Pedro Luis Garnbús

Background: Despite the known impact of propofol and remifentanil on hemodynamics and patient outcomes, there is a lack of comprehensive quantitative analysis, particularly in surgical settings, considering the influence of noxious stimuli. The aim of this study was to develop a quantitative semi-mechanistic population model that characterized the time course changes in mean arterial pressure (MAP) and heart rate (HR) due to the effects of propofol, remifentanil, and different types of noxious stimulation related to the clinical routine. Methods: Data from a prospective study were used; the study analyzed the effects of propofol and remifentanil general anesthesia on female patients in physical status of I-II according to the American Society of Anesthesiologists (ASA I-II) undergoing gynecology surgery. Patients were consecutively assigned to different administration schemes of propofol and remifentanil targeted at different effect-site concentrations. Esophageal instrumentation, laryngeal mask airway insertion, hysteroscopy, and tetanus stimuli were applied. Data from patients with chronic hypertension were discarded. Results: MAP and HR observations from 77 patients were analyzed. The hemodynamic effects were described using turn-over models incorporating feedback mechanisms. Analyses revealed that propofol and remifentanil elicited effects on the turn-over of MAP and HR, respectively, with estimates of plasma drug concentrations causing an inhibition-half of the maximum effect (C50) of 8.79 µg∙mL⁻¹ and 4.57 ng∙mL⁻¹. Hysteroscopy exerted an increase in MAP (but not in HR), which was well-characterized by the model, with a predicted typical increase of 28 mmHg and a dissipation half-life of 33 min. The impact of other noxious stimuli on MAP or HR could not be identified. Model simulations indicated that propofol and remifentanil, titrated to inhibit the motor response to noxious stimuli, regardless of dose combinations, cause a significant risk of hypotension, especially following induction and at the end of surgery (when surgical intervention is completed, before the awakening phase). Conclusions: The developed semi-mechanistic and fully identifiable model provides quantitative information on how propofol, remifentanil, and surgical stimulus (hysteroscopy) interact to produce the hemodynamic changes (of MAP and HR) commonly observed in clinical practice.

El gráfico de Poincaré es un método no lineal que permite analizar la variabilidad de una señal, dibujando dicha señal contra ella misma retardada en el tiempo. Aunque este método ha sido aplicado al análisis del electroencefalograma (EEG) para la medición de niveles de anestesia general, su aplicación en la medición de niveles de anestesia ligera aún no se ha abordado con profundidad. En este trabajo, se consideran varios tiempos de retardo en el gráfico de Poincaré para caracterizar el nivel de anestesia ligera en 110 pacientes sometidos a endoscopia digestiva. Los índices de Poincaré son combinados con parámetros espectrales de señales que contienen información del EEG y del EMG (electromiografía) para modelar los niveles de anestesia ligera, teniendo como referencia la escala de sedación Ramsay. La mejor predicción, utilizando índices del gráfico de Poincaré, del nivel de sedación y analgesia (Pk = 0,711) se obtiene usando un retardo de 8 ms en el rango de frecuencia de 30-110 Hz y de 6 ms en el rango de frecuencia de 0,5 - 30 Hz, respectivamente. La combinación de diferentes parámetros permitió obtener valores de Pk = 0,799.

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.

Rheoencephalography (REG) is a simple and inexpensive technique that intends to monitor cerebral blood flow (CBF), but its ability to reflect CBF changes has not been extensively proved. Based on the hypothesis that alterations in CBF during apnea should be reflected in REG signals under the form of increased complexity, several entropy metrics were assessed for REG analysis during apnea and resting periods in 16 healthy subjects: approximate entropy (ApEn), sample entropy (SampEn), fuzzy entropy (FuzzyEn), corrected conditional entropy (CCE) and Shannon entropy (SE). To compute these entropy metrics, a set of parameters must be defined a priori, such as, for example, the embedding dimension m, and the tolerance threshold r. A thorough analysis of the effects of parameter selection in the entropy metrics was performed, looking for the values optimizing differences between apnea and baseline signals. All entropy metrics, except SE, provided higher values for apnea periods (p-values < 0.025). FuzzyEn outperformed all other metrics, providing the lowest p-value (p = 0.0001), allowing to conclude that REG signals during apnea have higher complexity than in resting periods. Those findings suggest that REG signals reflect CBF changes provoked by apneas, even though further studies are needed to confirm this hypothesis.

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. 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. 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. 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.

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.

Objective: This works investigates the time-frequency content of impedance cardiography signals during a propofol-remifentanil anesthesia. Materials and Methods: In the last years, impedance cardiography (ICG) is a technique which has gained much attention. However, ICG signals need further investigation. Time-Frequency Distributions (TFDs) with 5 different kernels are used in order to analyze impedance cardiography signals (ICG) before the start of the anesthesia and after the loss of consciousness. In total, ICG signals from one hundred and thirty-one consecutive patients undergoing major surgery under general anesthesia were analyzed. Several features were extracted from the calculated TFDs in order to characterize the time-frequency content of the ICG signals. Differences between those features before and after the loss of consciousness were studied. Results: The Extended Modified Beta Distribution (EMBD) was the kernel for which most features shows statistically significant changes between before and after the loss of consciousness. Among all analyzed features, those based on entropy showed a sensibility, specificity and area under the curve of the receiver operating characteristic above 60%. Conclusion: The anesthetic state of the patient is reflected on linear and non-linear features extracted from the TFDs of the ICG signals. Especially, the EMBD is a suitable kernel for the analysis of ICG signals and offers a great range of features which change according to the patient’s anesthesia state in a statistically significant way. Author Contribution J Escrivá Muñoz did the data base analysis and writing of the manuscript, and P Gambús collected the cases for the data base; EW Jensen and M Vallverdú act as academic advisors in the corresponding author’s PhD program.

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.