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Trauma and hemorrhagic shock (T/HS) is a major cause of morbidity and mortality. Existing treatment options are largely limited to source control and fluid and blood repletion. Previously, we have shown that enteral protease inhibition improves outcomes in experimental models of T/HS by protecting the gut from malperfusion and ischemia. However, enteral protease inhibition was achieved invasively, by laparotomy and direct injection of tranexamic acid (TXA) into the small intestine. In this study, we tested a minimally invasive method of enteral protease inhibitor infusion in experimental T/HS that can be readily adapted for clinical use. Wistar rats were exsanguinated to a mean arterial blood pressure (MABP) of 40 mmHg, with laparotomy to induce trauma. Hypovolemia was maintained for 120 min and was followed by reperfusion of shed blood. Animals were monitored for an additional 120 min. A modified orogastric multi-lumen tube was developed to enable rapid enteral infusion of a protease inhibitor solution while simultaneously mitigating risk of reflux aspiration into the airways. The catheter was used to deliver TXA (T/HS + TXA) or vehicle (T/HS) continuously into the proximal small intestine, starting 20 min into the ischemic period. Rats treated with enteral protease inhibition (T/HS + TXA) displayed improved outcomes compared to control animals (T/HS), including significantly improved MABP (p = 0.022) and lactate (p = 0.044). Mass spectrometry-based analysis of the plasma peptidome after T/HS indicated mitigation of systemic proteolysis in T/HS + TXA. Minimally invasive, continuous enteral protease inhibitor delivery improves outcomes in T/HS and is readily translatable to the clinical arena.

Infection by SARS-CoV-2 and subsequent COVID-19 can cause viral sepsis and septic shock. Several complications have been observed in patients admitted to the intensive care unit (ICU) with COVID-19, one of those being bacterial superinfection. Based on prior evidence that dysregulated systemwide proteolysis is associated with death in bacterial septic shock, we investigated whether protease activity and proteolysis could be elevated in COVID-19-induced sepsis with bacterial superinfection. In particular, we sought to assess the possible implications on the regulation of protein systems, such as for instance the proteins and enzymes involved in the clotting cascade.Blood samples collected at multiple time points during the ICU stay of four COVID-19 patients were analyzed to quantify: a) the circulating proteome and peptidome by mass spectrometry; b) plasma enzymatic activity of trypsin-like substrates and five clotting factors (plasmin, thrombin, factor VII, factor IX, factor X) by a fluorogenic assay.Of the four patients, one was diagnosed with bacterial superinfection on day 7 after beginning of the study and later died. The other three patients all survived (ICU length-of-stay 11.25±6.55 days, hospital stay of 15.25±7.18 days). Spikes in protease activity (factor VII, trypsin-like activity) were detected on day 7 for the patient who died. Corresponding increases in the total intensity of peptides derived by hydrolysis of plasma proteins, especially of fibrinogen degradation products, and a general reduction of coagulation proteins, were measured as well. A downregulation of endogenous enzymatic inhibitors, in particular trypsin inhibitors, characterized the non-surviving patient throughout her ICU stay. Enzymatic activity was stable in the patients who survived.Our study highlights the potential of multiomics approaches, combined with quantitative analysis of enzymatic activity, to i) shed light on proteolysis as a possible pathological mechanism in sepsis and septic shock, including COVID-19-induced sepsis; ii) provide additional insight into malfunctioning protease-mediated systems, such as the coagulation cascade; and iii) describe the progression of COVID-19 with bacterial superinfection.

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., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Septic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock. Methods: We performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes with p value < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock. Results: In both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend. Conclusions: This pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS., SCOPUS: ar.j, info:eu-repo/semantics/published

The mechanisms for cardiac injury after hemorrhagic shock (HS) are unresolved. We hypothesize that remote organ damage can be caused by uncontrolled pancreatic proteolytic activity, as enteral protease inhibition improves outcomes in experimental HS. Uncontrolled proteolysis in the heart may disrupt cardiac metabolism and adrenergic control with subsequent deleterious outcomes. To test this hypothesis, the heart rate–pressure product (RPP) as an index of myocardial oxygen consumption and the levels of fatty acid transporter proteins CD36 and FATP6 as surrogates for metabolic activity in the heart were measured in rats subjected to experimental HS (n = 6/group) with and without the enteral protease inhibitor tranexamic acid (TXA). Plasma troponin I and heart fatty acid-binding protein (HFABP) concentrations were measured as indices of myocardial damage. Expression of the adrenergic receptors β1, α1D, and β2 was also measured in the heart to determine the possible effects of shock with and without enteral TXA on the adrenergic control of heart function. Hemorrhagic shock was induced by reduction in mean arterial blood pressure to 35 mm Hg for 2 hours before reperfusion of shed blood. The RPP was maintained in shocked animals treated enterally with TXA but not in those subjected to HS alone; this group also demonstrated decreased HFABP and plasma troponin I levels. Serine protease (trypsin, chymotrypsin, and elastase) and matrix metalloproteinase (MMP)-2 and MMP-9 activity was elevated in cardiac tissue and plasma after HS and abrogated by enteral TXA. Levels of CD36, FATP6, β1, α1D, and β2 were also increased after HS in cardiac tissue, and the increases were mitigated by TXA treatment. These results suggest that increased proteolytic activity may contribute to cardiac injury after HS. Enteral TXA prevents these changes, indicating a potential therapeutic option in the management of shock with resultant cardiac injury.

