Autoinflammatory diseases as a cause of acute abdominal pain in the emergency department.

Autoinflammatory diseases (AIDs) usually present with acute abdominal pain and fever, both of which are also the main causes of referral in the emergency department. As some patients with acute abdominal pain may be discharged from the emergency department without a definitive diagnosis, it is not surprising that, due to their rarity, most cases of AID remain undiagnosed or are misdiagnosed as acute appendicitis. Indeed, the diagnosis of familial Mediterranean fever and autoinflammatory syndromes requires a high index of suspicion and careful assessment of clinical history. Age of onset and clinical features, in particular the self-limiting acute attacks, together with prodromal symptoms and trigger factors, are useful to suspect these dis- orders. In addition, discrepancies in laboratory tests that show an increase in acute phase reactants as well as diagnostic imaging, which usually fails to show specific abdominal disorders, may help in the identification of patients who require genetic testing to confirm a diagnosis of AID.

Pulse photoplethysmographic amplitude and heart rate variability during laparoscopic cholecystectomy: A prospective observational study.

BACKGROUND: Surgical stress affects the autonomic nervous system by increasing sympathetic outflow. One method of monitoring sympathetic activity is pulse photoplethysmographic analysis. From this two indices can be derived - autonomic nervous system state (ANSS) and ANSS index (ANSSi). It has recently been claimed that these indices can be used to measure sympathetic activity in anaesthetised patients, but their validity has not yet been demonstrated. OBJECTIVE: To measure changes in pulse photoplethysmographic indices and determine any agreement with autonomic nervous system modulation of the cardiovascular system in healthy study participants during surgery under general anaesthesia. DESIGN: Prospective observational study. SETTING: Single-centre study based at a tertiary care centre in Milan, Italy. PATIENTS: Healthy patients undergoing general anaesthesia for elective laparoscopic cholecystectomy. INTERVENTIONS: ANSS, ANSSi, and heart rate variability (HRV) were analysed at three main times: baseline, after induction of general anaesthesia, and after pneumoperitoneum insufflation. MAIN OUTCOME MEASURES: The magnitude of changes in photoplethysmographic and HRV indices was measured. The agreement between pulse photoplethysmographic and HRV-derived indices was assessed by Bland-Altman plots. RESULTS: In total, 52 patients were enrolled and their data analysed. Both pulse photoplethysmographic and HRV indices changed during the study phases. An agreement was found between ANSSi and low frequency spectral components of HRV [bias 10.2nu, 95% confidence interval (CI) -13 to 33.4], high frequency spectral components of HRV (bias 6.1 nu, 95% CI -16.3 to 28.6), and low frequency/high frequency ratio (bias 16.1nu, 95% CI -1.4 to 33.5). The agreement was weaker between ANSSI and HRV indices. CONCLUSION: The study endorses the use of pulse photoplethysmographic indices ANSS and ANSSi as surrogates to estimate changes of autonomic modulation of the cardiovascular system in healthy adults during surgery under general anaesthesia.Orcid ID: orcid.org/0000-0002-9616-803X.

Pulse Photoplethysmographic Analysis Estimates the Sympathetic Activity Directed to Heart and Vessels.

BACKGROUND: Novel pulse photoplethysmographic-derived indices have been proposed as tools to measure autonomic nervous system (ANS) modulation in anesthetized and awake patients, but nowadays their experimental validation is lacking. The authors aimed to investigate the ability of pulse photoplethysmographic amplitude (PPGA), ANS state (ANSS), and ANSS index (ANSSi) to measure changes of ANS modulation in response to sympathetic stimulation. METHODS: Ten awake healthy volunteers underwent two passive head-up tilts at 45° and 90°. The heart rate variability (HRV) and systolic arterial pressure variability were analyzed in the frequency domain as a measure of ANS modulation directed to the heart and the vessels. HRV, baroreflex sensitivity, and pulse photoplethysmographic indices were measured at baseline and after tilt maneuvers. The agreement between HRV-derived indices and pulse photoplethysmographic indices was assessed using Bland-Altman plots. RESULTS: PPGA, ANSS, and ANSSi changed significantly during the study protocol. Head-up tilt decreased PPGA and ANSS and increased ANNSi. There was a good agreement between ANSSi and baroreflex sensitivity explored in the high-frequency band (bias, 0.23; 95% CI, -22.7 to 23.2 normalized units) and between ANSSi and the sympathovagal modulation directed to the heart (bias, 0.96; 95% CI, -8.7 to 10.8 normalized units). CONCLUSIONS: In controlled experimental conditions, novel pulse plethysmographic indices seem to estimate the changes of the sympathetic outflow directed to the vessels and the sympathovagal balance modulating heart rate. These indices might be useful in the future to monitor the fluctuation of sympathetic activity in anesthetized patients.

