Pediatric Death After Withdrawal of Life-Sustaining Therapies: A Scoping Review.

OBJECTIVES: Evaluate literature on the dying process in children after withdrawal of life sustaining measures (WLSM) in the PICU. We focused on the physiology of dying, prediction of time to death, impact of time to death, and uncertainty of the dying process on families, healthcare workers, and organ donation. DATA SOURCES: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, CINAHL, and Web of Science. STUDY SELECTION: We included studies that discussed the dying process after WLSM in the PICU, with no date or study type restrictions. We excluded studies focused exclusively on adult or neonatal populations, children outside the PICU, or on organ donation or adult/pediatric studies where pediatric data could not be isolated. DATA EXTRACTION: Inductive qualitative content analysis was performed. DATA SYNTHESIS: Six thousand two hundred twenty-five studies were screened and 24 included. Results were grouped into four categories: dying process, perspectives of healthcare professionals and family, WLSM and organ donation, and recommendations for future research. Few tools exist to predict time to death after WLSM in children. Most deaths after WLSM occur within 1 hour and during this process, healthcare providers must offer support to families regarding logistics, medications, and expectations. Providers describe the unpredictability of the dying process as emotionally challenging and stressful for family members and staff; however, no reports of families discussing the impact of time to death prediction were found. The unpredictability of death after WLSM makes families less likely to pursue donation. Future research priorities include developing death prediction tools of tools, provider and parental decision-making, and interventions to improve end-of-life care. CONCLUSIONS: The dying process in children is poorly understood and understudied. This knowledge gap leaves families in a vulnerable position and the clinical team without the necessary tools to support patients, families, or themselves. Improving time to death prediction after WLSM may improve care provision and enable identification of potential organ donors.

Impact of COVID-19-related restricted family presence policies on Canadian pediatric intensive care unit clinicians: a qualitative study.

PURPOSE: Pediatric intensive care units (PICUs) worldwide restricted family presence in response to the COVID-19 pandemic. We aimed to explore the experiences and impact of restricted family presence policies on Canadian PICU clinicians. METHODS: We conducted a qualitative study that followed an interpretive phenomenological design. Participants were PICU clinicians providing direct patient care in Canada during periods of COVID-19-related restricted family presence. We purposively sampled for maximum variation among survey participants who consented to be contacted for further research on the same topic. In-depth interviews were conducted remotely via telephone or video-call, audio-recorded, and transcribed. Interviews were inductively coded and underwent thematic analysis. Proposed themes were member-checked by interviewees. RESULTS: Sixteen PICU clinicians completed interviews. Interviewees practiced across Canada, represented a range of disciplines (eight nurses, two physicians, two respiratory therapists, two child life specialists, two social workers) and years in profession (0-34 years). We identified four themes representing the most meaningful aspects of restricted family presence for participants: 1) balancing infection control and family presence; 2) feeling disempowered by hospital and policy-making hierarchies; 3) empathizing with family trauma; and 4) navigating threats to the therapeutic relationship. CONCLUSION: Pediatric intensive care unit clinicians were impacted by restricted family presence policies during the COVID-19 pandemic. These policies contributed to feelings of disempowerment and challenged clinicians' perceived ability to provide the best family-centred care possible. Frontline expertise should be incorporated into the design and implementation of policies to best support family-centred care in any context and minimize risks of moral distress for PICU clinicians.

RéSUMé: OBJECTIF: Les unités de soins intensifs pédiatriques (USIP) du monde entier ont restreint la présence des familles en réponse à la la pandémie de COVID-19. Notre objectif était d'explorer les expériences et l'impact des politiques de restriction de la présence familiale sur les clinicien·nes des USIP canadiennes. MéTHODE: Nous avons mené une étude qualitative qui a suivi un plan phénoménologique interprétatif. Les participant·es étaient des clinicien·nes des USIP qui dispensaient des soins directs aux patient·es au Canada pendant les périodes de présence restreinte des familles en raison de la COVID-19. Nous avons délibérément échantillonné pour obtenir une variation maximale parmi les participant·es à l'enquête qui ont accepté d'être contacté·es pour d'autres recherches sur le même sujet. Des entretiens approfondis ont été menés à distance par téléphone ou par appel vidéo, enregistrés et transcrits. Les entretiens ont été codés de manière inductive et ont fait l'objet d'une analyse thématique. Les thèmes proposés ont été contrôlés par membre par les personnes interrogées. RéSULTATS: Seize cliniciennes et cliniciens des USIP ont passé des entrevues. Les personnes interrogées exerçaient partout au Canada, représentaient un éventail de disciplines (huit infirmiers et infirmières, deux médecins, deux inhalothérapeutes, deux spécialistes du milieu de l'enfant, deux travailleuses et travailleurs sociaux) et d'années d'expérience professionnelle (de 0 à 34 ans). Nous avons identifié quatre thèmes représentant les aspects les plus significatifs de la présence restreinte de la famille pour les participant·es : 1) l'équilibre entre la prévention des infections et la présence de la famille; 2) le sentiment d'être dépossédé·e par les hiérarchies de l'hôpital et de ne pas pouvoir participer à l'élaboration des politiques; 3) le sentiment d'empathie à l'égard des traumatismes familiaux; et 4) la réponse aux menaces qui ont pesé sur la relation thérapeutique. CONCLUSION: Les cliniciens et cliniciennes des unités de soins intensifs pédiatriques ont été touché·es par les politiques de restriction de la présence familiale pendant la pandémie de COVID-19. Ces politiques ont contribué à un sentiment d'impuissance et ont remis en question la capacité perçue des équipes à fournir les meilleurs soins possibles axés sur la famille. L'expertise de première ligne devrait être intégrée à la conception et à la mise en œuvre des politiques afin de mieux soutenir les soins axés sur la famille dans n'importe quel contexte et de minimiser les risques de détresse morale pour les cliniciennes et cliniciens des USIP.

