Post-Intensive Care Sequelae in Pediatrics-Results of an Early Rehabilitation Implementation Study.

OBJECTIVES: To compare post-PICU discharge functioning, health-related quality of life (HRQL), and parental stress before and after the implementation of an early rehabilitation bundle. DESIGN AND SETTING: Prospective cohort substudy within an early rehabilitation implementation program, conducted at the PICUs at McMaster Children's Hospital and London Health Sciences, London, Ontario, Canada. INTERVENTIONS: A bundle consisting of: 1) analgesia-first sedation; 2) delirium monitoring and prevention; and 3) early mobilization. Patients with an anticipated 48-hour PICU length of stay were approached for consent to participate. PATIENTS: Critically ill children with an anticipated 48-hour PICU length of stay were approached for consent to participate. MEASUREMENTS AND MAIN RESULTS: Patient-/proxy-reported outcome measures were assessed at baseline, PICU discharge, and 1 and 3 months post-PICU discharge using: 1) Pediatric Evaluation of Disability Inventory Computer Adaptive Test to assess physical, social, cognitive, and responsibility/caregiver domains of functioning; 2) KIDSCREEN to assess HRQL; and 3) the Pediatric Inventory for Parents to assess caregiver stress. A total of 117 participants were enrolled. Patient demographic characteristics were similar in the pre- and post-intervention groups. Following bundle implementation, 30 of 47 respondents (63.8%) experienced functional decline and 18 of 45 (40%) experienced low HRQL at PICU discharge. Eighteen of 36 (50%) at 1 month and 14 of 38 (36.8%) at 3 months experienced either persistent functional decline and/or low HRQL; 2.8% and 2.6% at 1- and 3-month follow-up, respectively, experienced both persistent functional decline and low HRQL. There were no significant differences in the rates of persistent functional decline, low HRQL, or caregiver stress scores post-bundle compared with pre-rehabilitation bundle implementation. CONCLUSIONS: We were unable to adequately determine the efficacy of a rehabilitation bundle on patient-centered outcomes as this substudy was not powered for these outcomes. Our results did reveal that persistent low functioning is common in PICU survivors, more common than low HRQL, while experiencing both functional decline and low HRQL was uncommon.

Early Rehabilitation in Critically ill Children: A Two Center Implementation Study.

OBJECTIVES: To implement an early rehabilitation bundle in two Canadian PICUs. DESIGN AND SETTING: Implementation study in the PICUs at McMaster Children's Hospital (site 1) and London Health Sciences (site 2). PATIENTS: All children under 18 years old admitted to the PICU were eligible for the intervention. INTERVENTIONS: A bundle consisting of: 1) analgesia-first sedation; 2) delirium monitoring and prevention; and 3) early mobilization. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were the duration of implementation, bundle compliance, process of care, safety, and the factors influencing implementation. Secondary endpoints were the impact of the bundle on clinical outcomes such as pain, delirium, iatrogenic withdrawal, ventilator-free days, length of stay, and mortality. Implementation occurred over 26 months (August 2018 to October 2020). Data were collected on 1,036 patients representing 4,065 patient days. Bundle compliance was optimized within 6 months of roll-out. Goal setting for mobilization and level of arousal improved significantly (p < 0.01). Benzodiazepine, opioid, and dexmedetomidine use decreased in site 1 by 23.2% (95% CI, 30.8-15.5%), 26.1% (95% CI, 34.8-17.4%), and 9.2% (95% CI, 18.2-0.2%) patient exposure days, respectively, while at site 2, only dexmedetomidine exposure decreased significantly by 10.5% patient days (95% CI, 19.8-1.1%). Patient comfort, safety, and nursing workload were not adversely affected. There was no significant impact of the bundle on the rate of delirium, ventilator-free days, length of PICU stay, or mortality. Key facilitators to implementation included institutional support, unit-wide practice guidelines, dedicated PICU educators, easily accessible resources, and family engagement. CONCLUSIONS: A rehabilitation bundle can improve processes of care and reduce patient sedative exposure without increasing patient discomfort, nursing workload, or harm. We did not observe an impact on short-term clinical outcomes. The efficacy of a PICU-rehabilitation bundle requires ongoing study. Lessons learned in this study provide evidence to inform rehabilitation implementation in the PICU setting.

COVID-19 plasma proteome reveals novel temporal and cell-specific signatures for disease severity and high-precision disease management.

Coronavirus disease 2019 (COVID-19) is a systemic inflammatory condition with high mortality that may benefit from personalized medicine and high-precision approaches. COVID-19 patient plasma was analysed with targeted proteomics of 1161 proteins. Patients were monitored from Days 1 to 10 of their intensive care unit (ICU) stay. Age- and gender-matched COVID-19-negative sepsis ICU patients and healthy subjects were examined as controls. Proteomic data were resolved using both cell-specific annotation and deep-analysis for functional enrichment. COVID-19 caused extensive remodelling of the plasma microenvironment associated with a relative immunosuppressive milieu between ICU Days 3-7, and characterized by extensive organ damage. COVID-19 resulted in (1) reduced antigen presentation and B/T-cell function, (2) increased repurposed neutrophils and M1-type macrophages, (3) relatively immature or disrupted endothelia and fibroblasts with a defined secretome, and (4) reactive myeloid lines. Extracellular matrix changes identified in COVID-19 plasma could represent impaired immune cell homing and programmed cell death. The major functional modules disrupted in COVID-19 were exaggerated in patients with fatal outcome. Taken together, these findings provide systems-level insight into the mechanisms of COVID-19 inflammation and identify potential prognostic biomarkers. Therapeutic strategies could be tailored to the immune response of severely ill patients.

