Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cell Therapy in Preclinical Models of Sepsis: A Systematic Review and Meta-analysis.

BACKGROUND: In preclinical studies, mesenchymal stromal cells (MSCs), including umbilical cord-derived MSCs (UC-MSCs), demonstrate the ability to modulate numerous pathophysiological processes related to sepsis; however, a systematic synthesis of the literature is needed to assess the efficacy of UC-MSCs for treating sepsis. OBJECTIVE: To examine the effects of UC-MSCs on overall mortality (primary outcome) as well as on organ dysfunction, coagulopathy, endothelial permeability, pathogen clearance, and systemic inflammation (secondary outcomes) at prespecified time intervals in preclinical models of sepsis. METHODS: A systematic search was conducted on Embase, Ovid MEDLINE, and Web of Science up to June 20, 2023. Preclinical controlled studies using in vivo sepsis models with systemic UC-MSC administration were included. Meta-analyses were conducted and expressed as odds ratios (OR) and ratios of the weighted means with 95% CI for categorical and continuous data, respectively. Risk of bias was assessed with the SYRCLE tool. RESULTS: Twenty-six studies (34 experiments, n = 1258 animals) were included in this review. Overall mortality was significantly reduced with UC-MSC treatment as compared to controls (OR: 0.26, 95% CI: 0.18-0.36). At various prespecified time intervals, UC-MSCs reduced surrogate measures of organ dysfunction related to the kidney, liver, and lung; reduced coagulopathy and endothelial permeability; and enhanced pathogen clearance from multiple sites. UC-MSCs also modulated systemic inflammatory mediators. No studies were rated as low risk across all SYCLE domains. CONCLUSIONS: These results demonstrate the efficacy of UC-MSC treatment in preclinical sepsis models and highlight their potential as a therapeutic intervention for septic shock.

Metabolomics Analysis of Mesenchymal Stem Cell (MSC) Therapy in a Phase I Clinical Trial of Septic Shock: An Exploratory Study.

Sepsis is the result of an uncontrolled host inflammatory response to infection that may lead to septic shock with multiorgan failure and a high mortality rate. There is an urgent need to improve early diagnosis and to find markers identifying those who will develop septic shock and certainly a need to develop targeted treatments to prevent septic shock and its high mortality. Herein, we explore metabolic alterations due to mesenchymal stromal cell (MSC) treatment of septic shock. The clinical findings for this study were already reported; MSC therapy was well-tolerated and safe in patients in this phase I clinical trial. In this exploratory metabolomics study, 9 out of 30 patients received an escalating dose of MSC treatment, while 21 patients were without MSC treatment. Serum metabolomics profiling was performed to detect and characterize metabolite changes due to MSC treatment and to help determine the sample size needed for a phase II clinical trial and to define a metabolomic response to MSC treatment. Serum metabolites were measured using 1H-NMR and HILIC-MS at times 0, 24 and 72 h after MSC infusion. The results demonstrated the significant impact of MSC treatment on serum metabolic changes in a dose- and time-dependent manner compared to non-MSC-treated septic shock patients. This study suggests that plasma metabolomics can be used to assess the response to MSC therapy and that treatment-related metabolomics effects can be used to help determine the sample size needed in a phase II trial. As this study was not powered to detect outcome, how the treatment-induced metabolomic changes described in this study of MSC-treated septic shock patients are related to outcomes of septic shock in the short and long term will need to be explored in a larger adequately powered phase II clinical trial.

A Hospital-Wide Open-Label Cluster Crossover Pragmatic Comparative Effectiveness Randomized Trial Comparing Normal Saline to Ringer's Lactate: Protocol and Statistical Analysis Plan of The FLUID Trial.