Gene status in HER2 equivocal breast carcinomas: impact of distinct recommendations and contribution of a polymerase chain reaction-based method.

BACKGROUND: The primary objectives of this study on carcinomas with equivocal HER2 expression were to assess the impact of distinct recommendations with regard to identifying patients eligible for anti-HER2 agents by fluorescence in situ hybridization (FISH) and to elucidate whether multiplex ligation-dependent probe amplification (MLPA) may be of support in assessing HER2 gene status. METHODS: A cohort of 957 immunohistochemistry-evaluated HER2-equivocal cases was analyzed by dual-color FISH. The results were assessed according to U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines and American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) 2007 and 2013 guidelines for dual- and single-signal in situ hybridization (ISH) assays. A subgroup of 112 cases was subjected to MLPA. RESULTS: HER2 amplification varied from 15% (ASCO/CAP 2007 HER2/CEP17 ratio) to 29.5% (FDA/EMA HER2 copy number). According to the ASCO/CAP 2013 interpretation of the dual-signal HER2 assay, ISH-positive carcinomas accounted for 19.7%. In contrast with the ASCO/CAP 2007 ratio, this approach labeled as positive all 32 cases (3.34%) with a HER2/CEP17 ratio <2 and an average HER2 copy number ≥6.0 signals per cell. In contrast, only one case showing a HER2 copy number <4 but a ratio ≥2 was diagnosed as positive. MLPA data correlated poorly with FISH results because of the presence of heterogeneous HER2 amplification in 33.9% of all amplified carcinomas; however, MLPA ruled out HER2 amplification in 75% of ISH-evaluated HER2-equivocal carcinomas. CONCLUSION: The ASCO/CAP 2013 guidelines seem to improve the identification of HER2-positive carcinomas. Polymerase chain reaction-based methods such as MLPA can be of help, provided that heterogeneous amplification has been ruled out by ISH.

Comparison of the Surgical Pleth Index with autonomic nervous system modulation on cardiac activity during general anaesthesia: A randomised cross-over study.

BACKGROUND: Surgical plethysmographic index (SPI) has been proposed as a tool to measure the nociception/antinociception balance during general anaesthesia. Untreated nociception may increase sympathetic tone, but the relationship between SPI and the autonomic nervous system (ANS) is poorly understood. OBJECTIVE: We hypothesised that two different levels of SPI might be associated with differences in ANS modulation, measured by the frequency domain analysis of heart rate variability (HRV). DESIGN: A randomised, cross-over group study, conducted between February and November 2009. SETTING: University tertiary referral hospital in Milan, Italy. PATIENTS: Forty-two adult patients undergoing scheduled laparoscopic abdominal surgery. INTERVENTIONS: ECG, noninvasive arterial blood pressure and SPI were recorded during balanced general anaesthesia with inhaled sevoflurane and intravenous remifentanil. After pneumoperitoneum induction, the remifentanil infusion rate was set to obtain two different levels of SPI (>50, HI-SPI, and <50, LO-SPI) for each patient. MAIN OUTCOME MEASURES: Arterial pressure, heart rate (HR), low-frequency and high-frequency spectral components, the low frequency/high frequency ratio (measure of sympathovagal balance) and whole power spectrum density of HRV were measured at the two different levels of SPI. RESULTS: Thirty-nine patients were included in the final analysis. During LO-SPI, HR and systolic and mean blood pressures were significantly lower than HI-SPI. The median low frequency/high frequency ratio was reduced during LO-SPI [1.29 interquartile range (IQR) 0.66 to 2.05) vs. 2.36 (1.30 to 3.62), P = 0.008]. The sensitivity analysis revealed a significant correlation between SPI changes and changes of all ANS indices, arterial pressure and HR, with a slightly better correlation for low frequency/high frequency (Spearman ρ = 0.70, IQR 0.484 to 0.834, P < 0.001). CONCLUSION: In the context of a balanced general anaesthesia in healthy patients undergoing laparoscopic abdominal surgery, ANS modulation seems to correlate with changes in SPI. Further studies are warranted to assess whether this may reflect a change in nociception/antinociception balance or a pharmacodynamic effect of remifentanil.

