Mechanism-Based Modeling of Perioperative Variations in Hemoglobin Concentration in Patients Undergoing Laparoscopic Surgery.

BACKGROUND: Hemoglobin concentration ([Hb]) in the perioperative setting should be interpreted in the context of the variables and processes that may affect it to differentiate the dilution effects caused by changes in intravascular volume. However, it is unclear what variables and processes affect [Hb]. Here, we modeled the perioperative variations in [Hb] to identify the variables and processes that govern [Hb] and to describe their effects. METHODS: We first constructed a mechanistic framework based on the main variables and processes related to the perioperative [Hb] variations. We then prospectively studied patients undergoing laparoscopic surgery, divided into 2 consecutive cohorts for the development and validation of the model. The study protocol consisted of serial measurements of [Hb] along with recordings of hemoglobin mass loss, blood volume loss, fluid infusion, urine volume, and inflammatory biomarkers measurements, up to 96 hours postoperatively. Mathematical fitting was performed using nonlinear mixed-effects. Additionally, we performed simulations to explore the effects of blood loss and fluid therapy protocols on [Hb]. RESULTS: We studied 154 patients: 118 enrolled in the development group and 36 in the validation group. We characterized the perioperative course of [Hb] using a mass balance model that accounted for hemoglobin losses during surgery, and a 2-compartment model that estimated fluid kinetics and intravascular volume changes. During model development, we found that urinary fluid elimination represented only 24% of the total fluid elimination, and that total fluid elimination was inhibited after surgery in a time-dependent manner and influenced by age. Also, covariate evaluation showed a significant association between the type of surgery and proportion of fluid eliminated via urine. In contrast, neither the type of infused solution, blood volume loss nor inflammatory biomarkers were found to correlate with model parameters. In the validation analysis, the model demonstrated a considerable predictive capacity, with 95% of the predicted [Hb] within -4.4 and +5.5 g/L. Simulations demonstrated that hemoglobin mass loss determined most of the postoperative changes in [Hb], while intravascular volume changes due to fluid infusion, distribution, and elimination induced smaller but clinically relevant variations. Simulated patients receiving standard fluid therapy protocols exhibited a hemodilution effect that resulted in a [Hb] decrease between 7 and 15 g/L at the end of surgery, and which was responsible for the lowest [Hb] value during the perioperative period. CONCLUSIONS: Our model provides a mechanistic and quantitative understanding of the causes underlying the perioperative [Hb] variations.

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.

Current status of perioperative hypnotics, role of benzodiazepines, and the case for remimazolam: a narrative review.

Anaesthesiologists and non-anaesthesiologist sedationists have a limited set of available i.v. hypnotics, further reduced by the withdrawal of thiopental in the USA and its near disappearance in Europe. Meanwhile, demand for sedation increases and new clinical groups are using what traditionally are anaesthesiologists' drugs. Improved understanding of the determinants of perioperative morbidity and mortality has spotlighted hypotension as a potent cause of patient harm, and practice must be adjusted to respect this. High-dose propofol sedation may be harmful, and a critical reappraisal of drug choices and doses is needed. The development of remimazolam, initially for procedural sedation, allows reconsideration of benzodiazepines as the hypnotic component of a general anaesthetic even if their characterisation as i.v. anaesthetics is questionable. Early data suggest that a combination of remimazolam and remifentanil can induce and maintain anaesthesia. Further work is needed to define use cases for this technique and to determine the impact on patient outcomes.

Influence of an "Electroencephalogram-Based" Monitor Choice on the Delay Between the Predicted Propofol Effect-Site Concentration and the Measured Drug Effect.

