Childhood autoimmune hemolytic anemia: A scoping review.

BACKGROUND AND OBJECTIVE: Autoimmune hemolytic anemia (AIHA) is a rare but important cause of morbidity in pediatric hematology patients. Given its rarity, there is little high-quality evidence on which to base the investigation and management of pediatric AIHA. This scoping review aims to summarize the current evidence and highlight key gaps to inform future studies. METHODS: This review searched MEDLINE and the Cochrane CENTRAL Trials Register from 2000 to November 03, 2023. Experimental and observational studies reporting AIHA diagnostic criteria, laboratory workup, or treatment/management in populations with at least 20% of patients ≤18 years were included. RESULTS: Forty-three studies were included, with no randomized controlled trials identified. AIHA diagnostic criteria, diagnostic tests, and treatments were highly variable. First-line treatment approaches include corticosteroids, intravenous immunoglobulin, or both. Approaches to AIHA resistance to first-line therapy were widely variable between studies, but most commonly included rituximab and/or cyclosporine. CONCLUSIONS: We identify a heterogenous group of observational studies into this complex, immune-mediated disorder. Standardized definitions and classifications are needed to guide collaborative efforts needed to study this rare disease. The work done by the CEREVANCE group provides an important paradigm for future studies.

The response of Canada's clinical health research ecosystem to the COVID-19 pandemic.

BACKGROUND: The response of Canada's research community to the COVID-19 pandemic provides a unique opportunity to examine the country's clinical health research ecosystem. We sought to describe patterns of enrolment across Canadian Institutes of Health Research (CIHR)-funded studies on COVID-19. METHODS: We identified COVID-19 studies funded by the CIHR and that enrolled participants from Canadian acute care hospitals between January 2020 and April 2023. We collected information on study-and site-level variables from study leads, site investigators, and public domain sources. We described and evaluated factors associated with cumulative enrolment. RESULTS: We obtained information for 23 out of 26 (88%) eligible CIHR-funded studies (16 randomized controlled trials [RCTs] and 7 cohort studies). The 23 studies were managed by 12 Canadian and 3 international coordinating centres. Of 419 Canadian hospitals, 97 (23%) enrolled a total of 28 973 participants - 3876 in RCTs across 78 hospitals (median cumulative enrolment per hospital 30, interquartile range [IQR] 10-61), and 25 097 in cohort studies across 62 hospitals (median cumulative enrolment per hospital 158, IQR 6-348). Of 78 hospitals recruiting participants in RCTs, 13 (17%) enrolled 50% of all RCT participants, whereas 6 of 62 hospitals (9.7%) recruited 54% of participants in cohort studies. INTERPRETATION: A minority of Canadian hospitals enrolled the majority of participants in CIHR-funded studies on COVID-19. This analysis sheds light on the Canadian health research ecosystem and provides information for multiple key partners to consider ways to realize the full research potential of Canada's health systems.

Impact of Legal Guardian Absence on Research Enrollment in the PICU.

OBJECTIVES: To identify the frequency of which a legal guardian is at the bedside of children admitted to the PICU that are eligible for research studies. DESIGN: A prospective, observational study. SETTING: Three tertiary Canadian PICUs. PATIENTS: Two hundred one patients were admitted to the PICU between September 2021 and March 2023 (site 1), from March 2019 to March 2020 and March 2022 to March 2023 (site 2), and from March 2019 to March 2020 and July 2020 to November 2021 (site 3). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At each center, the duration of consent encounters was recorded for patients eligible for research by documenting the length of each attempt (min). The frequency of parental presence at bedside and the ability for a guardian to make a decision were also recorded. Thirty-five percent of patients eligible for research did not have a legal guardian at the bedside on the first attempted consent encounter. Twenty-three percent of approached patients were not enrolled due to an inability for a consent decision to be made by the child's legal guardian or an inability to contact the guardian before discharge. CONCLUSIONS: The absence of legal guardians in the PICU poses a barrier to the enrollment of critically ill children in pertinent research studies and suggests that a model of deferred consent or implied consent would aid in the future of critical care research.

Pediatric refractory immune thrombocytopenia: A systematic review.