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.

Approximately 3 billion people around the world have gone into some form of social separation to mitigate the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The uncontrolled influx of patients in need of emergency care has rapidly brought several national health systems to near-collapse with deadly consequences to those afflicted by Coronavirus Disease 2019 (COVID-19) and other critical diseases associated with COVID-19. Solid scientific evidence regarding SARS-CoV-2/COVID-19 remains scarce; there is an urgent need to expand our understanding of the SARS-CoV-2 pathophysiology to facilitate precise and targeted treatments. The capacity for rapid information dissemination has emerged as a double-edged sword; the existing gap of high-quality data is frequently filled by anecdotal reports, contradictory statements, and misinformation. This review addresses several important aspects unique to the SARS-CoV-2/COVID-19 pandemic highlighting the most relevant knowledge gaps and existing windows-of-opportunity. Specifically, focus is given on SARS-CoV-2 immunopathogenesis in the context of experimental therapies and preclinical evidence and their applicability in supporting efficacious clinical trial planning. The review discusses the existing challenges of SARS-CoV-2 diagnostics and the potential application of translational technology for epidemiological predictions, patient monitoring, and treatment decision-making in COVID-19. Furthermore, solutions for enhancing international strategies in translational research, cooperative networks, and regulatory partnerships are contemplated.

Microcirculatory preservation is essential for patient recovery from hemorrhagic shock. In hemorrhagic shock, microcirculatory flow and pressure are greatly reduced, creating an oxygen debt that may eventually become irreversible. During shock, tissues become hypoxic, cellular respiration turns to anaerobic metabolism, and the microcirculation rapidly begins to fail. This condition requires immediate fluid resuscitation to promote tissue reperfusion. The choice of fluid for resuscitation is whole blood; however, this may not be readily available and, on a larger scale, may be globally insufficient. Thus, extensive research on viable alternatives to blood has been undertaken in an effort to develop a clinically deployable blood substitute. This has not, as of yet, achieved fruition, in part due to an incomplete understanding of the complexities of the function of blood in the microcirculation. Hemodynamic resuscitation is acknowledged to be contingent on a number of factors other than volume expansion. The circulation of whole blood is carefully regulated to optimize oxygen delivery to the tissues via shear stress modulation through blood viscosity, inherent oxygen-carrying capacity, cell-free layer variation, and myogenic response, among other variables. Although plasma expanders can address a number of these issues, hemoglobin-based oxygen carriers (HBOCs) introduce a method of replenishing the intrinsic oxygen-carrying capacity of blood. There continue to be a number of issues related to HBOCs, but recent advances in the next-generation HBOCs show promise in the preservation of microcirculatory function and limiting toxicities. The development of HBOCs is now focused on viscosity and the degree of microvascular shear stress achieved in order to optimize vasoactive and oxygen delivery responses by leveraging the restoration and maintenance of physiological responses to blood flow in the microcirculation. Blood substitutes with higher viscous properties tend to improve oxygen delivery compared to those with lower viscosities. This review details current concepts in blood substitutes, particularly as they relate to trauma/hemorrhagic shock, with a specific focus on their complex interactions in the microcirculation.

Background: Uncontrolled proteolysis contributes to cell injury and organ dysfunction in animal models of circulatory shock. We investigated in humans the relationship between septic shock, proteolysis, and outcome. Methods: Intensive care patients with septic shock (n=29) or sepsis (n=6) and non-hospitalised subjects (n=9) were recruited as part of the prospective observational trial ‘ShockOmics’ (ClinicalTrials.gov Identifier NCT02141607). A mass spectrometry-based approach was used to analyse the plasma peptidomes and the origin of circulating peptides from proteolysis in the enrolled subjects. Results: Evidence of systemic proteolysis was indicated by a larger number of circulating peptides in septic shock patients, compared with septic patients and non-hospitalised healthy subjects. The peptide count and abundance in the septic shock patients were greater in patients who died (n=6) than in survivors (n=23), suggesting an association between magnitude of proteolysis and outcome. In silico analysis of the peptide sequences and of the sites of cleavage on the proteins of origin indicated a predominant role for serine proteases, such as chymotrypsin, and matrix metalloproteases in causing the observed proteolytic degradation. Conclusions: Systemic proteolysis is a novel fundamental pathological mechanism in septic shock. Plasma peptidomics is proposed as a new tool to monitor clinical trajectory in septic shock patients. Clinical trial registration: NCT02141607., SCOPUS: ar.j, info:eu-repo/semantics/published

