Search

Introduction COVID-19 induces venous, arterial and microvascular thrombosis, involving several pathophysiological processes. In patients with severe COVID-19 without macrovascular thrombosis, escalating into high-dose prophylactic anticoagulation (HD-PA) or therapeutic anticoagulation (TA) could be beneficial in limiting the extension of microvascular thrombosis and forestalling the evolution of lung and multiorgan microcirculatory dysfunction. In the absence of data from randomised trials, clinical practice varies widely.Methods and analysis This is a French multicentre, parallel-group, open-label, randomised controlled superiority trial to compare the efficacy and safety of three anticoagulation strategies in patients with COVID-19. Patients with oxygen-treated COVID-19 showing no pulmonary artery thrombosis on computed tomography with pulmonary angiogram will be randomised to receive either low-dose PA, HD-PA or TA for 14 days. Patients attaining the extremes of weight and those with severe renal failure will not be included. We will recruit 353 patients. Patients will be randomised on a 1:1:1 basis, and stratified by centre, use of invasive mechanical ventilation, D-dimer levels and body mass index. The primary endpoint is a hierarchical criterion at day 28 including all-cause mortality, followed by the time to clinical improvement defined as the time from randomisation to an improvement of at least two points on the ordinal clinical scale. Secondary outcomes include thrombotic and major bleeding events at day 28, individual components of the primary endpoint, number of oxygen-free, ventilator-free and vasopressor-free days at day 28, D-dimer and sepsis-induced coagulopathy score at day 7, intensive care unit and hospital stay at day 28 and day 90, and all-cause death and quality of life at day 90.Ethics and dissemination The study has been approved by an ethical committee (Ethics Committee, Ile de France VII, Paris, France; reference 2020-A03531-38). Patients will be included after obtaining their signed informed consent. The results will be submitted for publication in peer-reviewed journals.Trial registration number NCT04808882.

Ingestion of large amounts of cocaine packages is a well-known method for cross-border transportation. Intestinal obstruction and life-threatening sympathomimetic toxidrome including seizures, ventricular dysrhythmia, and cardiac arrest resulting from the rupture of cocaine packages may occur. Here, we report a case of a 34-year-old pregnant woman who had a sudden cardiac arrest while waiting for her bags at Paris-Charles de Gaulle Airport, France. According to the flight attendants, the patient travelled from Brazil and complained of abdominal pain during the flight. After resuscitation, the patient presented sustained tachycardia and convulsions suggesting cocaine overdose caused by body packing. Once admitted to the hospital, laparotomy was performed allowing the extraction of 50 cocaine packages. Cardiac symptoms were attributed to the rupture of five of the packages. Prehospital and emergency physicians need to be aware of the possibility of cocaine overdose by body packing in patients presenting sudden cardiac arrest in airports.

Abstract Background The STROMA-CoV-2 study was a French phase 2b, multicenter, double-blind, randomized, placebo-controlled clinical trial that did not identify a significant efficacy of umbilical cord-derived mesenchymal stromal cells in patients with SARS-CoV-2-induced acute respiratory distress syndrome. Safety on day 28 was found to be good. The aim of our extended study was to assess the 6- and 12-month safety of UC-MSCs administration in the STROMA-CoV-2 cohort. Methods A detailed multi-domain assessment was conducted at 6 and 12 months following hospital discharge focusing on adverse events, lung computed tomography-scan, pulmonary and muscular functional status, and quality of life in the STROMA-CoV-2 cohort including SARS–CoV-2-related early (

IMPORTANCE:. Ventilator-associated pneumonia (VAP) frequently occurs in patients with cardiac arrest. Diagnosis of VAP after cardiac arrest remains challenging, while the use of current biomarkers such as C-reactive protein (CRP) or procalcitonin (PCT) is debated. OBJECTIVES:. To evaluate biomarkers’ impact in helping VAP diagnosis after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS:. This is a prospective ancillary study of the randomized, multicenter, double-blind placebo-controlled ANtibiotherapy during Therapeutic HypothermiA to pRevenT Infectious Complications (ANTHARTIC) trial evaluating the impact of antibiotic prophylaxis to prevent VAP in out-of-hospital patients with cardiac arrest secondary to shockable rhythm and treated with therapeutic hypothermia. An adjudication committee blindly evaluated VAP according to predefined clinical, radiologic, and microbiological criteria. All patients with available biomarker(s), sample(s), and consent approval were included. MAIN OUTCOMES AND MEASURES:. The main endpoint was to evaluate the ability of biomarkers to correctly diagnose and predict VAP within 48 hours after sampling. The secondary endpoint was to study the combination of two biomarkers in discriminating VAP. Blood samples were collected at baseline on day 3. Routine and exploratory panel of inflammatory biomarkers measurements were blindly performed. Analyses were adjusted on the randomization group. RESULTS:. Among 161 patients of the ANTHARTIC trial with available biological sample(s), patients with VAP (n = 33) had higher body mass index and Acute Physiology and Chronic Health Evaluation II score, more unwitnessed cardiac arrest, more catecholamines, and experienced more prolonged therapeutic hypothermia duration than patients without VAP (n = 121). In univariate analyses, biomarkers significantly associated with VAP and showing an area under the curve (AUC) greater than 0.70 were CRP (AUC = 0.76), interleukin (IL) 17A and 17C (IL17C) (0.74), macrophage colony-stimulating factor 1 (0.73), PCT (0.72), and vascular endothelial growth factor A (VEGF-A) (0.71). Multivariate analysis combining novel biomarkers revealed several pairs with p value of less than 0.001 and odds ratio greater than 1: VEGF-A + IL12 subunit beta (IL12B), Fms-related tyrosine kinase 3 ligands (Flt3L) + C–C chemokine 20 (CCL20), Flt3L + IL17A, Flt3L + IL6, STAM-binding protein (STAMBP) + CCL20, STAMBP + IL6, CCL20 + 4EBP1, CCL20 + caspase-8 (CASP8), IL6 + 4EBP1, and IL6 + CASP8. Best AUCs were observed for CRP + IL6 (0.79), CRP + CCL20 (0.78), CRP + IL17A, and CRP + IL17C. CONCLUSIONS AND RELEVANCE:. Our exploratory study shows that specific biomarkers, especially CRP combined with IL6, could help to better diagnose or predict early VAP occurrence in cardiac arrest patients.