Atrial fibrillation in emergency department: prevalence of sinus rhythm 1 week after discharge.

BACKGROUND: Current guidelines do not provide definitive indications about the treatment in emergency departments (ED) of patients with recent-onset atrial fibrillation (AF). METHODS: A multicentre observational study involving four general hospitals of the same metropolitan area was conducted. All consecutive adult patients admitted to the ED with recent symptoms of AF (<48 h duration) and discharged home were considered. Patients who underwent ED early cardioversion were enrolled in group A. Patients managed with ventricular rate control were enrolled in group B. RESULTS: On the 24 h Holter recordings at 1-week follow-up, stable sinus rhythm was detected in 46/58 (79.3%; 95% CI 68.9 to 89.7) patients in group A and 8/33 (24.2%; 95% CI 9.6 to 38.9) patients in group B (p<0.01). CONCLUSION: According to the study results, rhythm at the time of ED discharge is a poor indicator of the short-term evolution of AF.

A Monocentric Retrospective Study about the Correlation between Histology and Cytology of Thyroid Indeterminate Nodules Classified as TIR 3A and TIR 3B, according to 2014 Italian Consensus for Classification and Reporting of Thyroid Cytology.

BACKGROUND: In 2014, the Italian Consensus for Classification and Reporting of Thyroid Cytology (ICCRTC) reviewed the previous cytological classification proposed in 2007 including the subdivision of TIR 3 category into low risk (TIR 3A) and high risk (TIR 3B). In Italian literature, different rates of malignancy have been correlated to these subcategories. OBJECTIVES: The aim of the study is to present our experience on this subclassification for the assessment of the malignancy risk of indeterminate thyroid nodules. We correlated the subdivision into TIR 3A and TIR 3B with the histological report by highlighting the rates of malignancy detected in the two subcategories. On the one hand, we aimed to check if the groups are associated with a real and significant difference risk of malignancy. On the other hand, we evaluated the use of this subdivision in the choice of the appropriate treatment. STUDY DESIGN: This is a retrospective review of all the patients with an indeterminate nodule who underwent US-FNA and had surgery at ASL Città di Torino between January 2005 and May 2018. RESULTS: 150 patients have been analyzed for the research; 62 (41.3%) had a malignant histological report. Rates of malignancy between TIR 3A (20.8%) and TIR 3B (60.3%) were significantly different (p < 0.0001). The subclassification had high sensitivity (75.8%; CI 63.3-85.8%) and NPV (79.3%; CI 68-87.8%) and low specificity (64.8%; CI 53.9-74.7%) and PPV (60.3; CI 48.5-71.2%). The measurement of the accuracy (AUC = 0.7) classified the test as "moderately accurate." Conclusions. Obtained data show a great rate of false negative (20.8%) and limited AUC (0.7). According to our logistic regression, we argue that the 2014 subclassification into TIR 3A and TIR 3B should be considered for the choice of patient treatment, but at the same time, we believe that the association with other screening tests is necessary to increase the accuracy in the future.

Multiple testing strategy for the detection of temporal irreversibility in stationary time series.

We propose a strategy for the detection of temporal irreversibility in stationary time series based on multiple bidimensional tests. The test is helpful to evaluate the displacement of irreversibility toward high dimensions. The test can be used independently of the theoretical functionals actually utilized to check irreversibility. The method was applied to simulated nonlinear signals generated by the delayed Henon map and a two-loop negative feedback model to show how the presence of a delay could produce the displacement of irreversibility toward higher dimensions. The method was applied also to series of a biological variable (i.e., heart period) that is known to be regulated by multiple feedback loops. Simulations and real data support the need of exploring progressively increasing embedding dimensions when assessing temporal irreversibility.

Association between autonomic control indexes and mortality in subjects admitted to intensive care unit.

