José F. Valencia

Refined Multiscale Entropy: Application to 24-h Holter Recordings of Heart Period Variability in Healthy and Aortic Stenosis Subjects

Multiscale entropy (MSE) was proposed to characterize complexity as a function of the time-scale factor tau. Despite its broad use, this technique suffers from two limitations: (1) the artificial MSE reduction due to the coarse graining procedure and (2) the introduction of spurious MSE oscillations due to the suboptimal procedure for the elimination of the fast temporal scales. We propose a refined MSE (RMSE), and we apply it to simulations and to 24-h Holter recordings of heart rate variability (HRV) obtained from healthy and aortic stenosis (AS) groups. The study showed that the refinement relevant to the elimination of the fast temporal scales was more helpful at short scales (spanning the range of short-term HRV oscillations), while that relevant to the procedure of coarse graining was more useful at large scales. In healthy subjects, during daytime, RMSE was smaller at short scales (i.e., tau =1-2) and larger at longer scales (i.e., tau =4-20) than during nighttime. In AS population, RMSE was smaller during daytime both at short and long time scales (i.e., tau = 1 -11) than during nighttime. RMSE was larger in healthy group than in AS population during both daytime (i.e., tau = 2 -9) and nighttime (i.e., tau = 2). RMSE overcomes two limitations of MSE and confirms the complementary information that can be derived by observing complexity as a function of the temporal scale.

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.

Multiscale Complexity Analysis of the Cardiac Control Identifies Asymptomatic and Symptomatic Patients in Long QT Syndrome Type 1

The study assesses complexity of the cardiac control directed to the sinus node and to ventricles in long QT syndrome type 1 (LQT1) patients with KCNQ1-A341V mutation. Complexity was assessed via refined multiscale entropy (RMSE) computed over the beat-to-beat variability series of heart period (HP) and QT interval. HP and QT interval were approximated respectively as the temporal distance between two consecutive R-wave peaks and between the R-wave apex and T-wave end. Both measures were automatically taken from 24-hour electrocardiographic Holter traces recorded during daily activities in non mutation carriers (NMCs, n = 14) and mutation carriers (MCs, n = 34) belonging to a South African LQT1 founder population. The MC group was divided into asymptomatic (ASYMP, n = 11) and symptomatic (SYMP, n = 23) patients according to the symptom severity. Analyses were carried out during daytime (DAY, from 2PM to 6PM) and nighttime (NIGHT, from 12PM to 4AM) off and on beta-adrenergic blockade (BBoff and BBon). We found that the complexity of the HP variability at short time scale was under vagal control, being significantly increased during NIGHT and BBon both in ASYMP and SYMP groups, while the complexity of both HP and QT variability at long time scales was under sympathetic control, being smaller during NIGHT and BBon in SYMP subjects. Complexity indexes at long time scales in ASYMP individuals were smaller than those in SYMP ones regardless of therapy (i.e. BBoff or BBon), thus suggesting that a reduced complexity of the sympathetic regulation is protective in ASYMP individuals. RMSE analysis of HP and QT interval variability derived from routine 24-hour electrocardiographic Holter recordings might provide additional insights into the physiology of the cardiac control and might be fruitfully exploited to improve risk stratification in LQT1 population.

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

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).

Complexity of the short-term heart-rate variability

This work has proposed a methodology based on the concept of entropy rates to study the complexity of the short-term heart-rate variability (HRV) for improving risk stratification to predict sudden cardiac death (SCD) of patients with established ischemic-dilated cardiomyopathy (IDC). The short-term HRV was analyzed during daytime and nighttime by means of RR series. An entropy rate was calculated on the RR series, previously transformed to symbol sequences by means of an alphabet. A statistical analysis permitted to stratify high- and low-risk patients of suffering SCD, with a specificity (SP) of 95% and sensitivity (SE) of 83.3%. To get a better characterization of short-term HRV, the study has also considered the adjustment of the parameters involved in the proposed methodology. Finally, a statistical analysis was applied to recognize valid prognostic markers.

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.

