Anthony Moreau

IntroductionCardiac arrest (CA) is a major cause of mortality and neurologic disability. Extracorporeal cardiopulmonary resuscitation (ECPR) may be used in refractory CA to potentially reduce hypoxic-ischemic brain injuries. Currently, no recommendation exists regarding optimal carbon dioxide levels in ECPR patients.MethodsTwelve pigs were submitted to 5 minutes of untreated ventricular fibrillation followed by 25 minutes of conventional CPR; 30 minutes after CA induction, ECPR was initiated and defibrillations delivered until ROSC. Pigs were then randomly assigned to normocapnia (NC; PaCO2 35-45mmHg, n=6) or hypercapnia (HC; PaCO2 50-55mmHg, n=6). Animals underwent continuous multimodal neurological and cardiovascular monitoring with blood samples collected at predefined time points. At 12 h post-ROSC, animals were euthanized and brain tissues were harvested for molecular analyses.ResultsMean brain oxygen tension (PbtO2) tended to be higher in the HC group (49.9 vs 36.4 mmHg; p = 0.13), while mean intracranial pressure was similar between the NC and HC groups (19.9 vs 22.6 mmHg; p = 0.42). Cerebral glucose concentrations were significantly higher in the HC group (p = 0.01), without differences in the lactate/pyruvate ratio, glycerol or glutamate concentrations. Caspase-8 gene expression in the parietal lobe was significantly lower in the HC group. No significant differences were observed in cortical activity on EEG or serum biomarkers of brain injury.ConclusionsHC induced selective metabolic and molecular changes, including increased cerebral glucose concentrations and reduced caspase-8 expression, along with a trend toward higher PbtO2, without changes in intracranial pressure, cortical activity, or biomarkers of brain injury.

Background: Cardiac arrest (CA) remains a leading cause of mortality and long-term neurological disability. In cases of refractory CA, extracorporeal cardiopulmonary resuscitation (ECPR) may be implemented as a salvage therapy to mitigate hypoxic-ischemic brain injury and improve outcomes. However, the optimal target temperature in the specific context of ECPR remains uncertain. The objective of this study was to evaluate the impact of hypothermia on brain function using a controlled experimental model of ECPR. Methods: Twelve pigs were subjected to 5 min of untreated ventricular fibrillation, followed by 25 min of conventional cardiopulmonary resuscitation (CPR). At 30 min, veno-arterial extracorporeal membrane oxygenation support was initiated, and defibrillation attempts were performed until the achievement of return of spontaneous circulation (ROSC). Following ROSC, animals were randomly assigned to one of two groups: hypothermia (HT), targeting a core body temperature of 33–34 °C, or controlled normothermia (NT), targeting 37–38 °C. All animals underwent continuous multimodal neurological and cardiovascular monitoring. Blood samples were collected at predefined time points to assess circulating biomarkers of organ injury. The primary outcome was the change of brain tissue oxygen tension (PbtO ₂ ) over time. Other neurological and hemodynamical parameters were treated as secondary analyses. At 12 h post-ROSC, animals were euthanized via intracardiac injection of potassium chloride. Brain tissues were immediately harvested and appropriately stored for molecular analyses. Results: A total of 12 pigs were included in the study, with six animals allocated to each group. Baseline characteristics were comparable between the groups and ROSC was achieved in all animals. Throughout the experiment, PbtO₂ gradually declined and intracranial pressure (ICP) increased in both groups; however, no significant differences were observed between groups. Similarly, there were no significant differences in cerebral metabolites, cortical activity, or gene expression in either frontal or parietal brain tissues. Notably, neurofilament light chain (NfL) concentrations were significantly lower at the end of the observation period in the HT group compared to NT ( p = 0.04), while neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP) levels did not differ significantly between the two groups. Conclusions: HT did not improve cerebral perfusion or metabolic parameters in this refractory cardiac arrest ECPR model; the early decrease in NfL levels requires cautious interpretation and further investigation.

Background: In patients requiring extracorporeal cardiopulmonary resuscitation (ECPR), there is a need for studies to assess the potential benefits of therapeutic interventions to improve survival and reduce hypoxic-ischemic brain injuries. However, conducting human studies may be challenging. This study aimed to describe two experimental models developed in our laboratory and to conduct a systematic review of existing animal models of ECPR reported in the literature. Results: In our experiments, pigs were subjected to 12 min (model 1) or 5 min (model 2) of untreated ventricular fibrillation, followed by 18 min (model 1) or 25 min (model 2) of conventional cardiopulmonary resuscitation. Results showed severe distributive shock, decreased brain oxygen pressure and increased intracranial pressure, with model 1 displaying more pronounced brain perfusion impairment. A systematic review of 52 studies, mostly conducted on pigs, revealed heterogeneity in cardiac arrest induction methods, cardiopulmonary resuscitation strategies, and evaluated outcomes. Conclusions: This review emphasizes the significant impact of no-flow and low-flow durations on brain injury severity following ECPR. However, the diversity in experimental models hinders direct comparisons, urging the standardization of ECPR models to enhance consistency and comparability across studies.

