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International audience; BACKGROUND Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

The incidence of chronic liver disease is on the rise. One of the primary causes of hospital admissions for patients with cirrhosis is hepatic encephalopathy (HE), a debilitating neurological complication. HE is defined as a reversible syndrome, yet there is growing evidence stating that, under certain conditions, HE is associated with permanent neuronal injury and irreversibility. The pathophysiology of HE primarily implicates a strong role for hyperammonemia, but it is believed other pathogenic factors are involved. The fibrotic scarring of the liver during the progression of chronic liver disease (cirrhosis) consequently leads to increased hepatic resistance and circulatory anomalies characterized by portal hypertension, hyperdynamic circulatory state and systemic hypotension. The possible repercussions of these circulatory anomalies on brain perfusion, including impaired cerebral blood flow (CBF) autoregulation, could be implicated in the development of HE and/or permanent brain injury. Furthermore, hypotensive insults incurring during gastrointestinal bleed, infection, or liver transplantation may also trigger or exacerbate brain dysfunction and cell damage. This review will focus on the role of hypotension in the onset of HE as well as in the occurrence of neuronal cell loss in cirrhosis.

Background: Proportional assist ventilation with load-adjustable gain factors (PAV+) is a mechanical ventilation mode that delivers assistance to breathe in proportion to the patient's effort. The proportional assistance, called the gain, can be adjusted by the clinician to maintain the patient's respiratory effort or workload within a normal range. Short-term and physiological benefits of this mode compared to pressure support ventilation (PSV) include better patient-ventilator synchrony and a more physiological response to changes in ventilatory demand. Methods: The objective of this multi-centre randomized controlled trial (RCT) is to determine if, for patients with acute respiratory failure, ventilation with PAV+ will result in a shorter time to successful extubation than with PSV. This multi-centre open-label clinical trial plans to involve approximately 20 sites in several continents. Once eligibility is determined, patients must tolerate a short-term PSV trial and either (1) not meet general weaning criteria or (2) fail a 2 minute- Zero Continuous Positive Airway Pressure (CPAP) Trial using the rapid shallow breathing index, or (3) fail a spontaneous breathing trial (SBT), in this sequence. Then, participants in this study will be randomized to either PSV or PAV+ in a 1:1 ratio. PAV+ will be set according to a target of muscular pressure. The weaning process will be identical in the two arms. Time to liberation will be the primary outcome; ventilator-free days and other outcomes will be measured. Discussion: Meta-analyses comparing PAV+ to PSV suggest PAV+ may benefit patients and decrease healthcare costs but no powered study to date has targeted the difficult to wean patient population most likely to benefit from the intervention, or used consistent timing for the implementation of PAV+. Our enrolment strategy, primary outcome measure and liberation approaches may be useful for studying mechanical ventilation and weaning and can offer important results for patients.

Intravenous immune globulin (IVIG) may improve survival in people with septic shock. Current utilization patterns of IVIG are unknown. We sought to characterize adult patients with septic shock requiring vasopressors who received IVIG, describes IVIG regimens, and evaluate determinants of IVIG use in patients with septic shock. We conducted a retrospective database study of adult patients with septic shock admitted to US hospitals in the Premier Healthcare Database (from July 2010 to June 2013). We described the proportion of patients with septic shock receiving IVIG, examined IVIG regimens across sites and employed random-effects multivariable regression techniques to identify predictors of IVIG use. Intravenous immune globulin was administered to 0.3% (n = 685) of patients with septic shock; with a median [interquartile range (IQR)] dose of 1 [0.5–1.8] g·kg-1 for a median [IQR] of 1 [1–2] day. Receipt of IVIG was less likely for Black patients (odds ratio [OR], 0.54; 95% confidence interval [CI] 0.41 to 0.72) and patients without private insurance (Medicare OR, 0.73; 95% CI 0.59 to 0.90; Medicaid OR, 0.41; 95% CI 0.30 to 0.57) and more likely for patients with immunocompromise (OR, 6.83; 95% CI 5.47 to 8.53), necrotizing fasciitis (OR, 9.78; 95% CI 6.97 to 13.72), and toxic shock (OR, 56.9; 95% CI 38.7 to 83.7). Intravenous immune globulin is used infrequently across the US in patients with septic shock. Regimens of IVIG in septic shock may be less intensive than those associated with a survival benefit in meta-analyses. Observed infrequent use supports apparent clinical equipoise, perhaps secondary to limitations of the primary literature. A clinical trial evaluating the role of IVIG in septic shock is needed.