Pediatric immune thrombocytopenia (ITP) is an acquired disorder associated with autoimmune destruction and impairment of platelet production in children. Some children exhibit poor or transient response to ITP-directed treatments and are referred to as having refractory ITP (rITP). There is currently no consensus on the definition of rITP, nor evidence-based treatment guidelines for patients with rITP. After a survey of pediatric ITP experts demonstrated lack of consensus on pediatric rITP, we pursued a systematic review to examine the reported clinical phenotypes and treatment outcomes in pediatric rITP. The search identified 253 relevant manuscripts; following review, 11 studies proposed a definition for pediatric rITP with no consensus amongst them. Most definitions included suboptimal response to medical management, while some outlined specific platelet thresholds to define this suboptimal response. Common attributes identified in this study should be used to propose a comprehensive definition, which will facilitate outcome comparisons of future rITP studies.

Assent in Pediatric Critical Care Research: A Cross-Sectional Stakeholder Survey of Canadian Research Ethics Boards, Research Coordinators, Pediatric Critical Care Researchers, and Nurses.

OBJECTIVES: Survey of four stakeholder groups involved in defining and obtaining assent for research in Canadian PICUs to better understand their perspectives and perceived barriers to assent. DESIGN: Cross-sectional survey. SETTING: Fourteen tertiary-care pediatric hospitals in Canada. PARTICIPANTS: Research Ethics Board Chairs, pediatric critical care nurses, research coordinators, and researchers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 193 participants responded. Thirty-seven percent (59/159) thought it was "Never/Almost Never" (59/159, 37%) feasible to obtain assent during the first 48 hours of PICU admission, and 112 of 170 (66%) indicated there are unique barriers to assent at the time of enrollment in PICU studies. Asking children for assent was most frequently rated as Important/Very Important for interviews/focus groups with the child (138/180, 77%), blood sample collection with a needle poke for research (137/178, 77%), and studies involving genetic testing with results communicated to the child/legal guardian (134/180, 74%). In two scenarios where a child and legal guardian disagreed about study participation, most respondents indicated that whether the child should still be enrolled would depend on the patient's age (34-36%), and/or the risk of the study (24-28%). There was a lack of consensus over how the assent process should be operationalized, and when and for how long children should be followed to seek assent for ongoing study participation. Most stakeholders (117/158, 74%) thought that children should have the opportunity to decide if their samples could stay in a biobank once they are old enough to do so. CONCLUSIONS: There was an overall lack of consensus on the feasibility of, and challenges associated with, obtaining assent at the time of study enrollment and on how key aspects of the assent process should be operationalized in the PICU. This highlights the need for guidelines to clarify the assent process in pediatric critical care research.

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.

Addressing health care inequities in Canadian critical care through inclusive science: a pilot tool for standardized data collection.

PURPOSE: Sociodemographic risks contributing to health inequities are often inadequately captured and reported in critical care studies. To address the lack of standardized terms and definitions, we sought to develop a practical and convenient resource of questions and response options for collecting sociodemographic variables for critical care research. SOURCE: To identify domains and variables that impact health equity, we searched: 1) PubMed for critical care randomized trials (2010 to 2021); 2) high-impact critical care and general medicine journals for special issues relating to equity; and 3) governmental and nongovernmental resources. PRINCIPAL FINDINGS: We identified 23 domains associated with health equity, including pronouns, age, sex, gender identity, sexual orientation, race and ethnicity, visible minorities, language, household income, marital/relationship status, education, disabilities, immigrant and refugee status, employment, primary care access, expanded health insurance, internet access, housing security, food security, dependents, religion, and postal code. For each domain we provided standardized questions and response options; for 13/23 domains, we included more than one version of the question and response categories. CONCLUSION: We developed a standardized, practical, and convenient demographic data collection tool for critical care research studies. Questions and response options can be adapted by researchers for inclusion in individual study questionnaires or case report forms.

