1.2-5.09) and procedure-related complications (odds ratio=2.27; 95% CI, 1.07-4.82) were independently associated with misdiagnosis. Conclusions- Misdiagnosis is an unresolved problem in SAH, and it is a missed opportunity for good outcome in patients with HH 1-2. The poor outcome is partially explained by a higher risk of delayed cerebral ischemia and procedure-related complications in misdiagnosed patients. There is a need to improve the diagnostic strategy in patients reporting only a headache (HH 1-2) after SAH.

Density spectral array during the intra and postoperative of a left frontal craniotomy / Matriz de Densidad Espectral durante el intra y el posoperatorio de una craneotomía frontal izquierda

Abstract We present the case of an adult with an extensive left frontal meningioma. He was scheduled for resection by craniotomy. During the surgery we used the density spectral array (DSA) and asymmetry obtained from Bispectral Index VISTA Monitoring System Bilateral. We observed a power increase in low frequency (0.1-1 Hz) and alpha bands (8-12 Hz) in the left hemisphere, where the meningioma was located. In this case, DSA was useful during and after the surgery because it provided information about the hemisphere with maximum brain activity and its subsequent normalization, which may reflect the effectiveness of the surgery.

Resumen Presentamos el caso de un paciente adulto con diagnóstico de un meningioma extenso a nivel frontal izquierdo, que fue programado para exéresis mediante craneotomía. Durante la cirugía se utilizó la Matriz de Densidad Espectral (MDE) y la asimetría obtenida del Sistema de Monitorización VISTATM del Índice Biespectral Bilateral (BVMS). Se observó un aumento de potencia en las bandas de baja frecuencia (0.1-1Hz) y en las bandas alfa (812 Hz) del hemisferio cerebral izquierdo, donde se encontraba el meningioma. En este caso la MDE demostró su utilidad durante y después de la cirugía, al proporcionar información sobre el hemisferio con registro de máxima actividad cerebral y su posterior normalización, reflejando así la efectividad de la cirugía.

Incidencia y causas de finalización anticipada de la cirugía con paciente despierto para mapeo del lenguaje, no relacionadas directamente con la elocuencia / Incidence and causes of early end in awake surgery for language mapping not directly related to eloquence

La incidencia y causas que pueden hacer finalizar de manera anticipada (sin finalizar el mapeo cortical/subcortical) la cirugía con paciente despierto para mapeo del lenguaje son poco conocidas. Se ha estudiado una serie de 41 pacientes con glioma en área del lenguaje en los que se ha realizado craneotomía y mapeo del lenguaje bajo sedación consciente. En 6 pacientes se tuvo que finalizar la cirugía de manera anticipada. Las causas fueron: crisis tónico-clónica (1), falta de colaboración por cansancio/sueño (4) con afectación o no en la articulación de la palabra, disminución del nivel de consciencia en contexto de encefalopatía por amonio que obligó a la intubación orotraqueal (1). Hay causas de finalización anticipada de la cirugía que podrían preverse y en algunos casos evitarse. La extensión de la lesión, la presencia de una afasia preoperatoria, el tratamiento con valproato y el tipo de anestesia empleado son variables a considerar para evitar el fracaso de la cirugía con paciente despierto para mapeo del lenguaje. Ante los resultados obtenidos, se proponen las siguientes medidas: l) si la lesión es extensa realizar la cirugía en dos tiempos para evitar el cansancio, 2) si el paciente presenta afectación del lenguaje previa, no utilizar sedación durante la cirugía para evitar que la somnolencia empeore la articulación de la palabra, 3) en pacientes en tratamiento con valproato habría que descartar que la sintomatología preoperatoria no se deba a una encefalopatía por amonio

The incidence and causes that may lead to an early end (unfinished cortical/subcortical mapping) of awake surgery for language mapping are little known. A study was conducted on 41 patients with brain glioma located in the language area that had awake surgery under conscious sedation. Surgery was ended early in 6 patients. The causes were: tonic-clonic seizure (1), lack of cooperation due to fatigue/sleep (4), whether or not word articulation was involved, a decreased level of consciousness for ammonia encephalopathy that required endotracheal intubation (1). There are causes that could be expected and in some cases avoided. Tumour size, preoperative aphasia, valproate treatment, and type of anaesthesia used are variables to consider to avoid failure in awake surgery for language mapping. With these results, the following measures are proposed: l) If the tumour is large, perform surgery in two times to avoid fatigue, 2) if patient has a preoperative aphasia, do not use sedation during surgery to ensure that sleepiness does not cause worse word articulation, 3) if the patient is on valproate treatment, it is necessary to rule out the pre-operative symptoms that are not due to ammonia encephalopathy

[Incidence and causes of early end in awake surgery for language mapping not directly related to eloquence]. / Incidencia y causas de finalización anticipada de la cirugía con paciente despierto para mapeo del lenguaje, no relacionadas directamente con la elocuencia.