Organ Donation in Canadian PICUs: A Cross-Sectional Survey, 2021-2022.

OBJECTIVES: To understand contemporary pediatric organ donation programs in Canadian PICUs, including: policies and practices, data collection and reporting, and system and process barriers. DESIGN: A cross-sectional survey carried out 2021-2022. SETTING: Canadian PICUs affiliated with a donor physician network. SUBJECTS: Pediatric intensivists identified as the donation program lead, or most knowledgeable about donation for their institution. MEASUREMENTS AND MAIN RESULTS: A 19-item survey was developed through collaboration with stakeholders from the organ donation and transplantation community within Canada. Domains and items were generated and reduced iteratively during an in-person workshop. Pretesting and pilot testing were completed to ensure readability, flow, clinical sensibility, and construct validity. Fifteen of 16 (94%) invited Canadian PICUs from seven provinces completed the survey representing 88% (15/18) of all noncardiac Canadian PICUs. Surveys were completed between June 2021 and September 2022. All units support donation after death by neurologic criteria (DNC); 14 of 15 indicated donation policies were in place and 1 of 15 indicated no policy but the ability to facilitate donation. Thirteen of 15 units (87%) support donation after death by circulatory criteria (DCC) with policies in place, with 11 of 13 of these indicating routine support of donation opportunities. The majority (13/15) of units identified a donation champion. Of the 16 identified champions across these centers, 13 were physicians and were registered nurses or nurse practitioners. Eight of 13 units (62%) with donation champions had positions supported financially, of which 5 units came from the Organ Donation Organization and the other 3 came from the provincial health authority. Finally, only 3 of 15 PICU donation programs have a pediatric donation committee with family involvement. Variability exists in identification (including determination of death practices), referral, and approach for donation between units. CONCLUSIONS: Although all Canadian PICUs support donation after DNC donation, and most support donation after DCC, variability exists in the identification, referral, and approach of potential donors. There is a notable lack of family involvement in pediatric donation programs. There are many opportunities for standardization of PICU donation programs which may result in improved rates of pediatric organ donation in Canada.

Defining Pediatric Chronic Critical Illness: A Scoping Review.

OBJECTIVES: Children with chronic critical illness (CCI) are hypothesized to be a high-risk patient population with persistent multiple organ dysfunction and functional morbidities resulting in recurrent or prolonged critical care; however, it is unclear how CCI should be defined. The aim of this scoping review was to evaluate the existing literature for case definitions of pediatric CCI and case definitions of prolonged PICU admission and to explore the methodologies used to derive these definitions. DATA SOURCES: Four electronic databases (Ovid Medline, Embase, CINAHL, and Web of Science) from inception to March 3, 2021. STUDY SELECTION: We included studies that provided a specific case definition for CCI or prolonged PICU admission. Crowdsourcing was used to screen citations independently and in duplicate. A machine-learning algorithm was developed and validated using 6,284 citations assessed in duplicate by trained crowd reviewers. A hybrid of crowdsourcing and machine-learning methods was used to complete the remaining citation screening. DATA EXTRACTION: We extracted details of case definitions, study demographics, participant characteristics, and outcomes assessed. DATA SYNTHESIS: Sixty-seven studies were included. Twelve studies (18%) provided a definition for CCI that included concepts of PICU length of stay (n = 12), medical complexity or chronic conditions (n = 9), recurrent admissions (n = 9), technology dependence (n = 5), and uncertain prognosis (n = 1). Definitions were commonly referenced from another source (n = 6) or opinion-based (n = 5). The remaining 55 studies (82%) provided a definition for prolonged PICU admission, most frequently greater than or equal to 14 (n = 11) or greater than or equal to 28 days (n = 10). Most of these definitions were derived by investigator opinion (n = 24) or statistical method (n = 18). CONCLUSIONS: Pediatric CCI has been variably defined with regard to the concepts of patient complexity and chronicity of critical illness. A consensus definition is needed to advance this emerging and important area of pediatric critical care research.

