COVID-19 critical care triage across Canada: a narrative synthesis and ethical analysis of early provincial triage protocols.

PURPOSE: The COVID-19 pandemic created conditions of scarcity that led many provinces within Canada to develop triage protocols for critical care resources. In this study, we sought to undertake a narrative synthesis and ethical analysis of early provincial pandemic triage protocols. METHODS: We collected provincial triage protocols through personal correspondence with academic and political stakeholders between June and August 2020. Protocol data were extracted independently by two researchers and compared for accuracy and agreement. We separated data into three categories for comparative content analysis: protocol development, ethical framework, and protocol content. Our ethical analysis was informed by a procedural justice framework. RESULTS: We obtained a total of eight provincial triage protocols. Protocols were similar in content, although age, physiologic scores, and functional status were variably incorporated. Most protocols were developed through a multidisciplinary, expert-driven, consensus process, and many were informed by influenza pandemic guidelines previously developed in Ontario. All protocols employed tiered morality-focused exclusion criteria to determine scarce resource allocation at the level of regional health care systems. None included a public engagement phase, although targeted consultation with public advocacy groups and relevant stakeholders was undertaken in select provinces. Most protocols were not publicly available in 2020. CONCLUSIONS: Early provincial COVID-19 triage protocols were developed by dedicated expert committees under challenging circumstances. Nonetheless, few were publicly available, and public consultation was limited. No protocols were ever implemented, including during periods of extreme critical care surge. A national approach to pandemic triage that incorporates additional aspects of procedural justice should be considered in preparation for future pandemics.

RéSUMé: OBJECTIF: La pandémie de COVID-19 a créé des conditions de pénurie qui ont amené de nombreuses provinces canadiennes à élaborer des protocoles de triage pour l'allocation des ressources en soins intensifs. Dans le cadre de cette étude, nous avons cherché à réaliser une synthèse narrative et une analyse éthique des premiers protocoles provinciaux de triage lors de la pandémie. MéTHODE: Nous avons recueilli les protocoles de triage provinciaux en correspondant de façon personnelle avec des intervenant·es universitaires et politiques entre juin et août 2020. Les données des protocoles ont été extraites indépendamment par deux personnes de l'équipe de recherche et comparées pour en vérifier l'exactitude et la concordance. Nous avons séparé les données en trois catégories pour l'analyse comparative du contenu : l'élaboration d'un protocole, le cadre éthique et le contenu du protocole. Notre analyse éthique s'est appuyée sur un cadre de justice procédurale. RéSULTATS: Nous avons obtenu un total de huit protocoles de triage provinciaux. Les protocoles étaient similaires dans leur contenu, bien que l'âge, les scores physiologiques et l'état fonctionnel aient été incorporés de manière variable. La plupart des protocoles ont été élaborés dans le cadre d'un processus consensuel multidisciplinaire dirigé par des expert·es, et bon nombre d'entre eux ont été élaborés en fonction des lignes directrices sur la pandémie de grippe élaborées antérieurement en Ontario. Tous les protocoles utilisaient des critères d'exclusion à plusieurs niveaux axés sur la moralité pour déterminer l'affectation de ressources limitées au niveau des systèmes de soins de santé régionaux. Aucun ne comportait de phase de mobilisation du public, bien que des consultations ciblées aient été menées auprès des groupes de défense des droits du public et des instances concernées dans certaines provinces. La plupart des protocoles n'étaient pas accessibles au public en 2020. CONCLUSION: Les premiers protocoles provinciaux de triage pour la COVID-19 ont été élaborés par des comités spécialisés d'expert·es dans des circonstances difficiles. Néanmoins, peu d'entre eux étaient accessibles au public et la consultation publique était limitée. Aucun protocole n'a été mis en œuvre, même pendant les périodes de pointe extrême en soins intensifs. Une approche nationale du triage en cas de pandémie qui intègre d'autres aspects de justice procédurale devrait être envisagée en prévision de futures pandémies.

Prevalence of long-term decision regret and associated risk factors in a large cohort of ICU surrogate decision makers.