This study checks whether autonomic markers derived from spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) and from their interactions with spontaneous or mechanical respiration (R) are associated with mortality in patients admitted to intensive care unit (ICU). Three-hundred consecutive HP, SAP and R values were recorded during the first day in ICU in 123 patients. Population was divided into survivors (SURVs, n = 83) and non-survivors (NonSURVs, n = 40) according to the outcome. SURVs and NonSURVs were aged- and gender-matched. All subjects underwent modified head-up tilt (MHUT) by tilting the bed back rest segment to 60°. Autonomic control indexes were computed using time-domain, spectral, cross-spectral, complexity, symbolic and causality techniques via univariate, bivariate and conditional approaches. SAP indexes derived from time-domain, model-free complexity and symbolic approaches were associated with the endpoint, while none of HP variability markers was. The association was more powerful during MHUT. Linear cross-spectral and causality indexes were useless to separate SURVs from NonSURVs, while nonlinear bivariate symbolic markers were successful. When indexes were combined with clinical scores, only SAP variance provided complementary information. Cardiovascular control variability indexes, especially when derived after an autonomic challenge such as MHUT, can improve mortality risk stratification in ICU.

Optimization of Vagal Stimulation Protocol Based on Spontaneous Breathing Rate.

Controlled breathing maneuver is being widely applied for cardiovascular autonomic control evaluation and cardiac vagal activation through reduction of breathing rate (BR). However, this maneuver presented contradictory results depending on the protocol and the chosen BR. These variations may be related to the individual intrinsic profile baseline sympathetic tonus, as described before by others. In this study, we evaluated the effect of controlled breathing maneuver on cardiovascular autonomic control in 26 healthy subjects allocated into two protocols: (1) controlled breathing in three different rates (10, 15, and 20 breaths/min) and (2) controlled breathing in rates normalized by the individual spontaneous breathing rate (SBR) at 100, 80, 70, and 50%. Our results showed autonomic responses favorable to vagal modulation with the lower BR maneuvers. Nevertheless, while this activation was variable using the standard protocol, all participants of the normalized protocol demonstrated an increase of vagal modulation at 80% BR (HFnu 80 = 67.5% vs. 48.2%, p < 0.0001). These results suggest that controlled breathing protocols to induce vagal activation should consider the SBR, being limited to values moderately lower than the baseline.

Progressive decrease of heart period variability entropy-based complexity during graded head-up tilt.

Complexity (or its opposite, regularity) of heart period variability has been related to age and disease but never linked to a progressive shift of the sympathovagal balance. We compare several well established estimates of complexity of heart period variability based on entropy rates [i.e., approximate entropy (ApEn), sample entropy (SampEn), and correct conditional entropy (CCE)] during an experimental protocol known to produce a gradual shift of the sympathovagal balance toward sympathetic activation and vagal withdrawal (i.e., the graded head-up tilt test). Complexity analysis was carried out in 17 healthy subjects over short heart period variability series ( approximately 250 cardiac beats) derived from ECG recordings during head-up tilt with table inclination randomly chosen inside the set {0, 15, 30, 45, 60, 75, 90}. We found that 1) ApEn does not change significantly during the protocol; 2) all indices measuring complexity based on entropy rates, including ad hoc corrections of the bias arising from their evaluation over short data sequences (i.e., corrected ApEn, SampEn, CCE), evidence a progressive decrease of complexity as a function of the tilt table inclination, thus indicating that complexity is under control of the autonomic nervous system; 3) corrected ApEn, SampEn, and CCE provide global indices that can be helpful to monitor sympathovagal balance.

Complexity and nonlinearity in short-term heart period variability: comparison of methods based on local nonlinear prediction.

This paper evaluates the paradigm that proposes to quantify short-term complexity and detect nonlinear dynamics by exploiting local nonlinear prediction. Local nonlinear prediction methods are classified according to how they judge similarity among patterns of L samples (i.e., according to different definitions of the cells utilized to discretize the phase space) and examined in connection with different types of surrogate data: 1) phase-randomized or Fourier transform based, FT; 2) amplitude-adjusted FT, AAFT; 3) iteratively-refined AAFT, IAAFT, preserving distribution IAAFT-1; 4) IAAFT preserving power spectrum, IAAFT-2. The methods were applied on ad-hoc simulations and on a large database of short heart period variability series (approximately 300 cardiac beats) recorded in healthy young subjects during experimental conditions inducing a sympathetic activation (head-up tilt, infusion of nitroprusside, or handgrip), a parasympathetic activation (low dose administration of atropine or infusion of phenylephrine), a complete parasympathetic blockade (high dose administration of atropine), or during controlled respiration at different breathing rates. As to complexity analysis we found that: 1) although complexity indexes derived from different methods were different in terms of absolute values, changes due to experimental conditions were consistently detected; 2) complexity was significantly decreased by all the experimental conditions provoking a sympathetic activation and by controlled respiration at slow breathing rates. As to detection of nonlinearities we found that: 1) IAAFT-1 and IAAFT-2 surrogates performed similarly in all protocols; 2) FT and IAAFT surrogates detected about the same percentage of nonlinear dynamics in all protocols; 3) AAFT surrogates were inappropriate with all the methods and should be dismissed in future applications; 4) methods based on overlapping cells with variable size were characterized by a larger rate of false detections of nonlinear dynamics; 5) short-term heart period variability at rest was mostly linear; 6) controlled respiration at slow breathing rates increased nonlinear components, while the separate activation of the two branches of the autonomic nervous system (i.e., sympathetic or parasympathetic) was ineffective at this regard.

