Effect of Polyethylene-glycolated Carboxyhemoglobin on Renal Microcirculation in a Rat Model of Hemorrhagic Shock

BACKGROUND: Primary resuscitation fluid to treat hemorrhagic shock remains controversial. Use of hydroxyethyl starches raised concerns of acute kidney injury. Polyethylene-glycolated carboxyhemoglobin, which has carbon monoxide-releasing molecules and oxygen-carrying properties, was hypothesized to sustain cortical renal microcirculatory PO2 after hemorrhagic shock and reduce kidney injury. METHODS: Anesthetized and ventilated rats (n = 42) were subjected to pressure-controlled hemorrhagic shock for 1 h. Renal cortical PO2 was measured in exposed kidneys using a phosphorescence quenching method. Rats were randomly assigned to six groups: polyethylene-glycolated carboxyhemoglobin 320 mg . kg, 6% hydroxyethyl starch (130/0.4) in Ringer's acetate, blood retransfusion, diluted blood retransfusion (~4 g . dl), nonresuscitated animals, and time control. Nitric oxide and heme oxygenase 1 levels were determined in plasma. Kidney immunohistochemistry (histologic scores of neutrophil gelatinase-associated lipocalin and tumor necrosis factor-alpha) and tubular histologic damages analyses were performed. RESULTS: Blood and diluted blood restored renal PO2 to 51 +/- 5 mmHg (mean difference, -18; 95% CI, -26 to -11; P < 0.0001) and 47 +/- 5 mmHg (mean difference, -23; 95% CI, -31 to -15; P < 0.0001), respectively, compared with 29 +/- 8 mmHg for hydroxyethyl starch. No differences between polyethylene-glycolated carboxyhemoglobin and hydroxyethyl starch were observed (33 +/- 7 mmHg vs. 29 +/- 8 mmHg; mean difference, -5; 95% CI, -12 to 3; P = 0.387), but significantly less volume was administered (4.5 [3.3-6.2] vs. 8.5[7.7-11.4] ml; mean rank difference, 11.98; P = 0.387). Blood and diluted blood increased the plasma bioavailability of nitric oxide compared with hydroxyethyl starch (mean rank difference, -20.97; P = 0.004; and -17.13; P = 0.029, respectively). No changes in heme oxygenase 1 levels were observed. Polyethylene-glycolated carboxyhemoglobin limited tubular histologic damages compared with hydroxyethyl starch (mean rank difference, 60.12; P = 0.0012) with reduced neutrophil gelatinase-associated lipocalin (mean rank difference, 84.43; P < 0.0001) and tumor necrosis factor-alpha (mean rank difference, 49.67; P = 0.026) histologic scores. CONCLUSIONS: Polyethylene-glycolated carboxyhemoglobin resuscitation did not improve renal PO2 but limited tubular histologic damages and neutrophil gelatinase-associated lipocalin upregulation after hemorrhage compared with hydroxyethyl starch, whereas a lower volume was required to sustain macrocirculation

Innovative Brain-Computer Interface based on motor cortex activity to detect accidental awareness during general anesthesia

International audienceAccidental Awareness during General Anesthesia (AAGA) occurs in 1-2% of high-risk practice patients and is responsible for severe psychological trauma, termed post-traumatic stress disorder (PTSD). Currently, monitoring techniques have limited accuracy in predicting or detecting AAGA. Since the first reflex of a patient experiencing AAGA is to move, a passive Brain-Computer Interface (BCI) based on the detection of an intention of movement would be conceivable to alert the anesthetist and prevent this phenomenon. However, the way in which the propofol (an anesthetic drug commonly used for inducing and maintaining general anesthesia) affects the motor brain activity and is reflected by the electroencephalo-graphic (EEG) signal has been poorly investigated and is not clearly understood. The goal of this forward-looking study is to investigate the motor activity behavior with step-wise increase of propofol doses in 4 healthy subjects and provide a proof of concept for such an innovative BCI

Detection of Motor Cerebral Activity After Median Nerve Stimulation During General Anesthesia (STIM-MOTANA): Protocol for a Prospective Interventional Study