BACKGROUND: Normal saline (NS) and Ringer's lactate (RL) are the most common crystalloids given to hospitalized patients. Despite concern about possible harm associated with NS (eg, hyperchloremic metabolic acidosis, impaired kidney function, and death), few large multicenter randomized trials focused on critically ill patients have compared these fluids. Uncertainty exists about the effects of these fluids on clinically important outcomes across all hospitalized patients. OBJECTIVE: The FLUID trial is a pragmatic, multicenter, 2×2 cluster crossover comparative effectiveness randomized trial that aims to evaluate the effectiveness of a hospital-wide policy that stocks either NS or RL as the main crystalloid fluid in 16 hospitals across Ontario, Canada. METHODS: All hospitalized adult and pediatric patients (anticipated sample size 144,000 patients) with an incident admission to the hospital over the course of each study period will be included. Either NS or RL will be preferentially stocked throughout the hospital for 12 weeks before crossing to the alternate fluid for the subsequent 12 weeks. The primary outcome is a composite of death and hospital readmission within 90 days of hospitalization. Secondary outcomes include death, hospital readmission, dialysis, reoperation, postoperative reintubation, length of hospital stay, emergency department visits, and discharge to a facility other than home. All outcomes will be obtained from health administrative data, eliminating the need for individual case reports. The primary analysis will use cluster-level summaries to estimate cluster-average treatment effects. RESULTS: The statistical analysis plan has been prepared "a priori" in advance of receipt of the trial data set from ICES and any analyses. CONCLUSIONS: We describe the protocol and statistical analysis plan for the evaluation of primary and secondary outcomes for the FLUID trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04512950; https://classic.clinicaltrials.gov/ct2/show/NCT04512950. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51783.

Anemia and Red Blood Cell Transfusion in Aneurysmal Subarachnoid Hemorrhage.

Anemia is very common in aneurysmal subarachnoid hemorrhage (aSAH), with approximately half of the aSAH patient population developing moderate anemia during their hospital stay. The available evidence (both physiologic and clinical) generally supports an association of anemia with unfavorable outcomes. Although aSAH shares a number of common mechanisms of secondary insult with other forms of acute brain injury, aSAH also has specific features that make it unique: an early phase (in which early brain injury predominates) and a delayed phase (in which delayed cerebral ischemia and vasospasm predominate). The effects of both anemia and transfusion are potentially variable between these phases, which may have unique considerations and possibly different risk-benefit profiles. Data on transfusion in this population are almost exclusively limited to observational studies, which suffer from significant heterogeneity and risk of bias. Overall, the results are conflicting, with the balance of the studies suggesting that transfusion is associated with unfavorable outcomes. The transfusion targets that are well established in other critically ill populations should not be automatically applied to patients with aSAH because of the unique disease characteristics of this population and the limited representation of aSAH in the clinical trials that established these targets. There are two upcoming clinical trials evaluating transfusion in aSAH that should help clarify specific transfusion targets. Until then, it is reasonable to base transfusion decisions on the current guidelines and use an individualized approach incorporating physiologic and clinical data when available.

A phase II dose evaluation pilot feasibility randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study).

BACKGROUND: Vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (ICU) and associated with worse clinical course. Trials in adult ICU demonstrate rapid restoration of vitamin D status using an enteral loading dose is safe and may improve outcomes. There have been no published trials of rapid normalization of VDD in the pediatric ICU. METHODS: We conducted a multicenter placebo-controlled phase II pilot feasibility randomized clinical trial from 2016 to 2017. We randomized 67 critically ill children with VDD from ICUs in Canada, Chile and Austria using a 2:1 randomization ratio to receive a loading dose of enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or placebo. Participants, care givers, and outcomes assessors were blinded. The primary objective was to determine whether the loading dose normalized vitamin D status (25(OH)D > 75 nmol/L). Secondary objectives were to evaluate for adverse events and assess the feasibility of a phase III trial. RESULTS: Of 67 randomized participants, one was withdrawn and seven received more than one dose of cholecalciferol before the protocol was amended to a single loading dose, leaving 59 participants in the primary analyses (40 treatment, 19 placebo). Thirty-one/38 (81.6%) participants in the treatment arm achieved a plasma 25(OH)D concentration > 75 nmol/L versus 1/18 (5.6%) the placebo arm. The mean 25(OH)D concentration in the treatment arm was 125.9 nmol/L (SD 63.4). There was no evidence of vitamin D toxicity and no major drug or safety protocol violations. The accrual rate was 3.4 patients/month, supporting feasibility of a larger trial. A day 7 blood sample was collected for 84% of patients. A survey administered to 40 participating families showed that health-related quality of life (HRQL) was the most important outcome for families for the main trial (30, 75%). CONCLUSIONS: A single 10,000 IU/kg dose can rapidly and safely normalize plasma 25(OH)D concentrations in critically ill children with VDD, but with significant variability in 25(OH)D concentrations. We established that a phase III multicentre trial is feasible. Using an outcome collected after hospital discharge (HRQL) will require strategies to minimize loss-to-follow-up. CLINICALTRIALS: gov NCT02452762 Registered 25/05/2015.

Association of age with death and withdrawal of life-sustaining therapy after severe traumatic brain injury.