A survey of pediatric intensive care unit clinician experience with restricted family presence during COVID-19.

PURPOSE: Limiting family presence runs counter to the family-centred values of Canadian pediatric intensive care units (PICUs). This study explores how implementing and enforcing COVID-19-related restricted family presence (RFP) policies impacted PICU clinicians nationally. METHODS: We conducted a cross-sectional, online, self-administered survey of Canadian PICU clinicians to assess experience and opinions of restrictions, moral distress (Moral Distress Thermometer, range 0-10), and mental health impacts (Impact of Event Scale [IES], range 0-75 and attributable stress [five-point Likert scale]). For analysis, we used descriptive statistics, multivariate regression modelling, and a general inductive approach for free text. RESULTS: Representing 17/19 Canadian PICUs, 368 of 388 respondents (94%) experienced RFP policies and were predominantly female (333/368, 91%), English speaking (338/368, 92%), and nurses (240/368, 65%). The mean (standard deviation [SD]) reported moral distress score was 4.5 (2.4) and was associated with perceived differential impact on families. The mean (SD) total IES score was 29.7 (10.5), suggesting moderate traumatic stress with 56% (176/317) reporting increased/significantly increased stress from restrictions related to separating families, denying access, and concern for family impacts. Incongruence between RFP policies/practices and PICU values was perceived by 66% of respondents (217/330). Most respondents (235/330, 71%) felt their opinions were not valued when implementing policies. Though respondents perceived that restrictions were implemented for the benefit of clinicians (252/332, 76%) and to protect families (236/315, 75%), 57% (188/332) disagreed that their RFP experience was mainly positive. CONCLUSION: Pediatric intensive care unit-based RFP rules, largely designed and implemented without bedside clinician input, caused increased psychological burden for clinicians, characterized as moderate moral distress and trauma triggered by perceived impacts on families.

RéSUMé: OBJECTIF: Limiter la présence de la famille va à l'encontre des valeurs centrées sur la famille des unités de soins intensifs pédiatriques (USIP) canadiennes. Cette étude explore comment la mise en œuvre et l'application des politiques de restriction de la présence familiale liées à la COVID-19 ont eu une incidence sur les cliniciennes et cliniciens des USIP à l'échelle nationale. MéTHODE: Nous avons mené un sondage transversal, en ligne et auto-administré auprès des cliniciens et cliniciennes des USIP canadiennes afin d'évaluer leur expérience et opinions sur les restrictions, la détresse morale (thermomètre de détresse morale, intervalle de 0 à 10) et les impacts sur la santé mentale (échelle d'impact des événements [EIE], intervalle de 0 à 75, et le stress qui peut y être attribué [échelle de Likert à cinq points]). Pour l'analyse, nous avons utilisé des statistiques descriptives, une modélisation de régression multivariée et une analyse inductive générale pour le texte libre. RéSULTATS: Représentant 17/19 USIP canadiennes, 368 des 388 personnes répondantes (94 %) ont vécu des politiques de restriction de la présence familiale et étaient principalement des femmes (333/368, 91 %), anglophones (338/368, 92 %) et infirmières (240/368, 65 %). Le score moyen (écart type [ET]) rapporté de détresse morale était de 4,5 (2,4) et était associé à l'impact différentiel perçu sur les familles. Le score moyen (ET) total de l'EIE était de 29,7 (10,5), ce qui suggère un stress traumatique modéré, 56 % (176/317) des personnes répondantes déclarant une augmentation ou une augmentation significative du stress associé aux restrictions liées à la séparation des familles, au refus d'accès et à la préoccupation pour les impacts familiaux. L'incongruité entre les politiques et les pratiques de restriction des visites familiales et les valeurs des USIP était perçue par 66 % des personnes répondantes (217/330). La plupart (235/330, 71 %) estimaient que leurs opinions n'étaient pas prises en compte lors de la mise en œuvre de politiques. Bien que les répondant·es aient perçu que les restrictions avaient été mises en œuvre dans l'intérêt des cliniciens et cliniciennes (252/332, 76 %) et pour protéger les familles (236/315, 75 %), 57 % (188/332) n'étaient pas d'accord pour dire que leur expérience de la restriction des visites familiales était principalement positive. CONCLUSION: Les règles de restriction de la présence familiale dans les unités de soins intensifs pédiatriques, en grande partie conçues et mises en œuvre sans l'avis du personnel clinique au chevet des patient·es, ont entraîné une augmentation du fardeau psychologique pour le personnel clinique, caractérisée par une détresse morale modérée et un traumatisme déclenché par des répercussions perçues sur les familles.

