Influence of general anaesthesia on the brainstem. / Influencia de la anestesia general sobre el tronco encefálico.

The exact role of the brainstem in the control of body functions is not yet well known and the same applies to the influence of general anaesthesia on brainstem functions. Nevertheless in all general anaesthesia the anaesthesiologist should be aware of the interaction of anaesthetic drugs and brainstem function in relation to whole body homeostasis. As a result of this interaction there will be changes in consciousness, protective reflexes, breathing pattern, heart rate, temperature or arterial blood pressure to name a few. Brainstem function can be explored using three different approaches: clinically, analyzing changes in brain electric activity or using neuroimaging techniques. With the aim of providing the clinician anaesthesiologist with a global view of the interaction between the anaesthetic state and homeostatic changes related to brainstem function, the present review article addresses the influence of anaesthetic drug effects on brainstem function through clinical exploration of cranial nerves and reflexes, analysis of electric signals such as electroencephalographic changes and what it is known about brainstem through the use of imaging techniques, more specifically functional magnetic resonance imaging.

Relation between acute and long-term cognitive decline after surgery: Influence of metabolic syndrome.

INTRODUCTION: The relationship between persistent postoperative cognitive decline and the more common acute variety remains unknown; using data acquired in preclinical studies of postoperative cognitive decline we attempted to characterize this relationship. METHODS: Low capacity runner (LCR) rats, which have all the features of the metabolic syndrome, were compared postoperatively with high capacity runner (HCR) rats for memory, assessed by trace fear conditioning (TFC) on the 7th postoperative day, and learning and memory (probe trial [PT]) assessed by the Morris water-maze (MWM) at 3 months postoperatively. Rate of learning (AL) data from the MWM test, were estimated by non-linear mixed effects modeling. The individual rat's TFC result at postoperative day (POD) 7 was correlated with its AL and PT from the MWM data sets at postoperative day POD 90. RESULTS: A single exponential decay model best described AL in the MWM with LCR and surgery (LCR-SURG) being the only significant covariates; first order AL rate constant was 0.07 s(-1) in LCR-SURG and 0.16s(-1) in the remaining groups (p<0.05). TFC was significantly correlated with both AL (R=0.74; p<0.0001) and PT (R=0.49; p<0.01). CONCLUSION: Severity of memory decline at 1 week after surgery presaged long-lasting deteriorations in learning and memory.

Monitoring hypnotic effect and nociception with two EEG-derived indices, qCON and qNOX, during general anaesthesia.

BACKGROUND: The objective of the present study was to validate the qCON index of hypnotic effect and the qNOX index of nociception. Both indices are derived from the frontal electroencephalogram (EEG) and implemented in the qCON 2000 monitor (Quantium Medical, Barcelona, Spain). METHODS: The study was approved by the local ethics committee, including data from 60 patients scheduled for ambulatory surgery undergoing general anaesthesia with propofol and remifentanil, using TCI. The Bis (Covidien, Boulder, CO, USA) was recorded simultaneously with the qCON. Loss of eyelash reflex [loss of consciousness (LOC)] was recorded, and prediction probability for Bis and qCON was calculated. Movement as a response to noxious stimulation [laryngeal mask airway (LMA) insertion, laryngoscopy and tracheal intubation] was registered. The correlation coefficient between qCON and Bis was calculated. The patients were divided into movers/non-movers as a response to noxious stimulation. A paired t-test was used to assess significant difference for qCON and qNOX for movers/non-movers. RESULTS: The prediction probability (Pk) and the standard error (SE) for qCON and Bis for detecting LOC was 0.92 (0.02) and 0.94 (0.02) respectively (t-test, no significant difference). The R between qCON and Bis was 0.85. During the general anaesthesia (Ce propofol > 2 µg/ml, Ce remifentanil > 2 ng/ml), the mean value and standard deviation (SD) for qCON was 45 (8), while for qNOX it was 40 (6). The qNOX pre-stimuli values were significantly different (P < 0.05) for movers/non-movers as a response to LMA insertion [62.5 (24.0) vs. 45.5 (24.1)], tracheal intubation [58.7 (21.8) vs. 41.4 (20.9)], laryngoscopy [54.1 (21.4) vs. 41.0 (20.8)]. There were no significant differences in remifentanil or propofol effect-site concentrations for movers vs. non-movers. CONCLUSION: The qCON was able to reliably detect LOC during general anaesthesia with propofol and remifentanil. The qNOX showed significant overlap between movers and non-movers, but it was able to predict whether or not the patient would move as a response to noxious stimulation, although the anaesthetic concentrations were similar.

