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  • Preoperative sedentary behavior is neither a risk factor for perioperative neurocognitive disorders nor associated with an increase in peripheral inflammation, a prospective observational cohort study. BMC anesthesiology Saxena, S., Rodts, C., Nuyens, V., Lazaron, J., Sosnowski, V., Verdonk, F., Seidel, L., Albert, A., Boogaerts, J., Kruys, V., Maze, M., Vamecq, J. 2020; 20 (1): 284

    Abstract

    BACKGROUND: Surgical interventions result in a postoperative rise in circulating inflammatory cytokines and high molecular group box protein 1 (HMGB1). Herein, the impact of a sedentary lifestyle and other age-related factors on the development of perioperative neurocognitive disorders (PND) following non-cardiac surgical procedures was assessed in an older (55-75years-old) surgical population.METHODS: Prior to surgery, patients were asked questions regarding their sedentary behavior and daily habits. They also passed the Mini Mental State Examination (MMSE) and their blood circulating interleukin 6 (IL-6) and HMGB1 levels were assayed by ELISA. IL-6 and HMGB1 measurements were repeated respectively 6 and 24h after surgery. MMSE was re-evaluated 6weeks and whenever possible 3months after surgery.RESULTS: Thirty-eight patients were enrolled in the study from January until July 2019. The study identified self-sufficiency, multilinguism, and overall health score on the geriatric depression scale, as protectors against PND. No other demographic (age, sex), environmental (solitary/non-solitary housing, professional and physical activities, smoking, alcohol drinking), comorbidity (antipsychotic drug uptake, diabetic state) and type of surgery (orthopedic, general, genitourinary) influenced the development of PND. Although some factors (surgery type and age) influenced the surgery-induced rise in the circulating IL-6 levels, they did not impact HMGB1.CONCLUSION: Inflammaging, reflected by the greater increment of surgery-induced IL-6 in patients with advanced age, was present. As trauma-induced release of HMGB1 was not similarly affected by age, we surmise that HMGB1, rather than circulating cytokines, is the key driver of the trauma-induced inflammatory cascade leading to PND.TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03805685 .

    View details for DOI 10.1186/s12871-020-01200-w

    View details for PubMedID 33187477

  • The serotonin 2B receptor is required in neonatal microglia to limit neuroinflammation and sickness behavior in adulthood GLIA Bechade, C., D'Andrea, I., Etienne, F., Verdonk, F., Moutkine, I., Banas, S. M., Kolodziejczak, M., Diaz, S. L., Parkhurst, C. N., Gan, W. B., Maroteaux, L., Roumier, A. 2020

    Abstract

    Severe peripheral infections induce an adaptive sickness behavior and an innate immune reaction in various organs including the brain. On the long term, persistent alteration of microglia, the brain innate immune cells, is associated with an increased risk of psychiatric disorders. It is thus critical to identify genes and mechanisms controlling the intensity and duration of the neuroinflammation induced by peripheral immune challenges. We tested the hypothesis that the 5-HT2B receptor, the main serotonin receptor expressed by microglia, might represent a valuable candidate. First, we observed that Htr2b-/- mice, knock-out for the 5-HT2B receptor gene, developed, when exposed to a peripheral lipopolysaccharide (LPS) challenge, a stronger weight loss compared to wild-type mice; in addition, comparison of inflammatory markers in brain, 4 and 24 hr after LPS injection, showed that Htr2b deficiency leads to a prolonged neuroinflammation. Second, to assess the specific contribution of the microglial 5-HT2B receptor, we investigated the response to LPS of conditional knock-out mice invalidated for Htr2b in microglia only. We found that deletion of Htr2b in microglia since birth is sufficient to cause enhanced weight loss and increased neuroinflammatory response upon LPS injection at adult stage. In contrast, mice deleted for microglial Htr2b in adulthood responded normally to LPS, revealing a neonatal developmental effect. These results highlight the role of microglia in the response to a peripheral immune challenge and suggest the existence of a developmental, neonatal period, during which instruction of microglia through 5-HT2B receptors is necessary to prevent microglia overreactivity in adulthood.

    View details for DOI 10.1002/glia.23918

    View details for Web of Science ID 000581135800001

    View details for PubMedID 33095507

  • Nutritional support for critically ill patients with COVID-19: New strategy for a new disease? Anaesthesia, critical care & pain medicine Pardo, E., Constantin, J., Bonnet, F., Verdonk, F. 2020

    View details for DOI 10.1016/j.accpm.2020.10.002

    View details for PubMedID 33059104

  • Impact of Regional Block Failure in Ambulatory Hand Surgery on Patient Management: A Cohort Study. Journal of clinical medicine Picard, L., Belnou, P., Debes, C., Lapidus, N., Sung Tsai, E., Gaillard, J., Sautet, A., Bonnet, F., Lescot, T., Verdonk, F. 2020; 9 (8)

    Abstract

    Regional anesthesia (RA) is an anesthetic technique essential for the performance of ambulatory surgery. Failure rates range from 6% to 20%, and the consequences of these failures have been poorly investigated. We determined the incidence and the impact of regional block failure on patient management in the ambulatory setting. This retrospective cohort study includes all adult patients who were admitted to a French University Hospital (Hopital Saint-Antoine, AP-HP) between 1 January 2016 and 31 December 2017 for unplanned ambulatory distal upper limb surgery. Univariate and stepwise multivariate analyses were performed to determine factors associated with block failure. Among the 562 patients included, 48 (8.5%) had a block failure. RA failure was associated with a longer surgery duration (p = 0.02), more frequent intraoperative analgesics administration (p < 0.01), increased incidence of unplanned hospitalizations (p < 0.001), and a 39% prolongation of Post-Anesthesia Care Unit (PACU) length of stay (p < 0.0001). In the multivariate analysis, the risk factors associated with block failure were female sex (p = 0.04), an American Society of Anesthesiologists (ASA) score > 2 (p = 0.03), history of substance abuse (p = 0.01), and performance of the surgery outside of the specific ambulatory surgical unit (p = 0.01). Here, we have documented a significant incidence of block failure in ambulatory hand surgery, with impairment in the organization of care. Identifying patients at risk of failure could help improve their management, especially by focusing on providing care in a dedicated ambulatory circuit.