Risk Factors for Major Cardiovascular Events in Adult Sepsis Survivors: A Population-Based Cohort Study.

OBJECTIVES: To describe risk factors for major cardiovascular events in adults following hospital discharge after sepsis. DESIGN: Population-based cohort study. SETTING: Ontario, Canada (2008-2017). PATIENTS: Adult patients (age 18 yr or older) who survived a first sepsis hospitalization without preexisting cardiovascular disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary composite outcome was myocardial infarction, stroke, or cardiovascular death up to 5 years following hospital discharge. We used cause-specific Cox proportional hazards models that accounted for the competing risk of noncardiovascular death to describe factors associated with major cardiovascular events. We identified 268,259 adult patients without cardiovascular disease (median age, 72 yr), of whom 10.4% experienced a major cardiovascular event during a median follow-up of 3 years. After multivariable adjustment, age (hazard ratio [HR], 1.53 for every 10 yr; 95% CI, 1.51-1.54), male sex (HR, 1.23; 95% CI, 1.20-1.26), diabetes mellitus (HR, 1.24; 95% CI, 1.21-1.27), hypertension (HR, 1.34; 95% CI, 1.30-1.38), prevalent atrial fibrillation (HR, 1.46; 95% CI, 1.40-1.52), and chronic kidney disease (HR, 1.11; 95% CI, 1.06-1.16) were associated with major cardiovascular events during long-term follow-up. Sepsis characteristics such as site of infection (pneumonia vs other: HR, 1.09; 95% CI, 1.05-1.12), septic shock (HR, 1.08; 95% CI, 1.05-1.11), and renal replacement therapy (HR, 1.51; 95% CI, 1.38-1.64) were also associated with subsequent cardiovascular events. In an analysis restricting to patients with troponin values measured during the hospitalization (26,400 patients), an elevated troponin was also associated with subsequent cardiovascular events (HR, 1.23; 95% CI, 1.13-1.33). CONCLUSIONS: Classic cardiovascular risk factors, comorbid conditions, and characteristics of the sepsis episode were associated with a higher hazard of major cardiovascular events in adult sepsis survivors. These findings may inform enrichment strategies for future studies.

Safety Outcomes of Direct Discharge Home From ICUs: An Updated Systematic Review and Meta-Analysis (Direct From ICU Sent Home Study).

OBJECTIVE: To evaluate the impact of direct discharge home (DDH) from ICUs compared with ward transfer on safety outcomes of readmissions, emergency department (ED) visits, and mortality. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature from inception until March 28, 2022. STUDY SELECTION: Randomized and nonrandomized studies of DDH patients compared with ward transfer were eligible. DATA EXTRACTION: We screened and extracted studies independently and in duplicate. We assessed risk of bias using the Newcastle-Ottawa Scale for observational studies. A random-effects meta-analysis model and heterogeneity assessment was performed using pooled data (inverse variance) for propensity-matched and unadjusted cohorts. We assessed the overall certainty of evidence for each outcome using the Grading Recommendations Assessment, Development and Evaluation approach. DATA SYNTHESIS: Of 10,228 citations identified, we included six studies. Of these, three high-quality studies, which enrolled 49,376 patients in propensity-matched cohorts, could be pooled using meta-analysis. For DDH from ICU, compared with ward transfers, there was no difference in the risk of ED visits at 30-day (22.4% vs 22.7%; relative risk [RR], 0.99; 95% CI, 0.95-1.02; p = 0.39; low certainty); hospital readmissions at 30-day (9.8% vs 9.6%; RR, 1.02; 95% CI, 0.91-1.15; p = 0.71; very low-to-low certainty); or 90-day mortality (2.8% vs 2.6%; RR, 1.06; 95% CI, 0.95-1.18; p = 0.29; very low-to-low certainty). There were no important differences in the unmatched cohorts or across subgroup analyses. CONCLUSIONS: Very low-to-low certainty evidence from observational studies suggests that DDH from ICU may have no difference in safety outcomes compared with ward transfer of selected ICU patients. In the future, this research question could be further examined by randomized control trials to provide higher certainty data.

Prevalent diabetes and long-term cardiovascular outcomes in adult sepsis survivors: a population-based cohort study.

