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.

Missed opportunities for DCD kidney donors: Evaluation of warm ischemic time and associated functional warm ischemic time.

INTRODUCTION: Many transplant centers utilize a hard cutoff of 2 hours of warm ischemic time (WIT), defined as the time from withdrawal of life-sustaining measures to cold organ flush, to exclude donation after circulatory determination of death (DCD) kidney donation. As a result, almost a quarter of withdrawals to retrieve DCD organs fail to produce kidney transplants in Ontario. In order to assess our ability to increase organ yield, we wanted to characterize WIT and functional WIT (fWIT, time from systolic blood pressure <50 mm Hg to cold organ flush), as well as determine the time at which potential donors eventually die in those that did not become organ donors. METHODS: A retrospective review of all DCD kidney donors in Ontario was performed utilizing the Trillium Gift of Life Database from April 2013 to February 2018. RESULTS: Of 350 DCD kidney donors analyzed, 46.9% had < 0.5 hours, 51.7% between 0.5 and 2 hours, and 1.4% >2 hours of WIT. In each of these categories (WIT <0.5 hours, 0.5-2 hours and >2 hours), the percentage of patients with fWIT <30 minutes was 100%, 94.4%, and 100%, respectively (P = NS). There were 106 potential donors who did not end up donating due to WIT >2 hours. Of these, 20.8% died between 2 and 4 hours, 10.4% between 4 and 6 hours, and 68.8% beyond 6 hours. DISCUSSION: The percentage of donors with fWIT >30 minutes did not increase with increasing WIT in DCD donors that went on to donate organs. These data support assessment of waiting up to 4 hours for DCD kidney donation as long as fWIT remains low.

Deceased organ donation potential in Canada: a review of consecutive deaths in Alberta.

BACKGROUND: Transplantation is the most effective treatment for many patients with end-stage organ failure. There is a gap between the number of patients who would benefit from transplantation and availability of organs. We assessed maximum potential for deceased donation in Alberta and barriers to increasing the donation rate. METHODS: All deaths that occurred in Alberta in 2015 in areas where mechanical ventilation could be provided were retrospectively identified using administrative data. Medical records were reviewed by donation coordinators and critical care physicians with expertise in donation, using a standardized tool to determine whether deceased patients could potentially have been organ donors. RESULTS: There were 2,706 deaths occurring in either an intensive care unit or emergency department, of which 1,252 were attributable to a non-neurologic cause: 946 involved cardiac arrests with unsuccessful resuscitation, and 57 were not mechanically ventilated. Of the remaining 451 deaths, 117 (28 donors per million population [dpmp]) either were, or could potentially have been, organ donors after neurologic determination of death (NDD). Of these, 19 (4.5 dpmp) were not appropriately identified or referred, and 45 approached families (10.8 dpmp) did not provide consent. Non-identified NDD cases accounted for a larger proportion of deaths due to neurologic causes in emergency departments (18%) than in intensive care units (2%) (P < 0.0001) and in rural (9%) compared with urban centres (3%) (P = 0.05). If routinely available, donation after circulatory death (DCD) could potentially have been possible in as many as 113 (27 dpmp) cases. CONCLUSIONS: Maximum deceased organ donation potential in Alberta is approximately 55 dpmp. The current donation rate has potential to increase with more widespread availability of DCD and a higher consent rate.

Development of a national minimum data set to monitor deceased organ donation performance in Canada.