RéSUMé: OBJECTIF: Les risques sociodémographiques qui contribuent aux inégalités en matière de santé sont souvent mal saisis et rapportés dans les études de soins intensifs. Pour remédier au manque de termes et de définitions normalisés, nous avons cherché à élaborer une ressource à la fois pratique et utile de questions et d'options de réponse pour le recueil des variables sociodémographiques pour la recherche en soins intensifs. SOURCES: Pour identifier les domaines et les variables qui ont une incidence sur l'équité en santé, nous avons effectué des recherches dans : 1) PubMed, pour en extraire les études randomisées en soins intensifs (2010 à 2021); 2) des revues de soins intensifs et de médecine générale à impact élevé pour identifier les numéros spéciaux liés à l'équité; et 3) les ressources gouvernementales et non gouvernementales. CONSTATATIONS PRINCIPALES: Nous avons identifié 23 domaines associés à l'équité en santé, y compris les pronoms, l'âge, le sexe, l'identité de genre, l'orientation sexuelle, la race et l'origine ethnique, les minorités visibles, la langue, le revenu du ménage, l'état matrimonial / relationnel, l'éducation, les handicaps, le statut d'immigrant·e et de réfugié·e, l'emploi, l'accès aux soins primaires, l'assurance maladie élargie, l'accès à l'internet, la sécurité du logement, la sécurité alimentaire, les personnes à charge, la religion et le code postal. Pour chaque domaine, nous avons fourni des questions et des options de réponse normalisées; pour 13/23 domaines, nous avons inclus plus d'une version des catégories de questions et réponses. CONCLUSION: Nous avons mis au point un outil de collecte de données démographiques normalisé, pratique et utile pour la recherche en soins intensifs. Les options de questions et de réponses peuvent être adaptées par les chercheuses et chercheurs pour être incluses dans des questionnaires d'étude individuels ou des formulaires de présentation de cas.

A phase II dose evaluation pilot feasibility randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study).

BACKGROUND: Vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (ICU) and associated with worse clinical course. Trials in adult ICU demonstrate rapid restoration of vitamin D status using an enteral loading dose is safe and may improve outcomes. There have been no published trials of rapid normalization of VDD in the pediatric ICU. METHODS: We conducted a multicenter placebo-controlled phase II pilot feasibility randomized clinical trial from 2016 to 2017. We randomized 67 critically ill children with VDD from ICUs in Canada, Chile and Austria using a 2:1 randomization ratio to receive a loading dose of enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or placebo. Participants, care givers, and outcomes assessors were blinded. The primary objective was to determine whether the loading dose normalized vitamin D status (25(OH)D > 75 nmol/L). Secondary objectives were to evaluate for adverse events and assess the feasibility of a phase III trial. RESULTS: Of 67 randomized participants, one was withdrawn and seven received more than one dose of cholecalciferol before the protocol was amended to a single loading dose, leaving 59 participants in the primary analyses (40 treatment, 19 placebo). Thirty-one/38 (81.6%) participants in the treatment arm achieved a plasma 25(OH)D concentration > 75 nmol/L versus 1/18 (5.6%) the placebo arm. The mean 25(OH)D concentration in the treatment arm was 125.9 nmol/L (SD 63.4). There was no evidence of vitamin D toxicity and no major drug or safety protocol violations. The accrual rate was 3.4 patients/month, supporting feasibility of a larger trial. A day 7 blood sample was collected for 84% of patients. A survey administered to 40 participating families showed that health-related quality of life (HRQL) was the most important outcome for families for the main trial (30, 75%). CONCLUSIONS: A single 10,000 IU/kg dose can rapidly and safely normalize plasma 25(OH)D concentrations in critically ill children with VDD, but with significant variability in 25(OH)D concentrations. We established that a phase III multicentre trial is feasible. Using an outcome collected after hospital discharge (HRQL) will require strategies to minimize loss-to-follow-up. CLINICALTRIALS: gov NCT02452762 Registered 25/05/2015.

A high-throughput platform for the rapid screening of vitamin D status by direct infusion-MS/MS.

Vitamin D is an important fat-soluble prohormone with pleiotropic effects on human health, such as immunomodulation of the innate and adaptive immune system. There is an unmet clinical need for a rapid screening platform for 25-hydroxyvitamin D (25OH-D) determination without chromatographic separation that offers better precision and accuracy than immunoassays. Here, we introduce a high-throughput method for assessing vitamin D status from blood specimens based on direct infusion-MS/MS (DI-MS/MS) following click derivatization using 2-nitrosopyridine. We developed an optimized liquid-phase extraction protocol to minimize ion suppression when directly infusing serum or plasma extracts via a capillary electrophoresis system for quantitative determination of 25OH-D. Acceptable reproducibility (mean coefficient of variation = 10.9%, n = 412), recovery (mean = 102% at 15, 30, and 45 nmol/l), and linearity (R2 > 0.998) were achieved for 25OH-D with lower detection limits (limit of detection ∼1.2 nmol/l, S/N ∼ 3), greater throughput (∼3 min/sample), and less bias than a commercial chemiluminescence immunoassay prone to batch effects. There was mutual agreement in 25OH-D concentrations from reference blood samples measured by DI-MS/MS as compared with LC-MS/MS (mean bias = 7.8%, n = 18). We also demonstrate that this method could reduce immunoassay misclassification of vitamin D deficiency in a cohort of critically ill children (n = 30). In conclusion, DI-MS/MS offers a viable alternative to LC-MS/MS for assessment of vitamin D status in support of large-scale studies in nutritional epidemiology as well as clinical trials to rapidly screen individual patients who may benefit from vitamin D supplementation.

