Diagnostic test accuracy for cessation of circulation during death determination: a systematic review.

PURPOSE: To synthesize the available evidence comparing noninvasive methods of measuring the cessation of circulation in patients who are potential organ donors undergoing death determination by circulatory criteria (DCC) with the current accepted standard of invasive arterial blood pressure (IAP) monitoring. SOURCE: We searched (from inception until 27 April 2021) MEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. We screened citations and manuscripts independently and in duplicate for eligible studies that compared noninvasive methodologies assessing circulation in patients who were monitored around a period of cessation of circulation. We performed risk of bias assessment, data abstraction, and quality assessment using Grading of Recommendations, Assessment, Development, and Evaluation in duplicate and independently. We presented findings narratively. PRINCIPAL FINDINGS: We included 21 eligible studies (N = 1,177 patients). Meta-analysis was not possible because of study heterogeneity. We identified low quality evidence from four indirect studies (n = 89) showing pulse palpation is less sensitive and specific than IAP (reported sensitivity range, 0.76-0.90; specificity, 0.41-0.79). Isoelectric electrocardiogram (ECG) had excellent specificity for death (two studies; 0% [0/510]), but likely increases the average time to death determination (moderate quality evidence). We are uncertain whether point-of-care ultrasound (POCUS) pulse check, cerebral near-infrared spectroscopy (NIRS), or POCUS cardiac motion assessment are accurate tests for the determination of circulatory cessation (very low-quality evidence). CONCLUSION: There is insufficient evidence that ECG, POCUS pulse check, cerebral NIRS, or POCUS cardiac motion assessment are superior or equivalent to IAP for DCC in the setting of organ donation. Isoelectric ECG is specific but can increase the time needed to determine death. Point-of-care ultrasound techniques are emerging therapies with promising initial data but are limited by indirectness and imprecision. STUDY REGISTRATION: PROSPERO (CRD42021258936); first submitted 16 June 2021.

RéSUMé: OBJECTIF: Synthétiser les données probantes disponibles comparant les méthodes non invasives de mesure de l'arrêt de la circulation chez les patients qui sont des donneurs d'organes potentiels soumis à une détermination du décès selon des critères circulatoires (DCC) avec la norme actuellement acceptée de surveillance invasive de la tension artérielle (TA). SOURCES: Nous avons mené des recherches dans les bases de données MEDLINE, EMBASE, Web of Science et le registre Cochrane des essais contrôlés de leur création jusqu'au 27 avril 2021. Nous avons examiné les citations et les manuscrits de manière indépendante et en double pour en tirer les études éligibles qui comparaient des méthodologies non invasives d'évaluation de la circulation chez les patients qui étaient sous surveillance avant, pendant et après une période d'arrêt de la circulation. Nous avons réalisé l'évaluation du risque de biais, l'extraction des données et l'évaluation de la qualité en nous fondant sur la méthodologie GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) en double et de manière indépendante. Nous présentons les résultats de façon narrative. CONSTATATIONS PRINCIPALES: Nous avons inclus 21 études éligibles (N = 1177 patients). Une méta-analyse n'a pas été possible en raison de l'hétérogénéité des études. Nous avons identifié des données de faible qualité issues de quatre études indirectes (n = 89) montrant que la palpation du pouls est moins sensible et spécifique que la mesure invasive de la TA (plage de sensibilité rapportée, 0,76-0,90; spécificité, 0,41-0,79). L'électrocardiogramme (ECG) isoélectrique avait une excellente spécificité pour le décès (deux études; 0 % [0/510]), mais augmente probablement le délai moyen avant la détermination du décès (données probantes de qualité modérée). Nous ne savons pas si la vérification du pouls par échographie ciblée (POCUS), la spectroscopie proche infrarouge (SPIR) cérébrale ou l'évaluation ciblée (POCUS) des mouvements cardiaques sont des examens précis pour la détermination de l'arrêt circulatoire (données probantes de très faible qualité). CONCLUSION: Il n'y a pas suffisamment de données probantes pour affirmer que l'ECG, la vérification ciblée du pouls, la SPIR cérébrale ou l'évaluation ciblée des mouvements cardiaques sont supérieurs ou équivalents à la mesure invasive de la TA pour un DCC dans le cadre du don d'organes. L'ECG isoélectrique est spécifique, mais peut augmenter le délai nécessaire avant de déterminer le décès. Les techniques d'échographie ciblée sont des thérapies émergentes avec des données initiales prometteuses, mais elles sont limitées par leur caractère indirect et l'imprécision de l'examen. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42021258936); soumis pour la première fois le 16 juin 2021.

