Creating enriched training sets of eligible studies for large systematic reviews: the utility of PubMed's Best Match algorithm.

INTRODUCTION: Solutions like crowd screening and machine learning can assist systematic reviewers with heavy screening burdens but require training sets containing a mix of eligible and ineligible studies. This study explores using PubMed's Best Match algorithm to create small training sets containing at least five relevant studies. METHODS: Six systematic reviews were examined retrospectively. MEDLINE searches were converted and run in PubMed. The ranking of included studies was studied under both Best Match and Most Recent sort conditions. RESULTS: Retrieval sizes for the systematic reviews ranged from 151 to 5,406 records and the numbers of relevant records ranged from 8 to 763. The median ranking of relevant records was higher in Best Match for all six reviews, when compared with Most Recent sort. Best Match placed a total of thirty relevant records in the first fifty, at least one for each systematic review. Most Recent sorting placed only ten relevant records in the first fifty. Best Match sorting outperformed Most Recent in all cases and placed five or more relevant records in the first fifty in three of six cases. DISCUSSION: Using a predetermined set size such as fifty may not provide enough true positives for an effective systematic review training set. However, screening PubMed records ranked by Best Match and continuing until the desired number of true positives are identified is efficient and effective. CONCLUSIONS: The Best Match sort in PubMed improves the ranking and increases the proportion of relevant records in the first fifty records relative to sorting by recency.

Parental Understanding of Research Consent Forms in the PICU: A Pilot Study.

OBJECTIVES: To describe legal guardians' understanding of key concepts in a research consent form presented within 24 hours of their child's admission to the PICU and to explore legal guardians' opinions of the format (language, length) of the consent form and the overall consent process. DESIGN: Single-center, exploratory pilot study. SETTING: PICU at a tertiary-care hospital in Canada. SUBJECTS: Forty-one English- and French-speaking legal guardians of children less than 18 years old, who had been admitted to the PICU within the past 24 hours and were expected to stay at least 48 hours, between October 2018 and February 2019. INTERVENTIONS: The consent form from a previous PICU trial was given and explained to legal guardians within 24 hours of their child's admission to the PICU. MEASUREMENTS AND MAIN RESULTS: Legal guardians' understanding of key concepts in the consent form was evaluated using a questionnaire the day after the form was explained, and opinions were collected verbally and using an additional survey. The median number of questions answered incorrectly was three of seven (interquartile range = 2-4). Participants best understood the topic of the study (5% incorrect), but 80% of participants were unable to recall a single risk. The median rating of the language in the form was five of five (very easy to understand; interquartile range = 4-5), and 88% of participants said it was a reasonable length. CONCLUSIONS: Despite positive opinions of the consent form, most legal guardians did not understand all key components of the consent information provided to them orally and in writing within 24 hours of their child's PICU admission. Future studies are required to determine barriers to understanding and explore alternative approaches to obtaining consent in this setting.

Ability to Assent in Pediatric Critical Care Research: A Prospective Environmental Scan of Two Canadian PICUs.

OBJECTIVES: To determine the number of patients considered not appropriate to approach for assent within the first 24 hours of PICU admission. DESIGN: Exploratory prospective 1-month environmental scan. SETTING: Two tertiary Canadian PICUs. PATIENTS: Ninety patients age newborn to 17 years old admitted to the PICU during September 2016 (Site 1) or May 2017 (Site 2). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At PICU admission, 81% of patients were deemed not appropriate to approach for assent most commonly due to age, influence of psychotropic medications, and/or mechanical ventilation. At PICU discharge, 74% of patients were considered not appropriate to approach, most commonly due to age and/or developmental delay. There was moderate to good agreement between the research team and care team assessments of appropriateness for assent. Only 8% of patients considered not approachable at admission become appropriate to approach for assent by PICU discharge. CONCLUSIONS: Very few patients were considered approachable for assent during the first 24 hours of PICU admission. Those who were considered appropriate to approach were less ill, spent less time in PICU, and were unlikely to be considered for enrollment in pediatric critical care research.

