Bench-to-bedside review: Circulating microparticles - a new player in sepsis?

In sepsis, inflammation and thrombosis are both the cause and the result of interactions between circulating (for example, leukocytes and platelets), endothelial and smooth muscle cells. Microparticles are proinflammatory and procoagulant fragments originating from plasma membrane generated after cellular activation and released in body fluids. In the vessel, they constitute a pool of bioactive effectors pulled from diverse cellular origins and may act as intercellular messengers. Microparticles expose phosphatidylserine, a procoagulant phospholipid made accessible after membrane remodelling, and tissue factor, the initiator of blood coagulation at the endothelial and leukocyte surface. They constitute a secretion pathway for IL-1β and up-regulate the proinflammatory response of target cells. Microparticles circulate at low levels in healthy individuals, but undergo phenotypic and quantitative changes that could play a pathophysiological role in inflammatory diseases. Microparticles may participate in the pathogenesis of sepsis through multiple ways. They are able to regulate vascular tone and are potent vascular proinflammatory and procoagulant mediators. Microparticles' abilities are of increasing interest in deciphering the mechanisms underlying the multiple organ dysfunction of septic shock

TLRs1-10 Protein Expression in Circulating Human White Blood Cells during Bacterial and COVID-19 Infections

Introduction: Toll-like receptors play crucial roles in the sepsis-induced systemic inflammatory response. Septic shock mortality correlates with overexpression of neutrophilic TLR2 and TLR9, while the role of TLR4 overexpression remains a debate. In addition, TLRs are involved in the pathogenesis of viral infections such as COVID-19, where the single-stranded RNA of SARS-CoV-2 is recognized by TLR7 and TLR8, and the spike protein activates TLR4. Methods: In this study, we conducted a comprehensive analysis of TLRs 1–10 expressions in white blood cells from 71 patients with bacterial and viral infections. Patients were divided into 4 groups based on disease type and severity (sepsis, septic shock, moderate, and severe COVID-19) and compared to 7 healthy volunteers. Results: We observed a significant reduction in the expression of TLR4 and its co-receptor CD14 in septic shock neutrophils compared to the control group (p < 0.001). Severe COVID-19 patients exhibited a significant increase in TLR3 and TLR7 levels in neutrophils compared to controls (p < 0.05). Septic shock patients also showed a similar increase in TLR7 in neutrophils along with elevated intermediate monocytes (CD14+CD16+) compared to the control group (p < 0.005 and p < 0.001, respectively). However, TLR expression remained unchanged in lymphocytes. Conclusion: This study provides further insights into the mechanisms of TLR activation in various infectious conditions. Additional analysis is needed to assess their correlation with patient outcome and to evaluate the impact of TLR-pathway modulation during septic shock and severe COVID-19

Epinephrine Versus Norepinephrine for Cardiogenic Shock After Acute Myocardial Infarction

BACKGROUND Vasopressor agents could have certain specific effects in patients with cardiogenic shock (CS) after myocardial infarction, which may influence outcome. Although norepinephrine and epinephrine are currently the most commonly used agents, no randomized trial has compared their effects, and intervention data are lacking. OBJECTIVES The goal of this paper was to compare in a prospective, double-blind, multicenter, randomized study, the efficacy and safety of epinephrine and norepinephrine in patients with CS after acute myocardial infarction. METHODS The primary efficacy outcome was cardiac index evolution, and the primary safety outcome was the occurrence of refractory CS. Refractory CS was defined as CS with sustained hypotension, end-organ hypoperfusion and hyperlactatemia, and high inotrope and vasopressor doses. RESULTS Fifty-seven patients were randomized into 2 study arms, epinephrine and norepinephrine. For the primary efficacy endpoint, cardiac index evolution was similar between the 2 groups (p = 0.43) from baseline (H0) to H72. For the main safety endpoint, the observed higher incidence of refractory shock in the epinephrine group (10 of 27 [37%] vs. norepinephrine 2 of 30 [7%]; p = 0.008) led to early termination of the study. Heart rate increased significantly with epinephrine from H2 to H24 while remaining unchanged with norepinephrine (p <0.0001). Several metabolic changes were unfavorable to epinephrine compared with norepinephrine, including an increase in cardiac double product (p = 0.0002) and lactic acidosis from H2 to H24 (p <0.0001). CONCLUSIONS In patients with CS secondary to acute myocardial infarction, the use of epinephrine compared with norepinephrine was associated with similar effects on arterial pressure and cardiac index and a higher incidence of refractory shock. (Study Comparing the Efficacy and Tolerability of Epinephrine and Norepinephrine in Cardiogenic Shock [OptimaCC]; NCT01367743) (J AmColl Cardiol 2018; 72: 173-82) (C) 2018 by the American College of Cardiology Foundation.Peer reviewe