    View details for DOI 10.3390/jcm9082453

    View details for PubMedID 32751880

  • How machine learning could be used in clinical practice during an epidemic. Critical care (London, England) Verdonk, C., Verdonk, F., Dreyfus, G. 2020; 24 (1): 265

    View details for DOI 10.1186/s13054-020-02962-y

    View details for PubMedID 32456690

  • VoPo leverages cellular heterogeneity for predictive modeling of single-cell data. Nature communications Stanley, N., Stelzer, I. A., Tsai, A. S., Fallahzadeh, R., Ganio, E., Becker, M., Phongpreecha, T., Nassar, H., Ghaemi, S., Maric, I., Culos, A., Chang, A. L., Xenochristou, M., Han, X., Espinosa, C., Rumer, K., Peterson, L., Verdonk, F., Gaudilliere, D., Tsai, E., Feyaerts, D., Einhaus, J., Ando, K., Wong, R. J., Obermoser, G., Shaw, G. M., Stevenson, D. K., Angst, M. S., Gaudilliere, B., Aghaeepour, N. 2020; 11 (1): 3738

    Abstract

    High-throughput single-cell analysis technologies produce an abundance of data that is critical for profiling the heterogeneity of cellular systems. We introduce VoPo (https://github.com/stanleyn/VoPo), a machine learning algorithm for predictive modeling and comprehensive visualization of the heterogeneity captured in large single-cell datasets. In three mass cytometry datasets, with the largest measuring hundreds of millions of cells over hundreds of samples, VoPo defines phenotypically and functionally homogeneous cell populations. VoPo further outperforms state-of-the-art machine learning algorithms in classification tasks, and identified immune-correlates of clinically-relevant parameters.

    View details for DOI 10.1038/s41467-020-17569-8

    View details for PubMedID 32719375

  • Ketamine/xylazine and barbiturates modulate microglial morphology and motility differently in a mouse model. PloS one Hristovska, I., Verdonk, F., Comte, J. C., Tsai, E. S., Desestret, V., Honnorat, J., Chrétien, F., Pascual, O. 2020; 15 (8): e0236594

    Abstract

    Microglia, the resident immune cells of the brain, are highly ramified and motile and their morphology is strongly linked to their function. Microglia constantly monitor the brain parenchyma and are crucial for maintaining brain homeostasis and fine-tuning neuronal networks. Besides affecting neurons, anesthetics may have wide-ranging effects mediated by non-neuronal cells and in particular microglia. We thus examined the effect of two commonly used anesthetic agents, ketamine/xylazine and barbiturates, on microglial motility and morphology. A combination of two-photon in vivo imaging and electroencephalography (EEG) recordings in unanesthetized and anesthetized mice as well as automated analysis of ex vivo sections were used to assess morphology and dynamics of microglia. We found that administration of ketamine/xylazine and pentobarbital anesthesia resulted in quite distinct EEG profiles. Both anesthetics reduced microglial motility, but only ketamine/xylazine administration led to reduction of microglial complexity in vivo. The change of cellular dynamics in vivo was associated with a region-dependent reduction of several features of microglial cells ex vivo, such as the complexity index and the ramification length, whereas thiopental altered the size of the cytoplasm. Our results show that anesthetics have considerable effects on neuronal activity and microglial morphodynamics and that barbiturates may be a preferred anesthetic agent for the study of microglial morphology. These findings will undoubtedly raise compelling questions about the functional relevance of anesthetics on microglial cells in neuronal physiology and anesthesia-induced neurotoxicity.

    View details for DOI 10.1371/journal.pone.0236594

    View details for PubMedID 32760073

  • Virtual Reality for PEripheral Regional Anesthesia (VR-PERLA Study). Journal of clinical medicine Alaterre, C., Duceau, B., Sung Tsai, E., Zriouel, S., Bonnet, F., Lescot, T., Verdonk, F. 2020; 9 (1)

    Abstract

    When used as an add-on to regional anesthesia, virtual reality (VR) has been reported to provide anxiety-reducing benefits and sedation-sparing effects. However, its impact on patient satisfaction is still a matter of controversy. We investigated the feasibility and benefits of implementing intraoperative VR distraction in a French University Hospital (Hôpital Saint-Antoine, AP-HP). This monocentric observational before-after study included 100 patients who underwent ambulatory upper limb surgery under peripheral nerve block in January 2019, 50 before and 50 after implementation of an intraoperative VR distraction protocol. Primary outcome was patient self-rated satisfaction score evaluated right after surgery. Secondary outcomes included 2-month patient-reported satisfaction score, perioperative self-rated anxiety and intraoperative hemodynamic changes. Compared to former standard care, VR distraction was associated with significantly higher postoperative satisfaction scores (10 [IQR 9; 10] vs. 9 [8; 10], p < 0.001) still reported two months after surgery (10 [10;10] vs. 10 [8.5;10], p = 0.06). Patient median intraoperative anxiety score was lower in the VR group, compared to Standard Care group (0 [0; 2] vs. 3 [0.25; 7], p < 0.001), and occurrence of intraoperative hemodynamic changes was also lessened in the VR group (2% vs. 16%, 0R = 0.11[95% CI 0.002-0.87], p = 0.031). The present findings suggest that VR distraction program in the operating room could effectively improve patient satisfaction with anxiety-reduction and hemodynamic benefits.

    View details for DOI 10.3390/jcm9010215

    View details for PubMedID 31941129

  • Non-invasive ventilation for acute respiratory failure (in COVID-19 patients): the non-ending story? Anaesthesia, critical care & pain medicine James, A., Verdonk, F., Bougle, A., Constantin, J. M. 2020; 39 (5): 549?50

    View details for DOI 10.1016/j.accpm.2020.08.004

    View details for PubMedID 32860987

    View details for PubMedCentralID PMC7449884

  • [Neurological complications of COVID-19]. Le praticien en anesthesie reanimation Flis-Richard, H., Verdonk, F. 2020; 24 (4): 186?89

    Abstract

    Neurological manifestations are likely to be more frequent and complex during COVID-19 than originally anticipated.