First-degree relatives of diabetes patients, despite being euglycemic, presented impaired BRS and exacerbation of sympathetic modulation after ingestion of a high fructose drink when challenged to orthostatic stress. This finding alerts the importance of early autonomic dysfunction even in clinically healthy people, especially in face of a stressful situation.

It has been previously shown that intestinal proteases translocate into the circulation during hemorrhagic shock and contribute to proteolysis in distal organs. However, consequences of this phenomenon have not previously been investigated using high-throughput approaches. Here, a shotgun label-free quantitative proteomic approach was utilized to compare the peptidome of plasma samples from healthy and hemorrhagic shock rats to verify the possible role of uncontrolled proteolytic activity in shock. Plasma was collected from rats after hemorrhagic shock (HS) consisting of 2-h hypovolemia followed by 2-h reperfusion, and from healthy control (CTRL) rats. A new two-step enrichment method was applied to selectively extract peptides and low molecular weight proteins from plasma, and directly analyze these samples by tandem mass spectrometry. One hundred twenty-six circulating peptides were identified in CTRL and 295 in HS animals. Ninety-six peptides were present in both conditions; of these, 57 increased and 30 decreased in shock. In total, 256 peptides were increased or present only in HS confirming a general increase in proteolytic activity in shock. Analysis of the proteases that potentially generated the identified peptides suggests that the larger relative contribution to the proteolytic activity in shock is due to chymotryptic-like proteases. These results provide quantitative confirmation that extensive, system-wide proteolysis is part of the complex pathologic phenomena occurring in hemorrhagic shock.

The assessment of signal quality has been a research topic since the late 1970s, as it is mainly related to the problem of false alarms in bedside monitors in the intensive care unit (ICU), the incidence of which can be as high as 90 %, leading to alarm fatigue and a drop in the overall level of nurses and clinicians attention. The development of efficient algorithms for the quality control of long diagnostic electrocardiographic (ECG) recordings, both single- and multi-lead, and of the arterial blood pressure (ABP) signal is therefore essential for the enhancement of care quality. The ECG signal is often corrupted by noise, which can be within the frequency band of interest and can manifest similar morphologies as the ECG itself. Similarly to ECG, also the ABP signal is often corrupted by non-Gaussian, nonlinear and non-stationary noise and artifacts, especially in ICU recordings. Moreover, the reliability of several important parameters derived from ABP such as systolic blood pressure or pulse pressure is strongly affected by the quality of the ABP waveform. In this work, several up-to-date algorithms for the quality scoring of a single- or multi-lead ECG recording, based on time-domain approaches, frequency-domain approaches or a combination of the two will be reviewed, as well as methods for the quality assessment of ABP. Additionally, algorithms exploiting the relationship between ECG and pulsatile signals, such as ABP and photoplethysmographic recordings, for the reduction in the false alarm rate will be presented. Finally, some considerations will be drawn taking into account the large heterogeneity of clinical settings, applications and goals that the reviewed algorithms have to deal with.

Author(s): Maffioli, E; Aletti, F; Grassi Scalvini, F; Nonnis, S; Santagata, F; Morelli, S; Kistler, EB; Schmid-Schoenbein, GW; Negri, A; Tedeschi, G

BackgroundIrreversible hemorrhagic shock is characterized by hyporesponsiveness to vasopressor and fluid therapy. Little is known, however, about the mechanisms that contribute to this phenomenon. Previous studies have shown that decreased intestinal perfusion in hemorrhagic shock leads to proteolytically mediated increases in gut permeability, with subsequent egress of vasoactive substances systemically. Maintenance of blood pressure is achieved in part by α1 receptor modulation, which may be affected by vasoactive factors; we thus hypothesized that decreases in hemodynamic stability and vasopressor response in shock can be prevented by enteral protease inhibition.MethodsRats were exposed to experimental hemorrhagic shock (35 mm Hg mean arterial blood pressure for 2 hours, followed by reperfusion for 2 hours) and challenged with phenylephrine (2 μg/kg) at discrete intervals to measure vasopressor responsiveness. A second group of animals received enteral injections with the protease inhibitor tranexamic acid (TXA) (127 mM) along the small intestine and cecum 1 hour after induction of hemorrhagic shock.ResultsBlood pressure response (duration and amplitude) to phenylephrine after reperfusion was significantly attenuated in animals subjected to hemorrhagic shock compared with baseline and control nonshocked animals and was restored to near baseline by enteral TXA. Arteries from shocked animals also displayed decreased α1 receptor density with restoration to baseline after enteral TXA treatment. In vitro, rat shock plasma decreased α1 receptor density in smooth muscle cells, which was also abrogated by enteral TXA treatment.ConclusionResults from this study demonstrate that experimental hemorrhagic shock leads to decreased response to the α1-selective agonist phenylephrine and decreased α1 receptor density via circulating shock factors. These changes are mitigated by enteral TXA with correspondingly improved hemodynamics. Proteolytic inhibition in the lumen of the small intestine improves hemodynamics in hemorrhagic shock, possibly by restoring α1 adrenergic functionality necessary to maintain systemic blood pressure and perfusion.