Needs Assessment Survey Identifying Research Processes Which may be Improved by Automation or Artificial Intelligence: ICU Community Modeling and Artificial Intelligence to Improve Efficiency (ICU-Comma).

BACKGROUND: Critical care research in Canada is conducted primarily in academically-affiliated intensive care units with established research infrastructure, including research coordinators (RCs). Recently, efforts have been made to engage community hospital ICUs in research albeit with barriers. Automation or artificial intelligence (AI) could aid the performance of routine research tasks. It is unclear which research study processes might be improved through AI automation. METHODS: We conducted a cross-sectional survey of Canadian ICU research personnel. The survey contained items characterizing opinions regarding research processes that may be amenable to AI automation. We distributed the questionnaire via email distribution lists of 3 Canadian research societies. Open-ended questions were analyzed using a thematic content analysis approach. RESULTS: A total of 49 survey responses were received (response rate: 8%). Tasks that respondents felt were time-consuming/tedious/tiresome included: screening for potentially eligible patients (74%), inputting data into case report forms (65%), and preparing internal tracking logs (53%). Tasks that respondents felt could be performed by AI automation included: screening for eligible patients (59%), inputting data into case report forms (55%), preparing internal tracking logs (51%), and randomizing patients into studies (45%). Open-ended questions identified enthusiasm for AI automation to improve information accuracy and efficiency while freeing up RCs to perform tasks that require human interaction. This enthusiasm was tempered by the need for proper AI education and oversight. CONCLUSIONS: There were balanced supportive (increased efficiency and re-allocation of tasks) and challenges (informational accuracy and oversight) with regards to AI automation in ICU research.

Consent models in Canadian critical care randomized controlled trials: a scoping review.

PURPOSE: Our primary objective was to describe consent models used in Canadian-led adult and pediatric intensive care unit (ICU/PICU) randomized controlled trials (RCTs). Our secondary objectives were to determine the consent rate of ICU/PICU RCTs that did and did not use an alternate consent model to describe consent procedures. SOURCE: Using scoping review methodology, we searched MEDLINE, Embase, and CENTRAL databases (from 1998 to June 2019) for trials published in English or French. We included Canadian-led RCTs that reported on the effects of an intervention on ICU/PICU patients or their families. Two independent reviewers assessed eligibility, abstracted data, and achieved consensus. PRINCIPAL FINDINGS: We identified 48 RCTs of 17,558 patients. Included RCTs had ethics approval to use prior informed consent (43/48; 90%), deferred consent (13/48; 27%), waived consent (5/48; 10%), and verbal consent (1/48; 2%) models. Fifteen RCTs (15/48; 31%) had ethics approval to use more than one consent model. Twice as many trials used alternate consent between 2010 and 2019 (13/19) than between 2000 and 2009 (6/19). The consent rate for RCTs using only prior informed consent ranged from 54 to 91% (ICU) and 43 to 94% (PICU) and from 78 to 100% (ICU) and 74 to 87% (PICU) in trials using an alternate/hybrid consent model. CONCLUSION: Alternate consent models were used in the minority of Canadian-led ICU/PICU RCTs but have been used more frequently over the last decade. This suggests that Canadian ethics boards and research communities are becoming more accepting of alternate consent models in ICU/PICU trials.