BACKGROUND: Sepsis survivors are at elevated risk for cardiovascular disease during long-term follow-up. Whether diabetes influences cardiovascular risk after sepsis survival remains unknown. We sought to describe the association of diabetes with long-term cardiovascular outcomes in adult sepsis survivors. METHODS: Population-based cohort study in the province of Ontario, Canada (2008-2017). Adult survivors of a first sepsis-associated hospitalization, without pre-existing cardiovascular disease, were included. Main exposure was pre-existing diabetes (any type). The primary outcome was the composite of myocardial infarction, stroke, and cardiovascular death. Patients were followed up to 5 years from discharge date until outcome occurrence or end of study period (March 2018). We used propensity score matching (i.e., 1:1 to patients with sepsis but no pre-existing diabetes) to adjust for measured confounding at baseline. Cause-specific Cox proportional hazards models with robust standard errors were used to estimate hazard ratios (HR) alongside 95% confidence intervals (CI). A main secondary analysis evaluated the modification of the association between sepsis and cardiovascular disease by pre-existing diabetes. RESULTS: 78,638 patients with pre-existing diabetes who had a sepsis-associated hospitalization were matched to patients hospitalized for sepsis but without diabetes. Mean age of patients was 71 years, and 55% were female. Median duration from diabetes diagnosis was 9.8 years; mean HbA1c was 7.1%. Adult sepsis survivors with pre-existing diabetes experienced a higher hazard of major cardiovascular disease (HR 1.25; 95% CI 1.22-1.29)-including myocardial infarction (HR 1.40; 95% CI 1.34-1.47) and stroke (HR 1.24; 95% CI 1.18-1.29)-during long-term follow-up compared to sepsis survivors without diabetes. Pre-existing diabetes modified the association between sepsis and cardiovascular disease (risk difference: 2.3%; 95% CI 2.0-2.6 and risk difference: 1.8%; 95% CI 1.6-2.0 for the effect of sepsis-compared to no sepsis-among patients with and without diabetes, respectively). CONCLUSIONS: Sepsis survivors with pre-existing diabetes experience a higher long-term hazard of major cardiovascular events when compared to sepsis survivors without diabetes. Compared to patients without sepsis, the absolute risk increase of cardiovascular events after sepsis is higher in patients with diabetes (i.e., diabetes intensified the higher cardiovascular risk induced by sepsis).

Outcomes After Direct Discharge Home From Critical Care Units: A Population-Based Cohort Analysis.

OBJECTIVES: To compare health service use and clinical outcomes for patients with and without direct discharge to home (DDH) from ICUs in Ontario. DESIGN: Population-based, observational, cohort study using propensity scoring to match patients who were DDH to those not DDH and a preference-based instrumental variable (IV) analysis using ICU-level DDH rate as the IV. SETTING: ICUs in Ontario. PATIENTS: Patients discharged home from a hospitalization either directly or within 48 hours of care in an ICU between April 1, 2015, and March 31, 2017. INTERVENTION: DDH from ICU. MEASUREMENTS AND MAIN RESULTS: Among 76,737 patients in our cohort, 46,859 (61%) were DDH from the ICU. In the propensity matched cohort, the odds for our primary outcome of hospital readmission or emergency department (ED) visit within 30 days were not significantly different for patients DDH (odds ratio [OR], 1.00; 95% CI, 0.96-1.04), and there was no difference in mortality at 90 days for patients DDH (OR, 1.08; 95% CI, 0.97-1.21). The effect on hospital readmission or ED visits was similar in the subgroup of patients discharged from level 2 (OR, 0.98; 95% CI, 0.92-1.04) and level 3 ICUs (OR, 1.02; 95% CI, 0.96-1.09) and in the subgroups with cardiac conditions (OR, 1.03; 95% CI, 0.96-1.12) and noncardiac conditions (OR, 0.98; 95% CI, 0.94-1.03). Similar results were obtained in the IV analysis (coefficient for hospital readmission or ED visit within 30 d = -0.03 ± 0.03 ( se ); p = 0.3). CONCLUSIONS: There was no difference in outcomes for patients DDH compared with ward transfer prior to discharge when two approaches were used to minimize confounding within a large health systemwide observational cohort. We did not evaluate how patients are selected for DDH. Our results suggest that with careful patient selection, this practice might be feasible for routine implementation to ensure efficient and safe use of limited healthcare resources.

Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey.

OBJECTIVES: Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic. DESIGN: Cross-sectional survey using four validated instruments. SETTING: Sixty-two sites in Canada and the United States. SUBJECTS: Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures. CONCLUSIONS: Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

Novel plasma protein biomarkers from critically ill sepsis patients.

BACKGROUND: Despite the high morbidity and mortality associated with sepsis, the relationship between the plasma proteome and clinical outcome is poorly understood. In this study, we used targeted plasma proteomics to identify novel biomarkers of sepsis in critically ill patients. METHODS: Blood was obtained from 15 critically ill patients with suspected/confirmed sepsis (Sepsis-3.0 criteria) on intensive care unit (ICU) Day-1 and Day-3, as well as age- and sex-matched 15 healthy control subjects. A total of 1161 plasma proteins were measured with proximal extension assays. Promising sepsis biomarkers were narrowed with machine learning and then correlated with relevant clinical and laboratory variables. RESULTS: The median age for critically ill sepsis patients was 56 (IQR 51-61) years. The median MODS and SOFA values were 7 (IQR 5.0-8.0) and 7 (IQR 5.0-9.0) on ICU Day-1, and 4 (IQR 3.5-7.0) and 6 (IQR 3.5-7.0) on ICU Day-3, respectively. Targeted proteomics, together with feature selection, identified the leading proteins that distinguished sepsis patients from healthy control subjects with ≥ 90% classification accuracy; 25 proteins on ICU Day-1 and 26 proteins on ICU Day-3 (6 proteins overlapped both ICU days; PRTN3, UPAR, GDF8, NTRK3, WFDC2 and CXCL13). Only 7 of the leading proteins changed significantly between ICU Day-1 and Day-3 (IL10, CCL23, TGFα1, ST2, VSIG4, CNTN5, and ITGAV; P < 0.01). Significant correlations were observed between a variety of patient clinical/laboratory variables and the expression of 15 proteins on ICU Day-1 and 14 proteins on ICU Day-3 (P < 0.05). CONCLUSIONS: Targeted proteomics with feature selection identified proteins altered in critically ill sepsis patients relative to healthy control subjects. Correlations between protein expression and clinical/laboratory variables were identified, each providing pathophysiological insight. Our exploratory data provide a rationale for further hypothesis-driven sepsis research.