    View details for DOI 10.1016/j.pratan.2020.07.008

    View details for PubMedID 32837213

    View details for PubMedCentralID PMC7351425

  • Minimal alveolar concentration for deep sedation (MAC-DS) in intensive care unit patients sedated with sevoflurane: A physiological study. Anaesthesia, critical care & pain medicine Blanchard, F., Perbet, S., James, A., Verdonk, F., Godet, T., Bazin, J. E., Pereira, B., Lambert, C., Constantin, J. M. 2020; 39 (3): 429?34

    Abstract

    Volatile anaesthetic agents, especially sevoflurane, could be an alternative for sedating ICU patients. In the operating theatre, volatile anaesthetic agents are monitored using minimal alveolar concentration (MAC). In ICU, MAC may be used to assess sedation level and may replace clinical scale especially when they are unusable. Therefore, we sought to investigate the minimal sevoflurane end-tidal concentration to achieved deep sedation in critical ill patients: MAC-deep sedation (MAC-DS).In a prospective interventional study, we included patients with a Richmond Assessment Sedation Score (RASS) of 0 without any sedation. We stepwise increased sevoflurane concentration level before assessing for deep sedation (RASS?-3). MAC-DS was defined as the minimal sevoflurane MAC fraction or sevoflurane expiratory fraction (FeSevo) to get 90% and 95% of patients in deep sedation (MAC-DS 90 and MAC-DS 95, respectively).Between June and November 2014, 30 patients were included (median age=60 years [interquartile range: 47-69]). Increasing sevoflurane MAC was correlated with a decrease in RASS values (r=-0.83, P<0.001). MAC-DS 90 and MAC-DS 95 were achieved at 0.42 MAC (CI 95 [0.38-0.46]) and 0.46 MAC (CI 95 [0.42-0.51]), respectively. FeSevo to achieve MAC-DS 90 and MAC-DS 95 was 0.72 (CI 95 [0.65-0.79]) and 0.80 (CI 95 [0.72-0.89]), respectively.In this physiological study involving 30 ICU patients, MAC-DS, end-tidal sevoflurane concentration to get 95% of patients in deep sedation determined over more than 500 observations, is achieved at 0.8% of expired fraction of sevoflurane or at 0.5 age-adjusted MAC.

    View details for DOI 10.1016/j.accpm.2020.04.002

    View details for PubMedID 32376244

  • Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma. Nature communications Ganio, E. A., Stanley, N., Lindberg-Larsen, V., Einhaus, J., Tsai, A. S., Verdonk, F., Culos, A., Gahemi, S., Rumer, K. K., Stelzer, I. A., Gaudilliere, D., Tsai, E., Fallahzadeh, R., Choisy, B., Kehlet, H., Aghaeepour, N., Angst, M. S., Gaudilliere, B. 2020; 11 (1): 3737

    Abstract

    Glucocorticoids (GC) are a controversial yet commonly used intervention in the clinical management of acute inflammatory conditions, including sepsis or traumatic injury. In the context of major trauma such as surgery, concerns have been raised regarding adverse effects from GC, thereby necessitating a better understanding of how GCs modulate the immune response. Here we report the results of a randomized controlled trial (NCT02542592) in which we employ a high-dimensional mass cytometry approach to characterize innate and adaptive cell signaling dynamics after a major surgery (primary outcome) in patients treated with placebo or methylprednisolone (MP). A robust, unsupervised bootstrap clustering of immune cell subsets coupled with random forest analysis shows profound (AUC?=?0.92, p-value?=?3.16E-8) MP-induced alterations of immune cell signaling trajectories, particularly in the adaptive compartments. By contrast, key innate signaling responses previously associated with pain and functional recovery after surgery, including STAT3 and CREB phosphorylation, are not affected by MP. These results imply cell-specific and pathway-specific effects of GCs, and also prompt future studies to examine GCs' effects on clinical outcomes likely dependent on functional adaptive immune responses.

    View details for DOI 10.1038/s41467-020-17565-y

    View details for PubMedID 32719355

  • Author Correction: Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma. Nature communications Ganio, E. A., Stanley, N., Lindberg-Larsen, V., Einhaus, J., Tsai, A. S., Verdonk, F., Culos, A., Ghaemi, S., Rumer, K. K., Stelzer, I. A., Gaudilliere, D., Tsai, E., Fallahzadeh, R., Choisy, B., Kehlet, H., Aghaeepour, N., Angst, M. S., Gaudilliere, B. 2020; 11 (1): 4495

    Abstract

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    View details for DOI 10.1038/s41467-020-18410-y

    View details for PubMedID 32883978

  • Beneficial role of adipose-derived mesenchymal stem cells from microfragmented fat in a murine model of duchenne muscular dystrophy. Muscle & nerve Bouglé, A., Rocheteau, P., Briand, D., Hardy, D., Verdonk, F., Tremolada, C., Hivelin, M., Chrétien, F. 2019; 60 (3): 328?35

    Abstract

    No etiologic therapy is available for Duchenne muscular dystrophy (DMD), but mesenchymal stem cells were shown to be effective in preclinical models of DMD. The objective of this study is to investigate the effect of microfragmented fat extracted on a murine model of DMD.Fat tissue was extracted from healthy human participants and injected IM into DMD mice. Histological analysis, cytokines, and force measurement were performed up to 4 weeks after injection.Duchenne muscular dystrophy mice injected with microfragmented fat exhibited an improved muscle phenotype (decreased necrosis and fibrosis), a decrease of inflammatory cytokines, and increased strength.Administration of microfragmented fat in key muscles may improve muscular phenotype in patients with DMD. Muscle Nerve, 2019.

