Endocrine Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference

CONTEXT Endocrine dysfunction is common in critically ill children and is manifested by abnormalities in glucose, thyroid hormone, and cortisol metabolism. OBJECTIVE To develop consensus criteria for endocrine dysfunction in critically ill children by assessing the association of various biomarkers with clinical and functional outcomes. DATA SOURCES PubMed and Embase were searched from January 1992 to January 2020. STUDY SELECTION We included studies in which researchers evaluated critically ill children with abnormalities in glucose homeostasis, thyroid function and adrenal function, performance characteristics of assessment and/or scoring tools to screen for endocrine dysfunction, and outcomes related to mortality, organ-specific status, and patient-centered outcomes. Studies of adults, premature infants or animals, reviews and/or commentaries, case series with sample size ≤10, and non-English-language studies were excluded. DATA EXTRACTION Data extraction and risk-of-bias assessment for each eligible study were performed by 2 independent reviewers. RESULTS The systematic review supports the following criteria for abnormal glucose homeostasis (blood glucose [BG] concentrations >150 mg/dL [>8.3 mmol/L] and BG concentrations <50 mg/dL [<2.8 mmol/L]), abnormal thyroid function (serum total thyroxine [T4] <4.2 μg/dL [<54 nmol/L]), and abnormal adrenal function (peak serum cortisol concentration <18 μg/dL [500 nmol/L]) and/or an increment in serum cortisol concentration of <9 μg/dL (250 nmol/L) after adrenocorticotropic hormone stimulation. LIMITATIONS These included variable sampling for BG measurements, limited reporting of free T4 levels, and inconsistent interpretation of adrenal axis testing. CONCLUSIONS We present consensus criteria for endocrine dysfunction in critically ill children that include specific measures of BG, T4, and adrenal axis testing

Tight Glycemic Control After Pediatric Cardiac Surgery in High-Risk Patient Populations

Background—Our previous randomized, clinical trial showed that postoperative tight glycemic control (TGC) for children undergoing cardiac surgery did not reduce the rate of health care–associated infections compared with standard care (STD). Heterogeneity of treatment effect may exist within this population. Methods and Results—We performed a post hoc exploratory analysis of 980 children from birth to 36 months of age at the time of cardiac surgery who were randomized to postoperative TGC or STD in the intensive care unit. Significant interactions were observed between treatment group and both neonate (age ≤30 days; P=0.03) and intraoperative glucocorticoid exposure (P=0.03) on the risk of infection. The rate and incidence of infections in subjects ≤60 days old were significantly increased in the TGC compared with the STD group (rate: 13.5 versus 3.7 infections per 1000 cardiac intensive care unit days, P=0.01; incidence: 13% versus 4%, P=0.02), whereas infections among those \u3e60 days of age were significantly reduced in the TGC compared with the STD group (rate: 5.0 versus 14.1 infections per 1000 cardiac intensive care unit days, P=0.02; incidence: 2% versus 5%, P=0.03); the interaction of treatment group by age subgroup was highly significant (P=0.001). Multivariable logistic regression controlling for the main effects revealed that previous cardiac surgery, chromosomal anomaly, and delayed sternal closure were independently associated with increased risk of infection. Conclusions—This exploratory analysis demonstrated that TGC may lower the risk of infection in children \u3e60 days of age at the time of cardiac surgery compared with children receiving STD. Meta-analyses of past and ongoing clinical trials are necessary to confirm these findings before clinical practice is altered

Design and Rationale of Safe Pediatric Euglycemia After Cardiac Surgery (SPECS): A Randomized Controlled Trial of Tight Glycemic Control After Pediatric Cardiac Surgery