Determinants of Direct Discharge Home From Critical Care Units: A Population-Based Cohort Analysis.

OBJECTIVE: To describe trends and patient and system factors associated with direct discharge from critical care to home in a large health system. DESIGN: Population-based cohort study of direct discharge to home rates annually over 10 years. We used a multivariable, multilevel random-effects regression model to analyze current factors associated with direct discharge home in a subcohort from the most recent 2 years. SETTING: One hundred seventy-four ICUs in 101 hospitals in Ontario. PATIENTS: All patients discharged from an ICU between April 1, 2007, and March 31, 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Overall, 237,200 patients (21.1%) were discharged directly home from an ICU. The rate of direct discharge to home increased from 18.6% in 2007 to 23.1% in 2017 (annual increase of 1.02; 95% CI, 1.02-1.03). There were marked variations in rates of direct discharge to home across all critical care units. For medical and surgical units, the median odds ratio was 1.76 (95% CI, 1.59-1.92). In these units, direct discharge to home was associated with younger age (odds ratio, 0.36; 95% CI, 0.34-0.39 for age 80-105 vs age 18-39), fewer comorbidities (odds ratio, 1.74; 95% CI, 1.63-1.85 for Charlson comorbidity index of 0 vs 2), diagnoses of overdose/poisoning (odds ratio, 1.35; 95% CI, 1.23-1.47) and diabetic complications (odds ratio, 1.35; 95% CI, 1.2-1.51), and admission after a same-day procedure (odds ratio, 2.82; 95% CI, 2.46-3.23 compared with emergency department). ICU occupancy was inversely associated with direct discharge to home with an odds ratio of 0.88 (95% CI, 0.87-0.88) for each 10% increase. CONCLUSIONS: High rates of direct discharge to home with evidence of significant practice variation combined with identifiable patient characteristics suggest that further evaluation of this increasingly common transition in care is warranted.

External validation of a prognostic model for intensive care unit mortality: a retrospective study using the Ontario Critical Care Information System.

PURPOSE: To externally validate an intensive care unit (ICU) mortality prediction model that was created using the Ontario Critical Care Information System (CCIS), which includes the Multiple Organ Dysfunction Score (MODS). METHODS: We applied the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) recommendations to a prospective longitudinal cohort of patients discharged between 1 July 2015 and 31 December 31 2016 from 90 adult level-3 critical care units in Ontario. We used multivariable logistic regression with measures of discrimination, calibration-in-the-large, calibration slope, and flexible calibration plots to compare prediction model performance of the entire data set and for each ICU subtype. RESULTS: Among 121,201 CCIS records with ICU mortality of 11.3%, the C-statistic for the validation data set was 0.805. The C-statistic ranged from 0.775 to 0.846 among the ICU subtypes. After intercept recalibration to adjust the baseline risk, the mean predicted risk of death matched actual ICU mortality. The calibration slope was close to 1 with all CCIS data and ICU subtypes of cardiovascular and community hospitals with low ventilation rates. Calibration slopes significantly less than 1 were found for ICUs in teaching hospitals and community hospitals with high ventilation rates whereas coronary care units had a calibration slope significantly higher than 1. Calibration plots revealed over-prediction in high risk groups to a varying degree across all cohorts. CONCLUSIONS: A risk prediction model primarily based on the MODS shows reproducibility and transportability after intercept recalibration. Risk adjusting models that use existing and feasible data collection can support performance measurement at the individual ICU level.

RéSUMé: OBJECTIF: Nous souhaitions faire une validation externe d'un modèle de prédiction de la mortalité aux unités de soins intensifs (USI) créé en utilisant le Système d'information sur les soins aux malades en phase critique (SISMPC) de l'Ontario, qui comporte le Score de défaillance multisystémique (MODS). MéTHODE: Nous avons appliqué les recommandations de communication transparente d'un modèle de prédiction multivarié pour le pronostic ou le diagnostic individuel TRIPOD à une cohorte longitudinale prospective de patients. Ces patients devaient avoir reçu leur congé entre le 1er juillet 2015 et le 31 décembre 2016 de 90 unités de soins intensifs de niveau 3 pour adultes en Ontario. Nous avons utilisé une méthode de régression logistique multivariée accompagnée de mesures de discrimination, d'étalonnage global, de pentes d'étalonnage et de graphiques d'étalonnage afin de comparer la performance du modèle de prédiction pour l'ensemble des données dans son intégralité et pour chaque sous-type d'USI. RéSULTATS: Parmi les 121 201 dossiers du SISMPC présentant une mortalité à l'USI de 11,3 %, la statistique C pour l'ensemble de données de validation était 0,805. La statistique C allait de 0,775 à 0,846 parmi les sous-types d'USI. Après réétalonnage de l'ordonnée afin d'ajuster le risque de base, le risque prédit moyen de décès correspondait à la mortalité réelle à l'USI. La pente d'étalonnage était proche de 1 pour toutes les données du SISMPC et tous les sous-types d'USI des hôpitaux cardiovasculaires et communautaires ayant de faibles taux de patients ventilés. Des pentes d'étalonnage significativement inférieures à 1 ont été observées pour les USI dans les hôpitaux universitaires et les hôpitaux communautaires ayant des taux de patients ventilés élevés, alors que les unités de soins coronariens présentaient une pente d'étalonnage significativement supérieure à 1. Les courbes d'étalonnage ont révélé une sur-prédiction dans les groupes à risque élevé à des degrés variables dans toutes les cohortes. CONCLUSION: Un modèle de prédiction du risque se fondant principalement sur le score MODS a montré sa reproductibilité et son applicabilité après réétalonnage de l'ordonnée. Les modèles d'ajustement du risque qui s'appuient sur des collectes de données existantes et réalisables peuvent aider à mesurer la performance au niveau de l'USI individuelle.