The early metabolic signatures associated with the progression of septic shock and with responsiveness to therapy can be useful for developing target therapy. The Sequential Organ Failure Assessment (SOFA) score is used for stratifying risk and predicting mortality. This study aimed to verify whether different responses to therapy, assessed as changes in SOFA score at admission (T1, acute phase) and 48 h later (T2, post-resuscitation), are associated with different metabolite patterns. We examined the plasma metabolome of 21 septic shock patients (pts) enrolled in the Shockomics clinical trial (NCT02141607). Patients for which SOFAT2 was >8 and Δ = SOFAT1 − SOFAT2

© 2015, Springer Science+Business Media Dordrecht. The nature of hemodynamic instability typical of circulatory shock is not well understood, but an improved interpretation of its dynamic features could help in the management of critically ill patients. The objective of this work was to introduce new metrics for the analysis of arterial blood pressure (ABP) in order to characterize the risk of catastrophic outcome in splanchnic arterial occlusion (SAO) shock. Continuous ABP (fs = 1 kHz) was measured in rats during experimental SAO shock, which induced a fatal pressure drop (FPD) in ABP. The FPD could either be slow (SFPD) or fast (FFPD), with the latter causing cardiovascular collapse. Time series of mean arterial pressure, systolic blood pressure and heart period were derived from ABP. The sample asymmetry-based algorithm Heart Rate Characteristics was adapted to compute the Heart Period Characteristics (HPC) and the Blood Pressure Characteristics (BPC). Baroreflex sensitivity (BRS) was assessed by means of a bivariate model. The approach to FPD of the animals who collapsed (FFPD) was characterized by higher BRS in the low frequency band versus SFPD animals (0.36 ± 0.15 vs. 0.19 ± 0.12 ms/mmHg, p value = 0.0196), bradycardia as indicated by the HPC (0.76 ± 0.57 vs. 1.94 ± 1.27, p value = 0.0179) and higher but unstable blood pressure as indicated by BPC (3.02 ± 2.87 vs. 1.47 ± 1.29, p value = 0.0773). The HPC and BPC indices demonstrated promise as potential clinical markers of hemodynamic instability and impending cardiovascular collapse, and this animal study suggests their test in data from intensive care patients.

Background: The ShockOmics study (ClinicalTrials.gov identifier NCT02141607) is a multicenter prospective observational trial aimed at identifying new biomarkers of acute heart failure in circulatory shock, by means of a multiscale analysis of blood samples and hemodynamic data from subjects with circulatory shock. Methods and Design: Ninety septic shock and cardiogenic shock patients will be recruited in three intensive care units (ICU) (Hôpital Erasme, Université Libre de Bruxelles, Belgium; Hospital Universitari Mutua Terrassa, Spain; Hôpitaux Universitaires de Genève, Switzerland). Hemodynamic signals will be recorded every day for up to seven days from shock diagnosis (time T0). Clinical data and blood samples will be collected for analysis at: i) T1 < 16 h from T0; ii) T2 = 48 h after T0; iii) T3 = day 7 or before discharge or before discontinuation of therapy in case of fatal outcome; iv) T4 = day 100. The inclusion criteria are: shock, Sequential Organ Failure Assessment (SOFA) score > 5 and lactate levels ≥ 2 mmol/L. The exclusion criteria are: expected death within 24 h since ICU admission; > 4 units of red blood cells or >1 fresh frozen plasma transfused; active hematological malignancy; metastatic cancer; chronic immunodepression; pre-existing end stage renal disease requiring renal replacement therapy; recent cardiac surgery; Child-Pugh C cirrhosis; terminal illness. Enrollment will be preceded by the signature of the Informed Consent by the patient or his/her relatives and by the physician in charge. Three non-shock control groups will be included in the study: a) healthy blood donors (n = 5); b) septic patients (n = 10); c) acute myocardial infarction or patients with prolonged acute arrhythmia (n = 10). The hemodynamic data will be downloaded from the ICU monitors by means of dedicated software. The blood samples will be utilized for transcriptomics, proteomics and metabolomics ("-omics") analyses. Discussion:ShockOmics will provide new insights into the pathophysiological mechanisms underlying shock as well as new biomarkers for the timely diagnosis of cardiac dysfunction in shock and quantitative indices for assisting the therapeutic management of shock patients., SCOPUS: ar.j, info:eu-repo/semantics/published