PURPOSE: Deceased donation data requires standardization to enable accurate interprovincial and international comparisons of deceased donation performance. In Canada, most provincial organ donation organizations (ODOs) have developed different processes and infrastructures for referring potential donors and subsequent data collection. This has led to differing definitions of the performance measures used for each step in the donation process, from potential donor identification to consent to transplantation. The Deceased Donation Data Working Group (DDDWG), comprised of representatives from ODOs across Canada, was therefore convened by Canadian Blood Services to develop a national, comprehensive, standardized deceased donation minimum data set. METHODS: The DDDWG's scope encompassed considering all potential deceased organ donation data elements, including operational and performance data collected along the deceased donor pathway from donation potential to donation and disposition of organs. An environmental scan was conducted of other existing deceased donation registries from the Canadian and the international community. The DDDWG then engaged in regular face-to-face meetings and teleconferences to develop recommendations for the minimum data set that would satisfy key considerations, including the impact on existing ODO data collection processes, financial impact on stakeholders, the clinical and operational needs of multiple healthcare professionals involved in the deceased donation pathway, and availability of other existing national data sets that could be leveraged to reduce data collection burden. RESULTS: The key deceased donation data elements identified by the DDDWG are contained in an inverted pyramid framework that was derived from similar work conducted in other countries. CONCLUSION: The DDDWG developed recommendations for proposed definitions and data sources that should be adopted nationally to guide the collection of deceased donation data. The ultimate purpose of the final minimum data set is to harmonize and standardize donation data definitions in Canada and align with international standards; inform the development of operational and clinical practice standards at the provincial and national levels; develop a framework for deceased donation performance measures; and advance the science of deceased donation.

RéSUMé: OBJECTIF: Les données concernant les dons d'organes de personnes décédées doivent être normalisées pour permettre des comparaisons précises de l'efficacité de ces dons entre provinces et entre pays. Au Canada, la majorité des organismes provinciaux de dons d'organes (ODO) ont élaboré divers processus et infrastructures pour l'orientation des donneurs potentiels et la collecte subséquente des données. Cela a abouti à des définitions différentes des mesures de performances utilisées pour chaque étape du processus de don, de l'identification du donneur potentiel au consentement à la transplantation. Le Groupe de travail sur les données de donneurs décédés (DDDWG), constitué de représentants des ODO de tout le Canada a donc été réuni par la Société canadienne du sang (SCS) pour élaborer un ensemble national et complet de données minimums standardisées de dons d'organes de personnes décédées. MéTHODES: Le DDDWG avait pour mission d'envisager tous les éléments de données de dons d'organes potentiels de personnes décédées, y compris les données opérationnelles et de performance collectées le long du parcours du donneur décédé, depuis le don potentiel jusqu'à l'utilisation des organes. Une analyse environnementale des autres registres existants (canadiens et internationaux) de dons d'organes de personnes décédées a été effectuée. Le DDDWG a alors entrepris des entretiens en face à face et des téléconférences pour élaborer ses recommandations pour un ensemble minimum de données qui répondraient aux problèmes clés, y compris : leur impact sur les processus de collecte de données des ODO existants, l'impact financier pour les différents acteurs, les besoins cliniques et opérationnels des multiples professionnels de santé impliqués tout au long du parcours de don de la personne décédée, et la disponibilité d'autres ensembles de données qui pourraient être utilisés pour réduire le fardeau de la collecte des données. RéSULTATS: Les principales données de don d'organes de donneur décédé, identifiées par le DDDWG, tiennent dans un cadre en pyramide inversée tiré d'un travail semblable mené dans d'autres pays. CONCLUSION: Le DDDWG a élaboré des recommandations pour les définitions proposées et les sources de données qui devraient être adoptées à l'échelon national pour guider la collecte des données de dons d'organes de personnes décédées. Le but ultime de l'ensemble minimum final de données est d'harmoniser et standardiser les définitions des données concernant les dons au Canada et de s'aligner sur les normes internationales; d'informer le développement de normes opérationnelles et de pratique clinique au niveau des provinces et au niveau national; de développer un cadre pour la mesure des performances concernant les dons de donneurs décédés; et de faire progresser les connaissances sur ce type de dons.

Safety and Side Effects of Rifampin versus Isoniazid in Children.