This national survey evaluated the perceived efficacy and safety of intravenous immune globulin (IVIG) in septic shock, self-reported utilization patterns, barriers to use, the population of interest for further trials and willingness to participate in future research of IVIG in septic shock.We conducted a cross-sectional survey of critical care and infectious diseases physicians across Canada. We summarized categorical item responses as counts and proportions. We developed a multivariable logistic regression model to identify physician-level predictors of IVIG use in septic shock.Our survey was disseminated to 674 eligible respondents with a final response rate of 60%. Most (91%) respondents reported having prescribed IVIG to patients with septic shock at least once, 86% for septic shock due to necrotizing fasciitis, 52% for other bacterial toxin-mediated causes of septic shock, and 5% for undifferentiated septic shock. The majority of respondents expressed uncertainty regarding the impact of IVIG on mortality (97%) and safety (95%) in septic shock. Respondents were willing to participate in further IVIG research with 98% stating they would consider enrolling their patients into a trial of IVIG in septic shock. Familiarity with published evidence was the single greatest predictor of IVIG use in septic shock (odds ratio, 10.2; 95% confidence interval, 3.4 to 30.5; P0.001).Most Canadian critical care and infectious diseases specialist physicians reported previous experience using IVIG in septic shock. Respondents identified inadequacy of existing research as the greatest barrier to routine use of IVIG in septic shock. Most respondents support the need for further studies on IVIG in septic shock, and would consider enrolling their own patients into a trial of IVIG in septic shock.RéSUMé: OBJECTIF : Cette enquête nationale a évalué l’efficacité et l’innocuité perçues des immunoglobulines intraveineuses (IgIV) dans le contexte du choc septique, les habitudes d’utilisation autodéclarées, les obstacles à l’utilisation de cette modalité, les populations à explorer pour des études futures et la volonté de participer aux recherches futures sur les IgIV et le choc septique. MéTHODE : Nous avons mené une enquête transversale auprès de médecins intensivistes et spécialistes des maladies infectieuses au Canada. Nous avons résumé les réponses de chaque point catégorique en tant que dénombrement et proportions. Nous avons mis au point un modèle de régression logistique multivariée afin d’identifier les prédicteurs, au niveau des médecins, d’une utilisation des IgIV en cas de choc septique. RéSULTATS : Notre sondage a été acheminé à 674 médecins admissibles et nous avons obtenu un taux de réponse final de 60 %. La plupart (91%) des répondants ont indiqué avoir prescrit des IgIV aux patients en choc septique au moins une fois, 86 % pour un choc septique dû à une fasciite nécrosante, 52 % pour des chocs septiques d’autres étiologies médiées par des toxines bactériennes, et 5 % dans des cas de choc septique non différencié. La majorité des répondants ont exprimé de l’incertitude quant à l’incidence des IgIV sur la mortalité (97 %) et l’innocuité (95 %) lors de choc septique. Les répondants étaient disposés à participer à d’autres recherches sur les IgIV, 98 % déclarant qu’ils envisageraient d’inscrire leurs patients à une étude sur les IgIV et le choc septique. La familiarité avec les données probantes publiées était le plus grand prédicteur d’utilisation d’IgIV dans un contexte de choc septique (rapport de cotes, 10,2; intervalle de confiance à 95 %, 3,4 à 30,5; P0,001). CONCLUSION : La plupart des médecins intensivistes et spécialistes des maladies infectieuses canadiens ont rapporté avoir une expérience antérieure d’utilisation d’IgIV en cas de choc septique. Les répondants ont identifié l’insuffisance de la recherche existante comme le plus grand obstacle à l’utilisation systématique d’IgIV dans les cas de choc septique. La plupart des répondants appuient la nécessité d’études plus approfondies sur les IgIV et le choc septique et envisageraient d’inscrire leurs propres patients à une étude sur les IgIV dans un contexte de choc septique.

Background: Cardio-Pulmonary Resuscitation (CPR) decreases lung volume below the functional residual capacity and can generate intrathoracic airway closure. Conversely, large insufflations can induce thoracic distension and jeopardize circulation. The capnogram (CO2 signal) obtained during continuous chest compressions can reflect intrathoracic airway closure and we hypothesized here that it can also indicate thoracic distension. Objectives: to test whether a specific capnogram may identify thoracic distension during CPR and assess its impact on gas exchange and hemodynamics. Methods: 1. In out-of-hospital cardiac arrest patients, we identified on capnograms three patterns: intrathoracic airway closure, thoracic distension or regular pattern. An algorithm was designed to identify them automatically.2. To link CO2 patterns with ventilation, we conducted three experiments:i) Reproducing the CO2 patterns in human cadavers. ii) Assessing the influence of tidal volume and respiratory mechanics on thoracic distension using a mechanical lung model. iii) Exploring the impact of thoracic distension patterns on different circulation parameters during CPR on a pig model. Measurements and main results: Clinical data: 202 patients were included. Intrathoracic airway closure was present in 35%, thoracic distension in 22% and regular pattern in 43%. Experiments:i) Higher insufflated volumes reproduced thoracic distension CO2 patterns in 5 cadavers. ii) In the mechanical lung model, thoracic distension patterns were associated with higher volumes and longer time constants. iii) In six pigs during CPR with various tidal volumes, a CO2 pattern of thoracic distension, but not tidal volume per se, was associated with a significant decrease in blood pressure and cerebral perfusion. Conclusions: During CPR, intrathoracic airway closure, thoracic distension or regular pattern can be identified by capnogram analysis. A thoracic distension pattern on the capnogram may indicate a negative impact of ventilation on blood pressure and cerebral perfusion during CPR, not predicted by tidal volume per se.