Mild lower-body negative pressure (LBNP) has been utilized to selectively unload cardiopulmonary baroreceptors, but there is evidence that arterial baroreceptors can be transiently unloaded after the onset of mild LBNP. In this paper, a black box mathematical model for the prediction of diastolic blood pressure (DBP) variability from multiple inputs (systolic blood pressure, R-R interval duration, and central venous pressure) was applied to interpret the dynamics of blood pressure maintenance under the challenge of LBNP and in long-duration, head-down bed rest (HDBR). Hemodynamic recordings from seven participants in the WISE (Women's International Space Simulation for Exploration) Study collected during an experiment of incremental LBNP (−10 mmHg, −20 mmHg, −30 mmHg) were analyzed before and on day 50 of a 60-day-long HDBR campaign. Autoregressive spectral analysis focused on low-frequency (LF, ∼0.1 Hz) oscillations of DBP, which are related to fluctuations in vascular resistance due to sympathetic and baroreflex regulation of vasomotor tone. The arterial baroreflex-related component explained 49 ± 13% of LF variability of DBP in spontaneous conditions, and 89 ± 9% ( P < 0.05) on day 50 of HDBR, while the cardiopulmonary baroreflex component explained 17 ± 9% and 12 ± 4%, respectively. The arterial baroreflex-related variability was significantly increased in bed rest also for LBNP equal to −20 and −30 mmHg. The proposed technique provided a model interpretation of the proportional effect of arterial baroreflex vs. cardiopulmonary baroreflex-mediated components of blood pressure control and showed that arterial baroreflex was the main player in the mediation of DBP variability. Data during bed rest suggested that cardiopulmonary baroreflex-related effects are blunted and that blood pressure maintenance in the presence of an orthostatic stimulus relies mostly on arterial control.

The potential disturbance in the prefrontal cortex hemodynamic signal measured by functional near infrared spectroscopy (NIRS), due to forehead skin flowmotion, detected by laser Doppler flowmetry, was investigated by a standard protocol of hemodynamic challenge by Valsalva maneuver, aimed at assessing and disentangling local regulatory responses in skin vasomotion and in cerebral perfusion in presence of a strong systemic drive, and to quantify the common information in the two signals. The deep cortical NIRS signal did not appear to be affected by surface vasomotor activity, and autoregulation dynamics were dominant with respect to autonomic control of circulation. Highlights? Functional near infrared spectroscopy (fNIRS) prefrontal cortex measurements. ? Laser Doppler flowmetry (LDF) measurements of right and left temple vasomotions. ? Dynamic responses of prefrontal cortex autoregulation and skin vasomotion to a Valsalva maneuver. ? Cerebral and skin autoregulation were uncorrelated under the systemic stimulus due to Valsalva.

BACKGROUND: Physical activity has been considered an effective method to treat and prevent cardiovascular and metabolic disease. An important mechanism benefited by exercise training is the cardiovascular autonomic control, often impaired in cardiometabolic disease. Cycling used as a daily means of transport can be considered an interesting alternative to regular physical exercise practice. Therefore, this study intent to compare metabolic, hemodynamic and cardiovascular autonomic profiles of young adult men who were used to ride bicycles for transport (CT) with those considered insufficiently actives (IA). METHODS: Body composition, blood pressure, glucose, total cholesterol and triglycerides were evaluated at rest. Heart rate variability was analysed in time and frequence domains. RESULTS: No differences were observed for body composition, blood pressure, glycemia nor lipids between groups. CT group presented resting bradycardia. Heart rate variability was increased in cyclists, as well as the parameters of parasympathetic modulation. Sympathetic modulation was reduced in CT group when compared to IA group. Additionally, positive correlations were observed between resting heart rate and RMSSD and heart rate variability, while heart rate variability was correlated with sympathovagal balance. CONCLUSION: Our results demonstrated that bicycling regularly used as a means of transport is able to improve cardiovascular autonomic modulation, thus reducing the risk of cardiovascular disease. Language: en

The coupling of breathing and cardiovascular (CV) regulation is a main source of spontaneous short term CV variability signals. However, intense interaction with short term regulations involving baroreflex, vasomotion, and central drives and the ubiquitous presence of respiratory driven/modulated responses may render it a potent confounding factor, when not properly described. Major challenges are found in the acute clinical environment, e.g. ICU and OR, where monitoring cardiorespiratory coupling and CV regulation is of high impact, while sedation and forced ventilation extensively change the reflex portrait. A review is here attempted, finalized to approach ICU recordings in the ShockOmics EC project, aimed at integrating biomolecular and CV data in acute shock, under diffuse receptor cleavage and autonomic impairment.