Acceptability of cardiac donation after circulatory determination of death: a survey of the Canadian public.

PURPOSE: Cardiac transplantation is a definitive therapy for end-stage heart failure, but demand exceeds supply. Cardiac donation after circulatory determination of death (cardiac DCDD) can be performed using direct procurement and perfusion (DPP), where cardiac activity is restored after heart recovery, or (NRP), where brain blood supply is surgically interrupted, circulation to the thoraco-abdominal organs is restored within the donor's body, followed by heart recovery. While cardiac DCDD would increase the number of heart donors, uptake of programs has been slowed in part because of ethical concerns within the medical community. These debates have been largely devoid of discussion regarding public perceptions. We conducted a national survey of public perceptions regarding cardiac DCDD. METHODS: We surveyed 1,001 Canadians about their attitudes towards cardiac DCDD using a rigorously designed and pre-tested survey. RESULTS: We found that 843 of 1,001 respondents (84.2%; 95% confidence interval [CI], 81.8 to 86.3) accepted the DPP approach, 642 (64.1%; 95% CI, 61.1 to 67.0) would agree to donate their heart using DPP, and 696 (69.5%; 95% CI, 66.6 to 72.3) would consent to the same for a family member. We found that 779 respondents of 1,001 respondents (77.8%; 95% CI, 75.1 to 80.3) accepted the NRP approach, 587 (58.6%; 95% CI, 55.5 to 61.6) would agree to donate their heart using NRP, and 636 (63.5%; 95% CI, 60.5 to 66.4) would consent to the same for a family member. Most respondents supported the implementation of DPP (738 respondents or 73.7%; 95% CI, 70.9 to 76.3) and NRP (655 respondents or 65.4%; 95% CI, 62.4 to 68.3) in Canada. CONCLUSION: The results of this national survey of public attitudes towards cardiac DCDD will inform the implementation of cardiac DCDD programs in a manner that is consistent with public values.

Attitudes of healthcare providers towards cardiac donation after circulatory determination of death: a Canadian nation-wide survey.

PURPOSE: The number of patients on cardiac transplant waitlists exceeds the number of available donor organs. Cardiac donation is currently limited to those declared dead by neurologic criteria in all but three countries. Cardiac donation after circulatory determination of death (cardiac DCDD) can be conducted using direct procurement and perfusion (DPP) or normothermic regional perfusion (NRP). Implementation of cardiac DCDD in many countries has been slowed by ethical debates within the donation and transplantation community. We conducted a national survey to determine the perceptions of healthcare providers regarding cardiac DCDD. METHODS: We conducted an electronic survey of 398 healthcare providers who are involved in the management of heart donors and/or heart transplant recipients in Canada (226 nurses, 82 critical care physicians, 31 donation specialists, and 59 transplant specialists). Our primary outcomes were their attitudes towards and concerns regarding cardiac DCDD protocols and their implementation in Canada. We distributed the survey electronically through several Canadian donation and transplantation organizations. RESULTS: We identified that 361 of 391 respondents (92.3%; 95% confidence interval [CI], 89.6 to 95.1) believed that DPP is acceptable, and 329 of 377 respondents (87.3%; 95% CI, 83.9 to 90.7) supported its implementation in Canada. We found that 301 of 384 respondents (78.4%; 95% CI, 74.2 to 82.6) believed that NRP is acceptable and 266 of 377 respondents (70.6%; 95% CI, 66.0 to 75.2) supported its implementation in Canada. CONCLUSION: This is the first survey describing the attitudes of healthcare providers towards cardiac DCDD. We identified widespread support for cardiac DCDD and its implementation in Canada among Canadian healthcare providers within the organ donation and transplantation community in Canada.

Gender differences in career satisfaction, moral distress, and incivility: a national, cross-sectional survey of Canadian critical care physicians.