BACKGROUND: Whether surrogate decision makers regret decisions about the use of life support for incapacitated, critically ill patients remain uncertain. We sought to determine the prevalence of decision regret among surrogates of adult ICU patients and identify factors that influence regret. METHODS: We conducted a secondary analysis of data from the PARTNER 2 trial, which tested a family support intervention for surrogates of critically ill adults. At 6-month follow-up, surrogates rated their regret about life support decisions using the Decision Regret Scale (DRS), scored from 0 to 100, with higher scores indicating more regret. We used multiple linear regression to identify covariates associated with decision regret based on a psychological construct of regret. We constructed two models using the full cohort; model 1 included patient outcomes; model 2 focused on covariates known at the time of ICU decision-making. Subgroup analyses were also conducted based on patient survival status at hospital discharge and 6-month follow-up. RESULTS: 748 of 848 surrogates had complete DRS data. The median (IQR) DRS score was 15 (0, 25). Overall, 54% reported mild regret (DRS 5-25), 19% moderate-strong regret (DRS 30-100), and 27% no regret (DRS 0). Poor patient outcome at 6 months (death or severe functional dependence) was associated with more regret in model 1 (ß 10.1; 95% C.I. 3.2, 17.0). In model 2, palliative care consultation (3.0; 0.1, 5.9), limitations in life support (LS) prior to death (6.3; 3.1, 9.4) and surrogate black race (6.3; 0.3, 12.3) were associated with more regret. Other modulators of regret in subgroup analyses included surrogate age and education level, surrogate-patient relationship, death in hospital (compared to the post-discharge period), and code status at time of ICU admission. CONCLUSIONS: One in five ICU surrogate decision makers experience moderate to strong regret about life support decisions in ICU. Poor patient outcomes are linked to more regret. Decisions to limit life support prior to patient death may also increase regret. Future studies are needed to understand how regret relates to decision quality and how to lessen lasting regret.

Hastening Death in Canadian ICUs: End-of-Life Care in the Era of Medical Assistance in Dying.

OBJECTIVES: Since 2016, Canada has allowed for euthanasia based on strict criteria under federal medical assistance in dying legislation. The purpose of this study was to determine how Canadian intensivists perceive medical assistance in dying and whether they believe their approach to withdrawal of life-sustaining therapies has changed following introduction of medical assistance in dying. DESIGN: Electronic survey. SETTING: Participants were recruited from 11 PICU programs and 14 adult ICU programs across Canada. All program leaders for whom contact information was available were approached for participation. PARTICIPANTS: We invited intensivists and critical care trainees employed between December 2019 and May 2020 to participate using a snowball sampling technique in which department leaders distributed study information. All responses were anonymous. Quantitative data were analyzed using descriptive statistics. Categorical variables were analyzed using Pearson chi-square test. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: We obtained 150 complete questionnaires (33% response rate), of which 50% were adult practitioners and 50% pediatric. Most were from academic centers (81%, n = 121). Of respondents, 86% (n = 130) were familiar with medical assistance in dying legislation, 71% in favor, 14% conflicted, and 11% opposed. Only 5% (n = 8) thought it had influenced their approach to withdrawal of life-sustaining therapies. Half of participants had no standardized protocol for withdrawal of life-sustaining therapies in their unit, and 41% (n = 62) had observed medications given in disproportionately high doses during withdrawal of life-sustaining therapies, with 13% having personally administered such doses. Most (80%, n = 120) had experienced explicit requests from families to hasten death, and almost half (47%, n = 70) believed it was ethically permissible to intentionally hasten death following withdrawal of life-sustaining therapies. CONCLUSIONS: Most Canadian intensivists surveyed do not think that medical assistance in dying has changed their approach to end of life in the ICU. A significant minority are ethically conflicted about the current approach to assisted dying/euthanasia in Canada. Almost half believe it is ethical to intentionally hasten death during withdrawal of life-sustaining therapies if death is expected.

Brain natriuretic peptide to predict successful liberation from mechanical ventilation in critically ill patients: a systematic review and meta-analysis.