RéSUMé: OBJECTIF: Notre objectif principal était de décrire les modèles de consentement utilisés dans les études randomisées contrôlées (ERC) menées par des chercheurs canadiens dans les unités de soins intensifs adultes et pédiatriques (USI/USIP). Nos objectifs secondaires étaient de déterminer le taux de consentement aux ERC à l'USI et l'USIP qui utilisaient et n'utilisaient pas un autre modèle de consentement pour décrire les processus de consentement. SOURCES: À l'aide d'une méthodologie d'étude de portée, nous avons effectué des recherches dans les bases de données MEDLINE, Embase et CENTRAL (de 1998 à juin 2019) pour en tirer les études publiées en anglais ou en français. Nous avons inclus des ERC dirigées par des chercheurs canadiens qui rapportaient les effets d'une intervention sur les patients à l'USI/USIP ou leurs familles. Deux examinateurs indépendants ont évalué l'admissibilité, résumé les données et atteint un consensus. RéSULTATS PRINCIPAUX: Nous avons identifié 48 ERC portant sur 17 558 patients. Les ERC incluses avaient obtenu l'approbation du comité d'éthique pour l'utilisation de modèles de consentement éclairé préalable (43/48; 90 %), de consentement différé (13/48; 27 %), de renoncement au consentement (5/48; 10 %) et de consentement verbal (1/48; 2 %). Quinze ERC (15/48; 31 %) avaient reçu l'approbation du comité d'éthique pour utiliser plus d'un modèle de consentement. Deux fois plus d'études ont utilisé un autre type de consentement entre 2010 et 2019 (13/19) qu'entre 2000 et 2009 (6/19). Le taux de consentement pour les ERC utilisant uniquement un consentement éclairé préalable variait de 54 à 91 % (USI) et de 43 à 94 % (USIP), contre 78 à 100 % (USI) et 74 à 87 % (USIP) pour les études utilisant un modèle de consentement alternatif/hybride. CONCLUSION: Des modèles de consentement alternatif ont été utilisés dans une minorité des ERC en USI/USIP dirigées par des chercheurs canadiens, mais ils ont été utilisés plus fréquemment au cours de la dernière décennie. Cela donne à penser que les comités d'éthique et les communautés de recherche canadiens acceptent de plus en plus les modèles de consentement alternatifs dans les études réalisées en USI et en USIP.

Operationalization of assent for research participation in pre-adolescent children: a scoping review.

BACKGROUND: Seeking assent from children for participation in medical research is an ethical imperative of numerous institutions globally. However, none of these organizations provide specific guidance on the criteria or process to be used when obtaining assent. The primary objective of this scoping review was to determine the descriptions of assent discussed in the literature and the reported criteria used for seeking assent for research participation in pre-adolescent children. METHODS: Medline and Embase databases were searched until November 2020 using the term "assent" in the title or abstract. Inclusion criteria were (1) studies enrolling children which specifically described operationalization of the assent process and (2) studies of the assent process which provided a description of assent. Data collected included participant information, patient criteria for seeking assent, guidelines referenced, description of assent reported, how assent was obtained and assent information presented, and reported assent rate. For qualitative articles focusing on the assent process, important themes were identified. RESULTS: A total of 116 articles were included of which 79 (68.9%) operationalized assent and 57 studies (%) described the assent process. The most commonly reported criterion used to determine the ability of a child to assent was age (35.4%, 28/79). The reported minimal age for obtaining pediatric assent varied considerably across and within jurisdictions (5-13 years; median 7.5 years, IQR 7.0, 9.75). Cognitive ability was reported as a criterion for obtaining assent in 5.1% (4/79) of studies. Assent rates were only reported in 17.7% (14/79) of citations and ranged from 32.0 to 100%. Analysis of the 57 studies describing the assent process identified several themes, including age thresholds, assessment of capacity, variable knowledge of pediatric assent and parental roles. CONCLUSION: We found significant variation in criteria used for assessment of patient capacity, delivery of information used to obtain assent and documentation of the assent process. While we acknowledge that individual children, settings and jurisdictions may require different approaches to obtaining assent, there should be agreement on important principles to be followed with resulting common guidance on assessing capacity, delivering information and documentation of the assent process for publication.

Evaluating the relationship between citation set size, team size and screening methods used in systematic reviews: a cross-sectional study.