Despite decades of preclinical research, no experimentally derived therapies for sepsis have been successfully adopted into routine clinical practice. Factors that contribute to this crisis of translation include poor representation by preclinical models of the complex human condition of sepsis, bias in preclinical studies, as well as limitations of single-laboratory methodology. To overcome some of these shortcomings, multicentre preclinical studies—defined as a research experiment conducted in two or more research laboratories with a common protocol and analysis—are expected to maximize transparency, improve reproducibility, and enhance generalizability. The ultimate objective is to increase the efficiency and efficacy of bench-to-bedside translation for preclinical sepsis research and improve outcomes for patients with life-threatening infection. To this end, we organized the first meeting of the National Preclinical Sepsis Platform (NPSP). This multicentre preclinical research collaboration of Canadian sepsis researchers and stakeholders was established to study the pathophysiology of sepsis and accelerate movement of promising therapeutics into early phase clinical trials. Integrated knowledge translation and shared decision-making were emphasized to ensure the goals of the platform align with clinical researchers and patient partners. 29 participants from 10 independent labs attended and discussed four main topics: (1) objectives of the platform; (2) animal models of sepsis; (3) multicentre methodology and (4) outcomes for evaluation. A PIRO model (predisposition, insult, response, organ dysfunction) for experimental design was proposed to strengthen linkages with interdisciplinary researchers and key stakeholders. This platform represents an important resource for maximizing translational impact of preclinical sepsis research.

Secondary brain injury following hemorrhagic shock (HS) is a frequent complication in patients, even in the absence of direct brain trauma, leading to behavioral changes and more specifically anxiety and depression. Despite preclinical studies showing inflammation and apoptosis in the brain after HS, none have addressed the impact of circulating mediators. Our group demonstrated an increased uric acid (UA) circulation in rats following HS. Since UA is implicated in endothelial dysfunction and inflammatory response, we hypothesized UA could alter the blood-brain barrier (BBB) and impact the brain. Male Wistar rats were randomly assigned to: SHAM, HS (hemorrhagic shock) and HS + U (hemorrhagic shock + 1.5 mg/kg of uricase). The uricase intervention, specifically targeting UA, was administered during fluid resuscitation. It prevented BBB dysfunction (fluorescein sodium salt permeability and expression of intercellular adhesion molecule-1) following HS. As for neuroinflammation, all of the results obtained (MPO activity; Iba1 and GFAP expression) showed a significant increase after HS, also prevented by the uricase. The same pattern was observed after quantification of apoptosis (caspase-3 activity and TUNEL) and neurodegeneration (Fluoro-Jade). Finally, the forced swim, elevated plus maze, and social interaction tests detected anxiety-like behavior after HS, which was blunted in rats treated with the uricase. In conclusion, we have identified UA as a new circulatory inflammatory mediator, responsible for brain alterations and anxious behavior after HS in a murine model. The ability to target UA holds the potential of an adjunctive therapeutic solution to reduce brain dysfunction related to hemorrhagic shock in human.

Introduction: Despite availability of selection criteria, different interpretations can lead to variability in the appreciation of donor eligibility with possible viable organs missed. Our primary objective was to test the perception of feasibility of potential organ donors through the survey of a small sample of external evaluators.Methods: Clinical scenarios summarizing 66 potential donors managed in the first year of our Organ Recovery Center were sent to four critical care physicians to evaluate the feasibility of the potential donors and the probability of organ procurement.Results: Potential donors procuring at least one organ were identified in 55 of the 66 cases (83%). Unanimity was reached in 38 cases, encompassing 35 out of the 55 converted and 3 of the non-converted donors. The overall agreement was moderate (kappa = 0.60, 95% CI: 0.37–0.82). For the organs finally procured for transplantation, organ donation was predicted for the majority of the cases, but high discrepancy was present with the final outcome of organs not procured (particularly liver and kidney).Conclusion: The assessment of a potential donor is a complex dynamic process. In order to increase organ availability, standardized electronically clinical data, as well a “donor board” structure of decision might inform future systems.