International audienceBackground Accidental awareness during general anesthesia (AAGA) is defined as an unexpected awareness of the patient during general anesthesia. This phenomenon occurs in 1%-2% of high-risk practice patients and can cause physical suffering and psychological after-effects, called posttraumatic stress disorder. In fact, no monitoring techniques are satisfactory enough to effectively prevent AAGA; therefore, new alternatives are needed. Because the first reflex for a patient during an AAGA is to move, but cannot do so because of the neuromuscular blockers, we believe that it is possible to design a brain-computer interface (BCI) based on the detection of movement intention to warn the anesthetist. To do this, we propose to describe and detect the changes in terms of motor cortex oscillations during general anesthesia with propofol, while a median nerve stimulation is performed. We believe that our results could enable the design of a BCI based on median nerve stimulation, which could prevent AAGA. Objective To our knowledge, no published studies have investigated the detection of electroencephalographic (EEG) patterns in relation to peripheral nerve stimulation over the sensorimotor cortex during general anesthesia. The main objective of this study is to describe the changes in terms of event-related desynchronization and event-related synchronization modulations, in the EEG signal over the motor cortex during general anesthesia with propofol while a median nerve stimulation is performed. Methods STIM-MOTANA is an interventional and prospective study conducted with patients scheduled for surgery under general anesthesia, involving EEG measurements and median nerve stimulation at two different times: (1) when the patient is awake before surgery (2) and under general anesthesia. A total of 30 patients will receive surgery under complete intravenous anesthesia with a target-controlled infusion pump of propofol. Results The changes in event-related desynchronization and event-related synchronization during median nerve stimulation according to the various propofol concentrations for 30 patients will be analyzed. In addition, we will apply 4 different offline machine learning algorithms to detect the median nerve stimulation at the cerebral level. Recruitment began in December 2022. Data collection is expected to conclude in June 2024. Conclusions STIM-MOTANA will be the first protocol to investigate median nerve stimulation cerebral motor effect during general anesthesia for the detection of intraoperative awareness. Based on strong practical and theoretical scientific reasoning from our previous studies, our innovative median nerve stimulation–based BCI would provide a way to detect intraoperative awareness during general anesthesia. Trial Registration Clinicaltrials.gov NCT05272202; https://clinicaltrials.gov/ct2/show/NCT05272202 International Registered Report Identifier (IRRID) PRR1-10.2196/4387

Prognostic factors associated with mortality risk and disease progression in 639 critically ill patients with COVID-19 in Europe: Initial report of the international RISC-19-ICU prospective observational cohort

Background: Coronavirus disease 2019 (COVID-19) is associated with a high disease burden with 10% of confirmed cases progressing towards critical illness. Nevertheless, the disease course and predictors of mortality in critically ill patients are poorly understood. Methods: Following the critical developments in ICUs in regions experiencing early inception of the pandemic, the European-based, international RIsk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry was created to provide near real-time assessment of patients developing critical illness due to COVID-19. Findings: As of April 22, 2020, 639 critically ill patients with confirmed SARS-CoV-2 infection were included in the RISC-19-ICU registry. Of these, 398 had deceased or been discharged from the ICU. ICU-mortality was 24%, median length of stay 12 (IQR, 5–21) days. ARDS was diagnosed in 74%, with a minimum P/F-ratio of 110 (IQR, 80–148). Prone positioning, ECCO2R, or ECMO were applied in 57%. Off-label therapies were prescribed in 265 (67%) patients, and 89% of all bloodstream infections were observed in this subgroup (n = 66; RR=3·2, 95% CI [1·7–6·0]). While PCT and IL-6 levels remained similar in ICU survivors and non-survivors throughout the ICU stay (p = 0·35, 0·34), CRP, creatinine, troponin, D-dimer, lactate, neutrophil count, P/F-ratio diverged within the first seven days (p<0·01). On a multivariable Cox proportional-hazard regression model at admission, creatinine, D-dimer, lactate, potassium, P/F-ratio, alveolar-arterial gradient, and ischemic heart disease were independently associated with ICU-mortality. Interpretation: The European RISC-19-ICU cohort demonstrates a moderate mortality of 24% in critically ill patients with COVID-19. Despite high ARDS severity, mechanical ventilation incidence was low and associated with more rescue therapies. In contrast to risk factors in hospitalized patients reported in other studies, the main mortality predictors in these critically ill patients were markers of oxygenation deficit, renal and microvascular dysfunction, and coagulatory activation. Elevated risk of bloodstream infections underscores the need to exercise caution with off-label therapies

Dynamics of disease characteristics and clinical management of critically ill COVID-19 patients over the time course of the pandemic: an analysis of the prospective, international, multicentre RISC-19-ICU registry.

BACKGROUND It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic. METHODS Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic. RESULTS Four thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60-63] years vs 64 [62-66] years, p < 0.001) and the severity of organ dysfunction at ICU admission decreased (Sequential Organ Failure Assessment 8.2 [7.6-9.0] vs 5.8 [5.3-6.4], p < 0.001) and increased, while more female patients (26 [23-29]% vs 41 [35-48]%, p < 0.001) were admitted. The time span between symptom onset and hospitalization as well as ICU admission became longer later in the pandemic (6.7 [6.2-7.2| days vs 9.7 [8.9-10.5] days, p < 0.001). The PaO2/FiO2 at admission was lower (132 [123-141] mmHg vs 101 [91-113] mmHg, p < 0.001) but showed faster improvements over the initial 5 days of ICU stay in late 2021 compared to early 2020 (34 [20-48] mmHg vs 70 [41-100] mmHg, p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4-7]% vs 20 [14-29], p < 0.001) and non-invasive mechanical ventilation (14 [11-18]% vs 24 [17-33]%, p < 0.001) throughout the pandemic increased concomitant to a decrease in invasive mechanical ventilation (82 [76-86]% vs 74 [64-82]%, p < 0.001). The ICU mortality (23 [19-26]% vs 17 [12-25]%, p < 0.001) and length of stay (14 [13-16] days vs 11 [10-13] days, p < 0.001) decreased over 19 months of the pandemic. CONCLUSION Characteristics and disease course of critically ill COVID-19 patients have continuously evolved, concomitant to the clinical management, throughout the pandemic leading to a younger, less severely ill ICU population with distinctly different clinical, pulmonary and inflammatory presentations than at the onset of the pandemic