BACKGROUND: Compared to younger age, older age (≥ 65 yr) is associated with worse outcomes after severe traumatic brain injury (TBI). We sought to describe the association of older age with in-hospital death and aggressiveness of intervention. METHODS: We conducted a retrospective cohort study of adult (age ≥ 16 yr) patients with severe TBI admitted to a single academic tertiary care neurotrauma centre between January 2014 and December 2015. We collected data through chart review as well as from our institutional administrative database. We provided descriptive statistics and used multivariable logistic regression to evaluate the independent association of age with the primary outcome, in-hospital death. The secondary outcome was early withdrawal of life-sustaining therapy. RESULTS: There were 126 adult patients (median age 67 yr [Q1-Q3, 33-80 yr]) with severe TBI during the study period who met our eligibility criteria. The most common mechanism was high-velocity blunt injury (55 patients [43.6%]). The median Marshall score was 4 (Q1-Q3, 2-6), and the median Injury Severity Score was 26 (Q1-Q3, 25-35). After controlling for confounders including clinical frailty, pre-existing comorbidity, injury severity, Marshall score and neurologic examination at admission, we observed that older patients were more likely than younger patients to die in hospital (odds ratio 5.10, 95% confidence interval 1.65-15.78). Older patients were also more likely to experience early withdrawal of life-sustaining therapy and less likely to receive invasive interventions. CONCLUSION: After controlling for confounding factors relevant to older patients, we observed that age was an important and independent predictor of in-hospital death and early withdrawal of life-sustaining therapy. The mechanism by which age influences clinical decision-making independent of global and neurologic injury severity, clinical frailty and comorbidities remains unclear.

Mesenchymal stem cells induce dynamic immunomodulation of airway and systemic immune cells in vivo but do not improve survival for mice with H1N1 virus-induced acute lung injury.

Introduction: Influenza A virus (IAV)-induced acute lung injury (ALI) is characterized by pronounced proinflammatory activation and respiratory lung dysfunction. In this study, we performed deep immune profiling on airway and circulating immune cells to examine the effect of immunomodulation and therapeutic outcomes of mesenchymal stem cells (MSCs) therapy in mice with IAV-induced ALI. Methods: Animals were inoculated intranasally with H1N1 IAV, followed by intravenous administration of vehicle, or human clinical-grade, bone marrow-derived MSCs 24-h later, and monitored for six days to evaluate the survival. In another set of animals, bronchoalveolar lavage (BAL) fluid and whole blood were collected three days after infection for flow or mass cytometry (CyTOF) immune profiling analysis. Results: Immune cell population and phenotypic shifts in blood were mapped by CyTOF. Increases were observed in granulocytes and myeloid-derived cells in blood from vehicle-treated animals. While MSC treatment accentuated changes in these populations, naïve B, antibody-secreting B cells, and T cells were decreased in MSC-treated animals at day 3. Compared to sham animals, IAV infection induced a significant 5.5-fold increase in BAL total cell counts, including CD4+ and CD8+ T cells, CD19+ B cells, CD11b + Ly6G + neutrophils, and CD11b + Ly6C + monocytes. MSC treatment significantly decreased BAL total cell counts in IAV-infected mice, specifically the number of infiltrating CD4+ T cells and CD11b + Ly6G + neutrophils. In contrast, there were increases in CD8+ T cells, B cells, and monocytes in the alveolar space in MSC-treated animals. Phenotypic immune cell profiling of blood and BAL revealed a significantly higher proportion of the monocyte population with the M2 phenotype (CD206) in MSC-treated animals; however, this failed to confer protective effects in the survival of infected mice or reduce viral titer in the lung. Further investigation revealed that MSCs were susceptible to IAV infection, leading to increased cell death and potentially affecting their efficacy. Conclusion: These findings provided in vivo evidence that MSCs promote the selective recruitment of immune cells to the site of infection during IAV infection, with reductions in proinflammatory phenotypes. However, MSCs offered no survival benefit in IAV-infected animals, possibly due to MSCs' H1N1 IAV susceptibility and subsequent cell death.

Diagnostic accuracy of ancillary tests for death by neurologic criteria: a systematic review and meta-analysis.