BACKGROUND: The treatment of latent infection with Mycobacterium tuberculosis is important in children because of their vulnerability to life-threatening forms of tuberculosis disease. The current standard treatment - 9 months of isoniazid - has been associated with poor adherence and toxic effects, which have hampered the effectiveness of the drug. In adults, treatment with 4 months of rifampin has been shown to be safer and to have higher completion rates than 9 months of isoniazid. METHODS: In this multicenter, open-label trial, we randomly assigned 844 children (<18 years of age) with latent M. tuberculosis infection to receive either 4 months of rifampin or 9 months of isoniazid. The primary outcome was adverse events of grade 1 to 5 that resulted in the permanent discontinuation of a trial drug. Secondary outcomes were treatment adherence, side-effect profile, and efficacy. Independent review panels whose members were unaware of trial-group assignments adjudicated all adverse events and progression to active tuberculosis. RESULTS: Of the children who underwent randomization, 829 were eligible for inclusion in the modified intention-to-treat analysis. A total of 360 of 422 children (85.3%) in the rifampin group completed per-protocol therapy, as compared with 311 of 407 (76.4%) in the isoniazid group (adjusted difference in the rates of treatment completion, 13.4 percentage points; 95% confidence interval [CI], 7.5 to 19.3). There were no significant between-group differences in the rates of adverse events, with fewer than 5% of the children in the combined groups with grade 1 or 2 adverse events that were deemed to be possibly related to a trial drug. Active tuberculosis, including 1 case with resistance to isoniazid, was diagnosed in 2 children in the isoniazid group during 542 person-years of follow-up, as compared with no cases in the rifampin group during 562 person-years (rate difference, -0.37 cases per 100 person-years; 95% CI, -0.88 to 0.14). CONCLUSIONS: Among children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; ClinicalTrials.gov number, NCT00170209 .).

Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults.

BACKGROUND: A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic effects. METHODS: In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels. RESULTS: Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval [CI], -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events. CONCLUSIONS: The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).

Canadian Guidelines for Controlled Pediatric Donation After Circulatory Determination of Death-Summary Report.

OBJECTIVES: Create trustworthy, rigorous, national clinical practice guidelines for the practice of pediatric donation after circulatory determination of death in Canada. METHODS: We followed a process of clinical practice guideline development based on World Health Organization and Canadian Medical Association methods. This included application of Grading of Recommendations Assessment, Development, and Evaluation methodology. Questions requiring recommendations were generated based on 1) 2006 Canadian donation after circulatory determination of death guidelines (not pediatric specific), 2) a multidisciplinary symposium of national and international pediatric donation after circulatory determination of death leaders, and 3) a scoping review of the pediatric donation after circulatory determination of death literature. Input from these sources drove drafting of actionable questions and Good Practice Statements, as defined by the Grading of Recommendations Assessment, Development, and Evaluation group. We performed additional literature reviews for all actionable questions. Evidence was assessed for quality using Grading of Recommendations Assessment, Development, and Evaluation and then formulated into evidence profiles that informed recommendations through the evidence-to-decision framework. Recommendations were revised through consensus among members of seven topic-specific working groups and finalized during meetings of working group leads and the planning committee. External review was provided by pediatric, critical care, and critical care nursing professional societies and patient partners. RESULTS: We generated 63 Good Practice Statements and seven Grading of Recommendations Assessment, Development, and Evaluation recommendations covering 1) ethics, consent, and withdrawal of life-sustaining therapy, 2) eligibility, 3) withdrawal of life-sustaining therapy practices, 4) ante and postmortem interventions, 5) death determination, 6) neonatal pediatric donation after circulatory determination of death, 7) cardiac and innovative pediatric donation after circulatory determination of death, and 8) implementation. For brevity, 48 Good Practice Statement and truncated justification are included in this summary report. The remaining recommendations, detailed methodology, full Grading of Recommendations Assessment, Development, and Evaluation tables, and expanded justifications are available in the full text report. CONCLUSIONS: This process showed that rigorous, transparent clinical practice guideline development is possible in the domain of pediatric deceased donation. Application of these recommendations will increase access to pediatric donation after circulatory determination of death across Canada and may serve as a model for future clinical practice guideline development in deceased donation.

Housing and tuberculosis in an Inuit village in northern Quebec: a case-control study.