BACKGROUND: Clinicians can optimize propofol titration by using 2 sources of pharmacodynamic (PD) information: the predicted effect-site concentration for propofol (Ceprop) and the electroencephalographically (EEG) measured drug effect. Relation between these sources should be time independent, that is, perfectly synchronized. In reality, various issues corrupt time independency, leading to asynchrony or, in other words, hysteresis. This asynchrony can lead to conflicting information, making effective drug dosing challenging. In this study, we tried to quantify and minimize the hysteresis between the Ceprop (calculated using the Schnider model for propofol) and EEG measured drug effect, using nonlinear mixed-effects modeling (NONMEM). Further, we measured the influence of EEG-based monitor choice, namely Bispectral index (BIS) versus qCON index (qCON) monitor, on propofol PD hysteresis. METHODS: We analyzed the PD data from 165 patients undergoing propofol-remifentanil anesthesia for outpatient surgery. Drugs were administered using target-controlled infusion (TCI) pumps. Pumps were programmed with Schnider model for propofol and Minto model for remifentanil. We constructed 2 PD models (direct models) relating the Schnider Ceprop to the measured BIS and qCON monitor values. We quantified the models' misspecification due to hysteresis, on an individual level, using the root mean squared errors (RMSEs). Subsequently, we optimized the PD models' predictions by adding a lag term to both models (lag-time PD models) and quantified the optimization using the RMSE. RESULTS: There is a counterclockwise hysteresis between Ceprop and BIS/qCON values. Not accounting for this hysteresis results in a direct PD model with an effect-site concentration which produces 50% of the maximal drug effect (Ce50) of 6.24 and 8.62 µg/mL and RMSE (median and interquartile range [IQR]) of 9.38 (7.92-11.23) and 8.41(7.04-10.2) for BIS and qCON, respectively. Adding a modeled lag factor of 49 seconds to the BIS model and 53 seconds to the qCON model improved both models' prediction, resulting in similar Ce50 (3.66 and 3.62 µg/mL for BIS and qCON) and lower RMSE (median (IQR) of 7.87 (6.49-9.90) and 6.56 (5.28-8.57) for BIS and qCON. CONCLUSIONS: There is a significant "Ceprop versus EEG measured drug effect" hysteresis. Not accounting for it leads to conflicting PD information and false high Ce50 for propofol in both monitors. Adding a lag term improved the PD model performance, improved the "pump-monitor" synchrony, and made the estimates of Ce50 for propofol more realistic and less monitor dependent.

Computerized tests to evaluate recovery of cognitive function after deep sedation with propofol and remifentanil for colonoscopy.

The use of sedation for diagnostic procedures including gastrointestinal endoscopy is rapidly growing. Recovery of cognitive function after sedation is important because it would be important for most patients to resume safe, normal life soon after the procedure. Computerized tests have shown being accurate descriptors of cognitive function. The purpose of the present study was to evaluate the time course of cognitive function recovery after sedation with propofol and remifentanil. A prospective observational double blind clinical study conducted in 34 young healthy adults undergoing elective outpatient colonoscopy under sedation with the combination of propofol and remifentanil using a target controlled infusion system. Cognitive function was measured using a validated battery of computerized cognitive tests (Cogstate™, Melbourne, Australia) at different predefined times: prior to starting sedation (Tbaseline), and then 10 min (T10), 40 min (T40) and 120 min (T120) after the end of colonoscopy. Tests included the assessment of psychomotor function, attention, visual memory and working memory. All colonoscopies were completed (median time: 26 min) without significant adverse events. Patients received a median total dose of propofol and remifentanil of 149 mg and 98 µg, respectively. Psychomotor function and attention declined at T10 but were back to baseline values at T40 for all patients. The magnitude of psychomotor task reduction was large (d = 0.81) however 100% of patients were recovered at T40. Memory related tasks were not affected 10 min after ending sedation. Cognitive impairment in attention and psychomotor function after propofol and remifentanil sedation was significant and large and could be easily detected by computerized cognitive tests. Even though, patients were fully recovered 40 min after ending the procedure. From a cognitive recovery point of view, larger studies should be undertaken to propose adequate criteria for discharge after sedation.

Refined Multiscale Entropy Using Fuzzy Metrics: Validation and Application to Nociception Assessment.

