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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.

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.

Proteomic technologies have identified 234 peptidases in plasma but little quantitative information about the proteolytic activity has been uncovered. In this study, the substrate profile of plasma proteases was evaluated using two nano-LC-ESI-MS/MS methods. Multiplex substrate profiling by mass spectrometry (MSP-MS) quantifies plasma protease activity in vitro using a global and unbiased library of synthetic peptide reporter substrates, and shotgun peptidomics quantifies protein degradation products that have been generated in vivo by proteases. The two approaches gave complementary results since they both highlight key peptidase activities in plasma including amino- and carboxypeptidases with different substrate specificity profiles. These assays provide a significant advantage over traditional approaches, such as fluorogenic peptide reporter substrates, because they can detect active plasma proteases in a global and unbiased manner, in comparison to detecting select proteases using specific reporter substrates. We discovered that plasma proteins are cleaved by endoproteases and these peptide products are subsequently degraded by amino- and carboxypeptidases. The exopeptidases are more active and stable in plasma and therefore were found to be the most active proteases in the in vitro assay. The protocols presented here set the groundwork for studies to evaluate changes in plasma proteolytic activity in shock.

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

The high demand for lung transplants cannot be matched by an adequate number of lungs from donors. Since fully ex-novo lungs are far from being feasible, tissue engineering is actively considering implantation of engineered lungs where the devitalized structure of a donor is used as scaffold to be repopulated by stem cells of the receiving patient. A decellularized donated lung is treated inside a bioreactor where transport through the tracheobronchial tree (TBT) will allow for both deposition of stem cells and nourishment for their subsequent growth, thus developing new lung tissue. The key concern is to set optimally the boundary conditions to utilize in the bioreactor. We propose a predictive model of slow liquid ventilation, which combines a one-dimensional (1-D) mathematical model of the TBT and a solute deposition model strongly dependent on fluid velocity across the tree. With it, we were able to track and drive the concentration of a generic solute across the airways, looking for its optimal distribution. This was given by properly adjusting the pumps’ regime serving the bioreactor. A feedback system, created by coupling the two models, allowed us to derive the optimal pattern. The TBT model can be easily invertible, thus yielding a straightforward flow/pressure law at the inlet to optimize the efficiency of the bioreactor.

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.

Spontaneous mean arterial pressure (MAP) variability may be mainly due to fluctuations in cardiac output (CO) and total peripheral resistance (TPR). While high frequency (HF ∼ 0.25 Hz) oscillations in MAP are ultimately driven by respiration, the source of low frequency (LF ∼ 0.1 Hz) fluctuations has not been fully elucidated. It is known that CO buffers these oscillations, but there is no evidence on its potential role in also generating them. The main goal was to determine whether CO is a source of LF variability in MAP. Six dogs were chronically instrumented to obtain beat-to-beat measurements of CO and MAP while the dogs were fully awake and at rest. A causal dynamic model was identified to relate the fluctuations in CO to MAP. The model was then used to predict the MAP fluctuations from the CO fluctuations. The CO fluctuations were able to predict about 70% of the MAP oscillations in the HF band but showed no predictive value in the LF band. Hence, respiration induces CO fluctuations in the HF band that, in turn, cause MAP oscillations, while TPR fluctuations appear to be the dominant mediator of LF fluctuations of MAP. CO is not a significant source of these oscillations, and it may only be responsible for dampening them, likely through the baroreflex.

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.

Graphical abstract, Highlights • A protocol for peptidome plasma analysis has been set up. • The presence of heparin did not affect peptides detection in plasma specimens. • Plasma displays an increase in peptides after hemorrhagic shock., A preliminary mass spectrometry based shotgun protocol was set up to compare the peptidome of plasma samples from healthy and hemorrhagic shock rats with the aim of verifying the possible role of uncontrolled proteolytic activity in circulatory shock. Since the hemorrhagic shock model requires heparin as anticoagulant, a preliminary experiment using plasma sample obtained in the presence/absence of heparin from healthy rats was performed to determine whether its presence is fully compatible with the peptidomic protocol proposed. The entire protocol was tested in a pilot experiment to compare the peptidome of healthy or heparin-anticoagulated rats subjected to hemorrhagic shock.

Background This simulation study investigated potential modulations of total peripheral resistance (TPR), due to distributed peripheral vascular activity, by means of a lumped model of the arterial tree and a non linear model of microcirculation, inclusive of local controls of blood flow and tissue-capillary fluid exchange. Results Numerical simulations of circulation were carried out to compute TPR under different conditions of blood flow pulsatility, and to extract the pressure-flow characteristics of the cardiovascular system. Simulations showed that TPR seen by the large arteries was increased in absence of pulsatility, while it decreased with an augmented harmonic content. This is a typically non linear effect due to the contribution of active, non linear autoregulation of the peripheral microvascular beds, which also generated a nonlinear relationship between arterial blood pressure and cardiac output. Conclusion This simulation study, though focused on a simple effect attaining TPR modulation due to pulsatility, suggests that non-linear autoregulation mechanisms cannot be overlooked while studying the integrated behavior of the global cardiovascular system, including the arterial tree and the peripheral vascular bed.