Autonomic control of heart rate (HR) during prolonged intestinal ischemia was investigated by mathematical analysis of cardiac baroreflex. 24 Wistar rats underwent splanchnic arterial occlusion (SAO) under anesthesia and received different treatments, which included enteral saline or glucose, intramuscular xylazine and i.v. glycopyrrolate. High fidelity continuous arterial blood pressure (ABP) was measured by a catheter placed in the femoral artery. Time series of systolic blood pressure (SBP) and heart period (HP) were derived from the continuous ABP. Baroreflex gain (from SBP to HP) was calculated both in the low frequency (LF, 0.25-0.75 Hz) and high frequency (HF, 0.75-2.5 Hz) spectral bands. After a variable delay, ABP began to steadily decrease until either sacrifice at 4 hours after SAO or collapse by a sudden, fast fatal drop (FFD) of ABP. FFD was prevented by treatment with glycopyrrolate. Rats who displayed the FFD had a higher LF gain in the period (~ 5 mins) preceding the FFD with respect to th...

The expected response to fluid infusion is an increase of cardiac output (CO), and this response depends mostly on the current cardiac function of the patient. The importance of the prediction of fluid responsiveness (FR) is based on the fact that fluid loading in hemodynamic unstable patients may be hazardous and dangerous, e.g., by exposing them to the risk of developing pulmonary edema. The objective of this work is to improve the knowledge about the performance of the indices of FR prediction in association with different classification approaches in a particular setting, i.e., liver surgery. The specific aims are (1) the comparison of different CO estimators from invasive arterial blood pressure (ABP) measurement with particular attention to the assessment of CO variation after fluid administration and (2) the comparison of several indices for the prediction of FR to maneuvers classified from the CO measurements provided by a commercial monitor (PiCCO™, Pulsion Medical System, Munich, Germany). The main finding of this work is that pulse pressure variation (PPV) indices are more reliable and computationally feasible than stroke volume variation (SVV) indices. The PPV provided by PiCCO has the best performance in terms of area under curve, sensitivity, and specificity (0.92, 0.88, and 0.86, respectively), when the maneuvers are classified according to the maximum values of CO variation estimated during the second and third minutes after infusion. Moreover, PPVPiCCO is significantly correlated with the CO variation after infusion (rho = 0.51, p value

Obstructive sleep apnea (OSA) is a respiratory disorder that has the potential to negatively impact heart rate variability (HRV) during the sleep cycle. However, it is uncertain whether there is a chronic sleep stage-dependent linear and nonlinear cardiac autonomic impairment in OSA. The aim of this study was to perform HRV analysis in apnea-free samples as well as during stage 2 and rapid eye movement (REM) sleep in mild and moderate OSA (MiOSA and MOSA, respectively) subjects as well as health controls (NonOSA). This study included 20 MiOSA (37 ± 14 years), 20 MOSA (39 ± 8 years), and 18 NonOSA (36 ± 8 years) subjects. Subjects underwent in-laboratory overnight polysomnography with electrocardiography recording. HRV indices were obtained by analyzing the R–R intervals (RRis) in 5-min apnea-free samples by the linear frequency domain [low frequency (LF), high frequency (HF) and LF/HF], Poincare plot [standard deviation (SD1) and (SD2)], recurrence plot [mean line length (Lmean)], recurrence rate (REC), determinism (DET), and Shannon entropy (ShanEn). The MOSA group presented with higher LF, LF/HF, and DET indices compared to NonOSA as well as a lower parasympathetic index (HF), suggesting sympathetic hyperactivity in MOSA subjects. Interestingly, MiOSA subjects failed to show the expected linear HRV difference between sleep stages, as observed in NonOSA, which may represent an early onset of autonomic impairment at this stage of OSA. In OSA patients, there is a chronic sleep stage-dependent impairment of linear and nonlinear cardiac autonomic modulation. Interestingly, this impairment may be identifiable during the early stages of the disease.

The majority of studies on fluid responsiveness is focused on volume expansion maneuvers in intensive care unit (ICU), while fewer studies have analyzed the same problem during major surgery. Among them, the results are contrasting. The aim of this work was to compare the performance of different hemodynamic indices in the prediction of cardiac output variations following fast fluid infusion. The study was limited to a particular type of major surgery, i.e. liver transplantation and hepatectomy. Our results showed that pulse pressure variation (PPV) estimated according to the definition, i.e. within single respiratory cycles, and PPV estimated by PiCCO monitor system are coherent and very similar. Moreover, PPV and stroke volume variation (SVV) produced good values of sensitivity and specificity in separating the subjects into responsive and non responsive to maneuvers.