Comparación de 3 combinaciones de levobupivacaína al 0,5 por ciento y de mepivacaína al 1 por ciento en el bloqueo del nervio ciático poplíteo, en la cirugía ambulatoria del hallux valgus / Comparison of 3 combinations of 0.5 percent levobupivacaine and 1percent mepivacaine in popliteal sciatic block in hallux valgus outpatient surgery

Objetivo: Comparar 3 combinaciones de levobupivacaína 0,5% con mepivacaína 1% en bloqueo del ciático poplíteo con dosis única para cirugía del hallux valgus. Métodos: Estudio prospectivo, doble ciego, en pacientes programados para cirugía ambulatoria de hallux valgus con bloqueo del nervio ciático poplíteo guíado por ultrasonidos. Los pacientes se distribuyeron aleatoriamente en 3 grupos, según el volumen de cada uno de los anestésicos locales: G1, levobupivacaína 20 mL + mepivacaína 10 mL, G2, levobupivacaína 10 mL + mepivacaína 20 mL y G3, levobupivacaína 15 mL + mepivacaína 15 mL. Fueron evauados el tiempo de inicio, de reversión y el tiempo total del bloqueo de los nervios tibial y peroneo; control del dolor postoperatorio a las 12, 24, 72 h y al séptimo día del postoperatorio mediante escala visual analógica (EVA), escala descriptiva simple (EDS) y la calidad del descanso nocturno; complicaciones postoperatorias y satisfacción del paciente. Resultados: Se incluyó a 120 pacientes, 40 por grupo. Los grupos fueron homogéneos y ningún paciente precisó anestesia complementaria. El tiempo de latencia del bloqueo fue significativamente mayor en el G1 respecto a G2 y G3 (39,4 ± 14,7 min frente a 32,2 ± 16,5 y 33,2 ± 12 min). El tiempo de reversión del bloqueo sensitivo y motor fue significativamente mayor en G1 respecto a G2 y G3 (29,5 ± 9,3 h frente a 22,2 ± 8,2 y 24,8 ± 7,9 h). El nivel máximo de dolor se registró a las 24 h del postoperatorio y fue significativamente superior en el G2 respecto al G1. El descanso nocturno también fue peor la primera noche en el G2 respecto al G1. La satisfacción del paciente fue buena o muy buena y no se registraron complicaciones. Conclusiones: El tiempo de latencia del bloqueo y la eficacia anestésica fueron adecuados en los 3 grupos. La combinación de levobupivacaína 0,5% 20 ml y mepivacaína 1% 10 ml es una buena alternativa para una analgesia postoperatoria más duradera(AU)

Background: To compare 3 combinations of 0.5% levobupivacaine (L) and 1% mepivacaine (M) for popliteal block for hallux valgus surgery. Methods: Prospective, double blind study of 120 patients undergoing unilateral hallux valgus outpatient surgery with posterior popliteal block with ultrasound-guided single injection. Patients were randomly allocated into three groups: G1: 20 mL L + 10 mL M; G2: 10 mL L + 20 mL M; and G3: 15 mL L + 15 mL M. Recorded variables were: time of block, onset and reversal times for tibial and peroneal nerves block; postoperative pain until the 7th day by means of visual analogue scale (VAS), simple descriptive scale and the quality of nocturnal rest, complications, and patient satisfaction. ANOVA and chi2 were applied in the statistical analysis, with a P < 0.05 considered significant. Results: Groups were homogeneous for demographic and surgical characteristics. None of the patients required intraoperative complementary analgesia or anaesthesia. Block onset was significantly longer in G1 than in G2 and G3 (39.4 ± 14.7 versus 32.2 ± 16.5 and 33.2 ± 12 minutes). Recovery time from sensory and motor block was significantly longer in G1 than in G2 and G3 (29.5 ± 9.3 versus 22.2 ± 8.2 and 24.8 ± 7.9 hours). Postoperative pain level was below VAS 30 (1-100) in the three groups; none of the patients experienced severe pain. Maximum pain level appeared at 24 h postoperatively. Patient satisfaction was high and there were no complications. Conclusions: Block onset time and anaesthetic efficacy was adequate in the three groups. The combination of 20 mL levobupivacaine 0.5% with 10 mL mepivacaine 1% provide a good alternative for a lasting postoperative analgesia(AU)

[Comparison of 3 combinations of 0.5% levobupivacaine and 1% mepivacaine in popliteal sciatic block in hallux valgus outpatient surgery]. / Comparación de 3 combinaciones de levobupivacaína al 0,5% y de mepivacaína al 1% en el bloqueo del nervio ciático poplíteo, en la cirugía ambulatoria del hallux valgus.