BACKGROUND: Predicting successful liberation from mechanical ventilation (MV) in critically ill patients is challenging. Brain natriuretic peptide (BNP) has been proposed to help guide decision-making for readiness to liberate from MV following a spontaneous breathing trial (SBT). METHODS: We performed a systematic review and meta-analysis of randomized and prospective observational studies that measured BNP levels at the time of SBT in patients receiving MV. The primary endpoint was successful liberation from MV (absence of reintubation or non-invasive ventilation at 48 h). Statistical analyses included bi-variate and Moses-Littenberg models and DerSimonian-Laird pooling of areas under ROC curve (AUROC). RESULTS: A total of 731 articles were screened. Eighteen adult and 2 pediatric studies were fulfilled pre-specified eligibility. The measure of the relative variation of BNP during SBT (ΔBNP%) after exclusion of SBT failure by clinical criteria in adults yielded a sensitivity and specificity of 0.889 [0.831-0.929] and 0.828 [0.730-0.896] for successful liberation from MV, respectively, with a pooled AUROC of 0.92 [0.88-0.97]. The pooled AUROC for any method of analysis for absolute variation of BNP (ΔBNP), pre-SBT BNP, and post-SBT BNP were 0.89 [0.83-0.95], 0.77 [0.63-0.91], and 0.85 [0.80-0.90], respectively. CONCLUSION: The relative change in BNP during a SBT has potential value as an incremental tool after successful SBT to predict successful liberation from MV in adults. There is insufficient data to support the use of BNP in children or as an alternate test to clinical indices of SBT, or the use of ΔBNP, BNP-pre, and BNP-post as an alternate or incremental test. TRIAL REGISTRATION: PROSPERO CRD42018087474 (6 February 2018).

Diminished white matter injury over time in a cohort of premature newborns.

OBJECTIVES: To determine the rate of magnetic resonance imaging (MRI)-detected noncystic white matter injury (WMI) in a prospective cohort of premature newborns, and to evaluate its associations with changes in clinical predictors of WMI over the study period. STUDY DESIGN: A prospective cohort of premature newborns (<33 weeks gestational age) was studied with MRI within 4 weeks of birth and near term-equivalent age. A pediatric neuroradiologist scored the severity of WMI on T1-weighted MRI according to published criteria. WMI was classified as none/mild or moderate/severe. Subjects with severe cystic WMI, periventricular hemorrhagic infarction, or motion artifact on MRI were excluded. Changes in clinical characteristics and predictors of WMI over the study period (1998-2011) were evaluated. Predictors of moderate/severe WMI, including birth year, were evaluated using multivariate logistic regression. RESULTS: Among 267 newborns, 45 (17%) had moderate/severe WMI. The rate of moderate/severe WMI decreased over the study period (P = .002, χ(2) test for trends). On multivariate logistic regression, the odds of moderate/severe WMI decreased by 11% for each birth year of the cohort (OR, 0.89; 95% CI, 0.81-0.98; P = .02). Prolonged exposure to indomethacin also was independently associated with reduced odds of moderate/severe WMI. CONCLUSION: The decreasing burden of MRI-detected moderate/severe noncystic WMI in our cohort of premature newborns is independent over time of changes in the known clinical predictors of WMI. Prolonged exposure to indomethacin is associated with reduced WMI.

Impaired cognitive performance in premature newborns with two or more surgeries prior to term-equivalent age.

BACKGROUND: Anesthesia in early childhood is associated with adverse neurodevelopmental outcome; however, it is not known if age at exposure affects the risk of adverse outcome. Our objective was to evaluate the association of the number and timing of anesthetic exposures for surgery with cognitive outcome in a cohort of premature newborns. METHODS: A cohort study of exposure to anesthesia for surgery in premature newborns (<33 wk gestation) prospectively evaluated with neonatal magnetic resonance imaging (MRI) and neurodevelopmental testing at 3-6 y was employed. Exposure to anesthesia for surgery was classified as before term-equivalent age (TEA, <42 wk postmenstrual age) or after (≥42 wk). Multivariate regression was performed to analyze the association of composite IQ scores with the number of surgeries before and after TEA. RESULTS: Among 137 newborns, 25 (18.2%) had one surgery before TEA and 18 (13.1%) had ≥2 surgeries. Two or more surgeries before TEA were associated with significantly reduced composite IQ scores at 4.6 ± 0.6 y after adjusting for gestational age and illness severity. Neither the number of surgeries after TEA nor sedation for MRI was associated with cognitive outcome. CONCLUSIONS: More than one surgery prior to TEA is independently associated with impaired cognitive performance in premature newborns.

