Xavier Borrat

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 (Cepro) and remifentanil (Ceremi) 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 Cepro and Ceremi 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 (Pk) 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. Pk 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 Pk values of 0.81, 0.8, and 0.8 for AAI/2, BIS, and IoC, respectively. CONCLUSION:A model relating Cepro and Ceremi to AAI/2, BIS, and IoC has been developed and prospectively validated. Based on these models, the (Cepro, Ceremi) concentration pairs that provide an RSS score of 4 range from (1.8 &mgr;g·mL−1, 1.5 ng·mL−1) to (2.7 &mgr;g·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 Cepro and Ceremi to achieve the same degree of sedative effects.

Modeling the influence of the A118G polymorphism in the OPRM1 gene and of noxious stimulation on the synergistic relation between propofol and remifentanil: sedation and analgesia in endoscopic procedures.

Background:The presence of the A118G single nucleotide polymorphism in the OPRM1 gene as well as noxious stimulation might affect the requirements of remifentanil for patients undergoing ultrasonographic endoscopy under sedation-analgesia with propofol and remifentanil. Bispectral index (BIS) was used as a surrogate measure of effect. Methods:A total of 207 patients were screened for A118G and randomly received different combinations of propofol and remifentanil, changed depending on the nausea response to endoscopy tube introduction. Nonlinear mixed effects modelling was used to establish the relation between propofol and remifentanil with respect to BIS and to investigate the influence of A118G or noxious stimulation. The value of ke0 for propofol and remifentanil was estimated to avoid the hysteresis between predicted effect site concentration (Ce) and BIS. Results:Data from 176 patients were analysed. Eleven were recessive homozygous for A118G (OPRM = 1). A total of 165 patients were either dominant homozygous or heterozygous and considered normal (OPRM = 0). The estimated values of ke0 for propofol and remifentanil were 0.122 and 0.148min−1. Propofol and remifentanil were synergistic with respect to the BIS (&agr; = 1.85). EC50 estimate for propofol was 3.86 µg/ml and for remifentanil 19.6 ng/ml in normal patients and 326ng/ml in OPRM = 1 patients. BIS increases around 4% for the same effect site concentrations with noxious stimulation. Conclusions:Predicted effect site concentration of remifentanil ranging 1–5ng/ml synergistically potentiates the effects of propofol on the BIS but has no effect in A118G patients. Noxious stimulation increases BIS values by 4% at the same concentrations of propofol and remifentanil.

Failed Tracheal Intubation with the LMA.CTrach™ in Two Patients with Lingual Tonsil Hyperplasia

The LMA-CTrach combines the features of the Intubating Laryngeal Mask Airway with a fiberoptic system and a screen for visualization of the airway. Local pathology, such as lingual tonsillar hyperplasia, may obstruct the view of the airway leading to unanticipated difficult intubation. We present two cases of failed intubation with the LMA-CTrach in patients with lingual tonsillar hyperplasia. In both cases, the LMA-CTrach maintained adequate ventilation, giving time to prepare alternative strategies.

Consolidación de un modelo asistencial basado en un equipo de anestesia: Experiencia en más de 12.000 casos en una Unidad de Endoscopia Digestiva

Resumen Objetivo La creciente demanda asistencial por parte de las Unidades de Endoscopia Digestiva (UED) y otras areas fuera de quirofano, tanto por el numero, como por el tipo de pacientes y procedimientos, obliga a un replanteamiento de los esquemas de trabajo de un servicio de anestesiologia. El presente articulo describe la experiencia durante los dos ultimos anos en la UED de nuestro centro donde hemos consolidado la implantacion de un modelo asistencial basado en un equipo de anestesia formado por enfermeras y medicos anestesiologos. Material y metodo Tras la revision de la historia clinica y encuesta de salud via telefonica en pacientes ambulatorios, enfermeras de anestesia administraron una combinacion de propofol/remifentanilo con sistema TCI (target-controlled infusion) siguiendo un estricto protocolo bajo la supervision directa del anestesiologo. Resultados El ratio anestesiologo:enfermera variaba en funcion de la complejidad de la exploracion (1:2 o 1:3). Mas de 12.000 exploraciones endoscopicas (simples y avanzadas) han sido realizadas con anestesia en este periodo en un total de 11.853 pacientes. Un 4,9% de los pacientes requirieron maniobras de modificacion de la via aerea, el 0,18% ventilacion con bolsa autoinflable por depresion respiratoria, el 0,084% precisaron de la administracion de algun bolus de vasopresor por hipotension, o atropina por bradicardia, y en 9 pacientes (0,07%) hubo que finalizar precozmente la exploracion. Ningun paciente requirio intubacion orotraqueal, no hubo muertes, ni se registraron otras complicaciones asociadas a la sedacion. Conclusion Los resultados sugieren que el modelo asistencial permite responder a la gran demanda asistencial de anestesia en optimas condiciones de seguridad y calidad.

Prediction of Nociceptive Responses during Sedation by Linear and Non-Linear Measures of EEG Signals in High Frequencies

The level of sedation in patients undergoing medical procedures evolves continuously, affected by the interaction between the effect of the anesthetic and analgesic agents and the pain stimuli. The monitors of depth of anesthesia, based on the analysis of the electroencephalogram (EEG), have been progressively introduced into the daily practice to provide additional information about the state of the patient. However, the quantification of analgesia still remains an open problem. The purpose of this work is to improve the prediction of nociceptive responses with linear and non-linear measures calculated from EEG signal filtered in frequency bands higher than the traditional bands. Power spectral density and auto-mutual information function was applied in order to predict the presence or absence of the nociceptive responses to different stimuli during sedation in endoscopy procedure. The proposed measures exhibit better performances than the bispectral index (BIS). Values of prediction probability of Pk above 0.75 and percentages of sensitivity and specificity above 70% were achieved combining EEG measures from the traditional frequency bands and higher frequency bands.