BACKGROUND: To compare 3 combinations of 0.5% levobupivacaine (L) and 1% mepivacaine (M) for popliteal block for hallux valgus surgery. METHODS: Prospective, double blind study of 120 patients undergoing unilateral hallux valgus outpatient surgery with posterior popliteal block with ultrasound-guided single injection. Patients were randomly allocated into three groups: G1: 20mL L+10mL M; G2: 10mL L+20mL M; and G3: 15mL L+15mL M. Recorded variables were: time of block, onset and reversal times for tibial and peroneal nerves block; postoperative pain until the 7(th) day by means of visual analogue scale (VAS), simple descriptive scale and the quality of nocturnal rest, complications, and patient satisfaction. ANOVA and chi2 were applied in the statistical analysis, with a P<0.05 considered significant. RESULTS: Groups were homogeneous for demographic and surgical characteristics. None of the patients required intraoperative complementary analgesia or anaesthesia. Block onset was significantly longer in G1 than in G2 and G3 (39.4±14.7 versus 32.2±16.5 and 33.2±12minutes). Recovery time from sensory and motor block was significantly longer in G1 than in G2 and G3 (29.5±9.3 versus 22.2±8.2 and 24.8±7.9hours). Postoperative pain level was below VAS 30 (1-100) in the three groups; none of the patients experienced severe pain. Maximum pain level appeared at 24h postoperatively. Patient satisfaction was high and there were no complications. CONCLUSIONS: Block onset time and anaesthetic efficacy was adequate in the three groups. The combination of 20mL levobupivacaine 0.5% with 10mL mepivacaine 1% provide a good alternative for a lasting postoperative analgesia.

Utilización de tramadol/paracetamol oral en única preparaciónfarmacéutica en analgesia multimodal en cirugía mayor ambulatoria / No disponible

La combinación en una misma presentación farmacológica de paracetamol y tramadol a dosis bajas permite un rápido inicio de acción y un efecto sostenido de la analgesia, con disminución de los efectos secundarios derivados de ambos fármacos, dosis dependiente. En cirugía mayor ambulatoria la analgesia multimodal es el tratamiento de elección para poder incluir cada vez procesos de mayor complejidad. Es por ello que la asociación a dosis bajas de un opioide menor, con paracetamol, presenta una analgesia superior por acción sinérgica de los dos componentes, utilizándose en dolor moderado-severo, evitando reingresos y facilitando el cumplimiento del tratamiento analgésico en el domicilio (AU)

The combination of paracetamol, and low doses of tramadol, enables an immediate and constant analgesic response, while at the same time avoiding the negative side effects of both these drugs. Multimodal analgesia in ambulatory surgery permits a better control of pain and the subsequent inclusion of more complex surgery. The use of both components in one tablet, presents a synergic action useful in moderate-severe pain, reducing hospital re-admittance and enhancing the probability of the completion of home treatment (AU)

Comparison of the LMA Supreme™ with the LMA Proseal™ for airway management in patients anaesthetized in prone position.

BACKGROUND: The laryngeal mask airway (LMA) has been successfully used in patients in the prone position either for rescue or elective airway management. The reusable Proseal™ LMA (PLMA) and the single use Supreme™ LMA (SLMA) have been reported to be suitable for this purpose but few comparative data are available. In this study, we compared the clinical use of both devices in adult patients anaesthetized in the prone position. METHODS: One hundred and twenty patients undergoing surgery in the prone position were randomized to receive either the PLMA or the SLMA for airway management. Patients positioned themselves in the prone position and after pre-oxygenation, anaesthesia was induced using a target-controlled i.v. infusion of propofol and remifentanil. All PLMAs and SLMAs were inserted by experienced anaesthetists using a guided and a standard technique respectively. Ease of facemask ventilation, time and number of attempts needed for insertion, quality of ventilation, airway seal pressure, fibreoptic view, and complications were compared. RESULTS: There were no differences between groups in insertion time or first attempt success (100% vs. 98%). The PLMA required fewer manipulations (3% vs. 15%; P=0.02) to achieve effective ventilation and provided a higher seal pressure (mean [sd] 31 [4] vs. 27 [4] cm H2O; P<0.01). The fibrescopic view of the vocal cords was similar, although easier to achieve with the PLMA. The complication rate was low and similar between the groups. Blood was present on masks in 7% vs. 8% and sore throat in 3% vs. 5% of patients with the PLMA and SLMA, respectively. CONCLUSIONS: Airway management in patients anaesthetized in the prone position was efficient with both devices, although the PLMA required fewer manipulations and achieved a higher seal pressure.