The refined multiscale entropy (RMSE) approach is commonly applied to assess complexity as a function of the time scale. RMSE is normally based on the computation of sample entropy (SampEn) estimating complexity as conditional entropy. However, SampEn is dependent on the length and standard deviation of the data. Recently, fuzzy entropy (FuzEn) has been proposed, including several refinements, as an alternative to counteract these limitations. In this work, FuzEn, translated FuzEn (TFuzEn), translated-reflected FuzEn (TRFuzEn), inherent FuzEn (IFuzEn), and inherent translated FuzEn (ITFuzEn) were exploited as entropy-based measures in the computation of RMSE and their performance was compared to that of SampEn. FuzEn metrics were applied to synthetic time series of different lengths to evaluate the consistency of the different approaches. In addition, electroencephalograms of patients under sedation-analgesia procedure were analyzed based on the patient's response after the application of painful stimulation, such as nail bed compression or endoscopy tube insertion. Significant differences in FuzEn metrics were observed over simulations and real data as a function of the data length and the pain responses. Findings indicated that FuzEn, when exploited in RMSE applications, showed similar behavior to SampEn in long series, but its consistency was better than that of SampEn in short series both over simulations and real data. Conversely, its variants should be utilized with more caution, especially whether processes exhibit an important deterministic component and/or in nociception prediction at long scales.

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 (ke 0) 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 ke 0 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.

Pharmacokinetic-pharmacodynamic modelling in anaesthesia.

Anaesthesiologists adjust drug dosing, administration system and kind of drug to the characteristics of the patient. They then observe the expected response and adjust dosing to the specific requirements according to the difference between observed response, expected response and the context of the surgery and the patient. The approach above can be achieved because on one hand quantification technology has made significant advances allowing the anaesthesiologist to measure almost any effect by using noninvasive, continuous measuring systems. On the other the knowledge on the relations between dosing, concentration, biophase dynamics and effect as well as detection of variability sources has been achieved as being the benchmark specialty for pharmacokinetic-pharmacodynamic (PKPD) modelling. The aim of the review is to revisit the most common PKPD models applied in the field of anaesthesia (i.e. effect compartmental, turnover, drug-receptor binding and drug interaction models) through representative examples. The effect compartmental model has been widely used in this field and there are multiple applications and examples. The use of turnover models has been limited mainly to describe respiratory effects. Similarly, cases in which the dissociation process of the drug-receptor complex is slow compared with other processes relevant to the time course of the anaesthetic effect are not frequent in anaesthesia, where in addition to a rapid onset, a fast offset of the response is required. With respect to the characterization of PD drug interactions different response surface models are discussed. Relevant applications that have changed the way modern anaesthesia is practiced are also provided.

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 (REMI 1) or 2 ng•mL (REMI 2) and propofol 2 µg•mL (PROP 2) or 3 µg•mL (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 µg•mL (that could be achieved with a bolus of 1 mg•kg) when remifentanil TCI was fixed at 1 ng•mL, and target propofol TCIs were between 2.15 and 2.88 µg•mL (that could be achieved with a bolus of 0.75 mg•kg) when remifentanil TCI was fixed at 2 ng•mL. Remifentanil ranges were 1.00 to 4.79 ng•mL and 0.72 to 3.19 ng•mL when propofol was fixed at 2 and 3 µg•mL, 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 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. METHOD: 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 k e0 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 k e0 for propofol and remifentanil were 0.122 and 0.148 min(-1). Propofol and remifentanil were synergistic with respect to the BIS (α = 1.85). EC50 estimate for propofol was 3.86 µg/ml and for remifentanil 19.6 ng/ml in normal patients and 326 ng/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 1-5 ng/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.

Bilateral Bispectral Index Monitoring Performance in the Detection of Seizures in Nonanesthetized Epileptic Patients: An Observational Study.

BACKGROUND: The aim of this observational study was to determine whether bilateral bispectral index (BIS) monitoring can detect seizures in epileptic patients. METHODS: Four-channel frontal BIS monitoring and standard 40-channel electroencephalography monitoring were conducted in epileptic patients undergoing evaluation for epilepsy surgery. The BIS numerical value, signal quality index, electromyography, suppression ratio, and color density spectral array were continuously recorded. In patients with electroencephalography-confirmed seizures, the mean value and trend (slope of linear regression) of bilateral BIS monitor parameters were analyzed from 1 minute before to 1 minute after seizure onset. RESULTS: Of 48 patients included in the study, 21 (43.8%) had at least 1 seizure. BIS numerical value was not able to detect focal or focal to bilateral tonic-clonic seizures. Considering all seizures, the only significant differences between recordings 1 minute before and 1 minute after seizure onset were a decrease in the signal quality index slope from 1 hemisphere (0.039±0.297 vs. -0.085±0.321, respectively; P =0.029) and in the mean signal quality index recorded from both hemispheres (left hemisphere: 65.775±30.599 vs. 61.032±26.285; P =0.016 and right hemisphere: 63.244±31.985 vs. 59.837±27.360; 0.029); these differences were not maintained after Hochberg adjustment for multiple comparisons. In seizures occurring during sleep, there was a change in the electromyography slope of 1 hemisphere before and after seizure onset (-0.141±0.176 vs. 0.162±0.140, respectively; P =0.038). There were variable responses in BIS parameters in the 3 patients who developed focal nonconvulsive seizure clusters. CONCLUSION: Bilateral BIS monitoring was not able to detect the occurrence of seizures in epileptic patients.