Hemostasis impairment represents the most threatening consequence of Viperidae envenoming, notably with Bothrops genus. In the French departments of America, B. atrox envenomation in French Guiana may lead to bleeding while B. lanceolatus envenomation in Martinique to thrombosis. Bleeding related to B. atrox envenomation is attributed to vascular damage mediated by venom metalloproteinases and blood uncoagulable state resulting from thrombocytopenia and consumptive coagulopathy. Thrombosis related to B. lanceolatus envenomation are poorly understood. We aimed to compare the effects of B. atrox and B. lanceolatus venoms in the rat to identify the determinants of the hemorrhagic versus thrombotic complications. Viscoelastometry (ROTEM), platelet count, plasma fibrinogen, thrombin generation assay, fibrinography, endothelial (von Willebrand factor, ADAMTS13 activity, ICAM-1, and soluble E-selectin), and inflammatory biomarkers (IL-1β, IL-6, TNF-α, MCP-1, and PAI-1) were determined in blood samples obtained at H3, H6, and H24 after the subcutaneous venom versus saline injection. In comparison to the control, initial fibrinogen consumption was observed with the two venoms while thrombocytopenia and reduction in the clot amplitude only with B. atrox venom. Moreover, we showed an increase in thrombin generation at H3 with the two venoms, an increase in fibrin generation accompanied with hyperfibrinogenemia at H24 and an increase in inflammatory biomarkers with B. lanceolatus venom. No endothelial damage was found with the two venoms. To conclude, our data support two-sided hemostasis complications in Bothrops envenoming with an initial risk of hemorrhage related to platelet consumption and hypocoagulability followed by an increased risk of thrombosis promoted by the activated inflammatory response and rapid-onset fibrinogen restoration.

Abstract Background Severe hypothyroidism (SH) is a rare but life-threatening endocrine emergency. Only a few data are available on its management and outcomes of the most severe forms requiring ICU admission. We aimed to describe the clinical manifestations, management, and in-ICU and 6-month survival rates of these patients. Methods We conducted a retrospective, multicenter study over 18 years in 32 French ICUs. The local medical records of patients from each participating ICU were screened using the International Classification of Disease 10th revision. Inclusion criteria were the presence of biological hypothyroidism associated with at least one cardinal sign among alteration of consciousness, hypothermia and circulatory failure, and at least one SH-related organ failure. Results Eighty-two patients were included in the study. Thyroiditis and thyroidectomy represented the main SH etiologies (29% and 19%, respectively), while hypothyroidism was unknown in 44 patients (54%) before ICU admission. The most frequent SH triggers were levothyroxine discontinuation (28%), sepsis (15%), and amiodarone-related hypothyroidism (11%). Clinical presentations included hypothermia (66%), hemodynamic failure (57%), and coma (52%). In-ICU and 6-month mortality rates were 26% and 39%, respectively. Multivariable analyses retained age > 70 years [odds ratio OR 6.01 (1.75–24.1)] Sequential Organ-Failure Assessment score cardiovascular component ≥ 2 [OR 11.1 (2.47–84.2)] and ventilation component ≥ 2 [OR 4.52 (1.27–18.6)] as being independently associated with in-ICU mortality. Conclusions SH is a rare life-threatening emergency with various clinical presentations. Hemodynamic and respiratory failures are strongly associated with worse outcomes. The very high mortality prompts early diagnosis and rapid levothyroxine administration with close cardiac and hemodynamic monitoring.

Abstract Background Sepsis prognosis correlates with antibiotic adequacy at the early phase. This adequacy is dependent on antibacterial spectrum, bacterial resistance profile and antibiotic dosage. Optimal efficacy of beta-lactams mandates concentrations above the minimal inhibitory concentration (MIC) of the targeted bacteria for the longest time possible over the day. Septic acute kidney injury (AKI) is the most common AKI syndrome in ICU and often mandates renal replacement therapy (RRT) initiation. Both severe AKI and RRT may increase outside target antibiotic concentrations and ultimately alter patient’s prognosis. Patients and methods This is a secondary analysis of a randomized controlled trial that compared an early RRT initiation strategy with a delayed one in 620 critically ill patients undergoing severe AKI (defined by KDIGO 3). We compared beta-lactam trough concentrations between the two RRT initiation strategies. The primary outcome was the proportion of patients with sufficient trough plasma concentration of beta-lactams defined by trough concentration above 4 times the MIC. We hypothesized that early initiation of RRT could be associated with an insufficient antibiotic plasma trough concentration compared to patients allocated to the delayed strategy. Results One hundred and twelve patients were included: 53 in the early group and 59 in the delayed group. Eighty-three patients (74%) had septic shock on inclusion. Trough beta-lactam plasma concentration was above 4 times the MIC breakpoint in 80.4% (n = 90) of patients of the whole population, without differences between the early and the delayed groups (79.2% vs. 81.4%, respectively, p = 0.78). On multivariate analysis, the presence of septic shock and a higher mean arterial pressure were significantly associated with a greater probability of adequate antibiotic trough concentration [OR 3.95 (1.14;13.64), p = 0.029 and OR 1.05 (1.01;1.10), p = 0.013, respectively). Evolution of procalcitonin level and catecholamine-free days as well as mortality did not differ whether beta-lactam trough concentration was above 4 times the MIC or not. Conclusions In this secondary analysis of a randomized controlled trial, renal replacement therapy initiation strategy did not significantly influence plasma trough concentrations of beta-lactams in ICU patients with severe AKI. Presence of septic shock on inclusion was the main variable associated with a sufficient beta-lactam concentration. Trial registration: The AKIKI trial was registered on ClinicalTrials.gov (Identifier: NCT01932190) before the inclusion of the first patient.

Abstract Ethylene glycol (EG) is metabolized into glycolate and oxalate and may cause metabolic acidemia, neurotoxicity, acute kidney injury (AKI), and death. Historically, treatment of EG toxicity included supportive care, correction of acid–base disturbances and antidotes (ethanol or fomepizole), and extracorporeal treatments (ECTRs), such as hemodialysis. With the wider availability of fomepizole, the indications for ECTRs in EG poisoning are debated. We conducted systematic reviews of the literature following published EXTRIP methods to determine the utility of ECTRs in the management of EG toxicity. The quality of the evidence and the strength of recommendations, either strong (“we recommend”) or weak/conditional (“we suggest”), were graded according to the GRADE approach. A total of 226 articles met inclusion criteria. EG was assessed as dialyzable by intermittent hemodialysis (level of evidence = B) as was glycolate (Level of evidence = C). Clinical data were available for analysis on 446 patients, in whom overall mortality was 18.7%. In the subgroup of patients with a glycolate concentration ≤ 12 mmol/L (or anion gap ≤ 28 mmol/L), mortality was 3.6%; in this subgroup, outcomes in patients receiving ECTR were not better than in those who did not receive ECTR. The EXTRIP workgroup made the following recommendations for the use of ECTR in addition to supportive care over supportive care alone in the management of EG poisoning (very low quality of evidence for all recommendations): i) Suggest ECTR if fomepizole is used and EG concentration > 50 mmol/L OR osmol gap > 50; or ii) Recommend ECTR if ethanol is used and EG concentration > 50 mmol/L OR osmol gap > 50; or iii) Recommend ECTR if glycolate concentration is > 12 mmol/L or anion gap > 27 mmol/L; or iv) Suggest ECTR if glycolate concentration 8–12 mmol/L or anion gap 23–27 mmol/L; or v) Recommend ECTR if there are severe clinical features (coma, seizures, or AKI). In most settings, the workgroup recommends using intermittent hemodialysis over other ECTRs. If intermittent hemodialysis is not available, CKRT is recommended over other types of ECTR. Cessation of ECTR is recommended once the anion gap is