The aim of this paper is to compare baroreflex sensitivity (BRS) following anesthesia induction via propofol to pre-induction baseline values through a systematic and mathematically robust analysis. Several mathematical methods for BRS quantification were applied to pre-operative and intra-operative data collected from patients undergoing major surgery, in order to track the trend in BRS variations following anesthesia induction, as well as following the onset of mechanical ventilation. Finally, a comparison of BRS trends in chronic hypertensive patients (CH) with respect to non hypertensive (NH) patients was performed. 10 NH and 7 CH patients undergoing major surgery with American Society of Anesthesiologists classification score 2.5 ± 0.5 and 2.6 ± 0.5 respectively, were enrolled in the study. A Granger causality test was carried out to verify the causal relationship between RR interval duration and systolic blood pressure (SBP), and four different mathematical methods were used to estimate the BRS: (1) ratio between autospectra of RR and SBP, (2) transfer function, (3) sequence method and (4) bivariate closed loop model. Three different surgical epochs were considered: baseline, anesthetic procedure and post-intubation. In NH patients, propofol administration caused a decrease in arterial blood pressure (ABP), due to its vasodilatory effects, and a reduction of BRS, while heart rate (HR) remained unaltered with respect to baseline values before induction. A larger decrease in ABP was observed in CH patients when compared to NH patients, whereas HR remained unaltered and BRS was found to be lower than in the NH group at baseline, with no significant changes in the following epochs when compared to baseline. To our knowledge, this is the first study in which the autonomic response to propofol induction in CH and NH patients was compared. The analysis of BRS through a mathematically rigorous procedure in the perioperative period could result in the availability of additional information to guide therapy and anesthesia in uncontrolled hypertensive patients, which are prone to a higher rate of hypotension events occurring during general anesthesia induction.

Congenital heart defects affect the efficiency and functionality of the heart, and autonomic control of heart rate and of circulation can display a pathologic behavior in order to compensate for the hemodynamic alterations due to disease. While previous works have investigated heart rate variability (HRV) in specific pathologies, e.g. tetralogy of Fallot, the goal of this study was to assess HRV in children with a congenital heart malformation taking into account the effects of cyanotic and acyanotic defects, and comparing pathologic children with age matched controls. HRV, approximate entropy (ApEn) and sample entropy (SampEn) were calculated to discuss the dynamics and complexity of heart rhythms, and to evaluate the potential impairment of control mechanisms. Analyses showed that low frequency (LF) power and total power of HRV were significantly higher in children with a condition than in healthy controls, independently of cyanosis. Non linear indices were also significantly higher in pathologic subjects. Significant differences in LF, total power, ApEn and SampEn were found among cyanotic, acyanotic and healthy children. These results suggested that children with a congenital heart condition display more complex HRV and sympathetic overactivity, which may be aimed at compensating for hemodynamic alterations. Further studies should investigate whether corrective surgery and rehabilitation can improve HRV and restore its physiological features.

This paper presents the analysis of autonomic nervous system (ANS) control of heart rate (HR) and of cardiac baroreflex sensitivity (BRS) in patients undergoing general anesthesia for major surgery through spectral analysis techniques and with the Granger causality approach that take into account the causal relationships between HR and arterial blood pressure (ABP) variability. Propofol produced a general decrease in ABP due to its vasodilatory effects, a reduction in BRS, while HR remained unaltered with respect to baseline values before induction of anesthesia. The bivariate model suggests that the feedback pathway of cardiac baroreflex could be blunted by propofol induced anesthesia and that the feedforward pathway could be unaffected by anesthesia.

Heart rate variability (HRV) and respiration recorded during sleep from 8 patients suffering from difficult-to-control asthma were studied to investigate autonomic nervous system control of cardiac and respiratory activities, and of cardio-respiratory coupling during different sleep stages.

The mutual relationship between global control of circulation and local control of peripheral hemodynamics has been marginally addressed by cardiovascular variability research, but quantifying this relationship may be relevant when dealing with tissue perfusion monitoring in pathologies affecting microcirculation.

