Wave separation analysis to assess cardiovascular alterations induced by sepsis.

OBJECTIVE: Sepsis induces a severe decompensation of arterial and cardiac functional properties, leading to important modifications of arterial blood pressure (ABP) waveform, not resolved by recommended therapy, as shown by previous works. The aim of this study is to quantify the changes in ABP waveform morphology and wave reflections during a long-term swine experiment of polymicrobial sepsis and resuscitation, to deepen the understanding of the cardiovascular response to standard resuscitation therapy. METHODS: We analyzed 14 pigs: polymicrobial sepsis was induced in 9 pigs followed by standard resuscitation and 5 pigs were treated as sham controls. Septic animals were studied at baseline (T1), after sepsis development (T2), and after 24h (T3) and 48h (T4) of therapy administration, and sham controls at the same time points. ABP and arterial blood flow were measured in the left and right carotid artery, respectively. Pulse wave analysis and wave separation techniques were used to estimate arterial input impedance, carotid characteristic impedance, forward and backward waves, indices of wave reflections such as reflection magnitude and reflection index, and augmentation index. RESULTS: Sepsis led to an acute alteration of ABP waveform passing from type A to type B or C; consistently, the reflection phenomena were significantly reduced. The resuscitation was successful in reaching targeted hemodynamic stability, but it failed in restoring a physiological blood propagation and reflection. CONCLUSION: Septic pigs persistently showed altered reflected waves even after 48 hours of successful therapy according to guidelines, suggesting a persistent hidden cardiovascular disorder. SIGNIFICANCE: The proposed indices may be useful to unravel the complex cardiovascular response to therapy administration in septic patients and could potentially be used for risk stratification of patient deterioration. Whether alterations of blood propagation and reflection contribute to persisting organ dysfunction after hemodynamic stabilization should be further investigated.

Improving Cardiology-Rehospitalization Prediction Through the Synergy of Process Mining and Deep Learning: An Innovative Approach.

Nowadays, hospitals are facing the need for an accurate prediction of rehospitalizations. Rehospitalizations, indeed, represent both a high financial burden for the hospital and a proxy measure of care quality. The current work aims to address such a problem with an innovative approach, by building a Process Mining-Deep Learning model for the prediction of 6-months rehospitalization of patients hospitalized in a Cardiology specialty at San Raffaele Hospital, starting from their medical history contained in the Patients Hospital Records, with the double purpose of supporting resource planning and identifying at-risk patients.

Pulse wave analysis as a tool for the evaluation of resuscitation therapy in septic shock.

Objective. Pulse wave analysis (PWA) can provide insights into cardiovascular biomechanical properties. The use of PWA in critically ill patients, such as septic shock patients, is still limited, but it can provide complementary information on the cardiovascular effects of treatment when compared to standard indices outlined in international guidelines. Previous works have highlighted how sepsis induces severe cardiovascular derangement with altered arterial blood pressure waveform morphology and how resuscitation according to standard haemodynamic targets is not able to restore the physiological functioning of the cardiovascular system. The aim of this work is to test the effectiveness of PWA in characterizing arterial waveforms obtained from a swine experiment involving polymicrobial septic shock and resuscitation with different drugs.Methods. During the experiment, morphological aortic waveform features, such as indices related to the dicrotic notch and inflection point, were extracted by means of PWA techniques. Finally, all the PWA indices were used to compute a clustering classification (mini batch K-means) of the pigs according to the different phases of the experiment. This analysis aimed to test if PWA features alone could be used to distinguish between the different responses to the administered therapies.Results. The PWA indices highlighted different cardiovascular conditions of the pigs in response to different treatments, despite the mean haemodynamic values typically used to guide therapy administration being similar in all animals. The clustering algorithm was able to distinguish between the different phases of the experiment and the different responses of the animals based on the unique information derived from the aortic PWA.Conclusion. Even when used alone, PWA indices were highly informative when assessing therapy responses in cases of septic shock.Significance. A complex pathological condition like septic shock requires extensive monitoring without neglecting important information from commonly measured signals such as arterial blood pressure. Future studies are needed to understand how individual differences in the response to therapy are associated with different cardiovascular conditions that may become specific therapy targets.