PURPOSE: In a national cross-sectional survey, we aimed to i) characterize work profile, workload, and income, ii) evaluate work satisfaction, work-life integration, burnout, incivility, mentorship, and promotion, iii) gauge future physician resource requirements, and iv) assess for differences by gender and specialty (adult vs pediatric). METHODS: We developed, tested, and administered an electronic questionnaire. RESULTS: We analyzed 265 fully and 18 partially completed questionnaires. Respondents were predominantly men (192; 72.5%) and adult intensivists (229; 87.7%). Most intensivists (226/272; 83.1%) were somewhat satisfied or strongly satisfied with their career. Over one third of respondents felt that their daily intensive care unit (ICU) clinical work (113/270; 41.9%), yearly non-ICU clinical work (86/248; 34.7%), administrative work (101/264; 38.3%), and in-house call coverage (78/198; 39.4%) were somewhat high or very high. Nearly half (129/273; 47.3%) felt that their work schedule did not leave enough time for personal/family life. Twenty-seven percent (74/272) of respondents were experiencing at least one symptom of burnout when surveyed and 171/272 (63%) experienced burnout symptoms more than once a month. Ten percent planned to retire in the next five years and 17-20% retired each five-year interval thereafter. Compared with men, women felt that their work schedule left significantly less time for personal/family life (χ2 [4] = 11.36, P < 0.05, odds ratio [OR] = 0.55), experienced more frequent and severe burnout symptoms (F [1,120.91] = 8.04, P < 0.01, OR = 2.0; F [1,112.80] = 4.91, P < 0.05, OR = 1.9), and more incivility in their division (χ2 [1] = 13.73, P < 0.001, OR = 2.8), hospital (χ2 [1] = 8.11, P < 0.01, OR = 2.2), and university (χ2 [1] = 4.91, P < 0.05, OR = 2.3). CONCLUSIONS: Although most intensivists were satisfied with their careers, many were dissatisfied with their workload, experienced work-life integration challenges, and acknowledged burnout symptoms. Women intensivists were significantly less satisfied with their careers, experienced greater work-life integration challenges, more frequent and severe burnout symptoms, and greater incivility.

RéSUMé: OBJECTIF: Nous avons créé un sondage transversal national qui avait pour objectif de i) caractériser le profil professionnel, la charge de travail et le revenu; ii) évaluer la satisfaction professionnelle, l'intégration travail ­ vie privée, l'épuisement professionnel, l'incivilité, le mentorat et les opportunités d'avancement professionnel, iii) évaluer les besoins futurs en ressources humaines, et iv) évaluer les différences hommes/femmes et entre spécialités (population adulte vs pédiatrique). MéTHODE: Nous avons mis au point, testé et administré un questionnaire électronique. RéSULTATS: Au total, 265 questionnaires intégralement complétés et 18 questionnaires partiellement complétés nous ont été retournés pour analyse. Les répondants étaient principalement des hommes intensivistes (192; 72,5 %) spécialisés en populations adultes (229; 87,7 %). La plupart des intensivistes (226/272; 83,1 %) se considéraient plutôt satisfaits ou très satisfaits de leur carrière. Plus d'un tiers des répondants étaient d'avis que leur travail clinique quotidien à l'unité des soins intensifs (USI) (113/270; 41,9 %), leur travail clinique annuel non lié à l'USI (86/248; 34,7 %), leur travail administratif (101/264; 38,3 %) et la couverture des gardes sur place (78/198; 39,4 %) étaient plutôt élevés ou très élevés. Près de la moitié (129/273; 47,3 %) des répondants étaient d'avis que leur horaire de travail ne laissait pas suffisamment de temps pour leur vie personnelle/de famille. Vingt-sept pour cent (74/272) des répondants présentaient au moins un symptôme d'épuisement professionnel au moment du sondage et 171/272 (63 %) souffraient de symptômes d'épuisement professionnel plus d'une fois par mois. Dix pour cent planifiaient prendre leur retraite au cours des cinq prochaines années, et 17­20 % planifiaient de le faire dans le courant de chaque intervalle de cinq ans subséquent. Par rapport à leurs collègues masculins, les femmes étaient d'avis que leur horaire de travail laissait significativement moins de temps pour leur vie personnelle/de famille (χ2 [4] = 11,36, P < 0,05, rapport de cotes [RC] = 0,55), souffraient de symptômes d'épuisement professionnel plus fréquents et plus graves (F [1120,91] = 8,04, P < 0,01, RC = 2,0; F [1112,80] = 4,91, P < 0,05, RC = 1,9), et de plus d'incivilité dans leur département (χ2 [1] = 13,73, P < 0,001, RC = 2,8), leur hôpital (χ2 [1] = 8,11, P < 0,01, RC = 2,2) et dans leur université (χ2 [1] = 4,91, P < 0,05, RC = 2,3). CONCLUSION: Bien que la plupart des intensivistes s'estiment satisfaits de leur carrière, bon nombre s'avouent mécontents de leur charge de travail, des défis d'intégration travail / vie de famille et reconnaissent souffrir de symptômes d'épuisement professionnel. Les femmes intensivistes sont significativement moins satisfaites de leur carrière, font face à des défis plus importants en matière d'intégration vie professionnelle / vie privée, souffrent de symptômes d'épuisement professionnel plus fréquents et plus prononcés ainsi que d'une plus grande incivilité.

The effect of aerosolized indomethacin on lung inflammation and injury in a rat model of blunt chest trauma

Background: Acute lung contusion from blunt chest trauma (BCT) is characterized by an intense inflammatory response in the pulmonary parenchyma, which is associated with acute lung injury (ALI), acute respiratory distress syndrome and ventilator-associated pneumonia. We hypothesized that aerosolized indomethacin may reduce pulmonary inflammation and ALI in a rat model of BCT. Methods: Sprague-Dawley rats were anesthetized and received a tracheotomy for administration of aerosolized medication through a catheter. The BCT procedure involved free-dropping a hollow metal weight (200 g) from a height of 25.5, 38.3 or 51.2 cm onto the right thorax. We administered 1 mg/kg of indomethacin or 1 mL/kg of saline intratracheally 15 minutes after BCT. The sham group had a similar procedure without the exposure to BCT and treatment. Three hours postimpact, we obtained arterial blood gas and analyzed bronchoalveolar lavage for protein concentration, polymorphonuclear leukocytes (PMN) and cytokine levels, and lung tissue samples were taken for histopathological analysis. Results: The rats' mean arterial pressure and heart rate dropped immediately postimpact but recovered close to that of the sham group after 30 minutes in both control and treatment groups. Compared to BCT alone, indomethacin significantly reduced the total protein level in the lungs (1.06 ± 0.39 mg/mL v. 3.75 ± 1.95 mg/mL, p = 0.006) and alveolar FD-70 leak (0.23 ± 0.19 µg/mL v. 0.53 ± 0.19 µg/mL, p = 0.02). Indomethacin also significantly attenuated the acute inflammatory response in percent PMN (13.33 ±7.5% v. 28.0 ± 12.96%, p = 0.04). Tumour necrosis factor-α and interleukin-6 decreased in the indomethacin group, but the decreases were not significant compared with other groups. Conclusion: Aerosolized indomethacin has a protective effect against alveloar tissue permeability and inflammatory response induced by BCT.