Abstract Background The anatomic site for central venous catheter insertion influences the risk of central venous catheter-related intravascular complications. We developed and validated a predictive score of required catheter dwell time to identify critically ill patients at higher risk of intravascular complications. Methods We retrospectively conducted a cohort study from three multicenter randomized controlled trials enrolling consecutive patients requiring central venous catheterization. The primary outcome was the required catheter dwell time, defined as the period between the first catheter insertion and removal of the last catheter for absence of utility. Predictors were identified in the training cohort (3SITES trial; 2336 patients) through multivariable analyses based on the subdistribution hazard function accounting for death as a competing event. Internal validation was performed in the training cohort by 500 bootstraps to derive the CVC-IN score from robust risk factors. External validation of the CVC-IN score were performed in the testing cohort (CLEAN, and DRESSING2; 2371 patients). Results The analysis was restricted to patients requiring mechanical ventilation to comply with model assumptions. Immunosuppression (2 points), high creatinine > 100 micromol/L (2 points), use of vasopressor (1 point), obesity (1 point) and older age (40–59, 1 point; ≥ 60, 2 points) were independently associated with the required catheter dwell time. At day 28, area under the ROC curve for the CVC-IN score was 0.69, 95% confidence interval (CI) [0.66–0.72] in the training cohort and 0.64, 95% CI [0.61–0.66] in the testing cohort. Patients with a CVC-IN score ≥ 4 in the overall cohort had a median required catheter dwell time of 24 days (versus 11 days for CVC-IN score 7 days required catheter dwell time in the testing cohort. Conclusion The CVC-IN score, which can be used for the first catheter, had a modest ability to discriminate required catheter dwell time. Nevertheless, preference of the subclavian site may contribute to limit the risk of intravascular complications, in particular among ventilated patients with high CVC-IN score. Trials Registration NCT01479153, NCT01629550, NCT01189682

Abstract Background In patients with septic shock, the impact of the mean arterial pressure (MAP) target on the course of mottling remains uncertain. In this post hoc analysis of the SEPSISPAM trial, we investigated whether a low-MAP (65 to 70 mmHg) or a high-MAP target (80 to 85 mmHg) would affect the course of mottling and arterial lactate in patients with septic shock. Methods The presence of mottling was assessed every 2 h from 2 h after inclusion to catecholamine weaning. We compared mottling and lactate time course between the two MAP target groups. We evaluated the patient’s outcome according to the presence or absence of mottling. Results We included 747 patients, 374 were assigned to the low-MAP group and 373 to the high-MAP group. There was no difference in mottling and lactate evolution during the first 24 h between the two MAP groups. After adjustment for MAP and confounding factors, the presence of mottling ≥ 6 h during the first 24 h was associated with a significantly higher risk of death at day 28 and 90. Patients without mottling or with mottling

Abstract Background The majority of central venous catheters (CVC) removed in the ICU are not colonized, including when a catheter-related infection (CRI) is suspected. We developed and validated a predictive score to reduce unnecessary CVC removal. Methods We conducted a retrospective cohort study from five multicenter randomized controlled trials with systematic catheter-tip culture of consecutive CVCs. Colonization was defined as growth of ≥103 colony-forming units per mL. Risk factors for colonization were identified in the training cohort (CATHEDIA and 3SITES trials; 3899 CVCs of which 575 (15%) were colonized) through multivariable analyses. After internal validation in 500 bootstrapped samples, the CVC-OUT score was computed by attaching points to the robust (> 50% of the bootstraps) risk factors. External validation was performed in the testing cohort (CLEAN, DRESSING2 and ELVIS trials; 6848 CVCs, of which 588 (9%) were colonized). Results In the training cohort, obesity (1 point), diabetes (1 point), type of CVC (dialysis catheter, 1 point), anatomical insertion site (jugular, 4 points; femoral 5 points), rank of the catheter (second or subsequent, 1 point) and catheterization duration (≥ 5 days, 2 points) were significantly and independently associated with colonization . Area under the ROC curve (AUC) for the CVC-OUT score was 0.69, 95% confidence interval (CI) [0.67–0.72]. In the testing cohort, AUC for the CVC-OUT score was 0.60, 95% CI [0.58–0.62]. Among 1,469 CVCs removed for suspected CRI in the overall population, 1200 (82%) were not colonized. The negative predictive value (NPV) of a CVC-OUT score

Bothrops venoms are rich in enzymes acting on platelets and coagulation. This action is dependent on two major co-factors, i.e., calcium and phospholipids, while antivenoms variably neutralize venom-related coagulopathy effects. Our aims were (i) to describe the composition of B. atrox and B. lanceolatus venoms; (ii) to study their activity on the whole blood using rotational thromboelastometry (ROTEM); (iii) to evaluate the contribution of calcium and phospholipids in their activity; and (iv) to compare the effectiveness of four antivenoms (Bothrofav™, Inoserp™ South America, Antivipmyn™ TRI, and PoliVal-ICP™) on the procoagulant activity of these two venoms. Venom composition was comparable. Both venoms exhibited hypercoagulant effects. B. lanceolatus venom was completely dependent on calcium but less dependent on phospholipids than B. atrox venom to induce in vitro coagulation. The four antivenoms neutralized the procoagulant activity of the two venoms; however, with quantitative differences. Bothrofav™ was more effective against both venoms than the three other antivenoms. The relatively similar venom-induced effects in vitro were unexpected considering the opposite clinical manifestations resulting from envenomation (i.e., systemic bleeding with B. atrox and thrombosis with B. lanceolatus). In vivo studies are warranted to better understand the pathophysiology of systemic bleeding and thrombosis associated with Bothrops bites.

In a neuropathological series of 20 COVID-19 cases, we analyzed six cases (three biopsies and three autopsies) with multiple foci predominantly affecting the white matter as shown by MRI. The cases presented with microhemorrhages evocative of small artery diseases. This COVID-19 associated cerebral microangiopathy (CCM) was characterized by perivascular changes: arterioles were surrounded by vacuolized tissue, clustered macrophages, large axonal swellings and a crown arrangement of aquaporin-4 immunoreactivity. There was evidence of blood-brain-barrier leakage. Fibrinoid necrosis, vascular occlusion, perivascular cuffing and demyelination were absent. While no viral particle or viral RNA was found in the brain, the SARS-CoV-2 spike protein was detected in the Golgi apparatus of brain endothelial cells where it closely associated with furin, a host protease known to play a key role in virus replication. Endothelial cells in culture were not permissive to SARS-CoV-2 replication. The distribution of the spike protein in brain endothelial cells differed from that observed in pneumocytes. In the latter, the diffuse cytoplasmic labeling suggested a complete replication cycle with viral release, notably through the lysosomal pathway. In contrast, in cerebral endothelial cells the excretion cycle was blocked in the Golgi apparatus. Interruption of the excretion cycle could explain the difficulty of SARS-CoV-2 to infect endothelial cells in vitro and to produce viral RNA in the brain. Specific metabolism of the virus in brain endothelial cells could weaken the cell walls and eventually lead to the characteristic lesions of COVID-19 associated cerebral microangiopathy. Furin as a modulator of vascular permeability could provide some clues for the control of late effects of microangiopathy.