BACKGROUND: Standard practice for conducting systematic reviews (SRs) is time consuming and involves the study team screening hundreds or thousands of citations. As the volume of medical literature grows, the citation set sizes and corresponding screening efforts increase. While larger team size and alternate screening methods have the potential to reduce workload and decrease SR completion times, it is unknown whether investigators adapt team size or methods in response to citation set sizes. Using a cross-sectional design, we sought to understand how citation set size impacts (1) the total number of authors or individuals contributing to screening and (2) screening methods. METHODS: MEDLINE was searched in April 2019 for SRs on any health topic. A total of 1880 unique publications were identified and sorted into five citation set size categories (after deduplication): < 1,000, 1,001-2,500, 2,501-5,000, 5,001-10,000, and > 10,000. A random sample of 259 SRs were selected (~ 50 per category) for data extraction and analysis. RESULTS: With the exception of the pairwise t test comparing the under 1000 and over 10,000 categories (median 5 vs. 6, p = 0.049) no statistically significant relationship was evident between author number and citation set size. While visual inspection was suggestive, statistical testing did not consistently identify a relationship between citation set size and number of screeners (title-abstract, full text) or data extractors. However, logistic regression identified investigators were significantly more likely to deviate from gold-standard screening methods (i.e. independent duplicate screening) with larger citation sets. For every doubling of citation size, the odds of using gold-standard screening decreased by 15 and 20% at title-abstract and full text review, respectively. Finally, few SRs reported using crowdsourcing (n = 2) or computer-assisted screening (n = 1). CONCLUSIONS: Large citation set sizes present a challenge to SR teams, especially when faced with time-sensitive health policy questions. Our study suggests that with increasing citation set size, authors are less likely to adhere to gold-standard screening methods. It is possible that adjunct screening methods, such as crowdsourcing (large team) and computer-assisted technologies, may provide a viable solution for authors to complete their SRs in a timely manner.

Patient-reported Outcome Measures in Pediatric Non-Malignant Hematology: A Systematic Review.

Patient-reported outcome measures (PROMs) are questionnaires completed by patients or caregivers without influence by health care professionals. As such, PROMs show subjective health experiences, enhance the clinical information available to providers, and inform clinical action. The objective of this systematic review is to identify and list which validated PROMs have been used to monitor health-related quality of life in pediatric patients with nonmalignant hematology (hemophilia, immune thrombocytopenia, sickle cell disease, and thalassemia). Databases (MEDLINE, Embase, HaPI, CINAHL, and PsycTESTS) were searched to identify publications that validated or used PROMs as an outcome measure in the 4 disease groups. Overall, 209 articles met the inclusion criteria, identifying 113 PROMs. Of the 113 identified PROMs, 95 are generic and can be used in multiple disease groups. The Pediatric Quality of Life Generic Core Scales was the most frequently used generic PROM (68 studies). The 18 remaining PROMs were disease specific. The results of this review, together with the COSMIN tool for selecting outcome measures, will allow clinicians to evaluate the PROMs that are best suited to their patient population. In addition, the focus groups are currently being conducted with patients, parents, and clinicians to determine the optimal use of PROMs in the clinical environment.

Factors Impacting Physician Recommendation for Tracheostomy Placement in Pediatric Prolonged Mechanical Ventilation: A Cross-Sectional Survey on Stated Practice.

OBJECTIVES: To characterize the stated practices of qualified Canadian physicians toward tracheostomy for pediatric prolonged mechanical ventilation and whether subspecialty and comorbid conditions impact attitudes toward tracheostomy. DESIGN: Cross sectional web-based survey. SUBJECTS: Pediatric intensivists, neonatologists, respirologists, and otolaryngology-head and neck surgeons practicing at 16 tertiary academic Canadian pediatric hospitals. INTERVENTIONS: Respondents answered a survey based on three cases (Case 1: neonate with bronchopulmonary dysplasia; Cases 2 and 3: children 1 and 10 years old with pediatric acute respiratory distress syndrome, respectively) including a series of alterations in relevant clinical variables. MEASUREMENTS AND MAIN RESULTS: We compared respondents' likelihood of recommending tracheostomy at 3 weeks of mechanical ventilation and evaluated the effects of various clinical changes on physician willingness to recommend tracheostomy and their impact on preferred timing (≤ 3 wk or > 3 wk of mechanical ventilation). Response rate was 165 of 396 (42%). Of those respondents who indicated they had the expertise, 47 of 121 (38.8%), 23 of 93 (24.7%), and 40 of 87 (46.0%) would recommend tracheostomy at less than or equal to 3 weeks of mechanical ventilation for cases 1, 2, and 3, respectively (p < 0.05 Case 2 vs 3). Upper airway obstruction was associated with increased willingness to recommend earlier tracheostomy. Life-limiting condition, severe neurologic injury, unrepaired congenital heart disease, multiple organ system failure, and noninvasive ventilation were associated with a decreased willingness to recommend tracheostomy. CONCLUSION: This survey provides insight in to the stated practice patterns of Canadian physicians who care for children requiring prolonged mechanical ventilation. Physicians remain reluctant to recommend tracheostomy for children requiring prolonged mechanical ventilation due to lung disease alone at 3 weeks of mechanical ventilation. Prospective studies characterizing actual physician practice toward tracheostomy for pediatric prolonged mechanical ventilation and evaluating the impact of tracheostomy timing on clinically important outcomes are needed as the next step toward harmonizing care delivery for such patients.