The objectives of this study were to systematically identify and describe guidelines for the care of neurologically deceased donors and to evaluate their methodological quality, with the aim of informing and supporting the new Canadian guidelines for the management of organ donors.Following a systematic search, we included any document endorsed by an organ donation organization, a professional society, or a government, that aims to direct the medical management of adult, neurologically deceased, multi-organ donors. We extracted recommendations pertaining to six domains: the autonomic storm, hemodynamic instability, hormone supplementation, ventilation, blood product transfusions, and general intensive care unit (ICU) care. Methodological quality of the guidelines was assessed by the validated AGREE-II tool.This review includes 27 clinical practice guidelines representing 26 countries published between 1993 and 2019. Using the AGREE-II validated tool for the evaluation of guidelines' quality, documents generally scored well on their scope and clarity of presentation. Nevertheless, quality was limited in terms of the scientific rigor of guideline development. Recommendations varied substantially across the domains of managing the autonomic storm, subsequent management of hemodynamic instability, hormone therapy, mechanical ventilation, blood product transfusion, and general ICU care. We found consistent recommendations for low tidal volume ventilation subsequent to the publication of a landmark clinical trial.Highly inconsistent recommendations for deceased donor care summarized in this review likely reflect the relatively slow emergence of high-quality clinical research in this field, as well as a late uptake of recent validated guideline methodology. Even in this context of few randomized-controlled trials, our group supported the need for new Canadian guidelines for the management of organ donors that follow rigorous recognized methodology and grading of the evidence.PROSPERO (CRD42018084012); registered 25 February 2016.RéSUMé: OBJECTIF: Les objectifs de cette étude étaient d’identifier et de décrire de façon systématique les lignes directrices concernant les soins à prodiguer aux donneurs suivant un décès neurologique et d’évaluer leur qualité méthodologique, avec pour but d’informer et d’appuyer les nouvelles lignes directrices canadiennes de prise en charge des donneurs d’organes. MéTHODOLOGIE: À la suite d’une recherche systématique, nous avons inclus tout document endossé par un organisme de dons d’organes, une société professionnelle ou un gouvernement et ayant pour but d’orienter la prise en charge médicale des donneurs adultes d’organes multiples à la suite d’un décès neurologique. Nous avons extrait les recommandations touchant six domaines : la tempête catécholaminergique, l’instabilité hémodynamique, la supplémentation hormonale, la ventilation, les transfusions de produits sanguins et les soins généraux à l’unité de soins intensifs (USI). La qualité méthodologique des lignes directrices a été évaluée avec l’outil validé AGREE-II. CONSTATIONS PRINCIPALES: Cette revue porte sur 27 guides d’exercice cliniques représentant 26 pays et publiés entre 1993 et 2019. En se fondant sur l’outil validé AGREE-II pour l’évaluation de la qualité des lignes directrices, les documents ont en règle générale obtenu un bon score en ce qui touchait à leurs objectifs et à la clarté de leur présentation. Toutefois, la qualité était limitée en matière de rigueur scientifique employée pour la mise au point des lignes directrices. Les recommandations variaient considérablement concernant les questions pertinentes à la prise en charge de la tempête catécholaminergique, à la prise en charge subséquente de l’instabilité hémodynamique, à l’hormonothérapie, à la ventilation mécanique, à la transfusion de produits sanguins, et aux soins généraux à l’USI. À la suite de la publication d’une étude clinique importante, les recommandations concernant la ventilation à volume courant bas étaient constantes. CONCLUSION: Le manque de cohérence des lignes directrices touchant les soins aux donneurs décédés résumées dans cette revue est probablement le reflet de l’émergence relativement lente de recherches cliniques de qualité élevée dans ce domaine, ainsi que de l’adoption tardive des méthodologies récentes et validées pour l’élaboration de lignes directrices. Même dans le contexte actuel de rareté d’études randomisées contrôlées, notre groupe appuie la nécessité de nouvelles lignes directrices canadiennes concernant la prise en charge des donneurs d’organes qui respectent une méthodologie reconnue et rigoureuse ainsi qu’une classification des données probantes. ENREGISTREMENT DE L’éTUDE: PROSPERO (CRD42018084012); enregistrée le 25 février 2016.

Background Multiorgan failure is a consequence of severe ischemia-reperfusion injury after traumatic hemorrhagic shock (HS), a major cause of mortality in trauma patients. Circulating uric acid (UA), released from cell lysis, is known to activate proinflammatory and proapoptotic pathways and has been associated with poor clinical outcomes among critically ill patients. Our group has recently shown a mediator role for UA in kidney and lung injury, but its role in liver and enteric damage after HS remains undefined. Therefore, the objective of this study was to evaluate the role of UA on liver and enteric injury after resuscitated HS. Methods A murine model of resuscitated HS was treated during resuscitation with a recombinant uricase, a urate oxidase enzyme (rasburicase; Sanofi-Aventis, Canada Inc, Laval, Canada), to metabolize and reduce circulating UA. Biochemical analyses (liver enzymes, liver apoptotic, and inflammatory markers) were performed at 24 hours and 72 hours after HS. Physiological testing for enteric permeability and gut bacterial product translocation measurement (plasma endotoxin) were performed 72 hours after HS. In vitro, HT-29 cells were exposed to UA, and the expression of intercellular adhesion proteins (ZO-1, E-cadherin) was measured to evaluate the influence of UA on enteric permeability. Results The addition of uricase to resuscitation significantly reduced circulating and liver UA levels after HS. It also prevented HS-induced hepatolysis and liver apoptotic/inflammatory mediators at 24 hours and 72 hours. Hemorrhagic shock-induced enteric hyperpermeability and endotoxemia were prevented with uricase. Conclusions After resuscitated HS, UA is an important mediator in liver and enteric injury. Uric acid represents a therapeutic target to minimize organ damage in polytrauma patients sustaining HS.