DSP hardware. Several algorithmic and programming optimizations were applied so that the algorithm runs in real time with a sampling rate of at least 12 kHz. Results: The algorithm achieved a 99.3% accuracy rate when evaluated using data (20 data sets) from the MIT-BIH Arrhythmia Database. Total beats, missed beats, false beats, correct beats, total errors, percent errors were 45 331, 195, 142, 45 136, 337, and 0.74, respectively. For the cardiac-gating applications, latency from the peak of the QRS complex to the trigger signal was 7 milliseconds. Sampling at 12 kHz, with a high-performance 16-bit DAC, resulted in a jitter of 193 microseconds. Conclusions: Radiofrequency pulses during MRI make it difficult to discern ECG signals from background static magnetic field and radiofrequency gradients. This technique of mathematical transformation may be useful in the improvement methods of real-time QRS detection and sampling during MRI.

In this paper we illustrate an ongoing project focused on intraoperative monitoring of haemodynamic stability and cardiorespiratory interactions, and present an example analysis of vital signs recorded synchronously from multiple monitoring devices through a LabView©-based acquisition software termed “Global Collect”. We present two moving average models for the black box estimation of the gains of the cardiopulmonary baroreflex control of arterial resistance and of ventricular contractility, based on invasive, continuous measurements of arterial blood pressure and central venous pressure. As a proof-of-concept, we analyze the effects of a fluid-challenge maneuver performed during major surgery, quantifying the mechanisms through which such maneuvers are able to increase cardiac performance and hence enhance venous return. These preliminary results of a pilot case study demonstrate the potential of investigating autonomic nervous system control of circulation under general anesthesia in advancing intraoperative patient monitoring and aiding maintenance of haemodynamic stability in patients undergoing major surgery.

In this paper, the effects of bed rest-induced cardiovascular deconditioning were investigated by means of a previously developed multivariate model for the assessment of arterial control of circulation. The vascular response to exercise and tilt, before and after a 14-day head down tilt bed rest, was identified and disentangled from the main mechanisms due to global, neural control of circulation. Results of the decomposition of diastolic pressure and pulse pressure beat-by-beat series and the relevant spectral analysis suggested that the autoregulation-related response is not affected by prolonged exposition to microgravity. As to the complex regulation of arterial blood pressure, a maintained responsiveness to sympathetic stimuli was found, even in presence of indications of the cardiovascular deconditioning, such as tachycardia, reset of baroreflex, cardiopulmonary unloading. These preliminary results emphasized the necessity for more complex analyses of the main alterations and compensatory mechanisms elicited by microgravity-induced-cardiovascular deconditioning, in order to develop more effective long term strategies to prevent it.

Summary Background: The baroreflex is one of the most important short-term cardiovascular autonomic control mechanisms. Its interactions with other reflexes, mainly cardio-pulmonary reflexes, are of paramount importance in controlling heart rate. Objectives: This study assesses the coupling between baroreflex and respiration during a progressive bicycle mild dynamical exercise. Methods: The coupling was assessed by symbolic analysis and conditional entropy. Results: Findings suggested the close relationship between the baroreflex sequences and the phase of respiratory signal and, thus, the interference between baroreflex and cardiopulmonary reflexes. Conclusions: Indexes describing baroreflex based on spontaneous variability are strongly affected by cardiopulmonary influences.

In order to analyze the information carried by arterial blood pressure (ABP) variability, a multivariate parametric model of interactions involving systolic ABP (SAP), diastolic ABP (DAP), pulse pressure (PP), heart period (HP), and respiration is proposed. The model defines SAP as sum of the preceding DAP and PP values; DAP model accounts for arterial baroreflex, diastolic runoff; PP reflects changes in stroke volume related to respiration and HP, afterload; equation residuals reveal other vascular and cardiac output modulations. The model was applied to data from nine young volunteers (aged 29plusmn6 years) during supine cycling at 10%, 20%, and 30% of their maximum effort. Significant basal values and changes across the epochs of the experiment were found in all hemodynamic parameters describing fast, beat-by-beat responses; in SAP and PP total power, DAP low- and high-frequency power (LF, HF), PP very low frequency (VLF), and LF and HF power. A primary role of vascular control through DAP and PP was emphasized by the considered feedbacks and the model residuals. The model proved to be able to assess beat-by-beat cardiovascular interactions and offer a comprehensive view of arterial tree control.

An algorithm to evaluate the sleep macrostructure based on heart rate fluctuations from ECG signal is presented. This algorithm is an attempt to evaluate the sleep quality out of sleep centers. The algorithm is made up by a) a time-variant autoregressive model used as feature extractor and b) a hidden Markov model used as classifier. Characteristics coming from the joint probability of HRV features were used to fed the HMM. 17 full polysomnography recordings from healthy subjects were used in the current analysis. When compared to Wake-NREM-REM given by experts, the automatic classifier achieved a total accuracy of 78.21+/-6.44% and a kappa index of 0.41+/-.1085 using two features and a total accuracy of 79.43+/-8.83% and kappa index of 0.42+/-.1493 using three features.