Interleukin-10 controls the protective effects of circulating microparticles from patients with septic shock on tissue-engineered vascular media

During sepsis, inflammation can be orchestrated by the interaction between circulating and vascular cells that, under activation, release MPs (microparticles). Previously, we reported that increased circulating MPs in patients with sepsis play a pivotal role in ex vivo vascular function suggesting that they are protective against vascular hyporeactivity. The present study was designed to investigate the effects of MPs from patients with sepsis on the contractile response of TEVM (tissue-engineered vascular media). TEVM that were composed only of a media layer were produced by tissue engineering from human arterial SMCs (smooth muscle cells) isolated from umbilical cords. TEVM was incubated with MPs isolated from whole blood of 16 patients with sepsis. TEVM were incubated for 24 h with MPs and used for the study of vascular contraction, direct measurements of NO and O2- (superoxide anion) production by EPR and quantification of mRNA cytokine expression. MPs from patients with sepsis increased contraction induced by histamine in TEVM. This effect was not associated with inflammation, neither linked to the activation of NF-kappaB (nuclear factor kappaB) pathway nor to the increase in iNOS (inducible NO synthase) and COX (cyclo-oxygenase)-2 expression. In contrast, mRNA expression of IL (interleukin)-10 was enhanced. Then, we investigated the effect of IL-10 on vascular hyporeactivity induced by LPS (lipopolysaccharide). Although IL-10 treatment did not modify the contractile response in TEVM by itself, this interleukin restored contraction in LPS-treated TEVM. In addition, IL-10 treatment both prevented vascular hyporeactivity induced by LPS injection in mice and improved survival of LPS-injected mice. These findings show an association between the capacity of MPs from patients with sepsis to restore vascular hyporeactivity induced by LPS and their ability to increase IL-10 in the tissue-engineered blood vessel model

Effects of hydrogen sulfide on hemodynamics, inflammatory response and oxidative stress during resuscitated hemorrhagic shock in rats

Introduction Hydrogen sulfide (H2S) has been shown to improve survival in rodent models of lethal hemorrhage. Conversely, other authors have reported that inhibition of endogenous H2S production improves hemodynamics and reduces organ injury after hemorrhagic shock. Since all of these data originate from unresuscitated models and/or the use of a pre-treatment design, we therefore tested the hypothesis that the H2S donor, sodium hydrosulfide (NaHS), may improve hemodynamics in resuscitated hemorrhagic shock and attenuate oxidative and nitrosative stresses. Methods Thirty-two rats were mechanically ventilated and instrumented to measure mean arterial pressure (MAP) and carotid blood flow (CBF). Animals were bled during 60 minutes in order to maintain MAP at 40 ± 2 mm Hg. Ten minutes prior to retransfusion of shed blood, rats randomly received either an intravenous bolus of NaHS (0.2 mg/kg) or vehicle (0.9% NaCl). At the end of the experiment (T = 300 minutes), blood, aorta and heart were harvested for Western blot (inductible Nitric Oxyde Synthase (iNOS), Nuclear factor-κB (NF-κB), phosphorylated Inhibitor κB (P-IκB), Inter-Cellular Adhesion Molecule (I-CAM), Heme oxygenase 1(HO-1), Heme oxygenase 2(HO-2), as well as nuclear respiratory factor 2 (Nrf2)). Nitric oxide (NO) and superoxide anion (O2 -) were also measured by electron paramagnetic resonance. Results At the end of the experiment, control rats exhibited a decrease in MAP which was attenuated by NaHS (65 ± 32 versus 101 ± 17 mmHg, P &lt; 0.05). CBF was better maintained in NaHS-treated rats (1.9 ± 1.6 versus 4.4 ± 1.9 ml/minute P &lt; 0.05). NaHS significantly limited shock-induced metabolic acidosis. NaHS also prevented iNOS expression and NO production in the heart and aorta while significantly reducing NF-kB, P-IκB and I-CAM in the aorta. Compared to the control group, NaHS significantly increased Nrf2, HO-1 and HO-2 and limited O2 - release in both aorta and heart (P &lt; 0.05). Conclusions NaHS is protective against the effects of ischemia reperfusion induced by controlled hemorrhage in rats. NaHS also improves hemodynamics in the early resuscitation phase after hemorrhagic shock, most likely as a result of attenuated oxidative stress. The use of NaHS hence appears promising in limiting the consequences of ischemia reperfusion (IR)

Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2)

BACKGROUND: Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock. METHODS/DESIGN: The NUTRIREA-2 study is a multicenter, open-label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs. DISCUSSION: The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01802099 (registered 27 February 2013)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Vascular reactivity during gestation : effects of parathyroid hormone-related peptide and of human-derived microparticles

Ce travail étudie les effets du système PTHrP/PTH1R et de microparticules humaines, sur la réactivité vasculaire de l'homme et de l'animal pendant la gestation. Le système PTHrP/PTH1R est impliqué dans la régulation du tonus de l'artère utérine et mésentéThis work aimed to investigate the effects of PTHrP/PTH1R system and human microparticles on human and animal vascular reactivity during pregnancy. We demonstrate for the first time that during pregnancy PTHrP is able to induce vasorelaxation in rat uter

Réactivité vasculaire et gestation: Effets du facteur hypercalcémiant lié à l’hormone parathyroïdienne (PTHrP) et des microparticules circulantes d’origine humaine

Ce travail étudie les effets du système PTHrP/PTH1R et de microparticules humaines, sur la réactivité vasculaire de l’homme et de l’animal pendant la gestation. Le système PTHrP/PTH1R est impliqué dans la régulation du tonus de l’artère utérine et mésentérique, car PTHrP(1-34) relaxe les artères utérines et mésentériques chez la rate. La gestation dérégule ce système, avec une surexpression de PTHrP et une diminution de la réponse vasorelaxante. Ce phénomène est susceptible d’être nocif en cas de surexpression pathologique, car il est inducteur d’un prostanoïde vasoconstricteur, impliqué dans nombre de lésions vasculaires qui caractérisent une mauvaise placentation, pouvant générer l’état de prééclampsie. Les microparticules sont des microvésicules qui circulent chez les femmes prééclamptiques en quantité plus importante qu’en cas de grossesse saine. Il s’agit de microparticules plaquettaires et leucocytaires qui entraînent une hyporéactivité en réponse à la sérotonine, aussi bien sur des vaisseaux humains, in vitro, que des vaisseaux de souris in vitro et in vivo. Cet effet est accompagné d’une intense activité proinflammatoire dans la paroi vasculaire, associée à un stress oxydant et nitrosant et entraînent la production concomitante de facteurs vasocontracturants et de NO. Nous rapportons de nouveaux éléments au domaine de la réactivité vasculaire pendant la gestation. Le système PTHrP/PTH1R reste à étudier sur des vaisseaux humains, normaux et pathologiques ainsi que sur une culture de cellules trophoblastiques. Les microparticules apparaissent capables de générer une dysfonction vasculaire dont le rôle exact reste à confirmer sur des modèles d’animaux "prééclamptiques" comme celui induit par le facteur antiangiogénique sFlt1. Des avancées sont sûrement à attendre des études de protéomique sur les microparticules, ce qui ouvrirait le champ à une application possible en thérapeutique