Abstract Background Severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2)-induced acute respiratory distress syndrome (ARDS) causes high mortality. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have potentially relevant immune-modulatory properties, whose place in ARDS treatment is not established. This phase 2b trial was undertaken to assess the efficacy of UC-MSCs in patients with SARS–CoV-2-induced ARDS. Methods This multicentre, double-blind, randomized, placebo-controlled trial (STROMA–CoV-2) recruited adults (≥ 18 years) with SARS–CoV-2-induced early (

Abstract Background Valproic acid (VPA) poisoning is responsible for life-threatening neurological and metabolic impairments. Despite only low-level evidence of effectiveness, L-carnitine has been used for years to prevent or reverse VPA-related toxicity. We aimed to evaluate the effects of L-carnitine used to treat acute VPA poisoning on the time-course of plasma VPA concentrations and VPA-related toxicity. We designed a single-center cohort study including all VPA-poisoned patients admitted to the intensive care unit. We studied VPA toxicokinetics using a nonlinear mixed-effects model-based population approach and modeled individual plasma VPA/blood lactate concentration relationships. Then, we evaluated L-carnitine-attributed effects by comparing VPA elimination half-lives and time-courses of blood lactate levels and organ dysfunction [assessed by the Sequential Organ Failure Assessment (SOFA) score] between matched L-carnitine-treated and non-treated patients using a multivariate analysis including a propensity score. Results Sixty-nine VPA-poisoned patients (40F/29 M; age, 41 years [32–47]) (median [25th–75th percentiles]; SOFA score, 4 [1–6]) were included. The presumed VPA ingested dose was 15 g [10–32]. Plasma VPA concentration on admission was 231 mg/L [147–415]. The most common manifestations were coma (70%), hyperlactatemia (3.9 mmol/L [2.7–4.9]) and hyperammonemia (127 mmol/L [92–159]). VPA toxicokinetics well fitted a one-compartment linear model with a mean elimination half-life of 22.9 h (coefficient of variation, 28.1%). Plasma VPA (C)/blood lactate concentration (E) relationships were well described by an exponential growth equation [ $$E={E}_{0}\times {e}^{k\cdot C}$$ E = E 0 × e k · C ; with baseline E 0 = 1.3 mmol/L (43.9%) and rate constant of the effect, k = 0.003 L/mg (59.5%)]. Based on a multivariate analysis, peak blood lactate concentration was the only factor independently associated with L-carnitine administration (odds ratio, 1.9, 95% confidence interval, 1.2–2.8; P = 0.004). We found no significant contribution of L-carnitine to enhancing VPA elimination, accelerating blood lactate level normalization and/or preventing organ dysfunction. Conclusions VPA poisoning results in severe toxicity. While L-carnitine does not contribute to enhancing VPA clearance, its impact on accelerating blood lactate level normalization and/or preventing organ dysfunction remains uncertain. Investigating VPA toxicokinetics and concentration/effect relationships may help understanding how to improve VPA-poisoned patient management.

Biodetoxification using intravenous lipid emulsion (ILE) in acute poisoning is of growing interest. As well as for local anesthetics, ILE is currently used to reverse toxicity caused by a broad-spectrum of lipophilic drugs. Both pharmacokinetic and pharmacodynamic mechanisms have been postulated to explain its possible benefits, mainly combining a scavenging effect called “lipid sink” and cardiotonic activity. Additional mechanisms based on ILE-attributed vasoactive and cytoprotective properties are still under investigation. Here, we present a narrative review on lipid resuscitation, focusing on the recent literature with advances in understanding ILE-attributed mechanisms of action and evaluating the evidence supporting ILE administration that enabled the international recommendations. Many practical aspects are still controversial, including the optimal dose, the optimal administration timing, and the optimal duration of infusion for clinical efficacy, as well as the threshold dose for adverse effects. Present evidence supports the use of ILE as first-line therapy to reverse local anesthetic-related systemic toxicity and as adjunct therapy in lipophilic non-local anesthetic drug overdoses refractory to well-established antidotes and supportive care. However, the level of evidence is low to very low, as for most other commonly used antidotes. Our review presents the internationally accepted recommendations according to the clinical poisoning scenario and provides the precautions of use to optimize the expected efficacy of ILE and limit the inconveniences of its futile administration. Based on their absorptive properties, the next generation of scavenging agents is additionally presented. Although emerging research shows great potential, several challenges need to be overcome before parenteral detoxifying agents could be considered as an established treatment for severe poisonings.

In toxicology, screenings are routinely performed using chromatographic methods coupled to detection systems such as high-resolution mass spectrometry (HR/MS). The increase in specificity and sensitivity of HRMS is responsible for the development of methods for alternative samples such as Volumetric Adsorptive Micro-Sampling. Whole blood overloaded with 90 drugs was sampled with 20 µL MitraTM to optimize the pre-analytical step as well as to determine the identification limits of drugs. Elution of chemicals was carried out in a solvent mixture through agitation and sonication. After dissolution, 10 μL was injected into the chromatographic system coupled to the OrbitrapTM HR/MS. Compounds were confirmed against the laboratory library. The clinical feasibility was assessed in fifteen poisoned patients using the simultaneous sampling of plasma, whole blood and MitraTM. The optimized extraction procedure allowed us to confirm 87 compounds out of the 90 present in the spiked whole blood. Cannabis derivatives were not detected. For 82.2% of the investigated drugs, the identification limits were below 12.5 ng·mL−1, with the extraction yields ranging from 80.6 to 108.7%. Regarding the patients’ analysis, 98% of the compounds in plasma were detected in MitraTM compared to whole blood, with a satisfying concordance (R2 = 0.827). Our novel screening approach opens new insights into different toxicologic fields appropriate for pediatrics, forensics or to perform mass screening.