Effects of laparoscopic radical prostatectomy on intraoperative autonomic nervous system control of hemodynamics.

BACKGROUND: Laparoscopic radical prostatectomy induces hemodynamic changes that have been supposed due to autonomic nervous system activity. The aim of this study is to measure the sympathetic and vagal modulation on hemodynamic response to steep Trendelenburg and pneumoperitoneum for laparoscopic surgery. METHODS: Autonomic nervous system modulation was assessed noninvasively through heart rate variability and arterial pressure variability analysis in patients undergoing elective laparoscopic radical prostatectomy and in awake volunteers during head-down tilt. RESULTS: Forty patients and 14 awake volunteers were studied. The induction of general anesthesia significantly decreased the heart rate, arterial pressure, vagal modulation, and sympathetic modulation. Steep Trendelenburg increased vagal and sympathetic modulation both in anesthetized and awake subjects. Pneumoperitoneum increased arterial pressure without effect on autonomic nervous system control in anesthetized patients. CONCLUSIONS: Hemodynamic changes occurring during laparoscopic radical prostatectomy reveal autonomic response to the challenges (i.e. general anesthesia and head down position), and non-neurally mediated increase of arterial pressure caused by pneumoperitoneum. This study supports the notion that during laparoscopic radical prostatectomy the association between the vagal stimulation due to Trendelenburg positioning and sympathetic withdrawal caused by general anesthesia could lead to severe bradycardia and cardiac arrest in risky patients.

Quantifying Net Synergy/Redundancy of Spontaneous Variability Regulation via Predictability and Transfer Entropy Decomposition Frameworks.

Objective: Indexes assessing the balance between redundancy and synergy were hypothesized to be helpful in characterizing cardiovascular control from spontaneous beat-to-beat variations of heart period (HP), systolic arterial pressure (SAP), and respiration (R). Methods: Net redundancy/synergy indexes were derived according to predictability and transfer entropy decomposition strategies via a multivariate linear regression approach. Indexes were tested in two protocols inducing modifications of the cardiovascular regulation via baroreflex loading/unloading (i.e., head-down tilt at -25° and graded head-up tilt at 15°, 30°, 45°, 60°, 75°, and 90°, respectively). The net redundancy/synergy of SAP and R to HP and of HP and R to SAP were estimated over stationary sequences of 256 successive values. Results: We found that: 1) regardless of the target (i.e., HP or SAP) redundancy was prevalent over synergy and this prevalence was independent of type and magnitude of the baroreflex challenge; 2) the prevalence of redundancy disappeared when decoupling inputs from output via a surrogate approach; 3) net redundancy was under autonomic control given that it varied in proportion to the vagal withdrawal during graded head-up tilt; and 4) conclusions held regardless of the decomposition strategy. Conclusion: Net redundancy indexes can monitor changes of cardiovascular control from a perspective completely different from that provided by more traditional univariate and multivariate methods. Significance: Net redundancy measures might provide a practical tool to quantify the reservoir of effective cardiovascular regulatory mechanisms sharing causal influences over a target variable.Objective: Indexes assessing the balance between redundancy and synergy were hypothesized to be helpful in characterizing cardiovascular control from spontaneous beat-to-beat variations of heart period (HP), systolic arterial pressure (SAP), and respiration (R). Methods: Net redundancy/synergy indexes were derived according to predictability and transfer entropy decomposition strategies via a multivariate linear regression approach. Indexes were tested in two protocols inducing modifications of the cardiovascular regulation via baroreflex loading/unloading (i.e., head-down tilt at -25° and graded head-up tilt at 15°, 30°, 45°, 60°, 75°, and 90°, respectively). The net redundancy/synergy of SAP and R to HP and of HP and R to SAP were estimated over stationary sequences of 256 successive values. Results: We found that: 1) regardless of the target (i.e., HP or SAP) redundancy was prevalent over synergy and this prevalence was independent of type and magnitude of the baroreflex challenge; 2) the prevalence of redundancy disappeared when decoupling inputs from output via a surrogate approach; 3) net redundancy was under autonomic control given that it varied in proportion to the vagal withdrawal during graded head-up tilt; and 4) conclusions held regardless of the decomposition strategy. Conclusion: Net redundancy indexes can monitor changes of cardiovascular control from a perspective completely different from that provided by more traditional univariate and multivariate methods. Significance: Net redundancy measures might provide a practical tool to quantify the reservoir of effective cardiovascular regulatory mechanisms sharing causal influences over a target variable.