Contexte: La contusion pulmonaire aiguë causée par un traumatisme thoracique fermé (TTF) se caractérise par une intense réaction inflammatoire dans le parenchyme pulmonaire, liée à une atteinte pulmonaire aiguë (APA), à un syndrome de détresse respiratoire et à la pneumonie associée à la ventilation mécanique. Nous avons émis l'hypothèse que l'indométacine en aérosol pouvait réduire l'inflammation pulmonaire et l'APA dans un modèle murin de TTF. Méthodes: Des rats Sprague-Dawley ont été anesthésiés et ont subi une trachéotomie pour l'administration du médicament en aérosol par un cathéter. Le TTF a été infligé par un poids de métal creux (200 g) en chute libre d'une hauteur de 25,5, 38,3 ou 51,2 cm sur le thorax droit. Nous avons administré 1 mg/kg d'indométacine ou 1 mL/kg de solution saline dans la trachée 15 minutes après le TTF. Un groupe a été soumis à une intervention similaire fictive, sans exposition au TTF ni au traitement. Trois heures après l'impact, nous avons obtenu des gaz artériels et analysé le liquide de lavage bronchoalvéolaire pour connaître les taux de protéines, de leucocytes polymorphonucléaires (PMN) et de cytokines; nous avons aussi prélevé des échantillons de tissu pulmonaire pour des analyses histopathologiques. Résultats: La pression artérielle et la fréquence cardiaque moyennes des rats ont immédiatement chuté après l'impact, mais sont revenues près des valeurs du groupe soumis à l'intervention fictive après 30 minutes dans le groupe témoin et le groupe traité. Comparativement au TTF seul, l'indométacine a significativement réduit le taux de protéines totales dans les poumons (1,06 ± 0,39 mg/mL c. 3,75 ± 1,95 mg/mL, p = 0,006) et la fuite alvéolaire de FD-70 (0,23 ± 0,19 µg/mL c. 0,53 ± 0,19 µg/mL, p = 0,02). L'indométacine a aussi significativement atténué la réaction inflammatoire aiguë en pourcentage de PMN (13,33 ±7,5 % c. 28,0 ± 12,96 %, p = 0,04). Le facteur de nécrose tumorale α et l'interleukine-6 ont diminué dans le groupe sous indométacine, mais ces baisses n'ont pas été significatives comparativement aux autres groupes. Conclusion: L'indométacine en aérosol exerce un effet protecteur contre la perméabilité du tissu alvéolaire et la réaction inflammatoire induite par le un TTF.

Carbon monoxide releasing molecule-3 improves myocardial function in mice with sepsis by inhibiting NLRP3 inflammasome activation in cardiac fibroblasts.

The NLRP3 inflammasome is an intracellular multiple-protein complex that controls the maturation and release of interleukin (IL)-1ß and IL-18. Endogenous carbon monoxide (CO) is anti-inflammatory. The aim of this study was to assess the effects/mechanisms of CO-releasing molecule-3 (CORM-3)-dependent modulation of the NLRP3 inflammasome in cardiac fibroblasts (CF) and its effect on myocardial function in sepsis. CF were treated with CORM-3 or inactive CORM-3 (iCORM-3) before NLRP3 inflammasome priming with lipopolysaccharides (LPS) or following activation with adenosine triphosphate (ATP). In parallel, cardiomyocytes (CM) were challenged with supernatants of LPS/ATP-stimulated CF or a cytokine mixture (Cyto-mix) containing IL-1ß, IL-18, and HMGB1. In vivo, mice were treated with CORM-3 before or after LPS to induce sepsis (endotoxemia). Pretreatment of CF with CORM-3 prevented an LPS-induced increase in NLRP3 and pro-IL-1ß expression. Treatment of CF with CORM-3 before ATP prevented ATP-induced activation of the NLRP3 inflammasome. Challenging CF with LPS/ATP promoted NLRP3 interactions with adaptor ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), which was prevented by CORM-3. Challenging CM with supernatants of CF with LPS/ATP or Cyto-mix (IL-1ß, IL-18, and HMGB1) resulted in CM apoptosis, which was attenuated with either a CORM-3 or IL-1 receptor antagonist. Finally, myocardial NLRP3 inflammasome activation and myocardial dysfunction in septic mice were abolished by CORM-3. In NLRP3-deficient mice with sepsis, CORM-3 did not show additional benefits in improving myocardial function. Our results indicate that CORM-3 suppresses NLRP3 inflammasome activation by blocking NLRP3 interactions with the adaptor protein ASC and attenuates myocardial dysfunction in mice with sepsis.