Sedation-analgesia with propofol and remifentanil: concentrations required to avoid gag reflex in upper gastrointestinal endoscopy.

BACKGROUND:The purpose of this study was to identify optimal target propofol and remifentanil concentrations to avoid a gag reflex in response to insertion of an upper gastrointestinal endoscope. METHODS:Patients presenting for endoscopy received target-controlled infusions (TCI) of both propofol and remifentanil for sedation-analgesia. Patients were randomized to 4 groups of fixed target effect-site concentrations: remifentanil 1 ng•mL−1 (REMI 1) or 2 ng•mL−1 (REMI 2) and propofol 2 &mgr;g•mL−1 (PROP 2) or 3 &mgr;g•mL−1 (PROP 3). For each group, the other drug (propofol for the REMI groups and vice versa) was increased or decreased using the “up-down” method based on the presence or absence of a gag response in the previous patient. A modified isotonic regression method was used to estimate the median effective Ce,50 from the up-down method in each group. A concentration-effect (sigmoid Emax) model was built to estimate the corresponding Ce,90 for each group. These data were used to estimate propofol bolus doses and remifentanil infusion rates that would achieve effect-site concentrations between Ce,50 and Ce,90 when a TCI system is not available for use. RESULTS:One hundred twenty-four patients were analyzed. To achieve between a 50% and 90% probability of no gag response, propofol TCIs were between 2.40 and 4.23 &mgr;g•mL−1 (that could be achieved with a bolus of 1 mg•kg−1) when remifentanil TCI was fixed at 1 ng•mL−1, and target propofol TCIs were between 2.15 and 2.88 &mgr;g•mL−1 (that could be achieved with a bolus of 0.75 mg•kg−1) when remifentanil TCI was fixed at 2 ng•mL−1. Remifentanil ranges were 1.00 to 4.79 ng•mL−1 and 0.72 to 3.19 ng•mL−1 when propofol was fixed at 2 and 3 &mgr;g•mL−1, respectively. CONCLUSIONS:We identified a set of propofol and remifentanil TCIs that blocked the gag response to endoscope insertion in patients undergoing endoscopy. Propofol bolus doses and remifentanil infusion rates designed to achieve similar effect-site concentrations can be used to prevent gag response when TCI is not available.

Modeling Respiratory Depression Induced by Remifentanil and Propofol during Sedation and Analgesia Using a Continuous Noninvasive Measurement of pCO2

Respiratory depression is a common adverse effect of propofol and remifentanil. We aimed to develop a model for respiratory depressant effects of propofol with remifentanil in patients undergoing endoscopy with sedation. Data were available for 136 patients undergoing endoscopy with sedation. Participants randomly received infusions of propofol and remifentanil. Predicted plasma concentrations, outputted by infusion pumps, were available. Transcutaneous arterial pressure of carbon dioxide (pCO2) was measured. Data were analyzed using nonlinear mixed-effects modeling methods. Covariate relationships were investigated for age, noxious stimuli (endoscopy tube insertion), and A118G genotype for the µ-opioid receptor (OPRM1). Participants had a median (range) age of 64.0 (25.0–88.0) years, weight of 70.0 (35.0–98.0) kg, and height of 164.0 (147.0–190.0) cm. Seven percent were recessive homozygous for OPRM1 polymorphism. An indirect-effect model with a “modulator” compartment best described pCO2 data (P < 0.001) over a direct-effect model. Remifentanil inhibited pCO2 removal with an IC50 of 1.13 ng/ml and first-order rate constant (ke0) of 0.28 minute−1. Propofol affected the modulator compartment with an IC50 of 4.97 µg/ml (no effect-site compartment). Propofol IC50 and remifentanil ke0 were reduced with increasing age. Noxious stimuli and genotype were not significant covariates. An indirect-effect model with a rebound mechanism can describe remifentanil- and propofol-induced changes in pCO2 in patients undergoing noxious procedures. The model may be useful for identifying optimal dosing schedules for these drugs in a combination that provides adequate sedation but avoids respiratory depression.

Assessment of sedation-analgesia by means of poincaré analysis of the electroencephalogram

Monitoring the levels of sedation-analgesia may be helpful for managing patient stress on minimally invasive medical procedures. Monitors based on EEG analysis and designed to assess general anesthesia cannot distinguish reliably between a light and deep sedation. In this work, the Poincaré plot is used as a nonlinear technique applied to EEG signals in order to characterize the levels of sedation-analgesia, according to observed categorical responses that were evaluated by means of Ramsay Sedation Scale (RSS). To study the effect of high frequencies due to EMG activity, three different frequency ranges (FR1=0.5-110 Hz, FR2=0.5-30 Hz and FR3=30-110 Hz) were considered. Indexes from power spectral analysis and plasma concentration of propofol and remifentanil were also compared with the bispectral index BIS. An adaptive Neurofuzzy Inference System was applied to model the interaction of the best indexes with respect to RSS score for each analysis, and leave-one-out cross validation method was used. The ability of the indexes to describe the level of sedation-analgesia, according with the RSS score, was evaluated using the prediction probability (Pk). The results showed that the ratio SD1/SD2FR3 contains useful information about the sedation level, and SD1FR2 and SD2FR2 had the best performance classifying response to noxious stimuli. Models including parameters from Poincaré plot emerge as a good estimator of sedation-analgesia levels.