    View details for DOI 10.1002/mus.26614

    View details for PubMedID 31228273

  • Decreased microglial Wnt/?-catenin signalling drives microglial pro-inflammatory activation in the developing brain. Brain : a journal of neurology Van Steenwinckel, J., Schang, A. L., Krishnan, M. L., Degos, V., Delahaye-Duriez, A., Bokobza, C., Csaba, Z., Verdonk, F., Montané, A., Sigaut, S., Hennebert, O., Lebon, S., Schwendimann, L., Le Charpentier, T., Hassan-Abdi, R., Ball, G., Aljabar, P., Saxena, A., Holloway, R. K., Birchmeier, W., Baud, O., Rowitch, D., Miron, V., Chretien, F., Leconte, C., Besson, V. C., Petretto, E. G., Edwards, A. D., Hagberg, H., Soussi-Yanicostas, N., Fleiss, B., Gressens, P. 2019; 142 (12): 3806?33

    Abstract

    Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/?-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.

    View details for DOI 10.1093/brain/awz319

    View details for PubMedID 31665242

    View details for PubMedCentralID PMC6906599

  • Sedation versus general anaesthesia in endovascular therapy for anterior circulation acute ischaemic stroke: the multicentre randomised controlled AMETIS trial study protocol. BMJ open Chabanne, R., Fernandez-Canal, C., Degos, V., Lukaszewicz, A. C., Velly, L., Mrozek, S., Perrigault, P. F., Molliex, S., Tavernier, B., Dahyot-Fizelier, C., Verdonk, F., Caumon, E., Masgrau, A., Begard, M., Chabert, E., Ferrier, A., Jaber, S., Bazin, J. E., Pereira, B., Futier, E. 2019; 9 (9): e027561

    Abstract

    Endovascular thrombectomy is the standard of care for anterior circulation acute ischaemic stroke (AIS) secondary to emergent large vessel occlusion in patients who qualify. General anaesthesia (GA) or conscious sedation (CS) is usually required to ensure patient comfort and avoid agitation and movement during thrombectomy. However, the question of whether the use of GA or CS might influence functional outcome remains debated. Indeed, conflicting results exist between observational studies with better outcomes associated with CS and small monocentric randomised controlled trials favouring GA. Therefore, we aim to evaluate the effect of CS versus GA on functional outcome and periprocedural complications in endovascular mechanical thrombectomy for anterior circulation AIS.Anesthesia Management in Endovascular Therapy for Ischemic Stroke (AMETIS) trial is an investigator initiated, multicentre, prospective, randomised controlled, two-arm trial. AMETIS trial will randomise 270 patients with anterior circulation AIS in a 1:1 ratio, stratified by centre, National Institutes of Health Stroke Scale (?15?or >15) and association of intravenous thrombolysis or not to receive either CS or GA. The primary outcome is a composite of functional independence at 3 months and absence of perioperative complication occurring by day 7 after endovascular therapy for anterior circulation AIS. Functional independence is defined as a modified Rankin Scale score of 0-2 by day 90. Perioperative complications are defined as intervention-associated arterial perforation or dissection, pneumonia or myocardial infarction or cardiogenic acute pulmonary oedema or malignant stroke evolution occurring by day 7.The AMETIS trial was approved by an independent ethics committee. Study began in august 2017. Results will be published in an international peer-reviewed medical journal.NCT03229148.

    View details for DOI 10.1136/bmjopen-2018-027561

    View details for PubMedID 31519668

    View details for PubMedCentralID PMC6747652

  • Publication outcome of abstracts presented at an Anesthesiology and Critical Care Medicine meeting: Does being a junior presenter matter? Journal of clinical anesthesia Mongardon, N., Bouglé, A., Sola, C., Bouroche, G., Verdonk, F., Le Gall, A., Bataille, A., Beylacq, L., Bourgeois, E., Charbit, J., Guerci, P., Chousterman, B. G. 2019; 60: 49?50

    View details for DOI 10.1016/j.jclinane.2019.08.019

    View details for PubMedID 31445178

  • Microglial production of quinolinic acid as a target and a biomarker of the antidepressant effect of ketamine. Brain, behavior, and immunity Verdonk, F., Petit, A. C., Abdel-Ahad, P., Vinckier, F., Jouvion, G., de Maricourt, P., De Medeiros, G. F., Danckaert, A., Van Steenwinckel, J., Blatzer, M., Maignan, A., Langeron, O., Sharshar, T., Callebert, J., Launay, J. M., Chrétien, F., Gaillard, R. 2019; 81: 361?73

    Abstract

    Major depressive disorder is a complex multifactorial condition with a so far poorly characterized underlying pathophysiology. Consequently, the available treatments are far from satisfactory as it is estimated that up to 30% of patients are resistant to conventional treatment. Recent comprehensive evidence has been accumulated which suggests that inflammation may be implied in the etiology of this disease. Here we investigated ketamine as an innovative treatment strategy due to its immune-modulating capacities. In a murine model of LPS-induced depressive-like behavior we demonstrated that a single dose of ketamine restores the LPS-induced depressive-like alterations. These behavioral effects are associated with i/ a reversal of anxiety and reduced self-care, ii/ a decrease in parenchymal cytokine production, iii/ a modulation of the microglial reactivity and iv/ a decrease in microglial quinolinic acid production that is correlated with plasmatic peripheral production. In a translational approach, we show that kynurenic acid to quinolinic acid ratio is a predictor of ketamine response in treatment-resistant depressed patients and that the reduction in quinolinic acid after a ketamine infusion is a predictor of the reduction in MADRS score. Our results suggest that microglia is a key therapeutic target and that quinolinic acid is a biomarker of ketamine response in major depressive disorder.

    View details for DOI 10.1016/j.bbi.2019.06.033

    View details for PubMedID 31255681

  • Implementation of a novel synchronous multi-site all day high-fidelity simulation. Advances in simulation (London, England) Abraham, P., Verdonk, F., Buleon, C., Tesniere, A., Lilot, M. 2018; 3: 2

    Abstract

    Integration of simulation in educational curricula for anesthesia and intensive care residents is a hot topic. There is a great interest for simulation centers to share their experiences through multi-site synchronous simulation sessions. The present study results from an experience conducted at three sites in France (Paris, Lyon, and Caen), which involved 16 instructors and 25 residents facing the same scenario across 1 day. Synchronous simulations were performed at each site with local and shared debriefing via teleconference. This innovative approach to simulation was found to be feasible, although certain difficulties were encountered with connectivity.