Impact of a family support intervention on hospitalization costs and hospital readmissions among ICU patients at high risk of death or severe functional impairment.

BACKGROUND: Patients with advanced critical illness often receive more intensive treatment than they would choose for themselves, which contributes to high health care costs near the end of life. The purpose of this study was to determine whether a family support intervention delivered by the interprofessional ICU team decreases hospitalization costs and hospital readmissions among critically ill patients at high risk of death or severe functional impairment. RESULTS: We examined index hospitalization costs as well as post-discharge utilization of acute care hospitals, rehabilitation and skilled nursing facilities, and hospice services for the PARTNER trial, a multicenter, stepped-wedge, cluster randomized trial of an interprofessional ICU family support intervention. We determined patients' total controllable and direct variable costs using a computerized accounting system. We determined post-discharge resource utilization (as defined above) by structured telephone interview at 6-month follow-up. We used multiple variable regression modelling to compare outcomes between groups. Compared to usual care, the PARTNER intervention resulted in significantly lower total controllable costs (geometric mean: $26,529 vs $32,105; log-linear coefficient: - 0.30; 95% CI - 0.49, - 0.11) and direct variable costs ($3912 vs $6034; - 0.33; 95% CI - 0.56, - 0.10). A larger cost reduction occurred for decedents ($20,304 vs. $26,610; - 0.66; 95% CI - 1.01, - 0.31) compared to survivors ($31,353 vs. $35,015; - 0.15; 95% CI - 0.35,0.05). A lower proportion in the intervention arm were re-admitted to an acute care hospital (34.9% vs 45.1%; 0.66; 95% CI 0.56, 0.77) or skilled nursing facility (25.3% vs 31.6%; 0.63; 95% CI 0.47, 0.84). CONCLUSIONS: A family support intervention delivered by the interprofessional ICU team significantly decreased index hospitalization costs and readmission rates over 6-month follow-up. Trial registration Trial registration number: NCT01844492.

Achieving Goals of Care Decisions in Chronic Critical Illness: A Multi-Institutional Qualitative Study.

BACKGROUND: Physicians, patients, and families alike perceive a need to improve how goals of care (GOC) decisions occur in chronic critical illness (CCI), but little is currently known about this decision-making process. RESEARCH QUESTION: How do intensivists from various health systems facilitate decision-making about GOC for patients with CCI? What are barriers to, and facilitators of, this decision-making process? STUDY DESIGN AND METHODS: We conducted semistructured interviews with a purposeful sample of intensivists from the United States and Canada using a mental models approach adapted from decision science. We analyzed transcripts inductively using qualitative description. RESULTS: We interviewed 29 intensivists from six institutions. Participants across all sites described GOC decision-making in CCI as a complex, longitudinal, and iterative process that involved substantial preparatory work, numerous stakeholders, and multiple family meetings. Intensivists required considerable time to collect information on prior events and conversations, and to arrive at a prognostic consensus with other involved physicians prior to meeting with families. Many intensivists stressed the importance of scheduling multiple family meetings to build trust and relationships prior to explicitly discussing GOC. Physician-identified barriers to GOC decision-making included 1-week staffing models, limited time and cognitive bandwidth, difficulty eliciting patient values, and interpersonal challenges with care team members or families. Potential facilitators included scheduled family meetings at regular intervals, greater interprofessional involvement in decisions, and consistent messaging from care team members. INTERPRETATION: Intensivists described a complex time- and labor-intensive group process to achieve GOC decision-making in CCI. System-level interventions that improve how information is shared between physicians and decrease logistical and relational barriers to timely and consistent communication are key to improving GOC decision-making in CCI.

Repression of Salmonella enterica phoP expression by small molecules from physiological bile.