PURPOSE: Ancillary tests are frequently used in death determination by neurologic criteria (DNC), particularly when the clinical neurologic examination is unreliable. Nevertheless, their diagnostic accuracy has not been extensively studied. Our objective was to synthesize the sensitivity and specificity of commonly used ancillary tests for DNC. SOURCE: We performed a systematic review and meta-analysis by searching MEDLINE, EMBASE, Cochrane databases, and CINAHL Ebsco from their inception to 4 February 2022. We selected cohort and case-control studies including patients with 1) clinically diagnosed death by neurologic criteria or 2) clinically suspected death by neurologic criteria who underwent ancillary testing for DNC. We excluded studies without a priori diagnostic criteria and studies conducted solely on pediatric patients. Accepted reference standards were clinical examination, four-vessel conventional angiography, and radionuclide imaging. Data were directly extracted from published reports. We assessed the methodological quality of studies with the QUADAS-2 tool and estimated ancillary test sensitivities and specificities using hierarchical Bayesian models with diffuse priors. PRINCIPAL FINDINGS: Overall, 137 records met the selection criteria. One study (0.7%) had a low risk of bias in all QUADAS-2 domains. Among clinically diagnosed death by neurologic criteria patients (n = 8,891), ancillary tests had similar pooled sensitivities (range, 0.82-0.93). Sensitivity heterogeneity was greater within (σ = 0.10-0.15) than between (σ = 0.04) ancillary test types. Among clinically suspected death by neurologic criteria patients (n = 2,732), pooled ancillary test sensitivities ranged between 0.81 and 1.00 and specificities between 0.87 and 1.00. Most estimates had high statistical uncertainty. CONCLUSION: Studies assessing ancillary test diagnostic accuracy have an unclear or high risk of bias. High-quality studies are required to thoroughly validate ancillary tests for DNC. STUDY REGISTRATION: PROSPERO (CRD42013005907); registered 7 October 2013.

RéSUMé: OBJECTIF: Les examens auxiliaires sont fréquemment utilisés dans la détermination du décès selon des critères neurologiques (DCN), en particulier lorsque l'examen neurologique clinique n'est pas fiable. Néanmoins, leur précision diagnostique n'a pas été étudiée de manière approfondie. Notre objectif était de synthétiser la sensibilité et la spécificité des examens auxiliaires couramment utilisés pour la DCN. SOURCES: Nous avons réalisé une revue systématique et une méta-analyse en effectuant des recherches dans les bases de données MEDLINE, EMBASE, Cochrane et CINAHL Ebsco de leur création jusqu'au 4 février 2022. Nous avons sélectionné des études de cohorte et cas témoins incluant des patients présentant 1) un décès selon des critères neurologiques diagnostiqué cliniquement ou 2) un décès selon des critères neurologiques soupçonné cliniquement qui ont été soumis à des examens auxiliaires pour un DCN. Nous avons exclu les études sans critères diagnostiques a priori et les études menées uniquement auprès de patients pédiatriques. Les normes de référence acceptées étaient l'examen clinique, l'angiographie conventionnelle à quatre vaisseaux et l'imagerie nucléaire. Les données ont été directement extraites de comptes rendus publiés. Nous avons évalué la qualité méthodologique des études avec l'outil QUADAS-2 et estimé les sensibilités et les spécificités des examens auxiliaires à l'aide de modèles hiérarchiques bayésiens avec des distributions préalables diffuses. CONSTATATIONS PRINCIPALES: Au total, 137 études répondaient aux critères de sélection. Une étude (0,7 %) présentait un faible risque de biais dans tous les domaines de QUADAS-2. Parmi les patients ayant reçu un diagnostic clinique de décès selon des critères neurologiques (n = 8891), les examens auxiliaires présentaient des sensibilités combinées similaires (intervalle de 0,82 à 0,93). L'hétérogénéité de sensibilité était plus grande au sein (σ = 0,10-0,15) plutôt qu'entre (σ = 0,04) les types d'examens auxiliaires. Parmi les patients cliniquement soupçonnés de décès selon des critères neurologiques (n = 2732), les sensibilités combinées des examens auxiliaires variaient entre 0,81 et 1,00 et les spécificités entre 0,87 et 1,00. La plupart des estimations comportaient une grande incertitude statistique. CONCLUSION: Les études évaluant la précision diagnostique des examens auxiliaires présentent un risque de biais incertain ou élevé. Des études de haute qualité sont nécessaires pour valider en profondeur les examens auxiliaires pour la DCN. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42013005907); enregistrée le 7 octobre 2013.

Patient Relevance of the Modified Rankin Scale in Subarachnoid Hemorrhage Research: An International Cross-sectional Survey.