    View details for DOI 10.1186/s41077-018-0063-8

    View details for PubMedID 29450028

    View details for PubMedCentralID PMC5810051

  • Reliability of ultrasound measurements of quadriceps muscle thickness in critically ill patients. BMC anesthesiology Pardo, E., El Behi, H., Boizeau, P., Verdonk, F., Alberti, C., Lescot, T. 2018; 18 (1): 205

    Abstract

    Muscle wasting in critically ill patients is associated with negative clinical outcomes. Ultrasound quadriceps femoris muscle assessment may constitute a convenient tool to evaluate muscle wasting. Nevertheless, its reliability remains uncertain. Our primary aim was to study the intra- and inter-observer reliability of this technique. Our secondary aim was to assess the evolution of the quadriceps muscle during the first 3 weeks after ICU admission and its possible association with nutritional intake.This observational study included patients expected to stay more than 7?days in the ICU. Ultrasound quadriceps muscle thickness was measured with a 12?MHz linear transducer, by two trained physicians, on D1, D3, D5, D7 and D21. Two measurements sites were evaluated: on the midpoint or on the two-thirds of the length between the anterior superior iliac spine and the upper border of the patella. Intra and inter-observer reliability was assessed by calculating the intra-class correlation coefficient (ICC).A total of 280 ultrasound quadriceps thickness measurements were performed on 29 critically ill patients. Intra-observer reliability's ICC was 0.74 [95% CI 0.63; 0.84] at the "midpoint" site and 0.83 [95% CI 0.75; 0.9] at the "two-thirds" site. Inter-observer reliability's ICC was 0.76 [95% CI, 0.66; 0.86] at the "midpoint" site and 0.81 [95% CI, 0.7; 0.9] at the "two-thirds" site. Quadriceps femoris muscle thickness decreased over 16% within the first week after ICU admission. No correlation was found between muscle loss and caloric (p?=?0.96) or protein (p?=?0.80) debt over the first week.The assessment by ultrasonography of the quadriceps muscle thickness reveals good intra- and inter-observer reliability and may constitute a promising tool to evaluate the effect of nutritional-based interventions on muscle wasting in critically ill patients."Committee for the Protection of Human Subjects in Biomedical Research" - Paris Ile de France VI Pitié-Salpêtrière - 10/07/2014. French Data Protection Committee ("Commission Nationale Informatique et Libertés") - #1771144.

    View details for DOI 10.1186/s12871-018-0647-9

    View details for PubMedID 30591032

    View details for PubMedCentralID PMC6309087

  • Minimally invasive drainage in critically ill patients with severe necrotizing pancreatitis is associated with better outcomes: an observational study. Critical care (London, England) Darrivere, L., Lapidus, N., Colignon, N., Chafai, N., Chaput, U., Verdonk, F., Paye, F., Lescot, T. 2018; 22 (1): 321

    Abstract

    Infected pancreatic necrosis, which occurs in about 40% of patients admitted for acute necrotizing pancreatitis, requires combined antibiotic therapy and local drainage. Since 2010, drainage by open surgical necrosectomy has been increasingly replaced by less invasive methods such as percutaneous radiological drainage, endoscopic necrosectomy, and laparoscopic surgery, which proved effective in small randomized controlled trials in highly selected patients. Few studies have evaluated minimally invasive drainage methods used under the conditions of everyday hospital practice. The aim of this study was to determine whether, compared with conventional open surgery, minimally invasive drainage was associated with improved outcomes of critically ill patients with infection complicating acute necrotizing pancreatitis.A single-center observational study was conducted in patients admitted to the intensive care unit for severe acute necrotizing pancreatitis to compare the characteristics, drainage techniques, and outcomes of the 62 patients managed between September 2006 and December 2010, chiefly with conventional open surgery, and of the 81 patients managed between January 2011 and August 2015 after the introduction of a minimally invasive drainage protocol.Surgical necrosectomy was more common in the early period (74% versus 41%; P?<0.001), and use of minimally invasive drainage increased between the early and late periods (19% and 52%, respectively; P?<0.001). The numbers of ventilator-free days and catecholamine-free days by day 30 were higher during the later period. The proportions of patients discharged from intensive care within the first 30?days and from the hospital within the first 90?days were higher during the second period. Hospital mortality was not significantly different between the early and late periods (19% and 22%, respectively).In our study, the implementation of a minimally invasive drainage protocol in patients with infected pancreatic necrosis was associated with shorter times spent with organ dysfunction, in the intensive care unit, and in the hospital. Mortality was not significantly different. These results should be interpreted bearing in mind the limitations inherent in the before-after study design.

    View details for DOI 10.1186/s13054-018-2256-x

    View details for PubMedID 30466472

    View details for PubMedCentralID PMC6249885

  • Low doses of ketamine reduce delirium but not opiate consumption in mechanically ventilated and sedated ICU patients: A randomised double-blind control trial. Anaesthesia, critical care & pain medicine Perbet, S., Verdonk, F., Godet, T., Jabaudon, M., Chartier, C., Cayot, S., Guerin, R., Morand, D., Bazin, J. E., Futier, E., Pereira, B., Constantin, J. M. 2018; 37 (6): 589?95

    Abstract

    Low doses of ketamine are commonly used to decrease opiates tolerance, hyperalgesia and delirium in perioperative theatre but these properties have never been studied in intensive care unit (ICU) patients.To determine the impact of ketamine infusion on opiates consumption when added to standard care in ICU patients requiring sedation for mechanical ventilation.Patients admitted in a general ICU of a university hospital and undergoing mechanical ventilation (n?=?162) with nurse-driven sedation protocol were randomly assigned into ketamine (2?mg/kg/h) or placebo in a double-blinded control trial. Patients were assessed for sedation and analgesia levels, opiates consumption and delirium (using the Confusion Assessment Method for ICU).Daily consumption of remifentanil (7.9?±?1.0 vs. 9.3?±?1.0??g/kg/h, P?=?0.548) and increase in remifentanil doses required for equianalgesia (0.107?±?0.17 and 0.11?±?0.18??g/kg/min, P?=?0.78) were not different between ketamine and control groups. The incidence was higher in the placebo group 30/82 (37%) than in the ketamine group 17/80 (21%) (P?=?0.03). The duration of delirium was lower in ketamine group (5.3?±?4.7 vs. 2.8?±?3 days, P?=?0.005). Mortality rates, ventilator-free days and ICU length of stay (LOS) were non-statistically different in both groups.When the best practices of sedation (nurse-driven sedation, a consistent light-to-moderate sedation level, and delirium monitoring) are used for all patients, the addition of low doses of ketamine does not decrease opiate consumption but reduces delirium incidence and its duration in medico-surgical ICU patients with no effect on mortality rate and ICU LOS.