Autonomic and circulatory alterations persist despite adequate resuscitation in a 5-day sepsis swine experiment.

Autonomic and vascular failures are common phenotypes of sepsis, typically characterized by tachycardia despite corrected hypotension/hypovolemia, vasopressor resistance, increased arterial stiffness and decreased peripheral vascular resistance. In a 5-day swine experiment of polymicrobial sepsis we aimed at characterizing arterial properties and autonomic mechanisms responsible for cardiovascular homeostasis regulation, with the final goal to verify whether the resuscitation therapy in agreement with standard guidelines was successful in restoring a physiological condition of hemodynamic profile, cardiovascular interactions and autonomic control. Twenty pigs were randomized to polymicrobial sepsis and protocol-based resuscitation or to prolonged mechanical ventilation and sedation without sepsis. The animals were studied at baseline, after sepsis development, and every 24 h during the 3-days resuscitation period. Beat-to-beat carotid blood pressure (BP), carotid blood flow, and central venous pressure were continuously recorded. The two-element Windkessel model was adopted to study carotid arterial compliance, systemic vascular resistance and characteristic time constant τ. Effective arterial elastance was calculated as a simple estimate of total arterial load. Cardiac baroreflex sensitivity (BRS) and low frequency (LF) spectral power of diastolic BP were computed to assess autonomic activity. Sepsis induced significant vascular and autonomic alterations, manifested as increased arterial stiffness, decreased vascular resistance and τ constant, reduced BRS and LF power, higher arterial afterload and elevated heart rate in septic pigs compared to sham animals. This compromised condition was persistent until the end of the experiment, despite achievement of recommended resuscitation goals by administered vasopressors and fluids. Vascular and autonomic alterations persist 3 days after goal-directed resuscitation in a clinically relevant sepsis model. We hypothesize that the addition of these variables to standard clinical markers may better profile patients' response to treatment and this could drive a more tailored therapy which could have a potential impact on long-term outcomes.

Metabolites Concentration in Plasma and Heart Tissue in Relation to High Sensitive Cardiac Troponin T Level in Septic Shock Pigs.

Elevated circulating cardiac troponin T (cTnT) is frequent in septic shock patients. Signs of myocardial ischemia and myocyte necrosis are not universally present, but the precise mechanism for elevated cTnT is unknown. We investigated plasma and heart tissue metabolites concentration in six septic shock (SS) and three sham swine undergoing a protocol of polymicrobial septic shock and resuscitation, in order to highlight possible pathways and biomarkers involved in troponin release (high sensitive cardiac troponin T, hs-cTnT). The animals were divided into two groups: the high cTnT group (n = 3) were pigs showing a significantly higher concentration of cTnT and lactate after resuscitation; the low cTnT group (n = 6, three sham and three septic shock) characterized by a lower value of cTnT and a lactate level < 2 mmol/L. Spearman correlation was assessed on plasma fold-change of cTnT, cytokines (TNF-α and IL-10), and metabolites. Finally, the fold-change between the end of resuscitation and baseline values (Res./BL) of plasma metabolites was used to perform a partial least square discriminant analysis (PLS-DA) with three latent variables. Before building the model, the number of features was reduced by summing up the metabolites of the same class that resulted similarly correlated to cTnT fold-change. Proline and glycine were significantly higher in the high cTnT group at the end of experiment both in the myocardium and plasma analyses. Moreover, plasma proline fold-change was found to be positively correlated with cTnT and cytokine fold-changes, and trans-4-hydroxyproline (t4-OH-Pro) fold-change was positively correlated with cTnT fold-change. The PLS-DA model was able to separate the two groups and, among the first ranked features based on VIP score, we found sugars, t4-OH-Pro, proline, creatinine, total amount of sphingomyelins, and glycine. Proline, t4-OH-Pro, and glycine are very abundant in collagen, and our results may suggest that collagen degradation could represent a possible mechanism contributing to septic myocardial injury. The common phenotype of septic cardiomyopathy could be associated to dysregulated collagen metabolism and/or degradation, further exacerbated by higher inflammation and oxidative stress.