Purpose Right ventricular RV dysfunction among transplant recipients correlates with transplant outcome, but its frequency in donors is unknown. The purpose of this study was to describe the epidemiology of RV dysfunction in potential heart donors.” Methods In a seven-year retrospective study of potential heart donors, we explored the incidence of RV dysfunction as observed on echocardiography and explored the association of four distinct factors with RV dysfunction: brain injury diagnosis, thoracic trauma, vasopressin infusion and left ventricular (LV) dysfunction. Results All 123 potential heart donors underwent echocardiography: 55 had RV dysfunction (44.7%). Fourty-one (33.3%) had LV dysfunction. Isolated RV dysfunction was present in 27 subjects (22%). LV dysfunction was the only factor significantly associated with RV dysfunction (OR = 4.6 (95% CI 1.9–11.4)). We observed no difference in heart acceptance between subjects with or without RV dysfunction. Conclusion We observed a high frequency of RV dysfunction in a sample of potential heart donors. However, the temporal evolution of RV dysfunction, the hemodynamic predictors of RV dysfunction, as well the link between donor RV dysfunction and recipient outcomes need to be assessed with further prospective studies.

IMPORTANCE: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. OBJECTIVE: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). DESIGN, SETTING, AND PARTICIPANTS: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). INTERVENTIONS: Enteral L rhamnosus GG (1 × 10(10) colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. MAIN OUTCOMES AND MEASURES: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. RESULTS: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, –2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P

Background: Although commonly prescribed, the efficacy of levothyroxine to improve heart function in neurologically deceased donors is unclear. We evaluated the feasibility of a randomized controlled trial to compare levothyroxine to placebo on the variation of left ventricular ejection fraction, in hemodynamically unstable donors. Methods: We conducted a pilot, double-blinded, randomized controlled trial. Deceased donors with reduced left ventricular ejection fraction or needing vasopressors were included. We randomized participants to a 20 μg bolus followed by a 20 μg/h infusion of levothyroxine or an identically appearing placebo. We report the proportion of recruited participants, the time to the administration of the study drug, and protocol violations. Results: Twenty-four participants (N = 24/104; 23.1%) were eligible. Five of them (N = 5/24; 20.8%) were excluded by the attending physician. Four others were not included, due to family refusal for research (n = 2/24;8.3%) and unavailability of research staff (n = 2/24; 8.3%). Fifteen participants were randomized (N = 15/104; 14.4%). Mean time between the echocardiography and the initiation of the drug was 1.73 hours, and14 (93.3%) of 15 of the participants received the drug within 2 hours after the echocardiography. We report no study violation. The study was stopped prematurely because of low recruitment. Conclusion: This pilot trial suggests that the success of a definitive randomized control trial to assess the efficacy of levothyroxine in deceased donors could benefit from a multicenter recruitment and education on the evidence surrounding the pharmacological management of organ donors. The need for consent to research interventions in deceased donors should also be clarified.

We sought to characterize Canadian physicians’ perspectives and stated practices regarding their hemodynamic care of deceased organ donors. We designed a 24-item electronic survey that was independently pretested for relevance, clarity, and intra-rater reliability by ten critical care clinicians. With the help of provincial organ donation organizations (ODO), we identified intensive care units (ICUs) with a high volume of adult deceased donors (defined by the management of five or more donors per year for two consecutive years). Medical directors of these high-volume ICUs helped identify ICU physicians to whom our survey was emailed. Of the 448 ICU physicians from 37 centres in nine provinces that were emailed, 184/448 (41.1%) responded to one or more survey questions. Respondents identified specialist nurses from ODOs as their primary source of guidance in donor care (107/165; 60%). They typically diagnosed an autonomic storm according to a rise in blood pressure (159/165; 96.4%) and/or heart rate (135/165; 81.8%); nevertheless, their stated management varied substantially. After termination of the autonomic storm, preferred first-line vasopressors were norepinephrine (93/164; 56.7%) and vasopressin (68/164; 41.5%). Twenty-one respondents (21/162; 13.0%) reported that they never administer inotropes to donors. Corticosteroid and thyroid hormone prescriptions for all donors was reported by 62/161 (37.6%) and 50/161 (31.1%) respondents, respectively. Respondents perceived an influence from ODO nurses or transplant physicians when prescribing corticosteroids (77/161; 47.8%) and/or thyroid hormones (33/161; 20.5%) We observed important variability in self-perceived practices of ICU physicians in the hemodynamic management of deceased donors, particularly in the treatment of the autonomic storm, in the prescription of hormone therapy, and in the administration of inotropes.