    View details for DOI 10.1016/j.accpm.2018.09.006

    View details for PubMedID 30268528

  • Statins prevent cognitive impairment after sepsis by reverting neuroinflammation, and microcirculatory/endothelial dysfunction. Brain, behavior, and immunity Reis, P. A., Alexandre, P. C., D'Avila, J. C., Siqueira, L. D., Antunes, B., Estato, V., Tibiriça, E. V., Verdonk, F., Sharshar, T., Chrétien, F., Castro-Faria-Neto, H. C., Bozza, F. A. 2017; 60: 293?303

    Abstract

    Acute brain dysfunction is a frequent condition in sepsis patients and is associated with increased mortality and long-term neurocognitive consequences. Impaired memory and executive function are common findings in sepsis survivors. Although neuroinflammation and blood-brain barrier dysfunction have been associated with acute brain dysfunction and its consequences, no specific treatments are available that prevent cognitive impairment after sepsis. Experimental sepsis was induced in Swiss Webster mice by intraperitoneal injection of cecal material (5mg/kg, 500?L). Control groups (n=5/group each experiment) received 500?L of saline. Support therapy recover (saline 0.9%, 1mL and imipenem 30mg/kg) were applied (6, 24 and 48h post injection, n=5-10/group, each experiment), together or not with additive orally treatment with statins (atorvastatin/simvastatin 20mg/kg b.w.). Survival rate was monitored at 6, 24 and 48h. In a setting of experiments, animals were euthanized at 6 and 24h after induction for biochemical, immunohistochemistry and intravital analysis. Statins did not prevented mortality in septic mice, however survivors presented lower clinical score. At another setting of experiments, after 15days, mice survivors from fecal supernatant peritoneal sepsis presented cognitive dysfunction for contextual hippocampal and aversive amygdala-dependent memories, which was prevented by atorvastatin/simvastatin treatment. Systemic and brain tissue levels of proinflammatory cytokines/chemokines and activation of microglial were lower in septic mice treated with statins. Brain lipid peroxidation and myeloperoxidase levels were also reduced by statins treatment. Intravital examination of the brain vessels of septic animals revealed decreased functional capillary density and increased rolling and adhesion of leukocytes, and blood flow impairment, which were reversed by treatment with statins. In addition, treatment with statins restored the cholinergic vasodilator response due to sepsis. Taken together, these data demonstrated that statins reverse microvascular dysfunction and reduce neuroinflammation during sepsis, preventing the development of long-term cognitive decline.

    View details for DOI 10.1016/j.bbi.2016.11.006

    View details for PubMedID 27833044

  • A novel paradigm links mitochondrial dysfunction with muscle stem cell impairment in sepsis. Biochimica et biophysica acta. Molecular basis of disease Chatre, L., Verdonk, F., Rocheteau, P., Crochemore, C., Chrétien, F., Ricchetti, M. 2017; 1863 (10 Pt B): 2546?53

    Abstract

    Sepsis is an acute systemic inflammatory response of the body to microbial infection and a life threatening condition associated with multiple organ failure. Survivors may display long-term disability with muscle weakness that remains poorly understood. Recent data suggest that long-term myopathy in sepsis survivors is due to failure of skeletal muscle stem cells (satellite cells) to regenerate the muscle. Satellite cells impairment in the acute phase of sepsis is linked to unusual mitochondrial dysfunctions, characterized by a dramatic reduction of the mitochondrial mass and hyperactivity of residual organelles. Survivors maintain the impairment of satellite cells, including alterations of the mitochondrial DNA (mtDNA), in the long-term. This condition can be rescued by treatment with mesenchymal stem cells (MSCs) that restore mtDNA alterations and mitochondrial function in satellite cells, and in fine their regenerative potential. Injection of MSCs in turn increases the force of isolated muscle fibers and of the whole animal, and improves the survival rate. These effects occur in the context of reduced inflammation markers that also raised during sepsis. Targeting muscle stem cells mitochondria, in a context of reduced inflammation, may represent a valuable strategy to reduce morbidity and long-term impairment of the muscle upon sepsis.

    View details for DOI 10.1016/j.bbadis.2017.04.019

    View details for PubMedID 28456665

  • Neuroanatomy of sepsis-associated encephalopathy. Critical care (London, England) Heming, N., Mazeraud, A., Verdonk, F., Bozza, F. A., Chrétien, F., Sharshar, T. 2017; 21 (1): 65

    Abstract

    This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2017. Other selected articles can be found online at http://ccforum.com/series/annualupdate2017 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .Originally published in the Annual Update in Intensive Care and Emergency Medicine 2017. The number of authors differs in the two versions due to constraints regarding the number of authors in the Annual Update in Intensive Care and Emergency Medicine. In the Annual Update version of the review, the three senior authors appear in the acknowledgement section. In the Critical Care version, these three senior authors appear as full authors of the manuscript. All authors helped draft and revise the manuscript for critical intellectual content.