EASY-FIA: A Readably Usable Standalone Tool for High-Resolution Mass Spectrometry Metabolomics Data Pre-Processing.

Flow injection analysis coupled with high-resolution mass spectrometry (FIA-HRMS) is a fair trade-off between resolution and speed. However, free software available for data pre-processing is few, web-based, and often requires advanced user specialization. These tools rarely embedded blank and noise evaluation strategies, and direct feature annotation. We developed EASY-FIA, a free standalone application that can be employed for FIA-HRMS metabolomic data pre-processing by users with no bioinformatics/programming skills. We validated the tool's performance and applicability in two clinical metabolomics case studies. The main functions of our application are blank subtraction, alignment of the metabolites, and direct feature annotation by means of the Human Metabolome Database (HMDB) using a minimum number of mass spectrometry parameters. In a scenario where FIA-HRMS is increasingly recognized as a reliable strategy for fast metabolomics analysis, EASY-FIA could become a standardized and feasible tool easily usable by all scientists dealing with MS-based metabolomics. EASY-FIA was implemented in MATLAB with the App Designer tool and it is freely available for download.

Application of an Exploratory Knowledge-Discovery Pipeline Based on Machine Learning to Multi-Scale OMICS Data to Characterise Myocardial Injury in a Cohort of Patients with Septic Shock: An Observational Study.

Currently, there is no therapy targeting septic cardiomyopathy (SC), a key contributor to organ dysfunction in sepsis. In this study, we used a machine learning (ML) pipeline to explore transcriptomic, proteomic, and metabolomic data from patients with septic shock, and prospectively collected measurements of high-sensitive cardiac troponin and echocardiography. The purposes of the study were to suggest an exploratory methodology to identify and characterise the multiOMICs profile of (i) myocardial injury in patients with septic shock, and of (ii) cardiac dysfunction in patients with myocardial injury. The study included 27 adult patients admitted for septic shock. Peripheral blood samples for OMICS analysis and measurements of high-sensitive cardiac troponin T (hscTnT) were collected at two time points during the ICU stay. A ML-based study was designed and implemented to untangle the relations among the OMICS domains and the aforesaid biomarkers. The resulting ML pipeline consisted of two main experimental phases: recursive feature selection (FS) assessing the stability of biomarkers, and classification to characterise the multiOMICS profile of the target biomarkers. The application of a ML pipeline to circulate OMICS data in patients with septic shock has the potential to predict the risk of myocardial injury and the risk of cardiac dysfunction.

Persistent hyperammonia and altered concentrations of urea cycle metabolites in a 5-day swine experiment of sepsis.

We measured plasma and cerebrospinal fluid (CSF) metabolite concentrations in a 5-day porcine sepsis model of fecal peritonitis. The objectives were: (i) to verify whether the expected pathways that had emerged in previous studies pertain only to the early inflammatory response or persist for the subsequent days; (ii) to identify metabolic derangements that arise later; (iii) to verify whether CSF metabolite concentrations were altered and if these alterations were similar to those in the blood or delayed. We observed an early response to inflammation and cytokine storms with alterations in lipid and glucose metabolism. The arginine/asymmetric dimethylarginine (ADMA) and phenylalanine/tyrosine balances changed 24 h after resuscitation in plasma, and later in CSF. There was a rise in ammonia concentration, with altered concentrations of metabolites in the urea cycle. Whether persistent derangement of these pathways have a role not only on short-term outcomes but also on longer-term comorbidities, such as septic encephalopathy, should be addressed in further studies.