BACKGROUND: Between November 2011 and November 2012, an Inuit village in Nunavik, Quebec experienced a surge in the occurrence of active TB; contact investigations showed that TB infection was highly prevalent (62.6%), particularly among those over age 14 years (78.8%). A nested case-control study showed that nutritional inadequacy was associated with acquisition of infection but not progression to disease. We performed a study to determine whether characteristics of one's dwelling were associated with 1) acquisition of newly diagnosed TB infection and 2) progression to confirmed or probable disease among those with TB infection. METHODS: In this nested case-control study, we enrolled 200 people who were household or social contacts of at least 1 person with active TB or had received a diagnosis of active TB and assessed whether characteristics of their dwellings were associated with their odds of having newly diagnosed TB infection and/or odds of progression to disease between November 2011 and November 2012. For our first objective, we compared participants with newly diagnosed TB infection (regardless of their disease status) to a control group of contacts who were uninfected. For the second objective, we compared participants with confirmed or probable disease to a control group consisting of those with infection but no disease. We used information collected during investigation of the contacts and from study questionnaires to determine whether participants may have been exposed to TB in their own home (if they had shared a dwelling with someone who had smear-positive TB during the outbreak) or in other dwellings that they visited at least weekly. RESULTS: The participants lived in 79 dwellings. The mean number of people per room was 1.1 (standard deviation [SD] 0.5). The mean room size and ventilation level of the common living space (kitchen and living/dining rooms) were 67.9 (SD 9.4) m3 and 1.69 (SD 0.26) air changes per hour, respectively. After adjustment for potential confounders, the number of people per room was positively associated with the odds of newly diagnosed infection and odds of disease, but only among participants who lived with someone with smear-positive TB (the minority of participants). Other dwelling characteristics were not associated with either outcome. INTERPRETATION: Reducing household crowding may contribute to TB prevention. Overall, our investigations have not identified associations that explain the elevated disease risk in this village. In light of our results and considering the high prevalence of TB infection, treatment of latent infection is an essential intervention for long-term reduction of TB incidence in this village.

Inadequate Diet Is Associated with Acquiring Mycobacterium tuberculosis Infection in an Inuit Community. A Case-Control Study.

BACKGROUND: Tuberculosis predominantly affects socioeconomically disadvantaged communities. The extent to which specific dietary and lifestyle factors contribute to tuberculosis susceptibility has not been established. METHODS: A total of 200 residents of a village in Northern Quebec were investigated during a tuberculosis outbreak and identified to have active tuberculosis, latent tuberculosis infection, or neither. Participants completed questionnaires about their intake of food from traditional and commercial sources, and provided blood samples. Adults were asked about recent smoking and drug and alcohol intake. Nutritional adequacy was evaluated with reference to North American standards. Multiple dietary, lifestyle, and housing factors were combined in a logistic regression model evaluating the contributions of each to disease and infection. FINDINGS: After adjusting for potential confounding, new infection was associated with inadequate intake of fruit and vegetables (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.03-4.3), carbohydrates (OR, 4.4; 95% CI, 1.2-16.3), and certain vitamins and minerals. A multivariable model, combining nutrition, housing, and lifestyle factors, found associations between new infection and inadequate fruit and vegetable intake (OR, 2.3; 95% CI, 1.0-5.1), living in the same house as a person with smear-positive tuberculosis (OR, 14.7; 95% CI, 1.6-137.3), and visiting a community gathering house (OR, 3.7; 95% CI, 1.7-8.3). Current smoking was associated with new infection (OR, 9.4; 95% CI, 1.2-72) among adults completing a detailed lifestyle survey. INTERPRETATION: Inadequate nutrition was associated with increased susceptibility to infection, but not active tuberculosis. Interventions addressed at improving nutrition may reduce susceptibility to infection in settings where access to healthy foods is limited.

Survey of determination of death after cardiac arrest by intensive care physicians.