    View details for DOI 10.1186/s13054-017-1643-z

    View details for PubMedID 28320461

    View details for PubMedCentralID PMC5360026

  • The new sepsis definition: limitations and contribution to research and diagnosis of sepsis. Current opinion in anaesthesiology Verdonk, F., Blet, A., Mebazaa, A. 2017; 30 (2): 200?204

    Abstract

    Based on recent clinical, epidemiological, and pathophysiological data, a third international consensus conference was carried out to define new criteria of sepsis in February 2016. This review presents the different items of this new definition, their limitations and their contribution to research and diagnosis of sepsis, in comparison with the previous definitions.Incidence, management, and pathophysiological knowledge of sepsis have improved over the past 20 years. However, sepsis still evolves to a mortal outcome, in one case out of five, with no new recent or specific therapy showing its efficacy on the patient's prognosis. These findings have led to the development of new definition.The new definition of sepsis incorporates relevant clinical and biological criteria such as SOFA score or serum lactate levels. It no longer takes into account the items of the systemic inflammatory response syndrome, which present a lack of specificity. It also simplifies the different stages of severity by deleting the term of 'severe sepsis' and by defining septic shock as a subset of sepsis. This definition, endorsed by only two international societies of intensive care, has some limitations and so merits prospective validation at different levels.

    View details for DOI 10.1097/ACO.0000000000000446

    View details for PubMedID 28207566

  • Neuroanatomy and Physiology of Brain Dysfunction in Sepsis. Clinics in chest medicine Mazeraud, A., Pascal, Q., Verdonk, F., Heming, N., Chrétien, F., Sharshar, T. 2016; 37 (2): 333?45

    Abstract

    Sepsis-associated encephalopathy (SAE), a complication of sepsis, is often complicated by acute and long-term brain dysfunction. SAE is associated with electroencephalogram pattern changes and abnormal neuroimaging findings. The major processes involved are neuroinflammation, circulatory dysfunction, and excitotoxicity. Neuroinflammation and microcirculatory alterations are diffuse, whereas excitotoxicity might occur in more specific structures involved in the response to stress and the control of vital functions. A dysfunction of the brainstem, amygdala, and hippocampus might account for the increased mortality, psychological disorders, and cognitive impairment. This review summarizes clinical and paraclinical features of SAE and describes its mechanisms at cellular and structural levels.

    View details for DOI 10.1016/j.ccm.2016.01.013

    View details for PubMedID 27229649

  • Phenotypic clustering: a novel method for microglial morphology analysis. Journal of neuroinflammation Verdonk, F., Roux, P., Flamant, P., Fiette, L., Bozza, F. A., Simard, S., Lemaire, M., Plaud, B., Shorte, S. L., Sharshar, T., Chrétien, F., Danckaert, A. 2016; 13 (1): 153

    Abstract

    Microglial cells are tissue-resident macrophages of the central nervous system. They are extremely dynamic, sensitive to their microenvironment and present a characteristic complex and heterogeneous morphology and distribution within the brain tissue. Many experimental clues highlight a strong link between their morphology and their function in response to aggression. However, due to their complex "dendritic-like" aspect that constitutes the major pool of murine microglial cells and their dense network, precise and powerful morphological studies are not easy to realize and complicate correlation with molecular or clinical parameters.Using the knock-in mouse model CX3CR1(GFP/+), we developed a 3D automated confocal tissue imaging system coupled with morphological modelling of many thousands of microglial cells revealing precise and quantitative assessment of major cell features: cell density, cell body area, cytoplasm area and number of primary, secondary and tertiary processes. We determined two morphological criteria that are the complexity index (CI) and the covered environment area (CEA) allowing an innovative approach lying in (i) an accurate and objective study of morphological changes in healthy or pathological condition, (ii) an in situ mapping of the microglial distribution in different neuroanatomical regions and (iii) a study of the clustering of numerous cells, allowing us to discriminate different sub-populations.Our results on more than 20,000 cells by condition confirm at baseline a regional heterogeneity of the microglial distribution and phenotype that persists after induction of neuroinflammation by systemic injection of lipopolysaccharide (LPS). Using clustering analysis, we highlight that, at resting state, microglial cells are distributed in four microglial sub-populations defined by their CI and CEA with a regional pattern and a specific behaviour after challenge.Our results counteract the classical view of a homogenous regional resting state of the microglial cells within the brain. Microglial cells are distributed in different defined sub-populations that present specific behaviour after pathological challenge, allowing postulating for a cellular and functional specialization. Moreover, this new experimental approach will provide a support not only to neuropathological diagnosis but also to study microglial function in various disease models while reducing the number of animals needed to approach the international ethical statements.

    View details for DOI 10.1186/s12974-016-0614-7

    View details for PubMedID 27317566

    View details for PubMedCentralID PMC4912769

  • Daily FOUR score assessment provides accurate prognosis of long-term outcome in out-of-hospital cardiac arrest. Revue neurologique Weiss, N., Venot, M., Verdonk, F., Chardon, A., Le Guennec, L., Llerena, M. C., Raimbourg, Q., Taldir, G., Luque, Y., Fagon, J. Y., Guerot, E., Diehl, J. L. 2015; 171 (5): 437?44

    Abstract

    The accurate prediction of outcome after out-of-hospital cardiac arrest (OHCA) is of major importance. The recently described Full Outline of UnResponsiveness (FOUR) is well adapted to mechanically ventilated patients and does not depend on verbal response.To evaluate the ability of FOUR assessed by intensivists to accurately predict outcome in OHCA.We prospectively identified patients admitted for OHCA with a Glasgow Coma Scale below 8. Neurological assessment was performed daily. Outcome was evaluated at 6 months using Glasgow-Pittsburgh Cerebral Performance Categories (GP-CPC).Eighty-five patients were included. At 6 months, 19 patients (22%) had a favorable outcome, GP-CPC 1-2, and 66 (78%) had an unfavorable outcome, GP-CPC 3-5. Compared to both brainstem responses at day 3 and evolution of Glasgow Coma Scale, evolution of FOUR score over the three first days was able to predict unfavorable outcome more precisely. Thus, absence of improvement or worsening from day 1 to day 3 of FOUR had 0.88 (0.79-0.97) specificity, 0.71 (0.66-0.76) sensitivity, 0.94 (0.84-1.00) PPV and 0.54 (0.49-0.59) NPV to predict unfavorable outcome. Similarly, the brainstem response of FOUR score at 0 evaluated at day 3 had 0.94 (0.89-0.99) specificity, 0.60 (0.50-0.70) sensitivity, 0.96 (0.92-1.00) PPV and 0.47 (0.37-0.57) NPV to predict unfavorable outcome.The absence of improvement or worsening from day 1 to day 3 of FOUR evaluated by intensivists provides an accurate prognosis of poor neurological outcome in OHCA.