Multiscale entropy analysis of heart rate variability in heart failure, hypertensive, and sinoaortic-denervated rats: classical and refined approaches

The analysis of heart rate variability (HRV) by nonlinear methods has been gaining increasing interest due to their ability to quantify the complexity of cardiovascular regulation. In this study, multiscale entropy (MSE) and refined MSE (RMSE) were applied to track the complexity of HRV as a function of time scale in three pathological conscious animal models: rats with heart failure (HF), spontaneously hypertensive rats (SHR), and rats with sinoaortic denervation (SAD). Results showed that HF did not change HRV complexity, although there was a tendency to decrease the entropy in HF animals. On the other hand, SHR group was characterized by reduced complexity at long time scales, whereas SAD animals exhibited a smaller short- and long-term irregularity. We propose that short time scales (1 to 4), accounting for fast oscillations, are more related to vagal and respiratory control, whereas long time scales (5 to 20), accounting for slow oscillations, are more related to sympathetic control. The increased sympathetic modulation is probably the main reason for the lower entropy observed at high scales for both SHR and SAD groups, acting as a negative factor for the cardiovascular complexity. This study highlights the contribution of the multiscale complexity analysis of HRV for understanding the physiological mechanisms involved in cardiovascular regulation.

Multiscale regularity analysis of the Heart Rate Variability: stratification of cardiac death risk

Subjects with ischemic dilated cardiomiopathy tend to suffer episodes of sudden cardiac death, thus risk stratification is essential to establish an adequate therapy for the patients. In this work, a new methodology was proposed for the study of the heart rate variability by using a multiscale analysis based on the concept of entropy rates, for improving risk prediction in cardiac patients. Symbolic dynamics were applied to RR time series and sets of words in several scales were constructed. The multiscale regularity analysis was proposed by comparing the entropies, calculated using Shannon and Renyi definitions, of the series of words in different scales. The study considered the selection of the best parameters for the length of the words (I) and the order of the entropies (q). Statistical analysis with repeated measures and discriminant analysis revealed statistically significant differences (p-value<0.05) and a high percentage of well classified subjects in their different risk groups, with sensitivity, specificity and positive predictive values of 100%.

Evaluation of acceleration and deceleration cardiac processes using phase-rectified signal averaging in healthy and idiopathic dilated cardiomyopathy subjects

The aim of the present study was to investigate the suitability of the Phase-Rectified Signal Averaging (PRSA) method for improved risk prediction in cardiac patients. Moreover, this technique, which separately evaluates acceleration and deceleration processes of cardiac rhythm, allows the effect of sympathetic and vagal modulations of beat-to-beat intervals to be characterized. Holter recordings of idiopathic dilated cardiomyopathy (IDC) patients were analyzed: high-risk (HR), who suffered sudden cardiac death (SCD) during the follow-up; and low-risk (LR), without any kind of cardiac-related death. Moreover, a control group of healthy subjects was analyzed. PRSA indexes were analyzed, for different time scales T and wavelet scales s, from RR series of 24 h-ECG recordings, awake periods and sleep periods. Also, the behavior of these indexes from simulated data was analyzed and compared with real data results. Outcomes demonstrated the PRSA capacity to significantly discriminate healthy subjects from IDC patients and HR from LR patients on a higher level than traditional temporal and spectral measures. The behavior of PRSA indexes agrees with experimental evidences related to cardiac autonomic modulations. Also, these parameters reflect more regularity of the autonomic nervous system (ANS) in HR patients.

Ischemic risk stratification by means of multivariate analysis of the heart rate variability

In this work, a univariate and multivariate statistical analysis of indexes derived from heart rate variability (HRV) was conducted to stratify patients with ischemic dilated cardiomyopathy (IDC) in cardiac risk groups. Indexes conditional entropy, refined multiscale entropy (RMSE), detrended fluctuation analysis, time and frequency analysis, were applied to the RR interval series (beat-to-beat series), for single and multiscale complexity analysis of the HRV in IDC patients. Also, clinical parameters were considered. Two different end-points after a follow-up of three years were considered: (i) analysis A, with 151 survivor patients as a low risk group and 13 patients that suffered sudden cardiac death as a high risk group; (ii) analysis B, with 192 survivor patients as a low risk group and 30 patients that suffered cardiac mortality as a high risk group. A univariate and multivariate linear discriminant analysis was used as a statistical technique for classifying patients in risk groups. Sensitivity (Sen) and specificity (Spe) were calculated as diagnostic criteria in order to evaluate the performance of the indexes and their linear combinations. Sen and Spe values of 80.0% and 72.9%, respectively, were obtained during daytime by combining one clinical parameter and one index from RMSE, and during nighttime Sen = 80% and Spe = 73.4% were attained by combining one clinical factor and two indexes from RMSE. In particular, relatively long time scales were more relevant for classifying patients into risk groups during nighttime, while during daytime shorter scales performed better. The results suggest that the left atrial size, indexed to body surface and RMSE indexes are those that allow enhanced classification of ischemic patients in their respective risk groups, confirming that a single measurement is not enough to fully characterize ischemic risk patients and the clinical relevance of HRV complexity measures.