The autonomic nervous system in septic shock and its role as a future therapeutic target: a narrative review.

The autonomic nervous system (ANS) regulates the cardiovascular system. A growing body of experimental and clinical evidence confirms significant dysfunction of this regulation during sepsis and septic shock. Clinical guidelines do not currently include any evaluation of ANS function during the resuscitation phase of septic shock despite the fact that the severity and persistence of ANS dysfunction are correlated with worse clinical outcomes. In the critical care setting, the clinical use of ANS-related hemodynamic indices is currently limited to preliminary investigations trying to predict and anticipate imminent clinical deterioration. In this review, we discuss the evidence supporting the concept that, in septic shock, restoration of ANS-mediated control of the cardiovascular system or alleviation of the clinical consequences induced by its dysfunction (e.g., excessive tachycardia, etc.), may be an important therapeutic goal, in combination with traditional resuscitation targets. Recent studies, which have used standard and advanced monitoring methods and mathematical models to investigate the ANS-mediated mechanisms of physiological regulation, have shown the feasibility and importance of monitoring ANS hemodynamic indices at the bedside, based on the acquisition of simple signals, such as heart rate and arterial blood pressure fluctuations. During the early phase of septic shock, experimental and/or clinical studies have shown the efficacy of negative-chronotropic agents (i.e., beta-blockers or ivabradine) in controlling persistent tachycardia despite adequate resuscitation. Central α-2 agonists have been shown to prevent peripheral adrenergic receptor desensitization by reducing catecholamine exposure. Whether these new therapeutic approaches can safely improve clinical outcomes remains to be confirmed in larger clinical trials. New technological solutions are now available to non-invasively modulate ANS outflow, such as transcutaneous vagal stimulation, with initial pre-clinical studies showing promising results and paving the way for ANS modulation to be considered as a new potential therapeutic target in patients with septic shock.

Evaluation of autonomic modulation of lung function and heart rate in children with cystic fibrosis.

The autonomic nervous system (ANS) plays an important role in modulating bronchial smooth muscle contractility, which is altered in cystic fibrosis (CF). A convenient approach to probe ANS regulation is the quantitative analysis of heart rate variability (HRV). The purpose of this study was to evaluate ANS regulation in children with CF and to investigate the influence of colonization by Pseudonomas aeruginosa via assessment of HRV in colonized CF (CCF) children and noncolonized CF (NCCF) children. Sixteen children with CF (7 CCF and 9 NCCF) and seven healthy age-matched control children were enrolled in the study. Heart rate was recorded for 10 min at rest in the supine and standing positions and HRV analysis was carried out using autoregressive spectral analysis. The CCF group was characterized by lower forced expiratory volume than NCCF, indicating an impairment of respiratory function. The HRV parameters further confirmed the possible sympathetic overactivity in CCF. Children with CF exhibited hyperactivity of the sympathetic nervous system. In particular, the CCF group presented a greater impairment of ANS modulation. Both CCF and NCCF children showed lower supine vagal activation in the HRV indices related to sympathetic activation and reduction of indices indicating vagal activity with the postural change from supine to standing when compared to the NCCF group.

Reducing tachycardia in septic shock patients: do esmolol and ivabradine have a chronotropic effect only?