Hypozincemia is prevalent in severe acute respiratory syndrome coronavirus-2 (SARS-COV-2)-infected patients and has been considered as a risk factor in severe coronavirus disease-2019 (COVID-19). Whereas zinc might affect SARS-COV-2 replication and cell entry, the link between zinc deficiency and COVID-19 severity could also be attributed to the effects of COVID-19 on the body metabolism and immune response. Zinc deficiency is more prevalent in the elderly and patients with underlying chronic diseases, with established deleterious consequences such as the increased risk of respiratory infection. We reviewed the expected effects of zinc deficiency on COVID-19-related pathophysiological mechanisms focusing on both the renin–angiotensin and kinin-kallikrein systems. Mechanisms and effects were extrapolated from the available scientific literature. Zinc deficiency alters angiotensin-converting enzyme-2 (ACE2) function, leading to the accumulation of angiotensin II, des-Arg9-bradykinin and Lys-des-Arg9-bradykinin, which results in an exaggerated pro-inflammatory response, vasoconstriction and pro-thrombotic effects. Additionally, zinc deficiency blocks the activation of the plasma contact system, a protease cascade initiated by factor VII activation. Suggested mechanisms include the inhibition of Factor XII activation and limitation of high-molecular-weight kininogen, prekallikrein and Factor XII to bind to endothelial cells. The subsequent accumulation of Factor XII and deficiency in bradykinin are responsible for increased production of inflammatory mediators and marked hypercoagulability, as typically observed in COVID-19 patients. To conclude, zinc deficiency may affect both the renin–angiotensin and kinin-kallikrein systems, leading to the exaggerated inflammatory manifestations characteristic of severe COVID-19.

Abstract Background Patients with SARS-CoV-2 infection are at higher risk for ventilator-associated pneumonia (VAP). No study has evaluated the relationship between VAP and mortality in this population, or compared this relationship between SARS-CoV-2 patients and other populations. The main objective of our study was to determine the relationship between VAP and mortality in SARS-CoV-2 patients. Methods Planned ancillary analysis of a multicenter retrospective European cohort. VAP was diagnosed using clinical, radiological and quantitative microbiological criteria. Univariable and multivariable marginal Cox’s regression models, with cause-specific hazard for duration of mechanical ventilation and ICU stay, were used to compare outcomes between study groups. Extubation, and ICU discharge alive were considered as events of interest, and mortality as competing event. Findings Of 1576 included patients, 568 were SARS-CoV-2 pneumonia, 482 influenza pneumonia, and 526 no evidence of viral infection at ICU admission. VAP was associated with significantly higher risk for 28-day mortality in SARS-CoV-2 (adjusted HR 1.70 (95% CI 1.16–2.47), p = 0.006), and influenza groups (1.75 (1.03–3.02), p = 0.045), but not in the no viral infection group (1.07 (0.64–1.78), p = 0.79). VAP was associated with significantly longer duration of mechanical ventilation in the SARS-CoV-2 group, but not in the influenza or no viral infection groups. VAP was associated with significantly longer duration of ICU stay in the 3 study groups. No significant difference was found in heterogeneity of outcomes related to VAP between the 3 groups, suggesting that the impact of VAP on mortality was not different between study groups. Interpretation VAP was associated with significantly increased 28-day mortality rate in SARS-CoV-2 patients. However, SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, did not significantly modify the relationship between VAP and 28-day mortality. Clinical trial registration The study was registered at ClinicalTrials.gov, number NCT04359693.

Summary: Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial. Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979. Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42–1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively. Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn. Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19–20–0151, PHRC COVID-19–20–0029], Fondation de l'Assistance Publique – Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale” (FRM). Tocilizumab was provided by Roche.

In 2020, fentanyl and its analogs contributed to ~65% of drug-attributed fatalities in the USA, with a threatening increasing trend during the last ten years. These synthetic opioids used as potent analgesics in human and veterinary medicine have been diverted to recreational aims, illegally produced and sold. Like all opioids, central nervous system depression resulting from overdose or misuse of fentanyl analogs is characterized clinically by the onset of consciousness impairment, pinpoint miosis and bradypnea. However, contrasting with what observed with most opioids, thoracic rigidity may occur rapidly with fentanyl analogs, contributing to increasing the risk of death in the absence of immediate life support. Various mechanisms have been proposed to explain this particularity associated with fentanyl analogs, including the activation of noradrenergic and glutamatergic coerulospinal neurons and dopaminergic basal ganglia neurons. Due to the high affinities to the mu-opioid receptor, the need for more elevated naloxone doses than usually required in morphine overdose to reverse the neurorespiratory depression induced by fentanyl analogs has been questioned. This review on the neurorespiratory toxicity of fentanyl and analogs highlights the need for specific research focused on these agents to better understand the involved mechanisms of toxicity and develop dedicated strategies to limit the resulting fatalities.

Metabolomics in clinical toxicology aim at reliably identifying and semi-quantifying a broad array of endogenous and exogenous metabolites using dedicated analytical methods. Here, we developed a three-step-based workflow to investigate the metabolic impact of the antidepressant drug venlafaxine in a poisoned patient who developed life-threatening cardiac failure managed with extracorporeal membrane oxygenation. Both targeted quantitative and untargeted semi-quantitative metabolomic analyses using liquid chromatography hyphenated to high-resolution tandem mass spectrometry were performed to determine the plasma kinetics of venlafaxine, O-desmethyl-venlafaxine, and N-desmethyl-venlafaxine and to identify sixteen different venlafaxine-derived metabolites including one unknown (i.e., venlafaxine conjugated to a hexosyl-radical), respectively. Correlations between the quantitative metabolomic data and annotated endogenous metabolites suggested impaired amino acid and lipid metabolism, Krebs cycle, and kynurenine pathway. This preliminary study represents a first step towards a more extensive application of toxicometabolomics in clinical toxicology and a useful workflow to identify the biomarkers of toxicity.

About one year ago, the journal published a large population-based cohort study from South Korea investigating the potential benefits associated with statins at preventing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection or improving the outcome of hospitalized coronavirus disease-2019 (COVID-19) patients [...]

Tramadol overdose is frequently associated with the onset of seizures, usually considered as serotonin syndrome manifestations. Recently, the serotoninergic mechanism of tramadol-attributed seizures has been questioned. This study’s aim was to identify the mechanisms involved in tramadol-induced seizures in overdose in rats. The investigations included (1) the effects of specific pretreatments on tramadol-induced seizure onset and brain monoamine concentrations, (2) the interaction between tramadol and γ-aminobutyric acid (GABA)A receptors in vivo in the brain using positron emission tomography (PET) imaging and 11C-flumazenil. Diazepam abolished tramadol-induced seizures, in contrast to naloxone, cyproheptadine and fexofenadine pretreatments. Despite seizure abolishment, diazepam significantly enhanced tramadol-induced increase in the brain serotonin (p < 0.01), histamine (p < 0.01), dopamine (p < 0.05) and norepinephrine (p < 0.05). No displacement of 11C-flumazenil brain kinetics was observed following tramadol administration in contrast to diazepam, suggesting that the observed interaction was not related to a competitive mechanism between tramadol and flumazenil at the benzodiazepine-binding site. Our findings do not support the involvement of serotoninergic, histaminergic, dopaminergic, norepinephrine or opioidergic pathways in tramadol-induced seizures in overdose, but they strongly suggest a tramadol-induced allosteric change of the benzodiazepine-binding site of GABAA receptors. Management of tramadol-poisoned patients should take into account that tramadol-induced seizures are mainly related to a GABAergic pathway.