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.

Prevalence of Acute Rehabilitation for Kids in the PICU: A Canadian Multicenter Point Prevalence Study.

OBJECTIVES: To evaluate mobilization practices, barriers, and mobility-related adverse events in Canadian PICUs. DESIGN: National 2-day point prevalence study. SETTING: Thirteen PICUs across Canada. PATIENTS: Children with a minimum 72-hour PICU length of stay on the allocated study day. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Outcomes of interest were the prevalence and nature of mobilization activities, rehabilitation resources, adverse events, and factors associated with out-of-bed mobility and therapist-provided mobility. Two PICUs (15%) had early mobilization practice guidelines, and one PICU (8%) reported a formal process for engaging families in the mobilization of patients. The prevalence of mobilization was 110 of 137 patient-days (80%). The commonest activity was out-of-bed mobility (87/137; 64% patient-days); there was no active mobilization on 46 patient-days (34%). Therapists provided mobility on 33% of patient-days. Mobility was most commonly facilitated by nurses (74% events) and family (49% events). Family participation was strongly associated with out-of-bed mobility (odds ratio 6.4; p = 0.001). Intubated, mechanically ventilated patients were mobilized out-of-bed on 18 of 50 patient-days (36%). However, the presence of an endotracheal tube, vasoactive infusions, and age greater than or equal to 3 years were independently associated with not being mobilized out-of-bed. Barriers were reported on 58 of 137 patient-days (42%), and adverse events occurred in 22 of 387 mobility events (6%). CONCLUSIONS: Mobilization is common and safe, and the majority of children in Canadian PICUs are being mobilized out-of-bed, even when mechanically ventilated. Family engagement in PICU-based rehabilitation is increasing. This study provides encouraging evidence that common barriers can be overcome in order to safely mobilize children in PICUs.

Comfort-holding in critically ill children: a scoping review.

PURPOSE: To understand and summarize the breadth of knowledge on comfort-holding in pediatric intensive care units (PICUs). SOURCES: This scoping review was conducted using PRISMA methodology. A literature search was conducted in MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane CENTRAL Register of Controlled Trials. Search strategies were developed with a medical librarian and revised through a peer review of electronic search strategies. All databases were searched from inception to 14 April 2020. Only full-text articles available in English were included. All identified articles were reviewed independently and in duplicate using predetermined criteria. All study designs were eligible if they reported on comfort-holding in a PICU. Data were extracted independently and in duplicate. PRINCIPAL FINDINGS: Of 13,326 studies identified, 13 were included. Comfort-holding was studied in the context of end-of-life care, developmental care, mobilization, and as a unique intervention. Comfort-holding is common during end-of-life care with 77.8% of children held, but rare during acute management (51% of children < three years, < 5% of children ≥ three years). Commonly reported outcomes included child outcomes (e.g., physiologic measurements), safety outcomes (e.g., accidental line removal), parent outcomes (e.g., psychological symptoms), and frequency of holding. CONCLUSION: There is a paucity of literature on comfort-holding in PICUs. This scoping review identifies significant gaps in the literature, including assessment of child-based outcomes of comfort-holding or safety assessment of comfort-holding, and highlights core outcomes to consider in future evaluations of this intervention including child-based outcomes, parent-based outcomes, and safety of the intervention.

RéSUMé: OBJECTIF: Comprendre et résumer l'étendue des connaissances sur la pratique des étreintes de réconfort dans les unités de soins intensifs pédiatriques (USIP). SOURCES: Cette étude de portée a été réalisée en utilisant la méthodologie PRISMA. Une recherche de la littérature a été menée dans les bases de données MEDLINE, EMBASE, PsycINFO, CINAHL et dans le registre Cochrane CENTRAL d'études contrôlées. Les stratégies de recherche ont été élaborées avec un bibliothécaire médical et révisées au moyen d'un examen par les pairs des stratégies de recherche électronique. Toutes les bases de données ont été passées en revue de leur création au 14 avril 2020. Seuls les articles en texte intégral disponibles en anglais ont été inclus. Tous les articles identifiés ont été révisés indépendamment et en double à l'aide de critères prédéterminés. Tous les types de plans d'étude étaient admissibles s'ils abordaient le thème des étreintes de réconfort dans une USIP. Les données ont été extraites indépendamment et en double. CONSTATATIONS PRINCIPALES: Sur les 13 326 études identifiées, 13 ont été incluses. Les étreintes de réconfort ont été étudiées dans le contexte des soins de fin de vie, des soins développementaux, de la mobilisation et en tant qu'intervention unique. Les étreintes de réconfort sont une approche courante dans le cadre de soins de fin de vie, durant lesquels 77,8 % des enfants sont étreints, mais plus rares pendant la prise en charge aiguë (51 % des enfants < trois ans, < 5 % des enfants ≥ trois ans). Les résultats couramment rapportés comprenaient les issues pour les enfants (p. ex. mesures physiologiques), les issues en matière de sécurité (p. ex. retrait accidentel d'une ligne), les issues pour les parents (p. ex. symptômes psychologiques) et la fréquence des étreintes. CONCLUSION: Il n'existe que très peu de littérature s'intéressant aux étreintes de réconfort dans les USIP. Cette étude de portée identifie d'importantes lacunes dans la littérature, notamment l'évaluation des issues pour l'enfant suite à une étreinte de réconfort ou l'évaluation de la sécurité de telles étreintes, et met en évidence les issues principales dont il faudra tenir compte dans les évaluations futures de cette intervention, y compris les issues axées sur l'enfant, les issues basées sur les parents et la sécurité de l'intervention.