BACKGROUND AND OBJECTIVES: There is significant heterogeneity in the reporting of outcome measures in aneurysmal subarachnoid hemorrhage (aSAH) research. The modified Rankin scale (mRS) is the most commonly reported functional outcome measure. The mRS focuses on physical disability; however, many aSAH survivors experience sequalae in other domains, and the mRS may therefore not capture outcomes important to aSAH survivors. The objective of this study was to assess the clinical relevance of the mRS as a research outcome measure to people with lived aSAH experience. METHODS: We conducted an international cross-sectional survey of 355 aSAH survivors, family members, and caregivers to evaluate patient-perceived outcomes in relation to the mRS. The mRS was assessed using a previously validated web-based tool. RESULTS: Response rate was 60%; respondents from 7 continents were composed of 86% aSAH survivors and 14% family members/caregivers. Agreement between self-assessed outcome and the mRS was poor (Kappa 0.26 [CI 0.14-0.39]). Of the 172 respondents who self-assessed as having had a good aSAH outcome, 122 (71%) had a score of 0-2 on the mRS. Approximately 19% of respondents with a good outcome, based on a measured mRS score of 0-2, self-assessed as having had a poor aSAH outcome. When the mRS score was dichotomized as 0-3 corresponding to a good outcome, agreement between the score and self-assessed outcome remained poor with a Kappa score of 0.40 (CI 0.20-0.60). Approximately 30% of respondents believed that the mRS should not be used as an outcome measure in future aSAH trials. DISCUSSION: The findings suggest that there is poor agreement between aSAH survivors' self-assessed outcome, their actual mRS score, and the dichotomization of the mRS score into good/poor outcomes. Patient-centered and patient-informed outcome measurement tools are needed to guide the aSAH research agenda.

FLUID trial: a hospital-wide open-label cluster cross-over pragmatic comparative effectiveness randomised pilot trial comparing normal saline to Ringer's lactate.

OBJECTIVES: Normal saline (NS) and Ringer's lactate (RL) are the most common crystalloids used for fluid therapy. Despite evidence of possible harm associated with NS (eg, hyperchloremic metabolic acidosis, impaired kidney function and death), few large multi-centre randomised trials have evaluated the effect of these fluids on clinically important outcomes. We conducted a pilot trial to explore the feasibility of a large trial powered for clinically important outcomes. DESIGN: FLUID was a pragmatic pilot cluster randomised cross-over trial. SETTING: Four hospitals in the province of Ontario, Canada PARTICIPANTS: All hospitalised adult and paediatric patients with an incident admission to the hospital over the course of each study period. INTERVENTIONS: A hospital wide policy/strategy which stocked either NS or RL throughout the hospital for 12 weeks before crossing over to the alternate fluid for the subsequent 12 weeks. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary feasibility outcome was study fluid protocol adherence. Secondary feasibility outcomes included time to Research Ethics Board (REB) approval and trial initiation. Primary (composite of death or re-admission to hospital in first 90 days of index hospitalisation) and secondary clinical outcomes were analysed descriptively. RESULTS: Among 24 905 included patients, mean age 59.1 (SD 20.5); 13 977 (56.1%) were female and 21 150 (85.0%) had medical or surgical admitting diagnoses. Overall, 96 821 L were administered in the NS arm, and 78 348 L in the RL arm. Study fluid adherence to NS and RL was 93.7% (site range: 91.6%-98.0%) and 79.8% (site range: 72.5%-83.9%), respectively. Time to REB approval ranged from 2 to 48 days and readiness for trial initiation from 51 to 331 days. 5544 (22.3%) patients died or required hospital re-admission in the first 90 days. CONCLUSIONS: The future large trial is feasible. Anticipating and addressing logistical challenges during the planning stages will be imperative. TRIAL REGISTRATION NUMBER: NCT02721485.

Comparison of freshly cultured versus cryopreserved mesenchymal stem cells in animal models of inflammation: A pre-clinical systematic review.