Infection with Salmonella enterica serovar Typhi in humans causes the life-threatening disease typhoid fever. In the laboratory, typhoid fever can be modeled through the inoculation of susceptible mice with Salmonella enterica serovar Typhimurium. Using this murine model, we previously characterized the interactions between Salmonella Typhimurium and host cells in the gallbladder and showed that this pathogen can successfully invade gallbladder epithelial cells and proliferate. Additionally, we showed that Salmonella Typhimurium can use bile phospholipids to grow at high rates. These abilities are likely important for quick colonization of the gallbladder during typhoid fever and further pathogen dissemination through fecal shedding. To further characterize the interactions between Salmonella and the gallbladder environment, we compared the transcriptomes of Salmonella cultures grown in LB broth or physiological murine bile. Our data showed that many genes involved in bacterial central metabolism are affected by bile, with the citric acid cycle being repressed and alternative respiratory systems being activated. Additionally, our study revealed a new aspect of Salmonella interactions with bile through the identification of the global regulator phoP as a bile-responsive gene. Repression of phoP expression could also be achieved using physiological, but not commercial, bovine bile. The biological activity does not involve PhoPQ sensing of a bile component and is not caused by bile acids, the most abundant organic components of bile. Bioactivity-guided purification allowed the identification of a subset of small molecules from bile that can elicit full activity; however, a single compound with phoP inhibitory activity could not be isolated, suggesting that multiple molecules may act in synergy to achieve this effect. Due to the critical role of phoP in Salmonella virulence, further studies in this area will likely reveal aspects of the interaction between Salmonella and bile that are relevant to disease.

Has medical assistance in dying changed end-of-life care in the ICU? A qualitative survey of Canadian intensivists.

PURPOSE: Since 2016, Canada has permitted medical assistance in dying (MAID). Our aims were to understand how Canadian intensivists view MAID and the impact of MAID on end-of-life care in the ICU. MATERIAL AND METHODS: This was a descriptive qualitative study of responses from a 41-item questionnaire. We recruited intensivists and trainees from 11 pediatric ICU programs and 14 adult ICU programs across Canada between December 2019 and May 2020. Two qualitative researchers inductively coded responses and then conducted preliminary thematic analysis. Themes were subsequently refined through group discussion. RESULTS: We obtained 150 complete questionnaires (33% response rate), of which 50% were adult practitioners and 50% pediatric. We identified six main themes including: intensivists have a wide range of opinions on MAID; MAID has not changed ICU practice; and moral distress has a diverse impact on practice. Physicians also discussed the role of provider intent and the importance of treating withdrawal of life-sustaining treatments (WLST) as a process to protect patients, families, and providers. CONCLUSIONS: Canadian intensivists hold a wide range of opinions on MAID, but most agree it has not changed ICU practice. Importantly, intensivists also hold differing views on the relevance of physician intent in medical ethics.

ProPACC: Protocol for a Trial of Integrated Specialty Palliative Care for Critically Ill Older Adults.

BACKGROUND: Each year, approximately one million older adults die in American intensive care units (ICUs) or survive with significant functional impairment. Inadequate symptom management, surrogates' psychological distress and inappropriate healthcare use are major concerns. Pioneering work by Dr. J. Randall Curtis paved the way for integrating palliative care (PC) specialists to address these needs, but convincing proof of efficacy has not yet been demonstrated. DESIGN: We will conduct a multicenter patient-randomized efficacy trial of integrated specialty PC (SPC) vs. usual care for 500 high-risk ICU patients over age 60 and their surrogate decision-makers from five hospitals in Pennsylvania. INTERVENTION: The intervention will follow recommended best practices for inpatient PC consultation. Patients will receive care from a multidisciplinary SPC team within 24 hours of enrollment that continues until hospital discharge or death. SPC clinicians will meet with patients, families, and the ICU team every weekday. SPC and ICU clinicians will jointly participate in proactive family meetings according to a predefined schedule. Patients in the control arm will receive routine ICU care. OUTCOMES: Our primary outcome is patient-centeredness of care, measured using the modified Patient Perceived Patient-Centeredness of Care scale. Secondary outcomes include surrogates' psychological symptom burden and health resource utilization. Other outcomes include patient survival, as well as interprofessional collaboration. We will also conduct prespecified subgroup analyses using variables such as PC needs, measured by the Needs of Social Nature, Existential Concerns, Symptoms, and Therapeutic Interaction scale. CONCLUSIONS: This trial will provide robust evidence about the impact of integrating SPC with critical care on patient, family, and health system outcomes.

Metabolomics reveals phospholipids as important nutrient sources during Salmonella growth in bile in vitro and in vivo.