A brain-based definition of death and criteria for its determination after arrest of circulation or neurologic function in Canada: a 2023 clinical practice guideline.

This 2023 Clinical Practice Guideline provides the biomedical definition of death based on permanent cessation of brain function that applies to all persons, as well as recommendations for death determination by circulatory criteria for potential organ donors and death determination by neurologic criteria for all mechanically ventilated patients regardless of organ donation potential. This Guideline is endorsed by the Canadian Critical Care Society, the Canadian Medical Association, the Canadian Association of Critical Care Nurses, Canadian Anesthesiologists' Society, the Canadian Neurological Sciences Federation (representing the Canadian Neurological Society, Canadian Neurosurgical Society, Canadian Society of Clinical Neurophysiologists, Canadian Association of Child Neurology, Canadian Society of Neuroradiology, and Canadian Stroke Consortium), Canadian Blood Services, the Canadian Donation and Transplantation Research Program, the Canadian Association of Emergency Physicians, the Nurse Practitioners Association of Canada, and the Canadian Cardiovascular Critical Care Society.

RéSUMé: Ces Lignes directrices de pratique clinique 2023 Lignes directrices de pratique clinique dicale du décès basée sur l'arrêt permanent de la fonction cérébrale qui s'applique à toute personne, ainsi que des recommandations pour la détermination du décès par des critères circulatoires pour des donneurs d'organes potentiels et des recommandations pour la détermination du décès par des critères neurologiques pour tous les patients sous ventilation mécanique, indépendamment de leur potentiel de donneur d'organes. Les présentes Lignes directrices sont approuvées par la Société canadienne de soins intensifs, l'Association médicale canadienne, l'Association canadienne des infirmiers/infirmières en soins intensifs, la Société canadienne des anesthésiologistes, la Fédération des sciences neurologiques du Canada (représentant la Société canadienne de neurologie, la Société canadienne de neurochirurgie, la Société canadienne de neurophysiologie clinique, l'Association canadienne de neurologie pédiatrique, la Société canadienne de neuroradiologie et le Consortium neurovasculaire canadien), la Société canadienne du sang, le Programme de recherche en don et transplantation du Canada, l'Association canadienne des médecins d'urgence, l'Association des infirmières et infirmiers praticiens du Canada, et la Société canadienne de soins intensifs cardiovasculaires (CANCARE) et la Société canadienne de pédiatrie.

The Association of Corticosteroids and Pediatric Sepsis Biomarker Risk Model (PERSEVERE)-II Biomarker Risk Stratification With Mortality in Pediatric Septic Shock.

OBJECTIVES: Mortality risk stratification may identify a subset of children who benefit from or are harmed by corticosteroid administration. The Pediatric Sepsis Biomarker Risk Model (PERSEVERE)-II score is a biomarker-based mortality risk stratification tool for pediatric sepsis. Our objective was to assess the association of corticosteroid administration with 28-day mortality within different levels of baseline mortality risk (PERSEVERE-II) in a cohort of children with septic shock. DESIGN: We performed a secondary analysis using prospectively collected data (January 2015 to December 2018). SETTING: PICUs in 13 tertiary care, academic centers in the United States. PATIENTS: Children with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed the association of corticosteroid administration within PERSEVERE-II risk score categories and 28-day mortality, ICU-free days, and maximum failed organs in children with septic shock. We analyzed a total of 461 patients (215 with corticosteroids exposure, 246 without corticosteroid exposure) with an average age of 7.1 years (interquartile range, 2.2-13.6 yr). In the subgroup of patients with a high PERSEVERE-II score, corticosteroid administration was associated with an increased adjusted risk of 28-day mortality (odds ratio [OR] 4.10 [95% CI 1.70-9.86]; p = 0.002), but not in the low risk group (OR 0.20 [95% CI 0.02-1.73]; p = 0.15). A significant interaction between PERSEVERE-II score and corticosteroids was seen for both secondary outcomes complicated course ( p = 0.01) and maximum failed organs ( p < 0.001). Corticosteroid exposure was associated with fewer ICU-free days ( p < 0.0001). CONCLUSIONS: In our multicenter observational study, corticosteroid administration was associated with increased mortality in a subgroup of children with a high PERSEVERE-II risk score.