Modeling the effect of propofol and remifentanil combinations for sedation-analgesia in endoscopic procedures using an Adaptive Neuro Fuzzy Inference System (ANFIS).

BACKGROUND: The increasing demand for anesthetic procedures in the gastrointestinal endoscopy area has not been followed by a similar increase in the methods to provide and control sedation and analgesia for these patients. In this study, we evaluated different combinations of propofol and remifentanil, administered through a target-controlled infusion system, to estimate the optimal concentrations as well as the best way to control the sedative effects induced by the combinations of drugs in patients undergoing ultrasonographic endoscopy. METHODS: One hundred twenty patients undergoing ultrasonographic endoscopy were randomized to receive, by means of a target-controlled infusion system, a fixed effect-site concentration of either propofol or remifentanil of 8 different possible concentrations, allowing adjustment of the concentrations of the other drug. Predicted effect-site propofol (C(e)pro) and remifentanil (C(e)remi) concentrations, parameters derived from auditory evoked potential, autoregressive auditory evoked potential index (AAI/2) and electroencephalogram (bispectral index [BIS] and index of consciousness [IoC]) signals, as well as categorical scores of sedation (Ramsay Sedation Scale [RSS] score) in the presence or absence of nociceptive stimulation, were collected, recorded, and analyzed using an Adaptive Neuro Fuzzy Inference System. The models described for the relationship between C(e)pro and C(e)remi versus AAI/2, BIS, and IoC were diagnosed for inaccuracy using median absolute performance error (MDAPE) and median root mean squared error (MDRMSE), and for bias using median performance error (MDPE). The models were validated in a prospective group of 68 new patients receiving different combinations of propofol and remifentanil. The predictive ability (P(k)) of AAI/2, BIS, and IoC with respect to the sedation level, RSS score, was also explored. RESULTS: Data from 110 patients were analyzed in the training group. The resulting estimated models had an MDAPE of 32.87, 12.89, and 8.77; an MDRMSE of 17.01, 12.81, and 9.40; and an MDPE of -1.86, 3.97, and 2.21 for AAI/2, BIS, and IoC, respectively, in the absence of stimulation and similar values under stimulation. P(k) values were 0.82, 0.81, and 0.85 for AAI/2, BIS, and IoC, respectively. The model predicted the prospective validation data with an MDAPE of 34.81, 14.78, and 10.25; an MDRMSE of 16.81, 15.91, and 11.81; an MDPE of -8.37, 5.65, and -1.43; and P(k) values of 0.81, 0.8, and 0.8 for AAI/2, BIS, and IoC, respectively. CONCLUSION: A model relating C(e)pro and C(e)remi to AAI/2, BIS, and IoC has been developed and prospectively validated. Based on these models, the (C(e)pro, C(e)remi) concentration pairs that provide an RSS score of 4 range from (1.8 µg·mL(-1), 1.5 ng·mL(-1)) to (2.7 µg·mL(-1), 0 ng·mL(-1)). These concentrations are associated with AAI/2 values of 25 to 30, BIS of 71 to 75, and IoC of 72 to 76. The presence of noxious stimulation increases the requirements of C(e)pro and C(e)remi to achieve the same degree of sedative effects.

Contribuciones de la anestesiología al desarrollo clínico de nuevos fármacos / Lessons learned ind rug development from anesthesia

No disponible

[Postoperative patient-controlled analgesia is more effective with epidural methadone than with intravenous methadone in thoracic surgery]. / La analgesia postoperatoria controlada por el paciente es más efectiva con metadona epidural que con metadona endovenosa en la cirugía torácica.