Widely available effective drugs to treat coronavirus disease-2019 (COVID-19) are still limited. Various studies suggested the potential contribution of selective serotonin-reuptake inhibitor (SSRI) antidepressants to alleviate the clinical course of COVID-19. Initially, SSRI antidepressant-attributed anti-COVID-19 activity was attributed to their direct agonistic or indirect serotonin-mediated stimulation of sigma-1 receptors (Sig1-R). Thereafter, attention was drawn to the property of SSRI antidepressants to decrease ceramide production, as functional inhibitors of acid sphingomyelinase. Ceramides are cell membrane waxy lipids formed by sphingosine and a fatty acid, playing a major role in receptor signaling and infection. In COVID-19 patients, ceramide production is increased due to acid sphingomyelinase activation. Here, we aimed to review the relationships between bradykinins and the proposed pathways supporting SSRI antidepressant-attributed effectiveness in COVID-19. In COVID-19 patients, bradykinin receptor-B1 stimulation is enhanced following the downregulation of angiotensin-converting enzyme-2, which is responsible for the inactivation of des-Arg9-bradykinin, a bradykinin metabolite, contrasting with the decrease in bradykinin receptor-B2 (BDKRB2) stimulation, which results from the inhibition of cathepsin L, a kininogenase involved in bradykinin production and present at the infection site. Sig1-R stimulation modulates the inflammatory response by regulating cytokine production and counterbalances COVID-19-attributed BDKRB2 inhibition by potentiating its effects on the cytosolic calcium concentration. Moreover, the beneficial effects obtained with acid sphingomyelinase inhibition are parallel to those expected with BDKRB2 stimulation in COVID-19. Altogether, these findings suggest that one ultimate pathway of SSRI antidepressant-attributed anti-COVID-19 activity is the potentiation of BDKRB2 effects shown to be inhibited in COVID-19. In conclusion, SSRI antidepressants are able to interact positively with the pathophysiological mechanisms involved in COVID-19. However, their exact benefits in preventing morbidities or improving the outcome in COVID-19 patients remain unknown.

(1) Background: Admission to the ICU and intensity of care provided to elderly COVID-19 patients are difficult choices guided by the expected patient-centered benefits. However, the impact of an early discussion of limitation of therapeutic effort (LTE) has been poorly investigated. (2) Methods: We performed a single-center retrospective cohort study including all ≥70-year-old COVID-19 patients admitted to the ICU. Factors associated with early LTE discussion (defined as before or up to 2 days post-ICU admission) and in-hospital mortality were evaluated. (3) Results: Eighty-two patients (59 M/23 F; 78 years (74–82) [median (interquartile range)]; 43/82 with LTE) were included. The in-hospital mortality rate was 55%. Early LTE was decided upon for 22/82 patients (27%), more frequently in older (p < 0.001) and frailer patients (p = 0.004). Using a multivariable logistic regression model including clinical frailty scale grade ≥4, hospital acquisition of COVID-19, ventilation support modality and SOFA score on admission, early LTE was not associated with mortality (adjusted odds ratio = 0.57 (0.15–2.00), p = 0.39). LTE resulted in less frequent invasive mechanical ventilation (23% versus 65%, p = 0.001), renal replacement therapy (5% versus 27%, p = 0.03) and norepinephrine infusion (23% versus 60%, p = 0.005), and shorter ICU stay (6 days (2–12) versus 14 days (7–24), p = 0.001). (4) Conclusions: In this small sample exploratory study, we were unable to demonstrate any increase in in-hospital mortality associated with early LTE discussion in elderly COVID-19 patients while reducing the use of organ support techniques. These findings require confirmation in larger studies.

Rubigine® is an anti-rust stain remover containing fluorides which is believed to have been the cause of many deaths in Martinique. However, after the modification of its composition in 2006, serious poisoning from old formulas containing fluorides persisted. Our main objective was to determine the clinical characteristics and prognostic factors of these intoxications. Methods: Any patient admitted to the Martinique University Hospital for acute Rubigine® poisoning was included from 1 January 2000 to 31 December 2016. Usual demographic and clinical data were collected and comparisons between surviving and deceased patients made using a univariate analysis and logistic regression. Results: Fifty-five patients were included (mean age: 43 years; sex ratio M/F: 1.1), and the main clinical characteristics were: changes in electrocardiogram (ECG) (80%), digestive system disorders (75%), and neurological disorders (12%). The main features linked to death were the presence of hydrofluoric acid (p < 0.0001), age over 55 years (p = 0.01), hypocalcemia after the initial intravenous calcium supplementation (p = 0.0003), diarrhea (p < 0.0001), hypersialorrhea (p < 0.0001), myocardial excitability (p < 0.0001), and state of shock (p < 0.0001). Three patients required circulatory support by venous-arterial ECMO. Mortality was 10.9%. Conclusions: Rubigine® poisoning is responsible for significant morbidity and mortality. Fortunately, its incidence as well as mortality has sharply decreased in Martinique thanks to the measures taken by the French state. This retrospective work nevertheless shows that acute intoxication by the old formula of Rubigine® remains the main factor of poor prognosis.

Ciguatera poisoning (CP) is one of the most common causes worldwide of marine poisoning associated with fish consumption from tropical areas. Its incidence is underreported. CP cases seem to increase with grouped cases reported during summer. Exposure to ciguatoxins, toxins responsible for CP with sodium-channel agonistic, voltage-gated potassium channel blocking, cholinergic, and adrenergic activities, may result in a large spectrum of manifestations. We aimed to describe the clinical characteristics, management, and outcome of CP in Martinique, French West Indies. We conducted an observational retrospective single-center study during six years (October 2012 to September 2018) including all CP patients managed by the prehospital medical services, admitted to the university hospital emergency department, or declared to the regional health agency. A total of 149 CP patients (81 females/63 males; median age, 46 years (interquartile range, 34–61)) were included. Acute features consisted in general (91%; mainly, myalgia pruritus, and asthenia), gastrointestinal (90%; mainly diarrhea, abdominal pain, and nausea), neurological (72%; mainly, paresthesia, dysgeusia, and impairment of hot/cold feeling), and cardiovascular manifestations (22%; bradycardia, hypotension, and heart conduction disorders). Management was supportive. No patient died but symptoms persisted in 40% of the 77 patients with follow-up at day 15. CP was mainly attributed to the ingestion of trevallies (59%), snappers (13%), and king mackerels (8%) with collective contaminations (71%). Unusual fish (tuna, salmon, and spider conchs) were suspected in rare cases. Ingestion of trevallies was associated with significantly higher persistent symptoms (odds ratio, 3.00; 95% confidence interval, (1.20–8.00); p = 0.03). CP incidence was 0.67 cases per 10,000 patient-years in Martinique over the study period. To conclude, CP represents an increasing public health issue in Martinique, as is the case in other Caribbean islands. Patients present usual but possibly life-threatening features. Outcome is excellent despite frequently prolonged manifestations.