Long-term Health Care Utilization and Associated Costs After Dialysis-Treated Acute Kidney Injury in Children.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is common among hospitalized children and is associated with increased hospital length of stay and costs. However, there are limited data on postdischarge health care utilization after AKI hospitalization. Our objectives were to evaluate health care utilization and physician follow-up patterns after dialysis-treated AKI in a pediatric population. STUDY DESIGN: Retrospective cohort study, using provincial health administrative databases. SETTING & PARTICIPANTS: All children (0-18 years) hospitalized between 1996 and 2017 in Ontario, Canada. Excluded individuals comprised non-Ontario residents; those with metabolic disorders or poisoning; and those who received dialysis or kidney transplant before admission, a kidney transplant by 104 days after discharge, or were receiving dialysis 76-104 days from dialysis start date. EXPOSURE: Episodes of dialysis-treated AKI, identified using validated health administrative codes. AKI survivors were matched to 4 hospitalized controls without dialysis-treated AKI by age, sex, and admission year. OUTCOME: Our primary outcome was postdischarge hospitalizations, emergency department visits, and outpatient physician visits. Secondary outcomes included outpatient visits by physician type and composite health care costs. ANALYTICAL APPROACH: Proportions with≥1 event and rates (per 1,000 person-years). Total and median composite health care costs. Adjusted rate ratios using negative binomial regression models. RESULTS: We included 1,688 pediatric dialysis-treated AKI survivors and 6,752 matched controls. Dialysis-treated AKI survivors had higher rehospitalization and emergency department visit rates during the analyzed follow-up periods (0-1, 0-5, and 0-10 years postdischarge, and throughout follow-up), and higher outpatient visit rates in the 0-1-year follow-up period. The overall adjusted rate ratio for rehospitalization was 1.46 (95% CI, 1.25-1.69; P<0.0001) and for outpatient visits was 1.16 (95% CI, 1.09-1.23; P=0.01). Dialysis-treated AKI survivors also had higher health care costs. Nephrologist follow-up was infrequent among dialysis-treated AKI survivors (18.6% by 1 year postdischarge). LIMITATIONS: Potential miscoding of study exposures or outcomes. Residual uncontrolled confounding. Data for health care costs and emergency department visits was unavailable before 2006 and 2001, respectively. CONCLUSIONS: Dialysis-treated AKI survivors had greater postdischarge health care utilization and costs versus hospitalized controls. Strategies are needed to improve follow-up care for children after dialysis-treated AKI to prevent long-term complications.

Erratum: Probe design for simultaneous, targeted capture of diverse metagenomic targets.

[This corrects the article DOI: 10.1016/j.crmeth.2021.100069.].

Diagnostic Potential of Coagulation-Related Biomarkers for Sepsis in the Emergency Department: Protocol for a Pilot Observational Cohort Study.

BACKGROUND: Between 75% and 80% of patients with sepsis arrive in the hospital through the emergency department. Early diagnosis is important to alter patient prognosis, but currently, there is no reliable biomarker. The innate immune response links inflammation and coagulation. Several coagulation -related biomarkers are associated with poor prognosis in the ICU. The role of coagulation biomarkers to aid in early sepsis diagnosis has not previously been investigated. The objective of our study is to determine the individual or combined accuracy of coagulation and inflammation biomarkers with standard biochemical tests to diagnose adult septic patients presenting to the emergency department. METHODS: in the Emergency Department is a prospective, observational cohort study with a target enrolment of 250 suspected septic patients from two Canadian emergency departments. The emergency physicians will enroll patients with suspected sepsis. Blood samples will be collected at two time points (initial presentation and 4 hr following). Patients will be adjudicated into septic, infected, or not infected status in accordance with the Sepsis-3 definitions. Patient demographics, cultures, diagnosis, and biomarkers will be reported using descriptive statistics. Optimal cut off values with sensitivity and specificity for each biomarker will be determined using C-statistics to distinguish between septic and nonseptic patients. Stepwise multiple logistic regression analysis with exclusion of nonsignificant covariates from the final model will be used to establish a panel of biomarkers. CONCLUSIONS: Our protocol describes the processes and methods for a pragmatic observational biomarker study in the emergency department. This study will seek to determine the potential diagnostic importance of early coagulation abnormalities to identify additional tools for sepsis diagnosis.