Random serum free cortisol and total cortisol measurements in pediatric septic shock.

Background The aim of the study was to examine the relationship between serum total cortisol (TC) and free cortisol (FC) levels in children with septic shock and the relationship of these levels with baseline illness severity. Methods A sub-study of a randomized controlled trial (RCT) of hydrocortisone vs. placebo in pediatric septic shock conducted in seven academic pediatric intensive care units (PICUs) in Canada on children aged newborn to 17 years. Thirty children with septic shock had serum sent for TC and FC measurement within 6 h of meeting the study eligibility criteria. Results Baseline FC and TC levels were strongly correlated with baseline Pediatric Risk of Mortality (PRISM) score (R2=0.759, p<0.001; R2=0.717, p<0.001) and moderately correlated with admission Vasotropic Inotropic Score (VIS) (R2=0.489, p<0.001; R2=0.316, p<0.001). Serum TC levels were highly correlated with FC levels (R2=0.92, p<0.001) and showed strong agreement (R2=0.98, p<0.001 on a Bland-Altman plot). The ratio of FC to TC moderately correlated with TC levels (R2=0.46, p<0.001) but did not correlate with baseline albumin levels (R2=0.19, p=0.13). Conclusions Random TC and FC levels are strongly correlated, show strong agreement and are reflective of illness severity in children with septic shock. As such, isolated FC measurement does not appear to provide added information relative to TC in acutely ill children with septic shock.

Study protocol for a phase II dose evaluation randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study).

BACKGROUND: Clinical research has recently demonstrated that vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (PICU) and associated with worse clinical course. Multiple adult ICU trials have suggested that optimization of vitamin D status through high-dose supplementation may reduce mortality and improve other clinically relevant outcomes; however, there have been no trials of rapid normalization in the PICU setting. The objective of this study is to evaluate the safety and efficacy of an enteral weight-based cholecalciferol loading dose regimen in critically ill children with VDD. METHODS/DESIGN: The VITdAL-PICU pilot study is designed as a multicenter placebo-controlled phase II dose evaluation pilot randomized controlled trial. We aim to randomize 67 VDD critically ill children using a 2:1 randomization schema to receive loading dose enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or a placebo solution. Participants, caregivers and outcome assessors will be blinded to allocation. Eligibility criteria include ICU patient, aged 37 weeks to 18 years, expected ICU length of stay more than 48 h, anticipated access to bloodwork at 7 days, and VDD (blood total 25 hydroxyvitamin D < 50 nmol/L). The primary objective is to determine whether the dosing protocol normalizes vitamin D status, defined as a blood total 25(OH)D concentration above 75 nmol/L. Secondary objectives include an examination of the safety of the dosing regimen (e.g. hypercalcemia, hypercalciuria, nephrocalcinosis), measures of vitamin D axis function (e.g. calcitriol levels, immune function), and protocol feasibility (eligibility criteria, protocol deviations, blinding). DISCUSSION: Despite significant observational literature suggesting VDD to be a modifiable risk factor in the PICU setting, there is no robust clinical trial evidence evaluating the benefits of rapid normalization. This phase II clinical trial will evaluate an innovative weight-based dosing regimen intended to rapidly and safely normalize vitamin D levels in critically ill children. Study findings will be used to inform the design of a multicenter phase III trial evaluating the clinical and economic benefits to rapid normalization. Recruitment for this trial was initiated in January 2016 and is expected to continue until November 30, 2017. TRIAL REGISTRATION: Clinicaltrials.gov NCT02452762.

The Relationship Between Remoteness and Outcomes in Critically Ill Children.