A phase IIb, randomised, parallel-group study: the efficacy, safety and tolerability of once-daily umeclidinium in patients with asthma receiving inhaled corticosteroids.

BACKGROUND: Patients with asthma uncontrolled on inhaled corticosteroids may benefit from umeclidinium (UMEC), a long-acting muscarinic antagonist. METHODS: This Phase IIb, double-blind study included patients with reversible, uncontrolled/partially-controlled asthma for ≥6 months, receiving ≥100 mcg/day fluticasone propionate (or equivalent) for ≥12 weeks. Following a 2-week run-in on open-label fluticasone furoate (FF) 100 mcg, patients were randomised (1:1:1) to receive UMEC 31.25 mcg, UMEC 62.5 mcg or placebo on top of FF 100 mcg once-daily for 24 weeks. As-needed salbutamol was provided. Primary and secondary endpoints were change from baseline in clinic trough forced expiratory volume in 1 s (FEV1) and clinic FEV1 3 h post-dose, respectively, at Week 24. Other endpoints included change from baseline in home daily spirometry (trough FEV1, evening FEV1, morning [pre-dose] and evening peak expiratory flow) over 24 weeks. Safety was assessed throughout the study. RESULTS: The intent-to-treat population comprised 421 patients (UMEC 31.25 mcg: n =139, UMEC 62.5 mcg: n =139, placebo: n =143). UMEC 31.25 mcg and 62.5 mcg demonstrated significantly greater improvements from baseline in clinic trough FEV1 at Week 24 (difference [95% CI]: 0.176 L [0.092, 0.260; p<0.001] and 0.184 L [0.101, 0.268; p<0.001], respectively), clinic FEV1 3 h post-dose at Week 24 (0.190 L [0.100, 0.279; p<0.001] and 0.198 L [0.109, 0.287; p<0.001], respectively) and mean change from baseline in daily home spirometry over 24 weeks versus placebo. No new safety signals were identified. CONCLUSIONS: UMEC is a highly effective bronchodilator that leads to improved lung function when administered as a single bronchodilator on top of FF in subjects with fully reversible, uncontrolled/partially-controlled moderate asthma. These data support a favourable benefit/risk profile for UMEC (31.25 mcg and 62.5 mcg). TRIAL REGISTRATION: GSK study ID: 205832; Clinicaltrials.gov ID: NCT03012061.

Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma.

BACKGROUND: Long-acting beta-agonists (LABAs) have been shown to increase the risk of asthma-related death among adults and the risk of asthma-related hospitalization among children. It is unknown whether the concomitant use of inhaled glucocorticoids with LABAs mitigates those risks. This trial prospectively evaluated the safety of the LABA salmeterol, added to fluticasone propionate, in a fixed-dose combination in children. METHODS: We randomly assigned, in a 1:1 ratio, children 4 to 11 years of age who required daily asthma medications and had a history of asthma exacerbations in the previous year to receive fluticasone propionate plus salmeterol or fluticasone alone for 26 weeks. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization), as assessed in a time-to-event analysis. The statistical design specified that noninferiority would be shown if the upper boundary of the 95% confidence interval of the hazard ratio for the primary safety end point was less than 2.675. The main efficacy end point was the first severe asthma exacerbation that led to treatment with systemic glucocorticoids, as assessed in a time-to-event analysis. RESULTS: Among the 6208 patients, 27 patients in the fluticasone-salmeterol group and 21 in the fluticasone-alone group had a serious asthma-related event (all were hospitalizations); the hazard ratio with fluticasone-salmeterol versus fluticasone alone was 1.28 (95% confidence interval [CI], 0.73 to 2.27), which showed the noninferiority of fluticasone-salmeterol (P=0.006). A total of 265 patients (8.5%) in the fluticasone-salmeterol group and 309 (10.0%) in the fluticasone-alone group had a severe asthma exacerbation (hazard ratio, 0.86; 95% CI, 0.73 to 1.01). CONCLUSIONS: In this trial involving children with asthma, salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone. (Funded by GlaxoSmithKline; VESTRI ClinicalTrials.gov number, NCT01462344 .).