Identification of xenobiotics and their phase I/II metabolites in poisoned patients remains challenging. Systematic approaches using bioinformatic tools are needed to detect all compounds as exhaustively as possible. Here, we aimed to assess an analytical workflow using liquid chromatography coupled to high-resolution mass spectrometry with data processing based on a molecular network to identify tramadol metabolites in urine and plasma in poisoned patients. The generated molecular network from liquid chromatography coupled to high-resolution tandem mass spectrometry data acquired in both positive and negative ion modes allowed for the identification of 25 tramadol metabolites in urine and plasma, including four methylated metabolites that have not been previously reported in humans or in vitro models. While positive ion mode is reliable for generating a network of tramadol metabolites displaying a dimethylamino radical in their structure, negative ion mode was useful to cluster phase II metabolites. In conclusion, the combined use of molecular networks in positive and negative ion modes is a suitable and robust tool to identify a broad range of metabolites in poisoned patients, as shown in a fatal tramadol-poisoned patient.

Abstract The 2018 Paris Intensive Care symposium entitled “Update in Neurocritical Care” was organized in Paris, June 21–22, 2018, under the auspices of the French Intensive Care Society. This 2-day post-graduate educational symposium comprised several chapters, aiming first to provide all-board intensivists with current standards for the clinical assessment of altered consciousness states (including coma and delirium) and peripheral nervous system in critically ill patients, monitoring of brain function (specifically, electro-encephalography) and best practices for sedation—analgesia—delirium management. An update on the treatment of specific severe brain pathologies—including ischaemic/haemorrhagic stroke, cerebral venous thrombosis, hypoxic-ischaemic brain injury, immune-mediated and infectious encephalitis and refractory status epilepticus—was also provided. Finally, we discuss how to approach some difficult decisions, namely the role of decompressive craniectomy and prognostication models in patients with head injury. For each chapter, the scope of the present review was to provide important issues and key messages, provide most recent and relevant literature in the field, and briefly describe new developments in the field.

Mushrooms account for a part of human diet due to their exquisite taste and protein content as well as their promising health effects unveiled by scientific research. Toxic and non-toxic mushrooms frequently share considerable morphological similarities, which mislead the collectors/consumers, resulting in mycotoxicity. Numerous mushroom species are considered “poisonous” as they produce dangerous toxins. For instance, members of the genus Amanita, especially A. phalloides, A. virosa and A. verna, are responsible for severe and even life-threatening noxious consequences. Globally, mushroom poisoning is a crucial healthcare issue as it leads to a considerable number of deaths annually. However, no definite antidote has been introduced to treat this poisoning. The present article discusses the characteristics of A. virosa in terms of epidemiology, mechanisms of toxicity, poisoning features and management. Keywords: Mushroom poisoning, Epidemiology, Phalloidin, Amanitin, Amanita virosa

Coronavirus disease 2019 (COVID-19) predisposes to deep vein thrombosis (DVT) and pulmonary embolism (PE) particularly in mechanically ventilated adults with severe pneumonia. The extremely high prevalence of DVT in the COVID-19 patients hospitalized in the intensive care unit (ICU) has been established between 25 and 84% based on studies including systematic duplex ultrasound of the lower limbs when prophylactic anticoagulation was systematically administrated. DVT prevalence has been shown to be markedly higher than in mechanically ventilated influenza patients (6–8%). Unusually high inflammatory and prothrombotic phenotype represents a striking feature of COVID-19 patients, as reflected by markedly elevated reactive protein C, fibrinogen, interleukin 6, von Willebrand factor, and factor VIII. Moreover, in critically ill patients, venous stasis has been associated with the prothrombotic phenotype attributed to COVID-19, which increases the risk of thrombosis. Venous stasis results among others from immobilization under muscular paralysis, mechanical ventilation with high positive end-expiratory pressure, and pulmonary microvascular network injuries or occlusions. Venous return to the heart is subsequently decreased with increase in central and peripheral venous pressures, marked proximal and distal veins dilation, and drops in venous blood flow velocities, leading to a spontaneous contrast “sludge pattern” in veins considered as prothrombotic. Together with endothelial lesions and hypercoagulability status, venous stasis completes the Virchow triad and considerably increases the prevalence of DVT and PE in critically ill COVID-19 patients, therefore raising questions regarding the optimal doses for thromboprophylaxis during ICU stay.

A new coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been responsible for a worldwide pandemic for two years, resulting in almost 280 million infections and 5 [...]

(1) Background: Corticosteroids lower 28-day all-cause mortality in critically ill COVID-19 patients. However, the outcome of COVID-19 patients referred to the intensive care unit (ICU) for respiratory deterioration despite corticosteroids initiated during hospitalization before ICU admission has been poorly investigated. Our objective was to determine survival according to corticosteroid initiation setting. (2) Methods: We conducted a cohort study including all successive critically ill COVID-19 patients treated with corticosteroids and managed in our ICU. We compared survival, whether corticosteroids were initiated before (Cb-group) or after ICU admission (Ca-group), using a propensity score matching. (3) Results: Overall, 228 patients (67 years (56–74); 168M/60F; invasive mechanical ventilation on admission, 17%) were included with 63 patients in the Cb-group and 165 patients in the Ca-group. Survival to hospital discharge was 43% versus 69%, respectively (p = 0.001). In a multivariable analysis, factors associated with death were age (odds ratio, 1.07; 95%-confidence interval, (1.04–1.11); p < 0.0001), the sequential organ failure assessment (SOFA) score on ICU admission (1.30 (1.14–1.50); p = 0.0001) and corticosteroid initiation before ICU admission (2.64 (1.30–5.43); p = 0.007). No significant differences in outcome related to corticosteroid regimen were found. (4) Conclusions: Critically ill COVID-19 patients transferred to the ICU with deterioration despite corticosteroids initiated before admission have a less favorable outcome than patients receiving corticosteroids initiated after ICU admission.