OBJECTIVE: A significant number of children live in remote geographic areas without direct access to tertiary care PICU. Our objective was to explore the relationship between remoteness and outcomes of critically ill children in Canada. DESIGN: Retrospective cohort study of patients admitted to the PICU from February 1, 2015, to January 31, 2016. SETTING: Pediatric tertiary care PICU in Canada. PATIENTS: All children admitted to PICU during the study period. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS:: Four hundred fifty-five unique PICU admissions were included. One hundred sixty-nine patients were transported from another center of whom 28 lived in remote areas. For transported patients, remoteness (hazard ratio, 2.76, p < 0.001; hazard ratio, 2.22, p = 0.006), admission Pediatric Risk of Mortality (hazard ratio, 1.11; p = 0.001; hazard ratio, 1.05, p = 0.016), and transport by a noncritical care trained team (hazard ratio, 0.61, p = 0.021; hazard ratio, 0.66, p = 0.045) were associated with increased PICU and hospital lengths of stay, respectively. PICU mortality increased with duration of transport (odds ratio, 1.46; 95% CI, 1.09-1.97; p = 0.012). The odds of a remote-area patient being refused admission during the winter were significantly higher (odds ratio, 8.2; 95% CI, 3.0-22.3; p < 0.001) than a patient not requiring transport. Admission Pediatric Risk of Mortality score (4, interquartile range, 1-8 vs 2, interquartile range, 0-5; p = 0.001) and mortality rate (7.1%, 12/169 vs 0%, 0/286; p < 0.001) were significantly higher for transported than for nontransported patients. CONCLUSIONS: Remoteness was associated with increased PICU and hospital length of stay, and duration of transport was associated with higher admission Pediatric Risk of Mortality (PRISM) scores and mortality rates. Patients requiring transport had a significantly higher PICU mortality rate than those presenting directly to a tertiary care center. Further studies are needed to explore potential policy and healthcare resource implications of these findings.

Comparison of Consent Models in a Randomized Trial of Corticosteroids in Pediatric Septic Shock.

OBJECTIVES: To describe the use of deferred and prior informed consent models in the context of a low additional risk to standard of care, placebo-controlled randomized controlled trial of corticosteroids in pediatric septic shock. DESIGN: An observational substudy of consent processes in a randomized controlled trial of hydrocortisone versus placebo. SETTING: Seven tertiary level PICUs in Canada. PATIENTS: Children newborn to 17 years inclusive admitted to PICU with suspected septic shock between July 2014 and March 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Information on the number of families approached, consent rates obtained, and spontaneously volunteered reasons for nonparticipation were collected for both deferred and informed consent. The research ethics board of five of seven centers approved a deferred consent model; however, implementation criteria for use of this model varied across sites. The consent rate using deferred versus prior informed consent was significantly higher (83%; 35/42 vs 58%; 15/26; p = 0.02). The mean times from meeting inclusion criteria to randomization (1.8 ± 1.8 vs 3.6 ± 2.1 hr; p = 0.007) and study drug administration (3.4 ± 2.7 hr vs 4.8 ± 2.1 hr; p = 0.05) were significantly shorter with the use of deferred consent versus prior informed consent. No family member or research ethics board expressed concern following use of deferred consent. CONCLUSIONS: Deferred consent was acceptable in time-sensitive critical care research to most research ethics boards, families, and healthcare providers and resulted in higher consent rates and more efficient recruitment. Larger studies on deferred consent and consistency interpreting jurisdictional guidelines are needed to advance pediatric acute care.

A Randomized Controlled Trial of Corticosteroids in Pediatric Septic Shock: A Pilot Feasibility Study.