Background Circulating cell-free DNA (cfDNA) may contribute to the pathophysiology of post-injury inflammation and coagulation in trauma. However, the source and mechanism of release of cfDNA in trauma is not well understood. One potential source of cfDNA is from Neutrophil Extracellular Traps (NETs), released by activated neutrophils during the process of NETosis. The primary objective of our study was to determine if cfDNA has prognostic utility in trauma. The secondary objective of this study was to determine the source of cfDNA in trauma compared to sepsis. Methods We studied trauma patients from two prospective observational cohort studies: the DNA as a Prognostic Marker in ICU Patients (DYNAMICS) study and the Endotoxin in Polytrauma (ENPOLY) study. We also studied septic patients from the DYNAMICS study. Citrated plasma samples were collected longitudinally from the patients (days 1 to 7). The following molecules were measured in the plasma samples: cfDNA, protein C (PC), myeloperoxidase (MPO) (a marker of neutrophil activation), citrullinated Histone H3 (H3Cit, a marker of NETosis), cyclophilin A (a marker of necrosis), and caspase-cleaved K18 (a marker of apoptosis). Results A total of 77 trauma patients were included (n = 38 from DYNAMICS and n = 39 from ENPOLY). The median age was 49 years; 27.3% were female, and mortality was 16.9% at 28 days. Levels of cfDNA were elevated compared to healthy values but not significantly different between survivors and non-survivors. There was a positive correlation between MPO and cfDNA in septic patients (r = 0.424, p < 0.001). In contrast, there was no correlation between MPO and cfDNA in trauma patients (r = – 0.192, p = 0.115). Levels of H3Cit, a marker of NETosis, were significantly elevated in septic patients compared to trauma patients (p < 0.01) while apoptosis and necrosis markers did not differ between the two groups. Conclusion Our studies suggest that the source and mechanism of release of cfDNA differ between trauma and sepsis patients. In sepsis, cfDNA is likely primarily released by activated neutrophils via the process of NETosis. In contrast, cfDNA in trauma appears to originate mainly from injured or necrotic cells. Although cfDNA is elevated in trauma and sepsis patients compared to healthy controls, cfDNA does not appear to have prognostic utility in trauma patients. Trial registration ClinicalTrials.gov Identifier: NCT01355042. Registered May 17, 2011 Electronic supplementary material The online version of this article (10.1186/s40635-019-0251-4) contains supplementary material, which is available to authorized users.

Rationale: End-tidal CO2 (EtCO2) is used to monitor cardiopulmonary resuscitation (CPR), but it can be affected by intrathoracic airway closure. Chest compressions induce oscillations in expired CO...

Background Multiple organ failure can develop after hemorrhagic shock (HS). Uric acid (UA) is released from dying cells and can be proinflammatory. We hypothesized that UA could be an alternative mediator of organ apoptosis and inflammation after HS. Methods Ventilated male Wistar rats were used for the HS model. Two durations of shock (5 minutes vs. 60 minutes) were compared, and shams were instrumented only; animals were resuscitated and observed for 24 hours/72 hours. Caspases-(8/3), myeloperoxidase (MPO), TNF-α were measured in lungs and kidneys. Plasma UA and cytokine (IL-1β, IL-18, TNF-α) were measured. A second set of animals were randomized to vehicle versus Rasburicase intraperitoneal intervention (to degrade UA) during resuscitation. Another group received exogenous UA intraperitoneally without HS. Measures mentioned above, in addition to organs UA, were performed at 24 hours. In vitro, caspases-(8/3) activity was tested in epithelial cells exposed to UA. Results Hemorrhagic shock increased organ (kidney and lung) TNF-α, MPO, and caspases activity in various patterns while caspase-8 remained elevated over time. Hemorrhagic shock led to increased plasma UA at 2 hours, which remained high until 72 hours; TNF-α and IL-18 were elevated at 24 hours. The exogenous UA administration in sham animals reproduced the activation of caspase-8 and MPO in organs, and TNF-α in the lung. The increased plasma and organ UA levels, plasma and lung TNF-α, as well as organ caspase-(8/3) and MPO, observed at 24 hours after HS, were prevented by the administration of Rasburicase during resuscitation. In vitro, soluble UA induced caspases-(3/8) activity in epithelial cells. Conclusion Uric acid is persistently high after HS and leads to the activation of caspases-8 and organ inflammation; these can be prevented by an intervention to degrade UA. Therefore, UA is an important biomarker and mediator that could be considered a therapeutic target during HS resuscitation in human.

Background Percutaneous dilatational tracheostomy (PDT) is the most frequently performed procedure in patients requiring prolonged mechanical ventilation. A crucial step in such procedures is needle insertion into the trachea. To simplify this procedure and increase its safety, we developed a new device, the translaryngeal Tracheostomy Needle Introducer (tTNI), for use with Fantoni’s method. This cadaver study was designed to assess the performance of the tTNI on human anatomy. Methods We tested the tTNI in a cadaver laboratory; the operators included two experts trained in PDT and three without specific training in the procedure. We performed 58 needle insertion attempts on 13 cadavers. We compared the tTNI technique with the standard needle insertion approach using external landmarks. We recorded the number of attempts needed to optimise needle insertion, time required in seconds, final position of the needle and complications related to needle insertion. Results tTNI use resulted in fewer puncture attempts (1.91 ± 1.34 vs. 1.19 ± 0.5, p