Levetiracetam Versus Phenytoin or Fosphenytoin for Second-Line Treatment of Pediatric Status Epilepticus: A Meta-Analysis.

OBJECTIVE: To synthesize the available evidence examining the efficacy and safety of levetiracetam compared with phenytoin or fosphenytoin in benzodiazepine-refractory pediatric status epilepticus. DATA SOURCES: We searched (from inception until April 27, 2020) Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. STUDY SELECTION: Two reviewers, independently and in duplicate, screened citations and manuscripts for eligible randomized controlled trials. DATA EXTRACTION AND SYNTHESIS: Independently and in duplicate, we performed data abstraction, risk of bias assessment, and certainty assessment using Grading of Recommendations, Assessment, Development, and Evaluation. We performed meta-analyses using random-effect models or, if insufficient data, presented findings narratively. RESULTS: We identified seven randomized controlled trials (n = 1,575). Pooled analysis demonstrated low certainty evidence for no difference of levetiracetam on time to seizure cessation (mean difference, -3.11 min; 95% CI, -6.67 to 0.45), early seizure cessation (relative risk, 1.09, 95% CI, 0.95-1.26), or late seizure cessation (relative risk, 1.05; 95% CI, 0.93-1.18). Adverse event outcomes were limited by low event numbers. We found low certainty evidence for less respiratory depression with levetiracetam (relative risk, 0.28; 95% CI, 0.12-0.69). CONCLUSIONS: The efficacy of levetiracetam is comparable with phenytoin or fosphenytoin in children with benzodiazepine-refractory status epilepticus (low certainty evidence). Levetiracetam may cause less respiratory depression. Clinicians and guideline developers should weigh safety profiles when choosing between these agents.

Incidence and short-term outcomes of Kawasaki disease.

OBJECTIVE: Kawasaki disease (KD) is a childhood vasculitis with conflicting reported North American trends in incidence and patient characteristics. OBJECTIVES: (1) determine KD incidence between 1995 and 2017; (2) compare patient characteristics by era and age group; (3) determine complication and cardiovascular follow-up rates. METHODS: We used population-based health administrative data to identify children (0-18 yr) hospitalized with KD in Ontario, Canada between 1995 and 2017. We excluded children with prior KD diagnosis or incomplete records. We determined the annualized incidence and follow-up trends. RESULTS: KD was diagnosed in 4,346 children between 1995 and 2017. Annual KD incidence was 22.0 (<5 yr), 6.1 (5-9 yr), and 0.6 (10-18 yr) per 100,000 children. KD incidence increased significantly for all age groups, including from 18.4 to 25.0 cases per 100,000 children <5 yr. Ninety-day mortality occurred in ≤5 children (≤0.1%). Coronary artery aneurysm (CAA) occurred in 106 children (2.4%, 95% confidence interval 2.0-2.9) during admission and 151 (3.5%, 95% confidence interval 3.0-4.1) during 11-year median follow-up. Children 10-18 yr had longer hospitalizations (4.3 vs. 3.5 days, p = 0.003) and more CAA (7.4% vs. 3.4%, p = 0.007). By 1-year post-diagnosis, 3970 (91.3%) and 2576 (59.3%) children had echocardiography and cardiology follow-up, respectively. CONCLUSIONS: KD incidence is increasing in Ontario, with greater healthcare utilization from hospitalizations and subsequent follow-up. IMPACT: 4346 children were hospitalized for Kawasaki disease over 22 years in Ontario, and Kawasaki disease incidence increased significantly for all age groups, males and females. Older children (10-18 years) had longer hospital length of stay, more PICU admissions and more frequent coronary artery aneurysms. Nearly all children with Kawasaki disease had follow-up echocardiography within 1 year.

Probe design for simultaneous, targeted capture of diverse metagenomic targets.