Agreement between venous and arterial blood gas analysis of acid-base status in critical care and ward patients: a retrospective cohort study.

PURPOSE: To determine whether the use of venous blood gases can be a suitable alternative to arterial sampling to evaluate acid-base status. METHODS: The database of the clinical laboratory in a large academic hospital was searched for records of venous blood gas analysis and an arterial sample taken within ten minutes from the same patient. Bland-Altman analyses of pH, pCO2, and lactate were performed for samples obtained from patients separately from within and outside the intensive care unit (ICU). RESULTS: In 2,296 paired arterial-venous samples from 351 ICU patients, the bias was 0.044, -6.2 mmHg, and -0.07 mEq·L-1 for pH, pCO2, and lactate, respectively. The range of agreement centred on this bias (upper minus lower level of agreement) was 0.134, 16.7 mmHg, and 1.35 mEq·L-1 for pH, pCO2, and lactate, respectively. Intraclass correlation coefficients (ICCs) were 0.79, 0.76, and 0.99 for pH, pCO2, and lactate, respectively, indicating excellent agreement. Multiple samples obtained from the same patient had a median standard deviation of 0.02, 2.77 mmHg, and 0.18 mEq·L-1 for pH, pCO2, and lactate, respectively. Similar agreement was observed in samples from patients outside the ICU, although the ICC was only 0.53 for pCO2. CONCLUSIONS: Venous gases are suitable for initial evaluation of acid-base status in critically ill patients. Based on clinical evaluation, an arterial sample may then be considered for confirmation, and thereafter, venous blood gases could be sufficient for monitoring response to treatment.

Duration of Antimicrobial Treatment for Bacteremia in Canadian Critically Ill Patients.

OBJECTIVES: The optimum duration of antimicrobial treatment for patients with bacteremia is unknown. Our objectives were to determine duration of antimicrobial treatment provided to patients who have bacteremia in ICUs, to assess pathogen/patient factors related to treatment duration, and to assess the relationship between treatment duration and survival. DESIGN: Retrospective cohort study. SETTINGS: Fourteen ICUs across Canada. PATIENTS: Patients with bacteremia and were present in the ICU at the time culture reported positive. INTERVENTIONS: Duration of antimicrobial treatment for patients who had bacteremia in ICU. MEASUREMENTS AND MAIN RESULTS: Among 1,202 ICU patients with bacteremia, the median duration of treatment was 14 days, but with wide variability (interquartile range, 9-17.5). Most patient characteristics were not associated with treatment duration. Coagulase-negative staphylococci were the only pathogens associated with shorter treatment (odds ratio, 2.82; 95% CI, 1.51-5.26). The urinary tract was the only source of infection associated with a trend toward lower likelihood of shorter treatment (odds ratio, 0.67; 95% CI, 0.42-1.08); an unknown source of infection was associated with a greater likelihood of shorter treatment (odds ratio, 2.14; 95% CI, 1.17-3.91). The association of treatment duration and survival was unstable when analyzed based on timing of death. CONCLUSIONS: Critically ill patients who have bacteremia typically receive long courses of antimicrobials. Most patient/pathogen characteristics are not associated with treatment duration; survivor bias precludes a valid assessment of the association between treatment duration and survival. A definitive randomized controlled trial is needed to compare shorter versus longer antimicrobial treatment in patients who have bacteremia.

Human severe sepsis cytokine mixture increases ß2-integrin-dependent polymorphonuclear leukocyte adhesion to cerebral microvascular endothelial cells in vitro.

INTRODUCTION: Sepsis-associated encephalopathy (SAE) is a state of acute brain dysfunction in response to a systemic infection. We propose that systemic inflammation during sepsis causes increased adhesion of leukocytes to the brain microvasculature, resulting in blood-brain barrier dysfunction. Thus, our objectives were to measure inflammatory analytes in plasma of severe sepsis patients to create an experimental cytokine mixture (CM), and to use this CM to investigate the activation and interactions of polymorphonuclear leukocytes (PMN) and human cerebrovascular endothelial cells (hCMEC/D3) in vitro. METHODS: The concentrations of 41 inflammatory analytes were quantified in plasma obtained from 20 severe sepsis patients and 20 age- and sex-matched healthy controls employing an antibody microarray. Two CMs were prepared to mimic severe sepsis (SSCM) and control (CCM), and these CMs were then used for PMN and hCMEC/D3 stimulation in vitro. PMN adhesion to hCMEC/D3 was assessed under conditions of flow (shear stress 0.7 dyn/cm(2)). RESULTS: Eight inflammatory analytes elevated in plasma obtained from severe sepsis patients were used to prepare SSCM and CCM. Stimulation of PMN with SSCM led to a marked increase in PMN adhesion to hCMEC/D3, as compared to CCM. PMN adhesion was abolished with neutralizing antibodies to either ß2 (CD18), αL/ß2 (CD11α/CD18; LFA-1) or αM/ß2 (CD11ß/CD18; Mac-1) integrins. In addition, immune-neutralization of the endothelial (hCMEC/D3) cell adhesion molecule, ICAM-1 (CD54) also suppressed PMN adhesion. CONCLUSIONS: Human SSCM up-regulates PMN pro-adhesive phenotype and promotes PMN adhesion to cerebrovascular endothelial cells through a ß2-integrin-ICAM-1-dependent mechanism. PMN adhesion to the brain microvasculature may contribute to SAE.