Background: Mesenchymal stem cells (MSCs) are multipotent cells that demonstrate therapeutic potential for the treatment of acute and chronic inflammatory-mediated conditions. Although controversial, some studies suggest that MSCs may lose their functionality with cryopreservation which could render them non-efficacious. Hence, we conducted a systematic review of comparative pre-clinical models of inflammation to determine if there are differences in in vivo measures of pre-clinical efficacy (primary outcomes) and in vitro potency (secondary outcomes) between freshly cultured and cryopreserved MSCs. Methods: A systematic search on OvidMEDLINE, EMBASE, BIOSIS, and Web of Science (until January 13, 2022) was conducted. The primary outcome included measures of in vivo pre-clinical efficacy; secondary outcomes included measures of in vitro MSC potency. Risk of bias was assessed by the SYRCLE 'Risk of Bias' assessment tool for pre-clinical studies. Results: Eighteen studies were included. A total of 257 in vivo pre-clinical efficacy experiments represented 101 distinct outcome measures. Of these outcomes, 2.3% (6/257) were significantly different at the 0.05 level or less; 2 favoured freshly cultured and 4 favoured cryopreserved MSCs. A total of 68 in vitro experiments represented 32 different potency measures; 13% (9/68) of the experiments were significantly different at the 0.05 level or less, with seven experiments favouring freshly cultured MSC and two favouring cryopreserved MSCs. Conclusions: The majority of preclinical primary in vivo efficacy and secondary in vitro potency outcomes were not significantly different (p<0.05) between freshly cultured and cryopreserved MSCs. Our systematic summary of the current evidence base may provide MSC basic and clinical research scientists additional rationale for considering a cryopreserved MSC product in their pre-clinical studies and clinical trials as well as help identify research gaps and guide future related research. Funding: Ontario Institute for Regenerative Medicine.

Poly(I:C) enhances mesenchymal stem cell control of myeloid cells from COVID-19 patients.

Mesenchymal stem cells (MSCs) are being studied for the treatment of COVID-19-associated critical illness, due to their immunomodulatory properties. Here, we hypothesized that viral mimic-priming improves MSCs' abilities to rebalance the dysregulated immune responses in COVID-19. Transcriptome analysis of poly(I:C)-primed MSCs (pIC-MSCs) showed upregulation of pathways in antiviral and immunomodulatory responses. Together with increased expression of antiviral proteins such as MX1, IFITM3, and OAS1, these changes translated to greater effector functions in regulating monocytes and granulocytes while further enhancing MSCs' ability to block SARS-CoV-2 pseudovirus entry into epithelial cells. Most importantly, the addition of pIC-MSCs to COVID-19 patient whole blood significantly reduced inflammatory neutrophils and increased M2 monocytes while enhancing their phagocytic effector function. We reveal for the first time that MSCs can be primed by Toll-like receptor 3 agonist to improve their ability to rebalance the dysregulated immune responses seen in severe SARS-CoV-2 infection.

Attitudes and acceptability of organ and tissue donation registration in the emergency department: a national survey of emergency physicians.

PURPOSE: There is a worldwide shortage of organs for transplantation. One method to increase the number of organs available for transplant is to increase the number of registered organ donors. The emergency department (ED) may be a suitable venue to disseminate knowledge to patients about organ donation, and to offer an immediate or future opportunity to register as an organ donor. This study aimed to assess emergency physicians' attitudes and acceptability of an ED-based organ donation registration initiative. METHODS: We developed and distributed a national postal survey using a modified Dillman's tailored design technique to a random sample of emergency physicians selected from the Canadian Medical Directory. RESULTS: From a total of 474 delivered surveys, we received 228 responses (48.1%). 98.5% of emergency physicians support the concept of deceased organ donation. 85.1% felt that the emergency department is an appropriate setting to disseminate information regarding organ donation and 77.6% felt that it is an appropriate location to offer an immediate opportunity to register as an organ donor. 74.1% of physicians who responded report to be personally registered as an organ donor. CONCLUSION: Most emergency physicians are supportive of organ donation promotion in the ED, including offering an immediate opportunity to register.

RéSUMé: OBJECTIF: Il y a une pénurie mondiale d'organes destinés à la transplantation. Une méthode pour augmenter le nombre d'organes disponibles pour la transplantation est d'augmenter le nombre de donneurs d'organes enregistrés. Le service des urgences (SU) peut être un lieu approprié pour informer les patients sur le don d'organes et leur offrir la possibilité, immédiate ou future, de s'inscrire comme donneur d'organes. Cette étude visait à évaluer les attitudes des médecins urgentistes et l'acceptabilité d'une initiative d'enregistrement des dons d'organes aux urgences. MéTHODES: Nous avons élaboré et distribué une enquête postale nationale en utilisant une technique modifiée de conception sur mesure de Dillman à un échantillon aléatoire de médecins urgentistes sélectionnés à partir de l'annuaire médical canadien. RéSULTATS: Sur un total de 474 questionnaires remis, nous avons reçu 228 réponses (48,1%). 98,5 % des médecins urgentistes soutiennent le concept du don d'organes de personnes décédées. 85,1 % ont estimé que le service des urgences est un lieu approprié pour diffuser des informations sur le don d'organes et 77,6 % ont estimé que c'est un lieu approprié pour offrir une possibilité immédiate de s'inscrire comme donneur d'organes. 74,1 % des médecins qui ont répondu déclarent être personnellement inscrits comme donneurs d'organes. CONCLUSION: La plupart des médecins urgentistes sont favorables à la promotion du don d'organes dans les urgences, notamment en offrant la possibilité de s'inscrire immédiatement.