The compounding challenges of low signal, high background, and uncertain targets plague many metagenomic sequencing efforts. One solution has been DNA capture, wherein probes are designed to hybridize with target sequences, enriching them in relation to their background. However, balancing probe depth with breadth of capture is challenging for diverse targets. To find this balance, we have developed the HUBDesign pipeline, which makes use of sequence homology to design probes at multiple taxonomic levels. This creates an efficient probe set capable of simultaneously and specifically capturing known and related sequences. We validated HUBDesign by generating probe sets targeting the breadth of coronavirus diversity, as well as a suite of bacterial pathogens often underlying sepsis. In separate experiments demonstrating significant, simultaneous enrichment, we captured SARS-CoV-2 and HCoV-NL63 in a human RNA background and seven bacterial strains in human blood. HUBDesign (https://github.com/zacherydickson/HUBDesign) has broad applicability wherever there are multiple organisms of interest.

Fast I(n)dentification of Pathogens in Neonates (FINDPATH-N): protocol for a prospective pilot cohort study of next-generation sequencing for pathogen identification in neonates with suspected sepsis.

INTRODUCTION: Sepsis is a major source of morbidity and mortality in neonates; however, identification of the causative pathogens is challenging. Many neonates have negative blood cultures despite clinical evidence of sepsis. Next-generation sequencing (NGS) is a high-throughput, parallel sequencing technique for DNA. Pathogen-targeted enrichment followed by NGS has the potential to be more sensitive and faster than current gold-standard blood culture. In this pilot study, we will test the feasibility and pathogen detection patterns of pathogen-targeted NGS in neonates with suspected sepsis. Additionally, the distribution and diagnostic accuracy of biomarkers cell-free DNA and protein C levels at two time points will be explored. METHODS AND ANALYSIS: We will conduct a prospective, pilot observational study. Neonates over 1 kg with suspected sepsis from a single tertiary care children's hospital will be recruited for the study. Recruitment will be censored at 200 events or 6 months' duration. Two blood study samples will be taken: the first simultaneous to the blood culture (time=0 hour, for NGS and biomarkers) via an exception to consent (deferred consent) and another 24 hours later after prospective consent (biomarkers only). Neonates will be adjudicated into those with clinical sepsis, culture-proven sepsis and without sepsis based on clinical criteria. Feasibility parameters (eg, recruitment) and NGS process time will be reported.For analysis, NGS results will be described in aggregate, compared with the simultaneous blood culture (sensitivity and specificity) and reviewed via expert panel for plausibility. Pilot data for biomarker distribution and diagnostic accuracy (sensitivity and specificity) for distinguishing between septic and non-septic neonates will be reported. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Hamilton Integrated Research Ethics Board. We will seek publication of study results in peer-reviewed journals.

Anterior Ischemic Optic Neuropathy in a Child Receiving Chronic Hemodialysis.

Anterior ischemic optic neuropathy (AION) occurs due to hypoperfusion of the optic nerve and is a rare complication in patients receiving maintenance dialysis. To date, AION has only been reported in 22 children, all of whom were receiving peritoneal dialysis. We report the first case of AION in a 2-year 11-month-old child receiving chronic hemodialysis secondary to polycystic kidney disease from a phosphomannomutase 2 gene mutation. This case highlights the consideration for frequent blood pressure monitoring and ophthalmic screening in a certain cohort of children receiving chronic dialysis.

Predictors of medical student interest and confidence in research during medical school.

BACKGROUND: Research education and opportunities are an important part of undergraduate medical education. This study's objectives were to determine students' interest in research, student self-rated research skills, and to assess potential predictors of research interest and confidence. METHODS: Stakeholder consultation and literature informed a 13-item cross-sectional survey. In 2014, all students enrolled in McMaster University's School of Medicine in Ontario, Canada were sent an electronic survey and two subsequent reminder e-mails. RESULTS: The response rate was 81% (498 of 618). Most (n=445, 89%) had prior research experiences. The majority of students (n=383, 86%) wanted more research education and opportunities. Higher rating of their supervisors' understanding of research was associated with greater interest in research (OR=2.08; 95% CI=1.27-3.41). Home campus (distributed vs. main) was not a significant predictor of research interest. In our adjusted linear regression model, the most significant predictors of higher self-rated research ability were prior thesis work and other prior research experience. CONCLUSION: In a survey of a three-year medical school, medical student interest in further research education and opportunities was high and positively predicted by student-rated supervisors' understanding of research, but not campus location. This study also identified several predictors of student self-rated research ability.