Calcitriol trend following pediatric cardiac surgery and association with clinical outcome.

BACKGROUND: Consistent with accepted practice in stable ambulatory populations, the majority of ICU research has evaluated vitamin D status using a single blood 25-hydroxyvitamin D (25(OH)D) level. Only a limited number of ICU studies have measured the active hormone, 1,25-dihydroxyvitamin D (calcitriol) and none have used change in calcitriol levels to evaluate axis functioning. The objective of this study was to describe the impact of Congenital Heart Disease (CHD) surgery on calcitriol levels and evaluate the relationship between change in postoperative levels and clinical course. METHODS: Secondary analysis of a prospective cohort study of 56 children undergoing surgery for CHD. RESULTS: Mean calcitriol levels dropped from 122.3 ± 69.1 pmol/L preoperatively to 65.3 ± 36.5 pmol/L (p < 0.0001) at PICU admission. The majority (61%, n = 34) were unable to increase calcitriol levels in the 48 h immediately following surgery. Post operative trend in calcitriol was inversely related to cardiovascular dysfunction, fluid requirements, ventilatory support and PICU length of stay (p < 0.01). CONCLUSION: CHD patients had significant dysfunction of the vitamin D axis immediately postoperatively, demonstrated by both a significant intraoperative decline in calcitriol and inability to increase levels. Interventional research will be required to determine whether the use of calcitriol, in addition to cholecalciferol, reduces postoperative illness severity.

Beyond Survival: Pediatric Critical Care Interventional Trial Outcome Measure Preferences of Families and Healthcare Professionals.

OBJECTIVES: To identify, in addition to survival, preferred outcome measures of PICU family care providers and PICU healthcare professionals for interventional trials enrolling critically ill children, and to describe general attitudes of family care providers and healthcare professionals regarding research in the PICU. DESIGN: Cross-sectional survey examining subject experience with clinical research and personal preferences for outcome measures for a hypothetical interventional clinical trial. SETTING: PICUs within four academic children's hospitals in the United States and Canada. SUBJECTS: Two cohorts including family members of critically ill children in PICUs (family care providers) and multidisciplinary staff working in the PICUs (healthcare professionals). INTERVENTIONS: Administration of a short, deidentified survey. MEASUREMENTS: Demographic data were collated for the two subject groups. Participants were queried regarding their attitudes related to research conducted in the PICU. In addition to survival, each group was asked to identify their three most important outcomes for an investigation examining whether or not an intervention helps seriously ill children recover. MAIN RESULTS: Demographics for family care providers (n = 40) and healthcare professionals (n = 53) were similarly distributed. Female respondents (79.8%) predominated. Participants (98.9%) ascertained the importance of conducting research in the PICU, but significant challenges associated with this goal in the high stress PICU environment. Both quality of life and functioning after leaving the hospital were chosen as the most preferred outcome measure, with 77.5% of family care providers and 84.9% of healthcare professionals indicating this choice. Duration of organ dysfunction was identified by 70.0% of family care providers and 40.7% of healthcare professionals as the second most preferred outcome measure. CONCLUSIONS: In addition to survival, long-term quality of life/functional status and duration of organ dysfunction represent important interventional trial outcome measures for both families of critically ill children, as well as the multidisciplinary team who provides critical care.

Vitamin D deficiency in critically ill children: a systematic review and meta-analysis.