OBJECTIVE: To determine the feasibility of conducting a randomized controlled trial of corticosteroids in pediatric septic shock. DESIGN: Randomized, double-blind, placebo controlled trial. SETTING: Seven tertiary level PICUs in Canada. PATIENTS: Children newborn to 17 years old inclusive with suspected septic shock. INTERVENTION: Administration of IV hydrocortisone versus placebo until hemodynamic stability is achieved or for a maximum of 7 days. MEASUREMENTS AND MAIN RESULTS: One hundred seventy-four patients were potentially eligible of whom 101 patients met eligibility criteria. Fifty-seven patients were randomized, and 49 patients (23 and 26 patients in the hydrocortisone and placebo groups, respectively) were included in the final analysis. The mean time from screening to randomization was 2.4 ± 2.1 hours and from screening to first dose of study drug was 3.8 ± 2.6 hours. Forty-two percent of potentially eligible patients (73/174) received corticosteroids prior to randomization: 38.5% (67/174) were already on corticosteroids for shock at the time of screening, and in 3.4% (6/174), the treating physician wished to administer corticosteroids. Six of 49 randomized patients (12.2%) received open-label steroids, three in each of the hydrocortisone and placebo groups. Time on vasopressors, days on mechanical ventilation, PICU and hospital length of stay, and the rate of adverse events were not statistically different between the two groups. CONCLUSIONS: This study suggests that a large randomized controlled trial on early use of corticosteroids in pediatric septic shock is potentially feasible. However, the frequent use of empiric corticosteroids in otherwise eligible patients remains a significant challenge. Knowledge translation activities, targeted recruitment, and alternative study designs are possible strategies to mitigate this challenge.

Steroids in fluid and/or vasoactive infusion dependent pediatric shock: study protocol for a randomized controlled trial.

BACKGROUND: Physicians often administer corticosteroids for the treatment of fluid and vasoactive infusion dependent pediatric shock. This use of corticosteroids is controversial, however, and has never been studied in a pediatric randomized controlled trial (RCT). This pilot trial will determine the feasibility of a larger RCT on the role of corticosteroids in pediatric shock. METHODS/DESIGN: Steroids in Fluid and/or Vasoactive Infusion Dependent Pediatric Shock (STRIPES) is a pragmatic, seven-center, double-blind, pilot RCT. We aim to randomize 72 pediatric patients with fluid and vasoactive infusion dependent shock to receive either hydrocortisone or a saline placebo for 7 days or until clinical stability, whichever occurs first. The primary outcome of this pilot trial is the feasibility of recruitment, defined as the number of patients enrolled over a 1-year period. Secondary outcomes include the frequency of, and reasons for, open-label steroid use, protocol adherence, incidence of mortality and corticosteroid-associated adverse events, time to discontinuation of inotropes, and feasibility of blood sampling. DISCUSSION: Corticosteroids are used for the treatment of pediatric shock without sufficient evidence to support this practice. While there is a scientific rationale and limited data supporting their use in this setting, there is also evidence from other populations suggesting potential harm. The STRIPES pilot study will assess the feasibility of a larger, much needed trial powered for clinically important outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02044159.

Heat exposure increases circulating fatty acids but not lipid oxidation at rest and during exercise.

Alterations in lipid oxidation during exercise have been well studied, but limited data exists on the effects of passive heat exposure and exercise in the heat on changes in lipid oxidation. This study was designed to examine: (1) the effects of heat exposure on lipid metabolism during passive heating and subsequent exercise in the heat by focusing on changes in whole-body lipid oxidation and plasma lipid concentrations, and (2) the effects of extended passive pre-heating on exercise performance in the heat. Male participants (n=8) were passively heated for 120 min at 42 °C, then exercised on a treadmill in the same temperature at 50% V̇O2 max for 30 min (HEAT). This same procedure was followed on a separate occasion at 23 °C (CON). Results showed that lipid oxidation rates were not different between HEAT and CON during passive heating or exercise. However, non-esterified fatty acid (NEFA) concentrations were significantly higher following passive heating (618 µM, 95% CI: 479-757) compared to CON (391 µM, 95% CI: 270-511). The same trend was observed following exercise (2036 µM, 95% CI: 1604-2469 for HEAT and 1351 µM, 95% CI: 1002-1699). Triacylglycerol, phospholipid and cholesterol levels were not different between HEAT and CON at any point. Four of 8 participants could not complete 30 min of exercise in HEAT, resulting in a 14% decline in total external work. Rate of perceived exertion over the final 5 min of exercise was higher in HEAT (9.5) than CON (5). We conclude that: (1) heat exposure results in increased circulating NEFA at rest and during exercise without changes in whole-body lipid utilization, and (2) passive pre-heating reduces work capacity during exercise in the heat and increases the perceived intensity of a given workload.