OBJECTIVE: To compare the efficacy and side effects of epidural and intravenous methadone for postoperative patient-controlled analgesia (PCA) after thoracic surgery. PATIENTS AND METHODS: A randomized, single-blind trial enrolling 30 patients distributed in 2 groups to receive intravenous methadone (ivPCA group) or epidural methadone (epPCA group). Patients in both groups were administered a loading dose of 0.05 mg.kg-1 followed by infusion of 0.5 mg.h-1. The patients could self-dose 0.5 mg with a lock-out interval of 10 minutes and a maximum of 4 doses per hour. Patient characteristics, type and duration of surgery and fentanyl dose were recorded. Pain was assessed on a visual analog scale (VAS). Level of sedation, respiratory rate and occurrence of nausea, vomiting and pruritus were also recorded over the first 24 hours. RESULTS: The 2 groups were comparable. Pain was greater in the ivPCA group than in the epPCA group in the second hour (VAS 3.93 +/- 1.9 and 2.4 +/- 1.65, respectively; P < .05) and the third hour (VAS 3.57 +/- 1.65 and 1.5 +/- 1.16, respectively; P < .05). The total dose of methadone administered was 25.34 +/- 5.65 mg in the ivPCA group and 18.82 +/- 3.52 mg in the epPCA group (P < .002). There were no significant differences in side effects. CONCLUSIONS: The results suggest that epidural methadone has an intrinsic spinal effect regardless of whether or not there is extra-spinal action arising from syste mic absorption. Epidural methadone provides a more adequate analgesic effect in less time and at a lower dose. Both approaches provide good postoperative analgesia with few side effects.

La analgesia postoperatoria controlada por el paciente es más efectiva con metadona epidural que con metadona endovenosa en la cirugía torácica / Epidural methadone is more effective than intravenous methadone in postoperative patient-controlled analgesia after thoracic surgery

OBJETIVO: Comparar la efectividad y efectos secundarios de la metadona administrada por vía epidural y endovenosa en la analgesia postoperatoria controlada por el paciente (PCA) en toracotomías. PACIENTES Y MÉTODOS: Estudio prospectivo y simple ciego en 30 pacientes divididos aleatoriamente en dos grupos según la vía de administración de la metadona: grupo PCAEV endovenosa y grupo PCAEP epidural. En ambos grupos se administraba un bolo inicial de 0,05 mg-Kg-1 seguido de una infusión de 0,5 mg-h-1. Los pacientes se podían autoadministrar bolos de 0,5 mg, con intervalo de cierre de 10 minutos y un máximo de 4 bolos a la hora. Se recogieron variables demográficas, tipo y duración de la cirugía y dosis de fentanilo. Se registró el dolor según la escala visual analógica (EVA), el grado de sedación, la frecuencia respiratoria y la incidencia de náuseas, vómitos y prurito en las primeras 24 horas. RESULTADOS: Ambos grupos resultaron homogéneos. El dolor fue superior en el grupo PCAEV sobre el PCAEP en la segunda hora (EVA 3,93 ñ 1,9 y 2,42 ñ 1,65; p<0,05) y en la tercera hora (EVA 3,57 ñ 1,65 y 1,5 ñ 1,16; p<0,05); posteriormente el valor de EVA fue inferior a 3 en ambos grupos. La dosis total de metadona administrada en el grupo PCAEV fue 25,34 ñ 5,65 mg y 18,82 ñ 3,52 mg en el PCAEP (p<0,002). No hubo diferencias significativas en los efectos secundarios. CONCLUSIONES: Los resultados sugieren que la metadona epidural posee un efecto espinal intrínseco, independientemente de que se añada una acción indirecta supraespinal por absorción sistémica. La metadona epidural produce un nivel analgésico más adecuado en menos tiempo y con menos dosis. Ambas vías proporcionan una buena analgesia postoperatoria con pocos efectos secundarios (AU)

Uses of pharmaco-EEG and pharmacokinetic-pharmacodynamic modeling in the clinical scenario.

In order to place pharmaco-EEG within the clinical context, the distinction between biomarkers, surrogate endpoints, clinical endpoints and clinical outcomes is introduced. State-of-the-art applications of pharmaco-EEG, together with pharmacokinetic-pharmacodynamic modeling in everyday clinical practice in anesthesiology (semilinear canonical correlation), psychiatry (discrimination between responders and nonresponders to pharmacological treatment using the test dose), neurology (antiepileptic field) and neurophysiology (first-order Markov model of sleep stage transitions) are discussed. The combination of both procedures, although successfully used during some drug development programs (opioids or benzodiazepines), is not widely applied in the clinical scenario where the central nervous system (CNS) is concerned. Much work is still need to develop fully the potentials that pharmaco-EEG together with pharmacokinetic-pharmacodynamic modeling could bring to therapeutics in neuroscience.