Circulating nucleosome levels are commonly elevated in physiological and pathological conditions. Their potential as biomarkers for diagnosing and prognosticating sepsis remains uncertain due, in part, to technical limitations in existing detection methods. This scoping review explores the possible role of nucleosome concentrations in the diagnosis, prognosis, and therapeutic management of sepsis. A comprehensive literature search of the Cochrane and Medline libraries from 1996 to 1 February 2024 identified 110 potentially eligible studies, of which 19 met the inclusion criteria, encompassing a total of 39 SIRS patients, 893 sepsis patients, 280 septic shock patients, 117 other ICU control patients, and 345 healthy volunteers. The enzyme-linked immunosorbent assay [ELISA] was the primary method of nucleosome measurement. Studies consistently reported significant correlations between nucleosome levels and other NET biomarkers. Nucleosome levels were higher in patients with sepsis than in healthy volunteers and associated with disease severity, as indicated by SOFA and APACHE II scores. Non-survivors had higher nucleosome levels than survivors. Circulating nucleosome levels, therefore, show promise as early markers of NETosis in sepsis, with moderate diagnostic accuracy and strong correlations with disease severity and prognosis. However, the available evidence is drawn mainly from single-center, observational studies with small sample sizes and varied detection methods, warranting further investigation.

Background: Extracellular histones have been associated with severity and outcome in sepsis. The aim of the present study was to assess the effects of sodium-β-O-Methyl cellobioside sulfate (mCBS), a histone-neutralizing polyanion, on the severity and outcome of sepsis in an experimental model. Methods: This randomized placebo-controlled experimental study was performed in 24 mechanically ventilated female sheep. Sepsis was induced by fecal peritonitis. Animals were randomized to three groups: control, early treatment, and late treatment (n = 8 each). mCBS was given as a bolus (1 mg/kg) followed by a continuous infusion (1 mg/kg/h) just after sepsis induction in the early treatment group, and 4 h later in the late treatment group. Fluid administration and antimicrobial therapy were initiated 4 h T4 after feces injection, peritoneal lavage performed, and a norepinephrine infusion titrated to maintain mean arterial pressure (MAP) between 65–75 mmHg. The experiment was blinded and lasted maximum 24 h. Results: During the first 4 h, MAP remained > 65 mmHg in the early treatment group but decreased significantly in the others (p < 0.01 for interaction, median value at T4: (79 [70–90] mmHg for early treatment, 57 [70–90] mmHg for late treatment, and 55 [49–60] mmHg for the control group). mCBS-treated animals required significantly less norepinephrine to maintain MAP than controls (p < 0.01 for interaction) and had lower creatinine (p < 0.01), lactate (p < 0.01), and interleukin-6 (p < 0.01) levels, associated with reduced changes in H3.1 nucleosome levels (p = 0.02). Early treatment was associated with lower norepinephrine requirements than later treatment. Two control animals died; all the mCBS-treated animals survived. Conclusions: Neutralization of extracellular histones with mCBS was associated with reduced norepinephrine requirements, improved tissue perfusion, less renal dysfunction, and lower circulating IL-6 in experimental septic shock and may represent a new therapeutic approach to be tested in clinical trials.

OBJECTIVES: RBCs from critically ill patients have depressed deformability, especially in sepsis. Prolonged exposure of RBCs from healthy volunteers to physiologic shear stress (the preconditioning technique) has been associated with improved deformability, but the effect of preconditioning on RBCs from critically ill patients with or without sepsis has never been studied. DESIGN: Prospective study. SETTING: A 32-bed medico-surgical ICU and a university-affiliated cell biology laboratory. SUBJECTS: RBCs from 26 healthy volunteers and 40 critically ill patients (20 with and 20 without sepsis). INTERVENTIONS: RBC deformability was measured using the elongation index (EI) with an ektacytometer, at shear stress levels ranging from 0.3 to 50 Pa. To assess the effects of preconditioning in the three groups, we measured EI after first applying a shear stress of 5 Pa for 300 seconds. To study the potential mechanisms involved in preconditioning, we looked at deformability after incubation of an RBC solution from the healthy volunteers with glutaraldehyde, a membrane-stabilizing protein, and neuraminidase, an enzyme that releases membrane sialic acid. MEASUREMENTS AND MAIN RESULTS: Baseline RBC deformability was significantly depressed in the septic patients compared with the volunteers at all shear stress levels greater than or equal to 4.89 Pa. Preconditioning improved deformability only in the volunteers (at shear stress levels of 0.48 and 0.76 Pa). Among the critically ill patients, preconditioning worsened RBC deformability at higher shear stress levels. After incubation (with glutaraldehyde or neuraminidase) of RBCs from five volunteers in whom preconditioning had significantly improved deformability, the positive effect of preconditioning was lost with glutaraldehyde. CONCLUSIONS: RBC deformability is depressed in septic patients. There was a deleterious effect of preconditioning on RBC deformability in septic patients, unlike the positive effect on RBCs from healthy volunteers. The effect of preconditioning may be associated with elasticity of the cell membrane.