Reliability, validity and responsiveness of E-RS:COPD in patients with spirometric asthma-COPD overlap.

BACKGROUND: The Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease (E-RS:COPD) is a patient-reported diary that assesses respiratory symptoms in stable COPD. METHODS: This post hoc analysis of a randomized, double-blind, parallel-arm trial (GSK ID: 200699; NCT02164539) assessed the structure, reliability, validity and responsiveness of the E-RS, and a separate wheeze item, for use in patients with a primary diagnosis of asthma or COPD, but with spirometric characteristics of both (fixed airflow obstruction and reversibility to salbutamol; a subset of patients referred to as spirometric asthma-COPD overlap [ACO]; N = 338). RESULTS: Factor analysis demonstrated that E-RS included Cough and Sputum, Chest Symptoms, and Breathlessness domains, with a Total score suitable for quantifying overall respiratory symptoms (comparative fit index: 0.9), consistent with the structure shown in COPD. The wheeze item did not fit the model. Total and domain scores were internally consistent (Cronbach's alpha: 0.7-0.9) and reproducible (intra-class correlations > 0.7). Moderate correlations between RS-Total and RS-Breathlessness scores were observed with St George's Respiratory Questionnaire (SGRQ) Total and Activity domain scores at baseline (r = 0.43 and r = 0.48, respectively). E-RS scores were sensitive to change when a patient global impression of change and SGRQ change scores were used to define responders, with changes of ≥ - 1.4 in RS-Total score interpreted as clinically meaningful. CONCLUSIONS: E-RS:COPD scores were reliable, valid and responsive in this sample, suggesting the measure may be suitable for evaluating the severity of respiratory symptoms and the effects of treatment in patients with asthma and COPD that exhibit spirometric characteristics of both fixed airflow obstruction and reversibility. Further study of this instrument and wheeze in new samples of patients with ACO is warranted.

Dose-response modelling of umeclidinium and fluticasone furoate/umeclidinium in asthma.

PURPOSE: In two dose-ranging crossover studies, the long-acting muscarinic antagonist umeclidinium (UMEC) was assessed as monotherapy in patients with asthma not treated with inhaled corticosteroids (ICS) (NCT01641692 [study 1]) and combined with the ICS fluticasone furoate (FF) in patients with asthma symptomatic on ICS (NCT01573624 [study 2]). The present study aimed to further characterise the UMEC dose-response relationship with change from baseline trough forced expiratory volume in one second (FEV1) (day 15). METHODS: A model-based approach using non-linear mixed-effects analyses was used to assess data from studies 1 and 2. RESULTS: Within the Study 1 dose range, no significant dose-response was demonstrated. In study 2, the slope-intercept on log-dose model showed a mild dose-response, with a 10 % probability of a 0.075-L FEV1 improvement with FF/UMEC 100/250 mcg; period 1 data (with an absent carryover effect) indicated an 88 % probability of a 0.075-L FEV1 improvement. CONCLUSION: The model-based approach in study 2 identified FF/UMEC doses warranting further investigation.

Improving family-centered care practices in the NICU.

Family presence and participation in care in the NICU is fundamental to the recovery and well-being of the sick neonate and family. However, some NICU visitation policies are not supportive of families. A new visitor-management program was initiated at a local hospital. The program included open visitation for parents and others chosen by parents to be a support during their hospital stay. This quality-improvement project evaluated if there was any improvement in parents' perceptions and experiences of family-centered care after the implementation of the new visitor-management program. The NICU parent survey data revealed a modest positive difference in parent responses after the implementation of the program.

Ocular safety of fluticasone furoate nasal spray in patients with perennial allergic rhinitis: a 2-year study.

BACKGROUND: This is the first study, to our knowledge, to evaluate the ocular effects of an intranasal corticosteroid during 2 years of treatment for perennial allergic rhinitis (PAR). OBJECTIVE: To assess ocular safety in adult and adolescent patients 12 years and older with PAR after 2 years of continuous treatment with fluticasone furoate nasal spray (FFNS), 110 µg once daily, and placebo. METHODS: This was a 2-year, randomized, double-blind, placebo-controlled study of once-daily FFNS, 110 ìg, and placebo in 548 patients 12 years and older with PAR. The primary ocular safety end points were time to first occurrence of an event for the Lens Opacities Classification System, Version III (LOCS III), posterior subcapsular opacity (PSO) and time to first occurrence of an event for intraocular pressure (IOP). RESULTS: On the basis of survival analyses, the difference between the treatment groups for time to first occurrence of a LOCS III PSO and time to first occurrence of an IOP event was not statistically significant (P = .39 and P = .34, respectively). Changes from baseline in visual acuity, LOCS III PSO, cortical opacity, LOCS III nuclear opacity and nuclear color, IOP, and horizontal cup-to-disc similar between treatment groups. There were no ophthalmic-related adverse events of LOCS III PSO or IOP that led to early withdrawal. The most common drug-related adverse event was epistaxis (FFNS, 28%; placebo, 14%). CONCLUSION: These data neither support nor negate current recommendations for regular ophthalmic monitoring in patients treated with intranasal corticosteroids. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00682643.