    View details for DOI 10.1016/j.neurol.2015.02.013

    View details for PubMedID 25912282

  • Early Standard Electroencephalogram Abnormalities Predict Mortality in Septic Intensive Care Unit Patients. PloS one Azabou, E., Magalhaes, E., Braconnier, A., Yahiaoui, L., Moneger, G., Heming, N., Annane, D., Mantz, J., Chrétien, F., Durand, M. C., Lofaso, F., Porcher, R., Sharshar, T. 2015; 10 (10): e0139969

    Abstract

    Sepsis is associated with increased mortality, delirium and long-term cognitive impairment in intensive care unit (ICU) patients. Electroencephalogram (EEG) abnormalities occurring at the acute stage of sepsis may correlate with severity of brain dysfunction. Predictive value of early standard EEG abnormalities for mortality in ICU septic patients remains to be assessed.In this prospective, single center, observational study, standard EEG was performed, analyzed and classified according to both Synek and Young EEG scales, in consecutive patients acutely admitted in ICU for sepsis. Delirium, coma and the level of sedation were assessed at the time of EEG recording; and duration of sedation, occurrence of in-ICU delirium or death were assessed during follow-up. Adjusted analyses were carried out using multiple logistic regression.One hundred ten patients were included, mean age 63.8 (±18.1) years, median SAPS-II score 38 (29-55). At the time of EEG recording, 46 patients (42%) were sedated and 22 (20%) suffered from delirium. Overall, 54 patients (49%) developed delirium, of which 32 (29%) in the days after EEG recording. 23 (21%) patients died in the ICU. Absence of EEG reactivity was observed in 27 patients (25%), periodic discharges (PDs) in 21 (19%) and electrographic seizures (ESZ) in 17 (15%). ICU mortality was independently associated with a delta-predominant background (OR: 3.36; 95% CI [1.08 to 10.4]), absence of EEG reactivity (OR: 4.44; 95% CI [1.37-14.3], PDs (OR: 3.24; 95% CI [1.03 to 10.2]), Synek grade ? 3 (OR: 5.35; 95% CI [1.66-17.2]) and Young grade > 1 (OR: 3.44; 95% CI [1.09-10.8]) after adjustment to Simplified Acute Physiology Score (SAPS-II) at admission and level of sedation. Delirium at the time of EEG was associated with ESZ in non-sedated patients (32% vs 10%, p = 0.037); with Synek grade ? 3 (36% vs 7%, p< 0.05) and Young grade > 1 (36% vs 17%, p< 0.001). Occurrence of delirium in the days after EEG was associated with a delta-predominant background (48% vs 15%, p = 0.001); absence of reactivity (39% vs 10%, p = 0.003), Synek grade ? 3 (42% vs 17%, p = 0.001) and Young grade >1 (58% vs 17%, p = 0.0001).In this prospective cohort of 110 septic ICU patients, early standard EEG was significantly disturbed. Absence of EEG reactivity, a delta-predominant background, PDs, Synek grade ? 3 and Young grade > 1 at day 1 to 3 following admission were independent predictors of ICU mortality and were associated with occurence of delirium. ESZ and PDs, found in about 20% of our patients. Their prevalence could have been higher, with a still higher predictive value, if they had been diagnosed more thoroughly using continuous EEG.

    View details for DOI 10.1371/journal.pone.0139969

    View details for PubMedID 26447697

    View details for PubMedCentralID PMC4598037

  • Brain perfusion in sepsis or to resolve the macro part of the micro. Critical care medicine Sharshar, T., Mazeraud, A., Verdonk, F., Chrétien, F. 2014; 42 (2): 485?86

    View details for DOI 10.1097/CCM.0000000000000007

    View details for PubMedID 24434464

  • Understanding brain dysfunction in sepsis. Annals of intensive care Sonneville, R., Verdonk, F., Rauturier, C., Klein, I. F., Wolff, M., Annane, D., Chretien, F., Sharshar, T. 2013; 3 (1): 15

    Abstract

    Sepsis often is characterized by an acute brain dysfunction, which is associated with increased morbidity and mortality. Its pathophysiology is highly complex, resulting from both inflammatory and noninflammatory processes, which may induce significant alterations in vulnerable areas of the brain. Important mechanisms include excessive microglial activation, impaired cerebral perfusion, blood-brain-barrier dysfunction, and altered neurotransmission. Systemic insults, such as prolonged inflammation, severe hypoxemia, and persistent hyperglycemia also may contribute to aggravate sepsis-induced brain dysfunction or injury. The diagnosis of brain dysfunction in sepsis relies essentially on neurological examination and neurological tests, such as EEG and neuroimaging. A brain MRI should be considered in case of persistent brain dysfunction after control of sepsis and exclusion of major confounding factors. Recent MRI studies suggest that septic shock can be associated with acute cerebrovascular lesions and white matter abnormalities. Currently, the management of brain dysfunction mainly consists of control of sepsis and prevention of all aggravating factors, including metabolic disturbances, drug overdoses, anticholinergic medications, withdrawal syndromes, and Wernicke's encephalopathy. Modulation of microglial activation, prevention of blood-brain-barrier alterations, and use of antioxidants represent relevant therapeutic targets that may impact significantly on neurologic outcomes. In the future, investigations in patients with sepsis should be undertaken to reduce the duration of brain dysfunction and to study the impact of this reduction on important health outcomes, including functional and cognitive status in survivors.

    View details for DOI 10.1186/2110-5820-3-15

    View details for PubMedID 23718252

    View details for PubMedCentralID PMC3673822

  • [Evaluation of residency training and needs of fellowships by anaesthesia and intensive care residents of Île-de-France]. Annales francaises d'anesthesie et de reanimation Chousterman, B. G., Bouroche, G., Verdonk, F., Chhor, V. 2012; 31 (9): 739?40

    View details for DOI 10.1016/j.annfar.2012.05.008

    View details for PubMedID 22840928

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