[Use of the electroencephalographic spectral edge frequency 90 to monitor sedation of chronically ill patients]. / Utilización del límite espectral 90% (LE90) del electroencefalograma como sistema de control de la sedación en los pacientes críticos.

INTRODUCTION: The depth of sedation required for patients in critical care units varies over time and should be subject to control. The clinical assessment scales used at present are inadequate, and several electroencephalographic variables have been investigated in recent years with the aim of quantifying depth of sedation. One such variable is the spectral edge frequency 90 (SEF90). OBJECTIVES: To establish the correlation between SEF90 and the Ramsay score as indicators of depth of sedation. To estimate the ability of SEF90 to predict sedation and a patient's hemodynamic response during aspiration of secretions through the orotracheal tube. PATIENTS AND METHODS: Patients in a surgical intensive care unit. The ability of SEF90 to predict a certain Ramsay score was assessed by logistic regression. We also calculated the predictive probability (Pk) of SEF90 for the appearance of hemodynamic change and of movement in the event of endotracheal aspiration. RESULTS: When SEF90 was < 16 Hz, the probability of a Ramsay score >= 4 was >= 90% (Pk = 0.91). Neither SEF90 nor the Ramsay score predicted hemodynamic response to orotracheal aspiration. CONCLUSIONS: SEF90 distinguishes superficial from deep sedation but does not differentiate further degrees of depth or the likelihood of hemodynamic instability or movement in response to aspiration.

Propofol dosing regimens for ICU sedation based upon an integrated pharmacokinetic-pharmacodynamic model.

BACKGROUND: The pharmacology of propofol infusions administered for long-term sedation of intensive care unit (ICU) patients has not been fully characterized. The aim of the study was to develop propofol dosing guidelines for ICU sedation based on an integrated pharmacokinetic-pharmacodynamic model of propofol infusions in ICU patients. METHODS: With Institutional Review Board approval, 30 adult male medical and surgical ICU patients were given target-controlled infusions of propofol for sedation, adjusted to maintain a Ramsay sedation scale score of 2-5. Propofol administration in the first 20 subjects was based on a previously derived pharmacokinetic model for propofol. The last 10 subjects were given propofol based on a pharmacokinetic model derived from the first 20 subjects. Plasma propofol concentrations were measured, together with sedation score. Population pharmacokinetic and pharmacodynamic parameters were estimated by means of nonlinear regression analysis in the first 20 subjects, then prospectively tested in the last 10 subjects. An integrated pharmacokinetic-pharmacodynamic model was used to construct dosing regimens for light and deep sedation with propofol in ICU patients. RESULTS: The pharmacokinetics of propofol were described by a three-compartment model with lean body mass and fat body mass as covariates. The pharmacodynamics of propofol were described by a sigmoid model, relating the probability of sedation to plasma propofol concentration. The pharmacodynamic model for propofol predicted light and deep levels of sedation with 73% accuracy. Plasma propofol concentrations corresponding to the probability modes for sedation scores of 2, 3, 4, and 5 were 0.25, 0.6, 1.0, and 2.0 microg/ml. Predicted emergence times in a typical subject after 24 h, 72 h, 7 days, and 14 days of light sedation (sedation score = 3 --> 2) with propofol were 13, 34, 198, and 203 min, respectively. Corresponding emergence times from deep sedation (sedation score = 5 --> 2) with propofol were 25, 59, 71, and 74 h. CONCLUSIONS: Emergence time from sedation with propofol in ICU patients varies with the depth of sedation, the duration of sedation, and the patient's body habitus. Maintaining a light level of sedation ensures a rapid emergence from sedation with long-term propofol administration.