Predictors of Pancreatitis Among Patients with Inflammatory Bowel Disease Treated with Vedolizumab: Observation from a Large Global Safety Database.

BACKGROUND: Patients with inflammatory bowel diseases (IBDs) are at increased risk of pancreatitis. Data from a global safety database (GSD) were queried to identify risk factors for pancreatitis in vedolizumab-treated patients with IBD. METHODS: Takeda's GSD was retrospectively queried for case reports (CRs) of adverse events (AEs) following vedolizumab treatment, from licensure (May 20, 2014) through March 31, 2021. Unsolicited and solicited CRs of pancreatitis were coded using the Medical Dictionary for Regulatory Activities (MedDRA) High-Level Term "Acute and chronic pancreatitis." To examine factors associated with severe pancreatitis, serious CRs (serious AEs [SAEs]) were compared with SAEs from a comparator group of 600 random non-pancreatitis AEs. Comparisons were performed using t, χ2, and Fisher's exact tests. Logistic regression was performed to adjust for covariates allowing backward selection. RESULTS: In total, 196 patients reported pancreatitis in > 700,000 patient-years of vedolizumab exposure. Pancreatitis was serious in 195 patients (99.5%), and non-pancreatitis AEs were serious in 195 of 600 (32.5%) in the random comparator group. In the pancreatitis group, 17 patients (8.7%) had a known history of pancreatitis versus none in the random comparator group. Younger age, vedolizumab indication of ulcerative colitis, concomitant medications (with a risk for pancreatitis), pancreatitis history, and comorbid conditions (especially ongoing pancreatitis) were associated with development of severe pancreatitis. CONCLUSIONS: These analyses identified factors associated with pancreatitis SAEs in patients with IBD treated with vedolizumab, but do not suggest an increased risk of pancreatitis with vedolizumab. These findings will help inform which patients treated for IBD might have an elevated risk, regardless of treatment.

People with inflammatory bowel diseases (IBDs) are at increased risk for inflammation of the pancreas (pancreatitis). Vedolizumab (VE-doe-LIZ-ue-mab), approved for the treatment of IBD, works by preventing cells that cause inflammation from entering the gut lining. We looked at a worldwide safety database to identify factors that may increase the risk for pancreatitis in people with IBD receiving vedolizumab. Since vedolizumab's approval in 2014, 196 people had pancreatitis in > 700,000 person-years of vedolizumab exposure. Person-years account for the number of people in the study and for duration of treatment. Most (195 of 196) people with pancreatitis had serious cases. In a comparator group of people with random side effects other than pancreatitis, about one in three people had serious side effects. Among the 195 people with serious pancreatitis, 17 had a history of pancreatitis, compared with none in the comparator group. We found several factors that may increase the risk for serious pancreatitis: younger age, treatment for ulcerative colitis, previous pancreatitis, taking other medicines, and having additional medical conditions. The relatively few identified cases of pancreatitis from over 700,000 years of patient exposure does not suggest an increased risk for developing pancreatitis. These findings could be used to identify people treated for IBD who may have an increased risk of developing pancreatitis.

Chronic Active Antibody-mediated Rejection: Opportunity to Determine the Role of Interleukin-6 Blockade.

Chronic active antibody-mediated rejection (caAMR) is arguably the most important cause of late kidney allograft failure. However, there are no US Food and Drug Administration (FDA)-approved treatments for acute or chronic AMR and there is no consensus on effective treatment. Many trials in transplantation have failed because of slow and/or inadequate enrollment, and no new agent has been approved by the FDA for transplantation in over a decade. Several lines of evidence suggest that interleukin-6 is an important driver of AMR, and clazakizumab, a humanized monoclonal antibody that neutralizes interleukin-6, has shown promising results in phase 2 studies. The IMAGINE trial (Interleukin-6 Blockade Modifying Antibody-mediated Graft Injury and Estimated Glomerular Filtration Rate Decline) (NCT03744910) is the first to be considered by the FDA using a reasonably likely surrogate endpoint (slope of estimated glomerular filtration rate decline >1 y) for accelerated approval and is the only ongoing clinical trial for the treatment of chronic rejection. This trial offers us the opportunity to advance the care for our patients in need, and this article is a call to action for all transplant providers caring for patients with caAMR.

Report From a Multidisciplinary Symposium on the Future of Living Kidney Donor Transplantation.