Intravenous immune globulin (IVIG) may improve survival in people with septic shock. Current utilization patterns of IVIG are unknown. We sought to characterize adult patients with septic shock requiring vasopressors who received IVIG, describes IVIG regimens, and evaluate determinants of IVIG use in patients with septic shock.We conducted a retrospective database study of adult patients with septic shock admitted to US hospitals in the Premier Healthcare Database (from July 2010 to June 2013). We described the proportion of patients with septic shock receiving IVIG, examined IVIG regimens across sites and employed random-effects multivariable regression techniques to identify predictors of IVIG use.Intravenous immune globulin was administered to 0.3% (n = 685) of patients with septic shock; with a median [interquartile range (IQR)] dose of 1 [0.5-1.8] g·kgIntravenous immune globulin is used infrequently across the US in patients with septic shock. Regimens of IVIG in septic shock may be less intensive than those associated with a survival benefit in meta-analyses. Observed infrequent use supports apparent clinical equipoise, perhaps secondary to limitations of the primary literature. A clinical trial evaluating the role of IVIG in septic shock is needed.RéSUMé: OBJECTIF: L’immunoglobuline intraveineuse (IGIV) peut améliorer la survie chez les personnes atteintes de choc septique. Les pratiques actuelles d’utilisation de l’IGIV sont inconnues. Nous avons cherché à caractériser les patients adultes en état de choc septique et nécessitant des vasopresseurs qui ont reçu de l’IGIV, à décrire les dosages administrés d’IGIV, et à évaluer les causes déterminantes d’une utilisation d’IGIV chez ces patients. MéTHODE: Nous avons réalisé une étude rétrospective de base de données portant sur des patients adultes atteints de choc septique admis dans des hôpitaux américains et inclus dans la base de données Premier Healthcare (de juillet 2010 à juin 2013). Nous avons décrit la proportion de patients en choc septique recevant de l’IGIV, examiné les posologies utilisées d’IGIV à travers les sites et employé des techniques de régression multivariable à effets aléatoires pour identifier les prédicteurs de l’utilisation d’IGIV. RéSULTATS: L’IGIV a été administrée à 0,3 % (n = 685) des patients présentant un choc septique, avec une dose médiane [écart interquartile (ÉIQ)] de 1 [0,5–1,8] g·kg

Purpose: This case report describes a patient with dabigatran accumulation due to acute kidney injury on chronic kidney disease, requiring multiple administration of idarucizumab along with renal replacement therapy because of rebound effect causing numerous episodes of bleeding. Summary: An 86-year-old man on dabigatran etexilate 110 mg twice daily for stroke prevention with atrial fibrillation was admitted to the hospital for bowel obstruction and severe acute kidney injury on chronic kidney disease. The patient had an abnormal coagulation profile and no history of bleeding. Initial laboratory values revealed a hemoglobin concentration of 10.7 g/dL, a platelet count of 115 × 103 platelets/μL, an activated partial thromboplastin time of 150.4 seconds, an international normalized ratio of 10.28, a thrombin time greater than 100 seconds and a serum creatinine of 5.54 mg/dL (490 μmol/L). An initial dose of idarucizumab was administered 1 hour prior to surgery to prevent bleeding. Significant bleeding and hemodynamic instability occurred following surgery. Three additional doses of idarucizumab, 2 sessions of intermittent hemodialysis, continuous venovenous hemofiltration and blood products were required to achieve normalization of coagulation parameters and hemodynamic stability due to rebound coagulopathy after each dose of idarucizumab. Conclusion: Acute kidney injury on chronic kidney disease and third-space redistribution could have led to important dabigatran accumulation and favored rebound coagulopathy. Multiple therapeutic approaches may be required in the management of complex dabigatran intoxication.

Background Persistent hypotension is a frequent complication after cardiac surgery with cardiopulmonary bypass (CPB). Midodrine, an orally administered alpha agonist, could potentially reduce intravenous vasopressor use and accelerate ICU discharge of otherwise stable patients. The main objective of this study was to explore the clinical impacts of administering midodrine in patients with persistent hypotension after CPB. Our hypothesis was that midodrine would safely accelerate ICU discharge and be associated with more days free from ICU at 30 days. Results We performed a retrospective cohort study that included all consecutive patients having received midodrine while being on vasopressor support in the ICU within the first week after cardiac surgery with CPB, between January 2014 and January 2018 at the Montreal Heart Institute. A contemporary propensity score matched control group that included patients who presented similarly prolonged hypotension after cardiac surgery was formed. After matching, 74 pairs of patients (1:1) fulfilled inclusion criteria for the study and control groups. Midodrine use was associated with fewer days free from ICU (25.8 [23.7–27.1] vs 27.2 [25.9–28] days, p = 0.002), higher mortality (10 (13.5%) vs 1 (1.4%), p = 0.036) and longer ICU length of stay (99 [68–146] vs 68 [48–99] hours, p = 0.001). There was no difference in length of intravenous vasopressors (63 [40–87] vs 44 [26–66] hours, p = 0.052), rate of ICU readmission (6 (8.1%) vs 2 (2.7%), p = 0.092) and occurrence of severe kidney injury (11 (14.9%) vs 10 (13.5%) patients, p = 0.462) between groups. Conclusion The administration of midodrine for sustained hypotension after cardiac surgery with CPB was associated with fewer days free from ICU and higher mortality. Routine prescription of midodrine to hasten ICU discharge after cardiac surgery should be used with caution until further prospective studies are conducted.