The incidence and causes that may lead to an early end (unfinished cortical/subcortical mapping) of awake surgery for language mapping are little known. A study was conducted on 41 patients with brain glioma located in the language area that had awake surgery under conscious sedation. Surgery was ended early in 6 patients. The causes were: tonic-clonic seizure (1), lack of cooperation due to fatigue/sleep (4), whether or not word articulation was involved, a decreased level of consciousness for ammonia encephalopathy that required endotracheal intubation (1). There are causes that could be expected and in some cases avoided. Tumour size, preoperative aphasia, valproate treatment, and type of anaesthesia used are variables to consider to avoid failure in awake surgery for language mapping. With these results, the following measures are proposed: l) If the tumour is large, perform surgery in two times to avoid fatigue, 2) if patient has a preoperative aphasia, do not use sedation during surgery to ensure that sleepiness does not cause worse word articulation, 3) if the patient is on valproate treatment, it is necessary to rule out the pre-operative symptoms that are not due to ammonia encephalopathy.

Surgical Position, Cause of Extracranial Internal Carotid Artery Dissection, Presenting as Pourfour Du Petit Syndrome: Case Report and Literature Review.

Dissection of the internal carotid artery is a rare cause of stroke overall, but causes 22% of strokes in younger patients. A common clinical presentation is as Claude Bernard Horner syndrome. We report a craniotomy with 30 degrees rotation of the neck (standard position) in a patient with no major risk factors for carotid dissection, who showed a Pourfour du Petit syndrome due to a dissection of the internal carotid artery. To the best of our knowledge, this is the first reported case in which a common surgical position causes an internal carotid artery dissection in a patient without relevant risk factors. The presentation with Pourfour du Petit syndrome is extremely unusual.

Feasibility of microdialysis to determine interstitial rocuronium concentration in the muscle tissue of anesthetized neurosurgical patients.

BACKGROUND: Microdialysis is used to determine the concentrations of substances in the extracellular fluid of tissues. To date, it has not been used to measure rocuronium concentrations in human muscle. We determined the ability of microdialysis to recover rocuronium from muscle interstitial tissue for the purpose of assessing the effect of chronic phenytoin therapy on muscle concentrations of rocuronium. METHODS: In a first phase, an in vitro study was performed to establish the ability of the assay to recover rocuronium. In a second phase, 17 patients undergoing brain surgery were enrolled. Eight patients were on chronic phenytoin therapy and the remaining 9 patients were not taking any antiepileptic agent (controls). Rocuronium was administered intravenously and muscle tissue samples for microdialysis were collected. RESULTS: The recovery rate of the in vitro assay was 36% at a pump rate of 1 microL/min. Rocuronium muscle tissue concentrations could be measured in 25 microdialysate samples. Rocuronium concentrations were similar in patients treated with phenytoin and in controls, although the doses required to obtain a similar effect were significantly higher in patients on chronic phenytoin treatment. CONCLUSIONS: Quantification of drug concentrations in muscle by means of microdialysis is technically feasible in the clinical setting and it might help in studying pharmacologic mechanisms of drug action. Based on our results the decrease in the degree of effect of rocuronium in the presence of chronic phenytoin therapy might seem to be due mainly to a pharmacokinetic mechanism.

Pharmacokinetic-pharmacodynamic modeling of the influence of chronic phenytoin therapy on the rocuronium bromide response in patients undergoing brain surgery.

BACKGROUND: Antiepileptic drugs decrease the intensity of the effect of neuromuscular blocking agents. The objective of this study was to evaluate the influence of chronic phenytoin therapy (CPT) on the pharmacokinetics (PK) and pharmacodynamics (PD) of rocuronium. METHODS: A total of 21 patients undergoing intracranial surgery were enrolled in the study. Ten of these were under CPT. Rocuronium was administered intravenously. Arterial blood samples were drawn, and the T1% (percentage change from the response to the supramaximal stimulus) derived from electromyogram was continuously recorded. NONMEM: software was used to construct, evaluate and validate the PKPD models. RESULTS: The PKPD of rocuronium was described using a three-compartment PK model and effect compartment model. The CPT therapy was found to increase the total plasma clearance from 0.26 to 0.75 L min(-1). The PD model parameter estimates were k(e0)= 0.073 min(-1), IC(50) (the steady-state plasma concentration eliciting half of the maximum response) = 836 ng mL(-1) and gamma = 3.13. CONCLUSIONS: Chronic phenytoin therapy increases the clearance of rocuronium from 0.26 to 0.75 L min(-1) but has no effect on the k(e0), IC(50) or gamma parameters.