Virtually all clinicians agree that living donor renal transplantation is the optimal treatment for permanent loss of kidney function. Yet, living donor kidney transplantation has not grown in the United States for more than 2 decades. A virtual symposium gathered experts to examine this shortcoming and to stimulate and clarify issues salient to improving living donation. The ethical principles of rewarding kidney donors and the limits of altruism as the exclusive compelling stimulus for donation were emphasized. Concepts that donor incentives could save up to 40 000 lives annually and considerable taxpayer dollars were examined, and survey data confirmed voter support for donor compensation. Objections to rewarding donors were also presented. Living donor kidney exchanges and limited numbers of deceased donor kidneys were reviewed. Discussants found consensus that attempts to increase living donation should include removing artificial barriers in donor evaluation, expansion of living donor chains, affirming the safety of live kidney donation, and assurance that donors incur no expense. If the current legal and practice standards persist, living kidney donation will fail to achieve its true potential to save lives.

"We Aren't Meant to Go Through the Hardest Parts of Our Lives Alone": Family Experience With Restricted PICU Presence During the COVID-19 Pandemic.

CONTEXT: PICUs across Canada restricted family presence (RFP) in response to the COVID-19 pandemic from allowing two or more family members to often only one family member at the bedside. The objective of this study was to describe the experiences and impact of RFP on families of critically ill children to inform future policy and practice. HYPOTHESIS: RFP policies negatively impacted families of PICU patients and caused moral distress. METHODS AND MODELS: National, cross-sectional, online, self-administered survey. Family members of children admitted to a Canadian PICU between March 2020 and February 2021 were invited to complete the survey. RFP-attributable distress was measured with a modified distress thermometer (0-10). Closed-ended questions were reported with descriptive statistics and multivariable linear regression assessed factors associated with RFP-attributable distress. Open-ended questions were analyzed using inductive content analysis. RESULTS: Of 250 respondents who experienced RFP, 124 (49.6%) were restricted to one family member at the bedside. The median amount of distress that families attributed to RFP policies was 6 (range: 0-10). Families described isolation, removal of supports, and perception of trauma related to RFP. Most families (183, 73.2%) felt that policies were enforced in a way that made them feel valued by PICU clinicians, which was associated with less RFP-attributable distress. Differential impact was seen where families with lower household income indicated higher RFP-attributable distress score (2.35; 95% CI, 0.53-4.17; p = 0.03). Most respondents suggested that future policies should allow at least two family members at the bedside. INTERPRETATIONS AND CONCLUSIONS: Families of children admitted to PICUs during the COVID-19 pandemic described increased distress, trauma, and removal of supports due to RFP policies. Vulnerable families showed an increased odds of higher distress. Healthcare professionals played an important role in mitigating distress. Allowance of at least two family members at the bedside should be considered for future policy.

Pilot and feasibility study: prospective proteomic profiling of mammary epithelial cells from high-risk women provides evidence of activation of pro-survival pathways.

Normal mammary gland homeostasis requires the coordinated regulation of protein signaling networks. However, we have little prospective information on whether activation of protein signaling occurs in premalignant mammary epithelial cells, as represented by cells with cytological atypia from women who are at high risk for breast cancer. This information is critical for understanding the role of deregulated signaling pathways in the initiation of breast cancer and for developing targeted prevention and/or treatment strategies for breast cancer in the future. In this pilot and feasibility study, we examined the expression of 52 phosphorylated, total, and cleaved proteins in 31 microdissected Random Periareolar Fine Needle Aspiration (RPFNA) samples by high-throughput Reverse Phase Protein Microarray. Unsupervised hierarchical clustering analysis indicated the presence of four clusters of proteins that represent the following signaling pathways: (1) receptor tyrosine kinase/Akt/mammalian target of rapamycin (RTK/Akt/mTOR), (2) RTK/Akt/extracellular signal-regulated kinase (RTK/Akt/ERK), (3) mitochondrial apoptosis, and (4) indeterminate. Clusters 1 through 3 comprised moderately to highly expressed proteins, while Cluster 4 comprised proteins that are lowly expressed in a majority of RPFNA samples. Our exploratory study showed that the interlinked components of mitochondrial apoptosis pathway are highly expressed in all mammary epithelial cells obtained from high-risk women. In particular, the expression levels of anti-apoptotic Bcl-xL and pro-apoptotic Bad are positively correlated in both non-atypical and atypical samples (unadjusted P < 0.0001), suggesting a delicate balance between the pro-apoptotic and anti-apoptotic regulation of cell proliferation during the early steps of mammary carcinogenesis. Our feasibility study suggests that the activation of key proteins along the RTK/Akt pathway may tip this balance to cell survival. Taken together, our results demonstrate the feasibility of mapping proteomic signaling networks in limited RPFNA samples obtained from high-risk women and the promise of developing rational drug targets or preventative strategies for breast cancer in future proteomic studies with a larger cohort of high-risk women.