BACKGROUND: Vitamin D deficiency (VDD) has been hypothesized not only to be common but also to represent a potentially modifiable risk factor for greater illness severity and clinical outcome during critical illness. The objective of this systematic review was to determine the frequency of VDD in pediatric critical illness and its association with clinical outcomes. METHODS: MEDLINE, Embase, and CENTRAL were searched through December 12, 2016, with no date or language restrictions. The primary objective was to estimate the prevalence of VDD in the pediatric intensive care unit (PICU) and compare vitamin D status with healthy control populations. Secondary objectives were to evaluate whether VDD is associated with mortality, increased illness severity, PICU interventions, and patient clinical course. Random effects meta-analysis was used to calculate pooled VDD event rate, compare levels with those of control subjects, and evaluate for associations between VDD and clinical outcome. RESULTS: Among 2700 citations, 17 studies meeting study eligibility were identified. The studies reported a total of 2783 critically ill children and had a median sample size of 120 (range 12-511). The majority of studies used a 25-hydroxyvitamin D [25(OH)D] level less than 50 nmol/L to define VDD, and the pooled VDD prevalence was 54.8 (95% CI 45.4-63.9). Average 25(OH)D levels were significantly lower in PICU patients than in healthy control subjects (pooled difference -17.3 nmol/L, 95% CI -14.0 to -20.6). In a meta-analysis calculation, we found that VDD was associated with increased mortality (OR 1.62, 95% CI 1.11-2.36), illness severity, and need for PICU interventions. CONCLUSIONS: Approximately 50% of critically ill children have VDD at the time of PICU admission, defined as a blood total 25(OH)D concentration under 50 nmol/L. VDD was further determined to be associated with greater illness severity, multiple organ dysfunction, and mortality in the PICU setting. Clinical trials are required to determine if optimization of vitamin D status improves patient outcome. TRIAL REGISTRATION: PROSPERO, CRD42016026617 . Registered on 11 January 2016.

Primary Outcome Measures in Pediatric Septic Shock Trials: A Systematic Review.

OBJECTIVE: To evaluate all published pediatric randomized controlled trials of patients with septic shock from any cause to examine the outcome measures used, the strengths and limitations of these measurements and whether the trial outcomes met feasibility criteria. DATA SOURCES: We used a previously published database of pediatric critical care randomized controlled trials (PICUtrials.net) derived from searches of MEDLINE, EMBASE, LILACS, and CENTRAL. STUDY SELECTION: We included randomized controlled trials of interventions to children admitted to a PICU with septic or dengue hemorrhagic shock which were published in English. DATA EXTRACTION: Study characteristics and outcomes were retrieved by two independent reviewers with disagreement being resolved by a third reviewer. We defined feasibility as 1) recruitment of at least 90% of the targeted sample size and agreement of the observed outcome rate in the control group with the rate used for the sample size calculation to within 10% or 2) finding of a statistically significant difference in an interim or final analysis. DATA SYNTHESIS: Nineteen of 321 identified articles were selected for review. Fourteen of 19 studies (74%) provided an a priori definition of their primary outcome measure in their "Methods section." Mortality rate was the most commonly reported primary outcome (8/14; 57%), followed by duration of shock (4/14; 29%) followed by organ failure (1/14; 7%). Only three of 19 included trials met feasibility criteria. CONCLUSIONS: Our review found that use of mortality alone as a primary outcome in pediatric septic shock trials was associated with significant limitations and that long-term patient-centered outcomes were not used in this setting. Composite outcomes incorporating mortality and long-term outcomes should be explored for use in future pediatric septic shock trials.

Efficacy of high-dose vitamin D in pediatric asthma: a systematic review and meta-analysis.

CONTEXT: Observational studies have suggested a relationship between vitamin D status and asthma-related respiratory outcomes. The benefit of vitamin D supplementation for pulmonary function, symptoms and exacerbations is not well established. OBJECTIVE: To systematically review paediatric clinical trials investigating the role of vitamin D on asthma-related respiratory outcomes. DATA SOURCES: MEDLINE, EMBASE and CENTRAL were searched until January 2014. No date or language restrictions. STUDY SELECTION: Clinical trials reporting asthma-related respiratory outcomes following vitamin D administration at a dose equal or greater than 500 IU per day were included and reviewed independently by two authors for full systematic review eligibility. DATA EXTRACTION: Two reviewers independently extracted and verified pre-defined data fields. RESULTS: We identified five studies that met study eligibility and assessed final data synthesis. The median trial size was 48 participants (range 17-430) and the average daily dose of cholecalciferol ranged from 500 to 2000 IU/day. Overall study methodological quality was high, but some heterogeneity in population and vitamin D dosing regimen was evident. Meta-analysis suggested a statistically significant reduction (RR 0.41, CI 0.27-0.63) in asthma exacerbation with vitamin D therapy. LIMITATIONS: Due to variability in outcome selection and missing data, it was not possible to perform meta-analysis for pulmonary function testing and asthma symptom scores. Vitamin D-related adverse events were not considered in four of five papers. CONCLUSIONS: Available evidence from this systematic review suggests that high dose vitamin D may prevent asthma exacerbation. This should be confirmed through larger well-designed randomised controlled trials.