Mechanical ventilatory modes and cardioventilatory phase synchronization in acute respiratory failure patients.

Cardioventilatory phase synchronization was studied in ten critically ill patients admitted in intensive care unit (ICU) for acute respiratory failure under two mechanical ventilatory modes: (i) pressure controlled ventilation (PCV); (ii) pressure support ventilation (PSV). The two modalities were administered to the same patient in different times in a random order. Cardioventilatory phase interactions were typified by plotting the relative position of a heartbeat, detected from the electrocardiogram and collected in n groups, within m ventilatory cycles as a function of the progressive cardiac beat number via the synchrogram. n:m phase synchronized patterns were detected by computing the variability of each phase group. The percent duration of the recording featuring phase synchronization was assessed as a measure of the strength of phase synchrony and tested against situations of full phase desynchronization between cardiac and ventilatory rhythms. Indexes quantifying the variability of the cardiac and ventilatory activities were computed as well. Findings proved that: (i) a significant presence of n:m phase synchronized patterns was detected in PCV; (ii) the strength of n:m phase synchronization was stronger during PCV than PSV; (iii) different strengths of cardioventilatory phase synchronization detected during PCV and PSV were found in presence of similar heart and ventilatory rates and alike variability. We conclude that mechanical ventilation can induce a significant presence of cardioventilatory phase synchronized patterns and this amount depends on the mode of mechanical ventilation. Future studies should test the eventual link of the level of phase coordination between heart and mechanical ventilation to a clinical outcome to understand whether featuring a certain degree of cardioventilatory phase synchronization is beneficial for the critical patient in ICU.

Symbolic dynamics of heart rate variability: a probe to investigate cardiac autonomic modulation.

BACKGROUND: Sympathetic and parasympathetic systems are considered the principal rapidly reacting systems that control heart rate. METHODS AND RESULTS: We propose a symbolic analysis series to quantify the prevalence of sympathetic or parasympathetic cardiac modulation. This analysis decomposes the heart rate variability series in patterns lasting 3 beats and classifies them into 3 categories: nonvariable, variable, and very variable patterns referred to as 0V, 1V, and 2V patterns. First, we applied this method to experimental and pharmacological conditions characterized by sympathetic activation (tilt test, handgrip, nitroprusside, and high-dose atropine administration) or parasympathetic activation (phenylephrine and low-dose atropine administration) in 60 healthy subjects. An increase in sympathetic modulation and a vagal withdrawal elicited a significant increase in 0V patterns and a decrease in 2V patterns, whereas parasympathetic dominance induced the opposite, reflecting a reciprocal sympathovagal balance. The second part of the study considered a series of 300 beats before the onset of major arrhythmic events in patients with an implantable cardioverter-defibrillator. Symbolic analysis detected an increase in the percentage of 0V patterns before the onset of major arrhythmias compared with baseline (41.6+/-3.9% and 24.4+/-2.9%, respectively; P<0.01), indicating a sympathetic prevalence. On the other hand, the 2V patterns did not decrease before major arrhythmias, suggesting the presence of nonreciprocal autonomic modulations. CONCLUSIONS: Symbolic analysis of 3 beat sequences takes into account the different time course of sympathetic and parasympathetic cardiac modulations and seems appropriate for elucidating the neural pathophysiological mechanisms occurring during the short periods that precede acute cardiac events.

Role of the autonomic nervous system in generating non-linear dynamics in short-term heart period variability.