An elevated heart rate (HR) often persists in resuscitated septic shock patients, increasing the risk of mortality. Several drugs for HR control, such as esmolol and ivabradine, have been tested in the recent years, but their benefit on the overall cardiovascular system is still under investigation. The aim of this study is to investigate the hemodynamic effects of the two drugs in a protocol of polymicrobial septic shock and resuscitation, mainly focusing on the vascular function. Twelve pigs were divided into three experimental groups: the esmolol-treated group (n=4), the ivabradine-treated group (n=5) and the control group (n=3). The characteristic arterial time constant τ was computed on aortic arterial pressure (AoP), together with estimates of total arterial compliance and peripheral resistance. Power spectral analysis of aortic and radial diastolic BP oscillations was performed to estimate the sympathetic autonomic control of vascular tone. Septic shock induced a severe cardiac and vascular disarray, only partially resolved by resuscitation. The administration of esmolol, but not ivabradine, was beneficial both for cardiac and vascular function, thereby its adjunction to standard therapies could help to improve patient's condition and optimize the resuscitation strategies.Clinical Relevance-This study shows a potential beneficial effect of esmolol on the arterial tree.

Tachycardia control in septic shock with esmolol and ivabradine: a comparison on heart function.

Persisting tachycardia is often observed in resuscitated septic shock patients, and it is an independent risk factor for increased mortality. Recently, several drugs, such as esmolol and ivabradine, have been proved to be beneficial in HR control, but their overall impact on cardiac functions needs further investigation. The aim of this study is to study the effects of the two drugs on heart function in a protocol of polymicrobial septic shock and resuscitation. Twelve pigs were divided into three experimental groups: the esmolol-treated group (n=4), the ivabradine-treated group (n=5) and the control group (n=3). Cardiac autonomic activity was estimated by heart rate variability (HRV) indices and baroreflex sensitivity (BRS). The Buckberg index was adopted to evaluate myocardial oxygenation efficiency. Septic shock induced a severe autonomic dysfunction and a lower cardiac efficiency, not resolved by fluids resuscitation. The administration of the drugs improved both the HRV and the BRS, but this favourable condition was preserved after noradrenaline administration only in the esmolol group. The interaction of esmolol with the autonomic system is beneficial in septic shock to restore an improved condition of HRV and control, while ivabradine is not as effective when administered in adjunction to noradrenaline.

Vascular Decoupling in Septic Shock: The Combined Role of Autonomic Nervous System, Arterial Stiffness, and Peripheral Vascular Tone.

BACKGROUND: Acute inflammation and sepsis are known to induce changes in vascular properties, leading to increased arterial stiffness; at the same time, the autonomic nervous system (ANS) also affects vascular properties by modulating the arterial smooth muscle tone, and it is widely reported that sepsis and septic shock severely impair ANS activity. Currently, clinical guidelines are mainly concerned to resuscitate septic shock patients from hypotension, hypovolemia, and hypoperfusion; however, if the current resuscitation maneuvers have a beneficial effect also on vascular properties and autonomic functionality is still unclear. The objective of this work is to assess the effects of standard resuscitation at vascular level and to verify if there is any association between alterations in vascular properties and ANS activity. METHODS: Six pigs underwent a protocol of polymicrobial septic shock and resuscitation (fluids and noradrenaline). The arterial blood pressure (ABP) waveform was recorded in the central aorta and in the peripheral radial and femoral artery. The characteristic arterial time constant was computed at the three arterial sites based on the two-element Windkessel model, to characterize the overall arterial vascular tree. Moreover, independent estimates of total arterial compliance (AC) and total peripheral resistance (TPR) were performed. Baroreflex sensitivity (BRS), low frequency (LF, 0.04-0.15 Hz) spectral power of diastolic blood pressure, and indices of heart rate variability (HRV) were computed to assess ANS functionality. RESULTS: Septic shock induced a severe vascular disarray, decoupling the usual pressure wave propagation from central to peripheral sites; this phenomenon appeared as an inversion of the physiological pulse pressure (PP) amplification, with a higher PP in the central aorta than in the peripheral arteries. The time constant was decreased, together with AC and TPR. ANS dysfunction was described by a reduced BRS, decreased LF power, and suppressed HRV. This compromised condition was not resolved by administration of fluids and noradrenaline. Thus, a persistent vascular and autonomic dysfunction were reported also in the resuscitated animals, and they were found to be significantly correlated. CONCLUSION: Measures of vascular function and ANS activity could add information to standard hemodynamic and clinical markers, and the current resuscitation strategies could benefit from the adjunction of these additional functional indices.