(1) Background: COVID-19 may lead to refractory hypoxemia requiring venovenous extracorporeal membrane oxygenation (ECMO). Survival rate if ECMO is implemented as rescue therapy after corticosteroid failure is unknown. We aimed to investigate if ECMO implemented after failure of the full-recommended 10-day corticosteroid course can improve outcome. (2) Methods: We conducted a three-center cohort study including consecutive dexamethasone-treated COVID-19 patients requiring ECMO between 03/2020 and 05/2021. We compared survival at hospital discharge between patients implemented after (ECMO-after group) and before the end of the 10-day dexamethasone course (ECMO-before group). (3) Results: Forty patients (28M/12F; age, 57 years (51–62) (median (25th–75th percentiles)) were included, 28 (70%) in the ECMO-before and 12 (30%) in the ECMO-after group. In the ECMO-before group, 9/28 patients (32%) received the 6 mg/day dexamethasone regimen versus 12/12 (100%) in the ECMO-after group (p < 0.0001). The rest of the patients received an alternative dexamethasone regimen consisting of 20 mg/day during 5 days followed by 10 mg/day during 5 days. Patients in the ECMO-before group tended to be younger (57 years (51–59) versus 62 years (57–67), p = 0.053). In the ECMO-after group, no patient (0%) survived while 12 patients (43%) survived in the ECMO-before group (p = 0.007). (4) Conclusions: Survival is poor in COVID-19 patients requiring ECMO implemented after the full-recommended 10-day dexamethasone course. Since these patients may have developed a particularly severe presentation, new therapeutic strategies are urgently required.

Toxins from Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins (snake venom metalloproteinases, snake venom serine proteases, phospholipases A2 and L-amino acid oxidases) and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in B. lanceolatus envenomation remains a unique entity, which exact pathophysiology remains poorly understood.

Abstract Background Little is known about the causes, clinical course and long-term outcome of comatose patients with prolonged hypoglycemic encephalopathy. Methods In a multicenter retrospective study conducted in patients hospitalized from July 1, 2004, to July 1, 2014, we investigated functional long-term prognosis and identified prognosis factors of patients admitted in an intensive care unit (ICU) with prolonged neurological manifestations related to hypoglycemia. Eligible patients were adults admitted to the ICU with a Glasgow Coma Score 3 improved enough to be in the good outcome group 1 year later. Twenty-two (45%) patients underwent therapeutic limitation, mainly related to no expected hope for improvement. On multivariate analysis, only low mRS prior to ICU admission (OR 2.6; 95% CI 1.1–6.3; P = 0.03) and normal brain imaging (OR 7.1; 95% CI 1.1–44; P = 0.03) were significantly predictive of a good outcome. All patients (n = 15) who remained hypoglycemic >480 min had a poor outcome. Conclusion Poor outcome was observed in about 60% of this population of hypoglycemic encephalopathy. However, some patients can recover satisfactorily over time.

Gastrointestinal (GI) diseases affect a large number of people all over the world. Uncontrolled acid secretion and occurrence of gastric ulcers are common disorders of GI tract which pose serious problems to human health. Many synthetic drugs have been used to treat GI disorders but a definite cure has not been discovered so far and the available medications cause several side effects. Nigella sativa (N. sativa) (Ranunculacea) has several therapeutic effects which are attributed to its constituents like nigellicine, nigellidine, thymoquinone, dithymoquinone, thymol and carvacrol. Several beneficial pharmacological properties of this plant such as anti-oxidant, anti-bacterial, anti-histaminic, anti-hypertensive, hypoglycemic, anti-fungal, anti-inflammatory, anti-cancer and immunomodulatory effects were reported and different therapeutic properties such as reliving bronchial asthma, jaundice, hydrophobia, paralysis, conjunctivitis, piles, skin diseases, anorexia, headache, dysentery, infections, obesity, back pain, hypertension and gastrointestinal problems, have been described for the seeds of N. sativa and its oil. The present review provides a detailed summery of scientific researches regarding gastrointestinal effect of N. sativa and its main constituent, thymoquinone.

Acute kidney injury (AKI) is the major complication of rhabdomyolysis. We aimed to identify the predictive factors for AKI and renal replacement therapy (RRT) requirement in poisoning-associated rhabdomyolysis. We conducted a cohort study including 273 successive poisoned patients (median age, 41 years) who developed rhabdomyolysis defined as creatine kinase (CK) >1000 IU/L. Factors associated with AKI and RRT requirement were identified using multivariate analyses. Poisonings mainly involved psychotropic drugs. AKI occurred in 88 patients (37%) including 43 patients (49%) who required RRT. Peak serum creatinine and CK were weakly correlated (R2 = 0.17, p < 0.001). Death (13%) was more frequent after AKI onset (32% vs. 2%, p < 0.001). On admission, lithium overdose (OR, 44.4 (5.3–371.5)), serum calcium ≤2.1 mmol/L (OR, 14.3 (2.04–112.4)), female gender (OR, 5.5 (1.8–16.9)), serum phosphate ≥1.5 mmol/L (OR, 2.0 (1.0–4.2)), lactate ≥ 3.3 mmol/L (OR, 1.2 (1.1–1.4)), serum creatinine ≥ 125 µmol/L (OR, 1.05 (1.03–1.06)) and age (OR, 1.04 (1.01–1.07)) independently predicted AKI onset. Calcium-channel blocker overdose (OR, 14.2 (3.8–53.6)), serum phosphate ≥ 2.3 mmol/L (OR, 1.6 (1.1–2.6)), Glasgow score ≤ 5 (OR, 1.12; (1.02–1.25)), prothrombin index ≤ 71% (OR, 1.03; (1.01–1.05)) and serum creatinine ≥ 125 µmol/L (OR, 1.01; (1.00–1.01)) independently predicted RRT requirement. We identified the predictive factors for AKI and RRT requirement on admission to improve management in poisoned patients presenting rhabdomyolysis.

Poisoning remains a major cause of hospital admission into the emergency department and intensive care unit. Proper diagnosis is the cornerstone for optimal management of poisoned patients. Since the definitive analytical confirmation of the nature of the toxicant involved in the poisoning cannot be rapidly obtained in the majority of healthcare facilities, diagnosis relies on the medical history and the rigorous clinical examination of the patients well as results of the routine biological tests and the electrocardiogram. Identification of the toxidromes addresses not only the correct diagnosis but also rules out other differential diagnoses. Despite no definitive predictive value, this clinical approach facilitates making decision on empirical treatments and emergent antidotes. Pharmacodynamic tests using specific antidotes including naloxone for opioids and flumazenil for benzodiazepines and its analogues are also helpful to assess the final diagnosis in comatose patients. The objective of this article is to review the toxidrome-based approach to common poisonings before toxicological analysis enables the confirmation of the initially suspected toxic etiology.

Bruno MégarbaneRéanimation Médicale et Toxicologique, Hôpital Lariboisière and Université Paris-Diderot, Paris, FranceAbstract: Ethylene glycol (EG) and methanol are responsible for life-threatening poisonings. Fomepizole, a potent alcohol dehydrogenase (ADH) inhibitor, is an efficient and safe antidote that prevents or reduces toxic EG and methanol metabolism. Although no study has compared its efficacy with ethanol, fomepizole is recommended as a first-line antidote. Treatment should be started as soon as possible, based on history and initial findings including anion gap metabolic acidosis, while awaiting measurement of alcohol concentration. Administration is easy (15 mg/kg-loading dose, either intravenously or orally, independent of alcohol concentration, followed by intermittent 10 mg/kg-doses every 12 hours until alcohol concentrations are