OBJECTIVE: The controversy regarding death determination in the context of organ donation after cardiocirculatory death requires investigation. We sought to describe the manner in which Canadian adult and pediatric intensive care physicians report death determination after cardiac arrest. DESIGN: Pilot-tested paper survey. SETTING: Mail out between June and November 2009. SUBJECTS: Canadian adult and pediatric intensive care physicians. INTERVENTION: Paper-based survey. MAIN RESULTS: Forty-nine percent of 501 Canadian intensive care physicians responded. Eighty-five percent practiced in tertiary care, university-affiliated centers, and 26% were from pediatric centers. Physicians had a median of 10 yrs (range 0-35) experience. Physicians reported that they performed determination of death after cardiac arrest a median of seven (range 0-60) times per year. Of 11 tests or procedures used, the absence of heart sounds by auscultation, palpable pulse, and breath sounds were the most common, although there was high variability in practice. No diagnostic test/procedure was uniformly performed or omitted. Sixty-five percent of respondents believed autoresuscitation exists and 37% of physicians reported to have seen a possible case during their career. Forty-eight percent had formal training for determining death after cardiac arrest and 22% used guidelines. The majority of respondents agreed that standardized methods for determination of death after cardiac arrest are required in general (69%) and specifically for donation after cardiocirculatory death (91%). CONCLUSIONS: Intensive care physicians in Canada report: 1) variability in the practice of determining death after cardiac arrest; 2) the existence of autoresuscitation; and 3) a need for standardization of practice. The results of this survey support the need to develop more robust education, guidelines, and standards for the determination of death after cardiac arrest, in general, as well as within the context of donation after cardiocirculatory death.

Non-utilization of hearts and lungs after consent for donation: a Canadian multicentre study.

PURPOSE: To identify reasons why hearts and lungs from consented adult organ donors are not transplanted and identify changes in practice aimed at increasing their utilization rates. A greater potential may exist in Canada to improve utilization rates for hearts and lungs given their comparatively suboptimal rates (kidneys 85%, livers 84%, hearts 35% and lungs 23% reported in 2001). METHODS: Four Canadian organ procurement organizations participated. All adult organ donation cases for the calendar year 2002 were reviewed and included if consent for organ donation was obtained. An organ donation framework was established to highlight key areas where organs are lost from the transplantation stream. Organ donor cases were analyzed through this framework. RESULTS: A utilization rate of 39% (42/107) for heart and 28% (29/105) for lung donors was found, comparable to Canadian and international rates. Organ function was the most frequently cited reason for non-utilization, followed by donor characteristics and logistical issues. Suggestions for alternate management, potentially resulting in organ utilization, were made in 20 of 65 (31%) hearts and 28 of 156 (18%) lungs. Variable practices, around consent for individual organs and offering of organs consented, remained significant barriers to successful transplantation. CONCLUSION: Target areas for changes in practice included consenting and offering of all organs. Management of "marginal" organs should include resuscitation and reevaluation thus allowing potential organ rescue and utilization. Although there is considerable pressure to increase organs for transplantation, any such mechanism will not be judged successful unless recipient graft survival rates remain acceptable.

Variability in hospital-based brain death guidelines in Canada.

PURPOSE: Variability has been reported in the practices to determine death by neurological criteria for adults and children. The objective of this study was to determine if this variability exists in the Canadian context. METHODS: A cross-sectional survey of the Canadian intensive care units (ICUs) involved in the care of potential organ donors, and Canadian organ procurement organizations (OPOs) was undertaken. We contacted the medical directors of these units and asked them to provide their guidelines for the neurological determination of death (NDD). A framework, which identifies key diagnostic criteria for NDD, was used to assess the content of all study documents. RESULTS: With a response rate of 68%, we found that key diagnostic criteria for NDD were incorporated inconsistently in the guidelines from Canadian ICUs and OPOs. Areas of concern include omissions in: the testing of brainstem reflexes; components of the apnea test; indications for the use of supplementary testing; wait intervals prior to performing the first NDD examination; the definition of NDD; and potential confounding factors. In addition, inconsistencies were found pertaining to wait intervals required between examinations and the legal timing of death. CONCLUSION: These findings reinforce the need to standardize the practice of the neurological determination of death in Canadian centres, which has the potential to reduce practice variation. Clear medical standards for NDD augment the quality, rigour and credibility of this determination.