Balanced Versus Unbalanced Fluid in Critically Ill Children: Systematic Review and Meta-Analysis.

OBJECTIVES: The ideal crystalloid fluid bolus therapy for fluid resuscitation in children remains unclear, but pediatric data are limited. Administration of 0.9% saline has been associated with hyperchloremic metabolic acidosis and acute kidney injury. The primary objective of this systematic review was to compare the effect of balanced versus unbalanced fluid bolus therapy on the mean change in serum bicarbonate or pH within 24 hours in critically ill children. DATA SOURCES: We searched MEDLINE including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, CENTRAL Trials Registry of the Cochrane Collaboration, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform. STUDY SELECTION: Using the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols guidelines, we retrieved all controlled trials and observational cohort studies comparing balanced and unbalanced resuscitative fluids in critically ill children. The primary outcome was the change in serum bicarbonate or blood pH. Secondary outcomes included the prevalence of hyperchloremia, acute kidney injury, renal replacement therapy, and mortality. DATA EXTRACTION: Study screening, inclusion, data extraction, and risk of bias assessments were performed independently by two authors. DATA SYNTHESIS: Among 481 references identified, 13 met inclusion criteria. In the meta-analysis of three randomized controlled trials with a population of 162 patients, we found a greater mean change in serum bicarbonate level (pooled estimate 1.60 mmol/L; 95% CI, 0.04-3.16; p = 0.04) and pH level (pooled mean difference 0.03; 95% CI, 0.00-0.06; p = 0.03) after 4-12 hours of rehydration with balanced versus unbalanced fluids. No differences were found in chloride serum level, acute kidney injury, renal replacement therapy, or mortality. CONCLUSIONS: Our systematic review found some evidence of improvement in blood pH and bicarbonate values in critically ill children after 4-12 hours of fluid bolus therapy with balanced fluid compared with the unbalanced fluid. However, a randomized controlled trial is needed to establish whether these findings have an impact on clinical outcomes before recommendations can be generated.

Clinical evaluation and ancillary testing for the diagnosis of death by neurologic criteria: a cross-sectional survey of Canadian intensivists.

PURPOSE: Trust in the deceased organ donation process relies on the expectation that the diagnosis of death by neurologic criteria (DNC) is accurate and reliable. The objective of this study was to assess the perceptions and approaches to DNC diagnosis among Canadian intensivists. METHODS: We conducted a self-administered, online, cross-sectional survey of Canadian intensivists. Our sampling frame included all intensivists practicing in Canadian institutions. Results are reported using descriptive statistics. RESULTS: Among 550 identified intensivists, 249 (45%) completed the survey. Respondents indicated they would be comfortable diagnosing DNC based on clinical criteria alone in cases where there is movement in response to stimulation (119/248; 48%); inability to evaluate upper/lower extremity responses (84/249; 34%); spontaneous peripheral movement (76/249; 31%); inability to evaluate both oculocephalic and oculo-caloric reflexes (40/249; 16%); presence of high cervical spinal cord injury (40/249; 16%); and within 24 hr of hypoxemic-ischemic brain injury (38/247; 15%). Most respondents agreed that an ancillary test should always be conducted when a complete clinical evaluation is impossible (225/241; 93%); when there is possibility of a residual sedative effect (216/242; 89%); when the mechanism for brain injury is unclear (172/241; 71%); and if isolated brainstem injury is suspected (142/242; 59%). Sixty-six percent (158/241) believed that ancillary tests are sensitive and 55% (132/241) that they are specific for DNC. Respondents considered the following ancillary tests useful for DNC: four-vessel conventional angiography (211/241; 88%), nuclear imaging (179/240; 75%), computed tomography (CT) angiography (156/240; 65%), and CT perfusion (134/240; 56%). CONCLUSION: There is variability in perceptions and approaches to DNC diagnosis among Canadian intensivists, and some practices are inconsistent with national recommendations.