A Mathematical Model of dP/dt Max for the Evaluation of the Dynamic Control of Heart Contractility in Septic Shock.

OBJECTIVE: Septic shock (SS) patients often show elevated heart rate (HR) despite resuscitation, and this condition is considered an early manifestation of myocardial dysfunction due to an impairment of autonomic nervous system (ANS). We aimed at proposing a mathematical model to assess the autonomic control of ventricular contractility (VC) and HR to track changes in heart functionality during an experimental animal model of SS and resuscitation. METHODS: SS was induced in six adult swine by polymicrobial peritonitis. We analyzed the beat-to-beat variability of the maximum positive time derivative of left ventricular pressure (dP/dt max), heart period (HP), and aortic blood pressure (ABP). We identified the transfer functions relating fluctuations in ABP and HP to dP/dt max to characterize the static and dynamic properties of the arterial baroreflex and the force-frequency relation mechanisms, respectively. Standard indices of autonomic dysfunction have also been considered as HR variability (HRV) and baroreflex sensitivity (BRS). RESULTS: During baseline, the baroreflex is predominant in controlling VC with a gain value of -5.8 (-7.5,-3) s-1, compared to -1.2 (-1.9,-0.5) mmHg/s ms-1 of the force-frequency autoregulation. During shock, both mechanisms increase their extent in VC control (higher gains and slightly faster dynamics for the baroreflex). After resuscitation, the physiological control of VC is not restored and all the animals still exhibit high HR and reduced HRV and BRS. CONCLUSION: A condition of cardiovascular inefficiency is persistent after resuscitation and this could be due to autonomic dysfunction. SIGNIFICANCE: The ANS in SS is crucial to restore homeostasis. Our model could be used to evaluate the efficacy of treatments on VC and related control mechanisms.

The Systemic Alterations of Lipids, Alanine-Glucose Cycle and Inter-Organ Amino Acid Metabolism in Swine Model Confirms the Role of Liver in Early Phase of Septic Shock.

Septic shock is a medical emergency and is one of the main causes of mortality in critically ill patients. Given the pathophysiological complexity of sepsis spectrum and progression in clinical settings, animal models become essential tools to improve patient care, and to understand key mechanisms that may remain masked from the heterogeneity of clinical practice. Our aim was to verify whether the metabolic constellations we previously reported for septic shock patients appear also in our septic shock swine model as systemic markers of early disturbances in energy metabolism and hepatic homeostasis. Septic shock was induced in anesthetized, instrumented, and ventilated adult swines by polymicrobial peritonitis. Hemodynamic and serial measurements of arterial and mixed venous blood gasses were made. Laboratory measurements and mass spectrometry-based targeted quantitative plasma metabolomics were performed in blood samples collected at baseline, at shock and at fully resuscitation after fluids and vasopressors administration. Data elaboration was performed by multilevel and multivariate analysis. Changes in hemodynamic, blood chemistry, and inflammatory markers were in line with a septic shock phenotype. Time course alteration of systemic metabolites were characterized by marked decreased in phosphatidylcholines and lysophosphatidylcholines species, altered alanine-glucose cycle and inter-organ amino acid metabolism, pointing toward an early hepatic impairment similarly to what we previously reported for septic shock. This is the first study in which an experimental swine model of septic shock recapitulates the main metabolic derangements reported in a clinical setting of shock. These events occur within hours from infections and may act as early metabolic features to assist in evaluating subclinical hepatic alterations and pave the way to improve the management of septic shock.

Modeling physiological responses induced by an emotion recognition task using latent class mixed models.