International audience; BACKGROUND: Studying ventilation and intrathoracic pressure (ITP) induced by chest compressions (CC) during Cardio Pulmonary Resuscitation is challenging and important aspects such as airway closure have been mostly ignored. We hypothesized that Thiel Embalmed Cadavers could constitute an appropriate model.METHODS: We assessed respiratory mechanics and ITP during CC in 11 cadavers, and we compared it to measurements obtained in 9 out-of-hospital cardiac arrest patients and to predicted values from a bench model. An oesophageal catheter was inserted to assess chest wall compliance, and ITP variation (ΔITP). Airway pressure variation (ΔPaw) at airway opening and ΔITP generated by CC were measured at decremental positive end expiratory pressure (PEEP) to test its impact on flow and ΔPaw. The patient's data were derived from flow and airway pressure captured via the ventilator during resuscitation.RESULTS: Resistance and Compliance of the respiratory system were comparable to those of the out-of-hospital cardiac arrest patients (C 42 ± 12 vs C 37.3 ± 10.9 mL/cmHO and Res 17.5 ± 7.5 vs Res 20.2 ± 5.3 cmHO/L/sec), and remained stable over time. During CC, ΔITP varied from 32 ± 12 cmHO to 69 ± 14 cmHO with manual and automatic CC respectively. Transmission of ΔITP at the airway opening was significantly affected by PEEP, suggesting dynamic small airway closure at low lung volumes. This phenomenon was similarly observed in patients.CONCLUSION: Respiratory mechanics and dynamic pressures during CC of cadavers behave as predicted by a theoretical model and similarly to patients. The Thiel model is a suitable to assess ITP variations induced by ventilation during CC.

Rationale Spinal cord injury (SCI) may induce significant respiratory muscle weakness and paralysis, which in turn may cause a patient to require ventilator support. Central nervous system alterations can also exacerbate local inflammatory responses with immune cell infiltration leading to additional risk of inflammation at the injury site. Although mechanical ventilation is the traditional treatment for respiratory insufficiency, evidence has shown that it may directly affect distant organs through systemic inflammation. Objectives This study aimed to better understand the impact of invasive mechanical ventilation on local spinal cord inflammatory responses following cervical or thoracic SCI. Methods Five groups of female Sprague-Dawley rats were anesthetised for 24 h. Three groups received mechanical ventilation: seven rats without SCI, seven rats with cervical injury (C4-C5), and seven rats with thoracic injury (T10); whereas, two groups were non-ventilated: six rats without SCI; and six rats with thoracic injury (T10). Changes in inflammatory responses were determined in the spinal cord tissues collected at the local site of injury. Cytokines were measured using ELISA. Main results SCI induced local pro-inflammatory cytokine IL-6 expression for all groups. Mechanical ventilation also had effects on pro-inflammatory cytokines and independently increased TNF-α and decreased IL-1β levels in the spinal cords of anesthetized rats. Conclusion These data provide the first evidence that mechanical ventilation contributes to local inflammation after SCI and in the absence of direct tissue injury.

Purpose Lung transplantation is the only therapeutic option for patients with a terminal lung condition. Unfortunately, survival rates after transplantation remains too low. Primary graft dysfunction (PGD) is the first cause of death in the perioperative period and is associated with acute respiratory distress syndrome (ARDS), higher risk of lung infections, chronic rejection, and lower survival rates. We hypothesized that the alveolar epithelial dysfunction in donor grafts and then in the recipient, is a critical component of PGD pathophysiology. Our goal was to identify markers of alveolar damage and dysfunction in the donor grafts associated with PGD development within recipients. Methods We collected human samples and the clinical data from 174 donors and their recipients at different time points (before, during and after lung transplantation, in the ICU and follow-ups at the transplantation clinic). We also isolated alveolar epithelial cells from donor lung biopsies to assess the expression of integrity (ZO-1) and functionality biomarkers (such as ENaC and CFTR channels, which play a key role in the resorption of lung edema, a key feature of ARDS/PGD). Results Among our cohort of 174 lung transplants, suffering from various lung diseases (i.e. CF, PF/IPF, COPD, PAH), 26% developed a PGD. Several phenotypic factors from donors and intervention/procedures during transplantations were analysed. Among them, we found that although below the defined acceptable limit (6h), the mean duration of cold ischemia of the donor grafts among recipients subsequently developing a PGD was significantly longer (266 min) than the one from non-PGD recipients (233 min). We also demonstrated that alveolar cells, isolated from donor grafts within recipients developing a PGD, featured a severe decrease in ZO-1, ENaC and CFTR expression. Moreover, longer cold ischemia duration was associated with the observed ENaC and CFTR downregulation. Conclusion This study provides novel insights on epithelial alteration within donor graft, associated with subsequent PGD development. Moreover, our data pave the way for the identification of novel biomarkers and therapeutic targets for the restoration of alveolar integrity and functionality, with the ultimate goal to prevent PGD in lung transplants.