RéSUMé: OBJECTIF: La confiance dans le processus de don d'organes de donneurs décédés repose sur l'attente que le diagnostic de décès déterminé par des critères neurologiques (DDN) soit précis et fiable. L'objectif de cette étude était d'évaluer les perceptions et les approches du diagnostic de DDN chez les intensivistes canadiens. MéTHODE: Nous avons mené un sondage transversal auto-administré et en ligne auprès des intensivistes canadiens. Notre base d'échantillonnage comprenait tous les intensivistes exerçant dans des établissements canadiens. Les résultats sont présentés à l'aide de statistiques descriptives. RéSULTATS: Parmi les 550 intensivistes identifiés, 249 (45 %) ont répondu au sondage. Les répondants ont indiqué qu'ils seraient à l'aise de diagnostiquer un DDN en fonction de critères cliniques seulement dans les cas où il y a : un mouvement en réponse à une stimulation (119/248; 48 %); une incapacité à évaluer les réponses des membres supérieurs et inférieurs (84/249; 34 %); un mouvement périphérique spontané (76/249; 31 %); une incapacité à évaluer à la fois les réflexes oculo-céphaliques et vestibulo-oculaires (40/249; 16 %); la présence de lésions médullaires cervicales hautes (40/249; 16 %); et dans les 24 heures suivant une lésion cérébrale hypoxémique-ischémique (38/247; 15 %). La plupart des répondants étaient d'accord pour dire qu'un test auxiliaire devrait toujours être réalisé lorsqu'une évaluation clinique complète est impossible (225/241; 93 %); lorsqu'il y a possibilité d'un effet sédatif résiduel (216/242; 89 %); lorsque le mécanisme de la lésion cérébrale n'est pas clair (172/241; 71 %); et si une lésion isolée du tronc cérébral est suspectée (142/242; 59 %). Soixante-six pour cent (158/241) des répondants étaient d'avis que les tests auxiliaires étaient sensibles et 55 % (132/241) qu'ils étaient spécifiques pour le DDN. Les répondants ont jugé utiles les tests auxiliaires suivants pour le DDN : l'angiographie conventionnelle des quatre vaisseaux (211/241; 88 %), l'imagerie nucléaire (179/240; 75 %), l'angiographie par tomodensitométrie (TDM) (156/240; 65 %) et la perfusion en TDM (134/240; 56 %). CONCLUSION: Les perceptions et les approches du diagnostic de DDN varient parmi les intensivistes canadiens, et certaines pratiques ne sont pas conformes aux recommandations nationales.

Intravenous albumin for the prevention of hemodynamic instability during sustained low-efficiency dialysis: a randomized controlled feasibility trial (The SAFER-SLED Study).

BACKGROUND: Hemodynamic instability is a frequent complication of sustained low-efficiency dialysis (SLED) treatments in the ICU. Intravenous hyperoncotic albumin may prevent hypotension and facilitate ultrafiltration. In this feasibility trial, we sought to determine if a future trial, powered to evaluate clinically relevant outcomes, is feasible. METHODS: This single-center, blinded, placebo-controlled, randomized feasibility trial included patients with acute kidney injury who started SLED in the ICU. Patients were randomized to receive 25% albumin versus 0.9% saline (control) as 100 mL boluses at the start and midway through SLED, for up to 10 sessions. The recruitment rate and other feasibility outcomes were determined. Secondary exploratory outcomes included ultrafiltration volumes and metrics of hemodynamic instability. RESULTS: Sixty patients (271 SLED sessions) were recruited over 10 months. Age and severity of illness were similar between study groups. Most had septic shock and required vasopressor support at baseline. Protocol adherence occurred for 244 sessions (90%); no patients were lost to follow-up; no study-related adverse events were observed; open label albumin use was 9% and 15% in the albumin and saline arms, respectively. Ultrafiltration volumes were not significantly different. Compared to the saline group, the albumin group experienced less hemodynamic instability across all definitions assessed including a smaller absolute decrease in systolic blood pressure (mean difference 10.0 mmHg, 95% confidence interval 5.2-14.8); however, there were significant baseline differences in the groups with respect to vasopressor use prior to SLED sessions (80% vs 61% for albumin and saline groups, respectively). CONCLUSIONS: The efficacy of using hyperoncotic albumin to prevent hemodynamic instability in critically ill patients receiving SLED remains unclear. A larger trial to evaluate its impact in this setting, including evaluating clinically relevant outcomes, is feasible. Trial registration ClinicalTrials.gov (NCT03665311); First Posted: Sept 11th, 2018. https://clinicaltrials.gov/ct2/show/NCT03665311?term=NCT03665311&draw=2&rank=1.