Correctly recognizing emotions is an essential skill to manage interpersonal relationships in everyday life. Facial expression represents the most powerful mean to convey important information on emotional and cognitive states during interactions with others. In this paper, we analyze physiological responses triggered by an emotion recognition test, which requires the processing of facial cues. In particular, we evaluate the modulation of several Heart Rate Variability indices, collected during the Reading the Mind in the Eyes Test, accounting for test difficulty (derived from a Rasch analysis), test performances, demographic and psychological characteristics of the participants. The main idea is that emotion recognition is associated with the Autonomic Nervous System and, as a consequence, with the Heart Rate Variability. The principal goal of our study was to explore the complexity of the collected measures and their possible interactions by applying a class of flexible models, i.e., the latent class mixed models. Actually, this modelling strategy allows for the identification of clusters of subjects characterized by similar longitudinal trajectories. Both univariate and multivariate latent class mixed models were used. In fact, while the interpretation of the Heart Rate Variability indices is very difficult when considered individually, a joint evaluation provides a better description of the Autonomic Nervous System state.

Supplementation with Qter® and Creatine improves functional performance in COPD patients on long term oxygen therapy.

BACKGROUND: Skeletal muscle dysfunction and poor functional capacity are important extra-pulmonary manifestations of chronic obstructive pulmonary disease (COPD), especially in COPD patients on long-term O2 therapy (LTOT). Beside the role of pulmonary rehabilitation, the effect of nutritional interventions is still controversial, and there are knowledge gaps on the effective role of nutraceutical supplementation on hard endpoints. The aim of this study was to investigate the effects of nutritional supplementation with Coenzyme Q10 (QTer®) - a powerful antioxidant with the potential to reduce oxidative stress and improve mitochondrial function - and Creatine on functional, nutritional, and metabolomic profile in COPD patients on long-term O2 therapy. METHODS: One-hundred and eight patients with COPD from 9 Italian hospitals were enrolled in this double-blinded randomized placebo-controlled clinical study. At baseline and after 2 months of therapy, the patients underwent spirometry, 6-minute walk test (6MWT), bioelectrical impedance analysis, and activities of daily living questionnaire (ADL). Also, dyspnea scores and BODE index were calculated. At both time points, plasma concentration of CoQ10 and metabolomic profiling were measured. FINDINGS: Ninety patients, who randomly received supplementation with QTer® and Creatine or placebo, completed the study. Compared with placebo, supplemented patients showed improvements in 6MWT (51 ±â€¯69 versus 15 ±â€¯91 m, p < 0.05), body cell mass and phase angle, sodium/potassium ratio, dyspnea indices and ADL score. The CoQ10 plasma concentration increased in the supplementation group whereas it did not change in the placebo group. The metabolomics profile also differed between groups. Adverse events were similar in both groups. INTERPRETATION: These results show that in patients with COPD, dietary supplementation with CoQ10 and Creatine improves functional performance, body composition and perception of dyspnea. A systemic increase in some anti-inflammatory metabolites supports a pathobiological mechanism as a reason for these benefits. Further trials should help clarifying the role of QTer® and Creatine supplementation in patients with COPD.

Blood pressure variability, heart functionality, and left ventricular tissue alterations in a protocol of severe hemorrhagic shock and resuscitation.