We evaluated the role played by the autonomic nervous system in producing non-linear dynamics in short heart period variability (HPV) series recorded in healthy young humans. Non-linear dynamics are detected using an index of predictability based on a local non-linear predictor and a surrogate data approach. Different types of surrogates are utilized: (i) phase-randomized Fourier-transform based (FT) data; (ii) amplitude-adjusted FT (AAFT) data; and (iii) iteratively refined AAFT (IAAFT) data of two types (IAAFT-1 and IAAFT-2). The approach was applied to experimental protocols activating or blocking the sympathetic or parasympathetic branches of the autonomic nervous system or periodically perturbing cardiovascular control via paced respiration at different breathing rates. We found that short-term HPV was mostly linear at rest. Experimental protocols activating the sympathetic or parasympathetic nervous system did not produce non-linear dynamics. In contrast, paced respiration, especially at slow breathing rates, elicited significantly non-linear dynamics. Therefore, in short-term HPV ( approximately 300 beats) the use of non-linear models is not supported by the data, except under conditions whereby the subject is constrained to a slow respiratory rate.

Effect of variations of the complexity of the target variable on the assessment of Wiener-Granger causality in cardiovascular control studies.

We hypothesized that Wiener-Granger causality (WGC) indexes might have different abilities in coping with modifications of the complexity of the target variable in the context of the assessment of the cardiovascular control from spontaneous fluctuations of heart period (HP), systolic arterial pressure (SAP) and respiratory activity (R). After having defined the universe of knowledge as the set Ω = {HP, SAP, R} and the unpredictability decrement (UPD) as the difference between the prediction error variances of the target signal computed in Ω after excluding the presumed cause (i.e. the restricted Ω) and in Ω, we computed the following frequently utilized WGC indexes: (i) the plain UPD; (ii) the fractional UPD (FUPD) by dividing UPD by the prediction error variance in the restricted Ω; (iii) the normalized UPD (NUPD) by dividing UPD by the prediction error variance in Ω; (iv) the log-unpredictability decrement (LUPD) by applying the logarithm transformation to the prediction error variances before computing the UPD. The hypothesis was tested over two experimental protocols known to produce modifications of the complexity of HP variability: graded head-up tilt (HUT) inducing a gradual decrease of the HP complexity with tilt table inclination and head-down tilt (HDT) inducing the opposite trend. We demonstrated that: (1) when the strength of the causal relations from SAP to HP during HUT and from R to HP during HDT is assessed in Ω, WGC indexes reach different conclusions; (2) UPD is biased by modifications of the complexity of HP dynamics; (3) FUPD, NUPD and LUPD are less sensitive to changes of the complexity of the target dynamic, even though they have slightly different statistical power, being the NUPD the weakest one and FUPD and LUPD the strongest ones. We conclude that UPD should be avoided when assessing WGC and FUPD and LUPD should be privileged over NUPD.

Univariate and bivariate symbolic analyses of cardiovascular variability differentiate general anesthesia procedures.

General anesthesia attenuates autonomic function and baroreflex control. This side effect should be prevented as much as possible because it limits the subject's ability in responding to physiological challenges during surgery (e.g. arterial pressure and ventricular contractility drops). This study is designed to rank two of the most commonly exploited general anesthesia treatments, i.e. intravenous anesthesia (IA) based on a propofol-opioid combination and volatile anesthesia (VA) based on a sevoflurane-opioid combination, according to their ability to maintain autonomic nervous system activity and baroreflex control. Univariate and bivariate symbolic techniques were applied to spontaneous heart period (HP) and systolic arterial pressure (SAP) variability series recorded during IA and VA procedures in 19 and 18 patients undergoing elective intracranial neurosurgery. Traditional linear univariate and bivariate frequency domain markers of the autonomic nervous system state and baroreflex control were evaluated as well. We found that: (i) univariate symbolic analysis of HP series suggests a better preservation of vagal modulation in VA than in IA; (ii) bivariate symbolic markers assessing the degree of HP-SAP association differentiate IA from VA, while baroreflex sensitivity and squared coherence function cannot; (iii) bivariate symbolic analysis indicates a better preservation of the HP-SAP association at slow frequencies in IA than in VA, thus suggesting a more active baroreflex control in IA. We conclude that symbolic indexes can be fruitfully exploited to rank general anesthesia treatments, and their performance appears to be superior to that of more traditional linear markers.