During the colonization of hosts, bacterial pathogens are presented with many challenges that must be overcome for colonization to occur successfully. This requires the bacterial sensing of the surroundings and adaptation to the conditions encountered. One of the major impediments to the pathogen colonization of the mammalian gastrointestinal tract is the antibacterial action of bile. Salmonella enterica serovar Typhimurium has specific mechanisms involved in resistance to bile. Additionally, Salmonella can successfully multiply in bile, using it as a source of nutrients. This accomplishment is highly relevant to pathogenesis, as Salmonella colonizes the gallbladder of hosts, where it can be carried asymptomatically and promote further host spread and transmission. To gain insights into the mechanisms used by Salmonella to grow in bile, we studied the changes elicited by Salmonella in the chemical composition of bile during growth in vitro and in vivo through a metabolomics approach. Our data suggest that phospholipids are an important source of carbon and energy for Salmonella during growth in the laboratory as well as during gallbladder infections of mice. Further studies in this area will generate a better understanding of how Salmonella exploits this generally hostile environment for its own benefit.

Early mortality in critical illness - A descriptive analysis of patients who died within 24 hours of ICU admission.

PURPOSE: To describe patients who die within 24 h of ICU admission in order to better optimize care delivery. METHODS: This was a retrospective cohort study of patients ≥18 years old admitted to 17 adult ICUs in Alberta, Canada from January 1, 2016 and June 30, 2017. Data were obtained from a provincial clinical information system and data repository. The primary outcome was incidence of ICU death within 24 h of admission. Secondary outcomes were patient and system factors associated with early death. Variables of interest were identified a priori and examined using multivariable logistic regression. RESULTS: Of 19,556 patients admitted to ICU in an 18-month period, 3.3% died within 24 h, representing 29.8% of ICU deaths. Factors associated with early death were age (adjusted-OR 0.99, 95% CI, 0.9-1.0), acuity (adjusted-OR 1.3, 95% CI, 1.3-1.4), admission from the Emergency Department (ED; adjusted-OR 1.5, 95% CI, 1.1-1.9) and surgical (adjusted-OR 2.27, 95% CI, 1.4-3.6), neurologic (adjusted-OR 4.6, 95% CI, 3.1-6.9) or trauma diagnosis (adjusted-OR 6.1, 95% CI, 2.4-15.6). CONCLUSION: Patients who die within 24 h constitute one third of ICU deaths. Age, acuity, admission from the ED and surgical, neurologic or trauma-related admission diagnosis correlate with early death.

Days at Home in the Last 6 Months of Life: A Patient-Determined Quality Indicator for Cancer Care.

PURPOSE: Quality end-of-life care (EoLC) is a key aspect of oncology. Days at home in the last 6 months of life represents a novel, patient-driven quality indicator of EoLC. We measured days at home in a large population of patients with cancer in Ontario, Canada. Trends over time and predictors of more or less time at home were also determined. METHODS: We conducted a population-based retrospective study using health administrative data linked by unique, encoded identifiers and analyzed at the ICES. Quantile regression was used to determine significant predictors of more or less time at home. RESULTS: Of 72,987 patients who died of cancer in Ontario, Canada and met our inclusion criteria, the median number of days spent at home in the last 6 months of life was 164 (interquartile range [IQR], 144 to 175 days) of a possible 180 days. Patients with hematologic cancers spent significantly fewer days at home (156; IQR, 134 to 170 days). The strongest predictors of more time at home were male sex (+2.87 days relative to female sex; CI, 2.43 to 3.31 days) and receipt of palliative care before the last 6 months of life (+2.38 days; CI, 1.95 to 2.08 days). Additional predictors included income, age, cancer type, comorbidity burden, and health region. The majority of patients (69.7%) did not die at home. CONCLUSION: Days at home in the last 6 months of life, obtained from administrative data, can be used as a measure of quality EoLC. Predictors of days at home may prove valuable targets for future policy intervention.

Plectosphaeroic acids A, B, and C, indoleamine 2,3-dioxygenase inhibitors produced in culture by a marine isolate of the fungus Plectosphaerella cucumerina.

Laboratory cultures of the fungus Plectosphaerella cucumerina obtained from marine sediments collected in Barkley Sound, British Columbia, yielded the novel alkaloids plectosphaeroic acids A (1) to C (3). The alkaloids 1-3 are inhibitors of indoleamine 2,3-dioxygenase (IDO).