Autonomic control of blood pressure (BP) and heart rate (HR) is crucial during bleeding and hemorrhagic shock (HS) to compensate for hypotension and hypoxia. Previous works have observed that at the point of hemodynamic decompensation a marked suppression of BP and HR variability occurs, leading to irreversible shock. We hypothesized that recovery of the autonomic control may be decisive for effective resuscitation, along with restoration of mean BP. We computed cardiovascular indexes of baroreflex sensitivity and BP and HR variability by analyzing hemodynamic recordings collected from five pigs during a protocol of severe hemorrhage and resuscitation; three pigs were sham-treated controls. Moreover, we assessed the effects of severe hemorrhage on heart functionality by integrating the hemodynamic findings with measures of plasma high-sensitivity cardiac troponin T and metabolite concentrations in left ventricular (LV) tissue. Resuscitation was performed with fluids and norepinephrine and then by reinfusion of shed blood. After first resuscitation, mean BP reached the target value, but cardiovascular indexes were not fully restored, hinting at a partial recovery of the autonomic mechanisms. Moreover, cardiac troponins were still elevated, suggesting a persistent myocardial sufferance. After blood reinfusion all the indexes returned to baseline. In the harvested heart, LV metabolic profile confirmed the acute stress condition sensed by the cardiomyocytes. Variability indexes and baroreflex trends can be valuable tools to evaluate the severity of HS, and they may represent a more useful end point for resuscitation in combination with standard measures such as mean values and biological measures. NEW & NOTEWORTHY Autonomic control of blood pressure was highly impaired during hemorrhagic shock, and it was not completely recovered after resuscitation despite global restoration of mean pressures. Moreover, a persistent myocardial sufferance emerged from measured cardiac troponin T and metabolite concentrations of left ventricular tissue. We highlight the importance of combining global mean values and biological markers with measures of variability and autonomic control for a better characterization of the effectiveness of the resuscitation strategy.

An Innovative Approach for The Integration of Proteomics and Metabolomics Data In Severe Septic Shock Patients Stratified for Mortality.

In this work, we examined plasma metabolome, proteome and clinical features in patients with severe septic shock enrolled in the multicenter ALBIOS study. The objective was to identify changes in the levels of metabolites involved in septic shock progression and to integrate this information with the variation occurring in proteins and clinical data. Mass spectrometry-based targeted metabolomics and untargeted proteomics allowed us to quantify absolute metabolites concentration and relative proteins abundance. We computed the ratio D7/D1 to take into account their variation from day 1 (D1) to day 7 (D7) after shock diagnosis. Patients were divided into two groups according to 28-day mortality. Three different elastic net logistic regression models were built: one on metabolites only, one on metabolites and proteins and one to integrate metabolomics and proteomics data with clinical parameters. Linear discriminant analysis and Partial least squares Discriminant Analysis were also implemented. All the obtained models correctly classified the observations in the testing set. By looking at the variable importance (VIP) and the selected features, the integration of metabolomics with proteomics data showed the importance of circulating lipids and coagulation cascade in septic shock progression, thus capturing a further layer of biological information complementary to metabolomics information.

Baroreflex Sensitivity and Blood Pressure Variability can Help in Understanding the Different Response to Therapy During Acute Phase of Septic Shock.

BACKGROUND: Mean values of hemodynamic variables are poorly effective in evaluating an actual recovery of the short-term autonomic mechanisms for blood pressure (BP) and heart rate (HR) regulation. The aim of this work is to analyze the response to therapy in the early phase of septic shock to verify possible associations between BP recovery and BP autonomic control. METHODS: This is an ancillary study from the multicenter prospective observational trial Shockomics (NCT02141607). A total of 21 septic shock patients were studied at two time points during the acute phase of shock and were classified according to changes in SOFA score. Time series of BP components and HR were analyzed in time and frequency domain. Baroreflex sensitivity (BRS) was assessed, and a mathematical model for the decomposition of diastolic arterial pressure (DAP) oscillations was used to understand the different contributions of BRS and HR on peripheral vascular resistance control. RESULTS: Only those patients, who significantly improved organ function (responders, R), showed an increase of mean value and low frequency (LF) power in BP time series. Fluid accumulation was higher in the non-responders (NR). BRS increased in NR and the model of DAP variability showed that the contribution of HR was highly reduced in NR. CONCLUSIONS: Although patients reached the mean BP target of 65 mmHg, our analyses highlighted important differences in terms of autonomic nervous system control. BP variability, HR variability and baroreflex trends can add information to individual vital sign measure such as mean BP, and can help in understanding the responsiveness to the combination of symphatomimetic drugs and fluid therapy.