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Effets de thérapies actuelles et nouvelles sur la microcirculation sévèrement endommagée

For the past 20 years, the microcirculation has been regarded as cornerstone in the development of organ failure in critically ill patients. Eventually, the microcirculation became a therapeutic target. Due to the complexity of the microarchitecture of this functional system, varying across organs, one therapy cannot “fit all”. The alterations observed in the critically injured microcirculation involve: (i) the container defined by the different layers of the vascular wall including the endothelial cells and a protective gel called the glycocalyx spread on the surface, where contact with blood is made, (ii) the contents representing the flowing plasma and the different elements of blood and (iii) the extraluminal surrounding tissue. The microcirculation can be injured in various ways, with different levels of injury to these constitutive elements. Thus, to appropriately resuscitate the injured microcirculation, the choice of the optimal therapy or bundle of therapies should be rationalized with a meticulous analysis of the damages suffered by the microcirculation. The evaluation of the microcirculation should be multivariate. In this thesis, the research was mainly focused on the kidney. The first part is dedicated to the review of the structural and functional mechanisms of the renal microcirculation in both healthy and septic states. The second part tries to identify the respective roles of each of the components of the microcirculation in critical conditions especially the glycocalyx and plasma viscosity. The vascular barrier permeability was investigated in hemorrhagic shock and hemodilution models in rodents. The main findings suggest that a gradation in the level of injury to the vascular barrier permeability exist.The last part of the thesis investigated how current and older therapies can modulate microcirculation in terms of oxygenation, inflammation and microcirculatory flow within the kidney. Among therapies investigated, N-acetylcysteine was efficient at limiting inflammation and increasing oxygenation within the kidney. A new generation of hemoglobin-based oxygen carrier showed some efficacy in murine endotoxemic model. Overall, these different findings coalesce to show the importance of having a multivariate analysis of the microcirculation, as each of the therapies acts on a specific aspect of it. Hopefully, this research helped pave the way for a more personalized medicine for the patients.Au cours des 20 dernières années, la microcirculation a été considérée comme la pierre angulaire du développement de la défaillance d’organe chez les patients critiques. De toute évidence, la microcirculation est devenue une cible thérapeutique. En raison de la complexité de la microarchitecture de ce système fonctionnel, variant d'un organe à l'autre, une thérapie ne peut pas «convenir pour tout». Les altérations observées dans la microcirculation sevèrement endommagée sont de 3 ordres: (i) le contenant défini par les différentes couches de la paroi vasculaire, y compris les cellules endothéliales et un gel protecteur appelé glycocalyx répandu à la surface, où le contact avec le sang est établi, (ii) le contenu représentant le plasma qui coule avec les différents éléments figures du sang et (iii) les tissus extraluminaux environnants. La microcirculation peut être endommagée de diverses manières, avec différents niveaux de dommage à ces éléments constitutifs. Ainsi, pour réanimer de manière appropriée la microcirculation lésée, le choix de la thérapie optimale ou du faisceau de thérapies doit être rationalisé avec une analyse méticuleuse des dommages subis par la microcirculation. Ainsi, l'évaluation de la microcirculation doit être obligatoirement multivariée. Dans cette thèse, la recherche s'est principalement concentrée sur un organe, le rein. La première partie est consacrée à la revue des mécanismes structurels et fonctionnels de la microcirculation rénale en condition physiologique et également septique. La deuxième partie tente d'identifier les rôles respectifs de chacun des composants de la microcirculation dans des conditions critiques notamment le glycocalyx et la viscosité du plasma. La perméabilité de la barrière vasculaire a été étudiée dans les modèles de choc hémorragique et d'hémodilution chez les rongeurs. Les principaux résultats suggèrent qu'il existe une gradation du niveau de lésion de la barrière vasculaire. La dernière partie de la thèse a examiné comment les thérapies actuelles et anciennes peuvent moduler la microcirculation en termes d'oxygénation, d'inflammation et de flux microcirculatoire dans le rein. Parmi les thérapies étudiées, la N-acétylcystéine était efficace pour limiter l'inflammation et augmenter l'oxygénation dans le rein. Une nouvelle génération de transporteur d'oxygène à base d'hémoglobine a montré une certaine efficacité dans le modèle endotoxémique murin. Dans l'ensemble, ces différents résultats se rejoignent pour montrer l'importance d'avoir une analyse multivariée de la microcirculation, car chacune des thérapies agit sur un aspect spécifique de celle-ci. Nous espérons que les résultats de cette recherche ouvrent la voie à une médecine plus personnalisée pour les patients