Semimechanistic models to relate noxious stimulation, movement, and pupillary dilation responses in the presence of opioids.

Intraoperative targeting of the analgesic effect still lacks an optimal solution. Opioids are currently the main drug used to achieve antinociception, and although underdosing can lead to an increased stress response, overdose can also lead to undesirable adverse effects. To better understand how to achieve the optimal analgesic effect of opioids, we studied the influence of remifentanil on the pupillary reflex dilation (PRD) and its relationship with the reflex movement response to a standardized noxious stimulus. The main objective was to generate population pharmacodynamic models relating remifentanil predicted concentrations to movement and to pupillary dilation during general anesthesia. A total of 78 patients undergoing gynecological surgery under general anesthesia were recruited for the study. PRD and movement response to a tetanic stimulus were measured multiple times before and after surgery. We used nonlinear mixed effects modeling to generate a population pharmacodynamic model to describe both the time profiles of PRD and movement responses to noxious stimulation. Our model demonstrated that movement and PRD are equally depressed by remifentanil. Using the developed model, we changed the intensity of stimulation and simulated remifentanil predicted concentrations maximizing the probability of absence of movement response. An estimated effect site concentration of 2 ng/ml of remifentanil was found to inhibit movement to a tetanic stimulation with a probability of 81%.

Perioperative blood loss: estimation of blood volume loss or haemoglobin mass loss?

BACKGROUND: Perioperative blood loss is an essential parameter in research into Patient Blood Management. However, currently there is no "gold standard" method to quantify it. Direct measurements of blood loss are considered unreliable methods, and the formulae to estimate it have proven to be significantly inaccurate. Given the need for better research tools, this study evaluated an estimation of haemoglobin mass loss as an alternative approach to estimate perioperative blood loss, and compared it to estimations based on blood volume loss. MATERIAL AND METHODS: We studied one hundred consecutive patients undergoing urological laparoscopic surgery. Both haemoglobin mass loss and blood volume loss were directly measured during surgery, under highly controlled conditions for a reliable direct measurement of blood loss. Three formulae were studied: 1) a haemoglobin mass loss formula, which estimated blood loss in terms of haemoglobin mass loss, 2) the López-Picado's formula and 3) an empirical volume formula that estimated blood loss in terms of blood volume loss. The empirical volume formula was developed within the study with the aim of providing the best possible estimation of blood volume loss in the studied population. The formulae were evaluated and compared by assessing their agreements with their respective direct measurements of blood loss. RESULTS: The haemoglobin mass loss formula met the predefined agreement criterion of ±71 g, with 95% limits of agreement ranging from 0.6 to 44.1 g and a moderate overestimation of 22.4. In comparison to both blood volume loss formulae, the haemoglobin mass loss formula was superior in every agreement parameter evaluated. DISCUSSION: In this study, the estimation of haemoglobin mass loss was found to be a more accurate method to estimate perioperative blood loss. This estimation method could be a robust research tool, although more studies are needed to establish its reliability.

Tools to screen and measure cognitive impairment after surgery and anesthesia.