Utilización del límite espectral 90 por ciento (le90) del electroencefalograma como sistema de control de la sedación en los pacientes críticos / Use of the electroencephalographic spectral edge frequency 90 to monitor sedation of chronically ill patients

INTRODUCCIÓN. La profundidad de la sedación requerida en los pacientes ingresados en unidades de cuidados críticos varía a lo largo del tiempo y debe ser controlable. Actualmente utilizamos escalas de valoración clínica que son insuficientes. En los últimos años se han empleado diferentes parámetros extraídos del electroencefalograma con la finalidad de cuantificar el nivel de sedación. Uno de estos parámetros es el 90 por ciento del límite de la frecuencia del espectro (LE90). OBJETIVOS. Establecer la correlación entre nivel de sedación según escala de Ramsay y LE90. Averiguar el poder discriminante del LE90 en predecir la profundidad de la sedación y también en prever la respuesta hemodinámica del paciente ante la maniobra de aspiración de secreciones a través del tubo orotraqueal. PACIENTES Y MÉTODOS. Pacientes ingresados en la unidad de cuidados intensivos quirúrgica. Mediante regresión logística buscamos la probabilidad de estar a un determinado nivel de la escala de sedación de Ramsay según el valor del LE90. También calculamos la probabilidad de predicción (Pk), según el valor del LE90, de aparición de respuestas hemodinámicas o de movimiento frente a la aspiración endotraqueal. RESULTADOS. A un valor de LE90 inferior a 16 Hz, la probabilidad de estar en un nivel igual o superior a 4 de la escala de Ramsay es igual o mayor al 90 por ciento (Pk = 0,91). Ni el LE90 ni la escala de Ramsay no predicen ninguna respuesta hemodinámica tras la aspiración orotraqueal. CONCLUSIONES. El LE90 permite discriminar entre sedación superficial y sedación profunda. El LE90 no permite precisar los diferentes grados de sedación ni la posibilidad de respuesta hemodinámica o movimiento frente a la aspiración (AU)

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The influence of age on propofol pharmacodynamics.

BACKGROUND: The authors studied the influence of age on the pharmacodynamics of propofol, including characterization of the relation between plasma concentration and the time course of drug effect. METHODS: The authors evaluated healthy volunteers aged 25-81 yr. A bolus dose (2 mg/kg or 1 mg/kg in persons older than 65 yr) and an infusion (25, 50, 100, or 200 microg x kg(-1) x min(-1)) of the older or the new (containing EDTA) formulation of propofol were given on each of two different study days. The propofol concentration was determined in frequent arterial samples. The electroencephalogram (EEG) was used to measure drug effect. A statistical technique called semilinear canonical correlation was used to select components of the EEG power spectrum that correlated optimally with the effect-site concentration. The effect-site concentration was related to drug effect with a biphasic pharmacodynamic model. The plasma effect-site equilibration rate constant was estimated parametrically. Estimates of this rate constant were validated by comparing the predicted time of peak effect with the time of peak EEG effect. The probability of being asleep, as a function of age, was determined from steady state concentrations after 60 min of propofol infusion. RESULTS: Twenty-four volunteers completed the study. Three parameters of the biphasic pharmacodynamic model were correlated linearly with age. The plasma effect-site equilibration rate constant was 0.456 min(-1). The predicted time to peak effect after bolus injection ranging was 1.7 min. The time to peak effect assessed visually was 1.6 min (range, 1-2.4 min). The steady state observations showed increasing sensitivity to propofol in elderly patients, with C50 values for loss of consciousness of 2.35, 1.8, and 1.25 microg/ml in volunteers who were 25, 50, and 75 yr old, respectively. CONCLUSIONS: Semilinear canonical correlation defined a new measure of propofol effect on the EEG, the canonical univariate parameter for propofol. Using this parameter, propofol plasma effect-site equilibration is faster than previously reported. This fast onset was confirmed by inspection of the EEG data. Elderly patients are more sensitive to the hypnotic and EEG effects of propofol than are younger persons.

[Characterization of dose profile of remifentanil with computer simulation: comparative study with fentanyl and alfentanyl]. / Caracterización del perfil de dosificación del remifentanilo mediante simulación con ordenador: estudio comparativo con fentanilo y alfentanilo.