Cognition is essential to all aspects of our everyday life. Although we take our cognitive function for granted, the perioperative period is prone to several aggressions that might impair it. Postoperative cognitive dysfunction, has been the aim of many studies recently, and was shown to be very common with an incidence that can reach 40%, yielding not only impairment in cognition, but also longer hospital stays, higher costs and greater mortality. While several studies have revealed some of the mechanisms contributing to postoperative cognitive dysfunction, the search for the perfect instrument to screen and measure cognitive (dys)function has proven more elusive. The present paper aims to review several cognitive evaluation methods, discussing their advantages and disadvantages as well as their potential clinical applications in evaluating the dynamics of the recovery of cognitive function after anesthesia and surgery. The current availability of easy to use computerized tests might provide the tools necessary to identify patients at risk, and promptly provide them with the adequate course of action.

Effects of Ketamine on Pupillary Reflex Dilation: A Case Report.

Ketamine is an important component of multimodal treatment and a commonly used anesthetic drug. However, its analgesic effects have not been fully assessed intraoperatively because of difficulties in measuring this effect. In this case report, a woman underwent general anesthesia with ketamine and its pupillary reflexes were measured to detect autonomic changes in response to pain. With increasing doses of ketamine, the pupillary light reflex and the pupillary dilation response decreased. This could be caused by N-methyl-D-aspartate receptor antagonism in the pupillary reflexes pathway or by the analgesic effects of ketamine.

Poincaré plot analysis of cerebral blood flow signals: Feature extraction and classification methods for apnea detection.

OBJECTIVE: Rheoencephalography is a simple and inexpensive technique for cerebral blood flow assessment, however, it is not used in clinical practice since its correlation to clinical conditions has not yet been extensively proved. The present study investigates the ability of Poincaré Plot descriptors from rheoencephalography signals to detect apneas in volunteers. METHODS: A group of 16 subjects participated in the study. Rheoencephalography data from baseline and apnea periods were recorded and Poincaré Plot descriptors were extracted from the reconstructed attractors with different time lags (τ). Among the set of extracted features, those presenting significant differences between baseline and apnea recordings were used as inputs to four different classifiers to optimize the apnea detection. RESULTS: Three features showed significant differences between apnea and baseline signals: the Poincaré Plot ratio (SDratio), its correlation (R) and the Complex Correlation Measure (CCM). Those differences were optimized for time lags smaller than those recommended in previous works for other biomedical signals, all of them being lower than the threshold established by the position of the inflection point in the CCM curves. The classifier showing the best performance was the classification tree, with 81% accuracy and an area under the curve of the receiver operating characteristic of 0.927. This performance was obtained using a single input parameter, either SDratio or R. CONCLUSIONS: Poincaré Plot features extracted from the attractors of rheoencephalographic signals were able to track cerebral blood flow changes provoked by breath holding. Even though further validation with independent datasets is needed, those results suggest that nonlinear analysis of rheoencephalography might be a useful approach to assess the correlation of cerebral impedance with clinical changes.

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.

Interaction between EEG and drug concentration to predict response to noxious stimulation during sedation-analgesia: effect of the A118G genetic polymorphism.

The level of sedation in patients undergoing medical procedures is affected by the interaction between the effect of the anesthetic and analgesic agents and the pain stimuli. The presence of the A118G single nucleotide polymorphism (SNP) in the OPRM1 gene affects the requirements of opioids for patients undergoing sedation-analgesia. The purpose of this work is to evaluate the influence of the SNP A118G in OPRM1 on EEG measures for the prediction of the response to pain stimulation during endoscopy procedure. The proposed measures were based on power spectral density and auto-mutual information function. It was found that the statistical performances of the EEG measures improved when the presence of the SNP was taken into account (prediction probability Pk>0.9).

Prediction of nociceptive responses during sedation by time-frequency representation.

The level of sedation in patients undergoing medical procedures evolves continuously, such as the effect of the anesthetic and analgesic agents is counteracted by 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 analyze the capability of prediction of nociceptive responses based on the time-frequency representation (TFR) of EEG signal. Functions of spectral entropy, instantaneous power and instantaneous frequency were calculated in order to predict the presence or absence of the nociceptive responses to different stimuli during sedation in endoscopy procedure. Values of prediction probability of Pk above 0.75 and percentages of sensitivity and specificity above 70% and 65% respectively were achieved combining TFR functions with bispectral index (BIS) and with concentrations of propofol (CeProp) and remifentanil (CeRemi).