OBJECTIVES: To estimate the optimum dosing regimen and delivery system for remifentanil, a new opioid, using computer simulations based on information from pharmacokinetic and pharmacodynamic models available for fentanyl, alfentanil and remifentanil, as well as from clinical trials of fentanyl and alfentanil. PATIENTS AND METHODS: We estimated the site concentration ranges likely to be needed to blunt response to anesthetic or surgical stimuli and to recover from spontaneous ventilation. Dosing guidelines for remifentanil, fentanyl and alfentanil were estimated for three methods of administration (bolus, bolus + variable continuous infusion or constant continuous infusion). To that end, the time course of opioid concentration was simulated for hypothetical balanced anesthesia lasting 60 min. We then studied the number of boluses, the number of infusion rate steps, time taken to reach the terapeutic threshold, and time from turning off the infusion until reaching a concentration compatible with spontaneous ventilation. RESULTS: The estimated "effect site" concentration ranges for remifentanil were 6 to 10 ng.ml-1 during intubation; 4 to 6 ng.ml-1 during cutaneous incision; 4 to 7 ng.ml-1 for maintenance; and less than 2.5 ng.ml-1 for recovery of spontaneous ventilation. Simulated bolus administration indicated that 21 boluses of remifentanil, 4 boluses of fentanyl and 7 boluses of alfentanil were needed during one hour. The therapeutic threshold was reached within the first minute with remifentanil, within 2 minutes with fentanyl and within 1 min with alfentanil. Time until recovery of spontaneous ventilation was 7 min with remifentanil, 22 min with fentanyl and 14 min with alfentanil. In the simulation of bolus plus variable infusion, the initial bolus of remifentanil was 100 micrograms, the infusion rate for induction and maintenance was 25 micrograms.min-1 and the maintenance rate was 15 micrograms.min-1. The initial bolus of fentanyl was 300 micrograms, the infusion rate for induction and maintenance was 5 micrograms.min-1. The initial bolus of alfentanil was 2,000 micrograms, the infusion rate for induction was 200 micrograms.min-1 and the maintenance rates were 75 and 25 micrograms.min-1. The therapeutic threshold was reached in 1 min with remifentanil, in 2 min with fentanyl and within 1 min with alfentanil. Spontaneous ventilation was recovered 4 min after turning off the infusion of remifentanil, 4 min afterwards with fentanyl and 6 min afterwards with alfentanil. The simulated constant infusion rate for remifentanil of 15 micrograms.min1 (8 micrograms.min-1 for fentanyl and 75 micrograms.min-1 for alfentanil) allowed the therapeutic threshold to be reached in 10 min with remifentanil, in 22 min with fentanyl and in 17 min with alfentanil. Recovery of spontaneous ventilation occurred 5 min after closure of the infusion pump with remifentanil (24 min with fentanyl and 17 min with alfentanil). CONCLUSIONS: Information from pharmacokinetic and pharmacodynamic models allows us to establish the effect site concentration ranges for remifentanil and determine the ideal administration technique for this drug. The simulation also allows us to compare the properties of remifentanil to those of other common opioids such as fentanyl and alfentanil. The results are fairly consistent with clinical evidence, demonstrating the power of pharmacokinetic and pharmacodynamic models for rationally establishing opioid dosing guidelines.

Pharmacokinetics of intravenous dynorphin A(1-13) in opioid-naive and opioid-treated human volunteers.

BACKGROUND: Dynorphin A(1-13) is a fragment of the endogenous opioid neuropeptide dynorphin A. Previous research suggested that intravenously administered dynorphin A(1-13) has the ability to modulate morphine-induced analgesia. We designed this study to characterize the disposition of intravenous dynorphin immunoreactivity in humans and to determine whether concomitant long-term opioid therapy influenced the pharmacokinetics or side-effects profile of dynorphin A(1-13). METHODS: The study subjects comprised 20 volunteers divided into two groups of 10 each, stratified by dose (low dose, 250 micrograms/kg; high dose, 1000 micrograms/kg). There were four volunteers receiving long-term opioid therapy and six opioid-naive volunteers (nonopioid group) within each dosing group. Dynorphin A(1-13) was infused over 10 minutes, and arterial blood samples were drawn and assayed for dynorphin immunoreactivity. A population modeling approach was used to characterize the pharmacokinetics. Dynorphin effects on heart rate and arterial blood pressure were also studied. RESULTS: The pharmacokinetics of dynorphin immunoreactivity were linear over the dose range studied and were best described by a three-compartment mammillary model whose parameters were volume 1, 5.0 L; volume 2, 0.80 L; volume 3, 12 L; clearance 1, 6.0 L/min; clearance 2, 0.054 L/min; and clearance 3, 0.044 L/min. Concomitant opioid medication did not affect the disposition of dynorphin immunoreactivity. Tachycardia and flushing were commonly observed side effects. The incidence of side effects was dose dependent and was not influenced by long-term opioid use. CONCLUSIONS: Intravenously administered dynorphin A(1-13) is very rapidly metabolized, on the basis of the time course of immunoreactivity in the blood. Long-term opioid therapy did not influence either the pharmacokinetics or incidence of side effects.