Objectives: To describe the design of a clinical trial testing the hypothesis that children randomized to tight glycemic control with intensive insulin therapy after cardiac surgery will have improved clinical outcomes compared to children randomized to conventional blood glucose management. Design: Two-center, randomized controlled trial. Setting: Cardiac ICUs at two large academic pediatric centers. Patients: Children from birth to those aged 36 months recovering in the cardiac ICU after surgery with cardiopulmonary bypass. Interventions: Subjects in the tight glycemic control (intervention) group receive an intravenous insulin infusion titrated to achieve normoglycemia (target blood glucose range of 80–110 mg/dL; 4.4–6.1 mmol/L). The intervention begins at admission to the cardiac ICU from the operating room and terminates when the patient is ready for discharge from the ICU. Continuous glucose monitoring is performed during insulin infusion to minimize the risks of hypoglycemia. The standard care group has no target blood glucose range. Measurements and Main Results: The primary outcome is the development of any nosocomial infection (bloodstream, urinary tract, and surgical site infection or nosocomial pneumonia). Secondary outcomes include mortality, measures of cardiorespiratory function and recovery, laboratory indices of nutritional balance, immunologic, endocrinologic, and neurologic function, cardiac ICU and hospital length of stay, and neurodevelopmental outcome at 1 and 3 yrs of age. A total of 980 subjects will be enrolled (490 in each treatment arm) for sufficient power to show a 50% reduction in the prevalence of the primary outcome. Conclusions: Pediatric cardiac surgery patients may recognize great benefit from tight glycemic control in the postoperative period, particularly with regard to reduction of nosocomial infections. The Safe Pediatric Euglycemia after Cardiac Surgery trial is designed to provide an unbiased answer to the question of whether this therapy is indeed beneficial and to define the associated risks of therapy

The correlation and level of agreement between end-tidal and blood gas pCO2 in children with respiratory distress: a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>To investigate the correlation and level of agreement between end-tidal carbon dioxide (EtCO₂) and blood gas pCO₂in non-intubated children with moderate to severe respiratory distress.</p> <p>Methods</p> <p>Retrospective study of patients admitted to an intermediate care unit (InCU) at a tertiary care center over a 20-month period with moderate to severe respiratory distress secondary to asthma, bronchiolitis, or pneumonia. Patients with venous pCO₂(vpCO₂) and EtCO₂measurements within 10 minutes of each other were eligible for inclusion. Patients with cardiac disease, chronic pulmonary disease, poor tissue perfusion, or metabolic abnormalities were excluded.</p> <p>Results</p> <p>Eighty EtCO₂-vpCO₂paired values were available from 62 patients. The mean ± <smcaps>SD</smcaps> for EtCO₂and vpCO₂was 35.7 ± 10.1 mmHg and 39.4 ± 10.9 mmHg respectively. EtCO₂and vpCO₂values were highly correlated (r = 0.90, p < 0.0001). The correlations for asthma, bronchiolitis and pneumonia were 0.74 (p < 0.0001), 0.83 (p = 0.0002) and 0.98 (p < 0.0001) respectively. The mean bias ± <smcaps>SD</smcaps> between EtCO₂and vpCO₂was -3.68 ± 4.70 mmHg. The 95% level of agreement ranged from -12.88 to +5.53 mmHg. EtCO₂was found to be more accurate when vpCO₂was 35 mmHg or lower.</p> <p>Conclusion</p> <p>EtCO₂is correlated highly with vpCO₂in non-intubated pediatric patients with moderate to severe respiratory distress across respiratory illnesses. Although the level of agreement between the two methods precludes the overall replacement of blood gas evaluation, EtCO₂monitoring remains a useful, continuous, non-invasive measure in the management of non-intubated children with moderate to severe respiratory distress.</p

Summary statistics in auditory perception

Sensory signals are transduced at high resolution, but their structure must be stored in a more compact format. Here we provide evidence that the auditory system summarizes the temporal details of sounds using time-averaged statistics. We measured discrimination of 'sound textures' that were characterized by particular statistical properties, as normally result from the superposition of many acoustic features in auditory scenes. When listeners discriminated examples of different textures, performance improved with excerpt duration. In contrast, when listeners discriminated different examples of the same texture, performance declined with duration, a paradoxical result given that the information available for discrimination grows with duration. These results indicate that once these sounds are of moderate length, the brain's representation is limited to time-averaged statistics, which, for different examples of the same texture, converge to the same values with increasing duration. Such statistical representations produce good categorical discrimination, but limit the ability to discern temporal detail.Howard Hughes Medical Institut

A 2 × 2 factorial, randomised, open-label trial to determine the clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care over 52 weeks in adults with bronchiectasis:a protocol for the CLEAR clinical trial

Background: Current guidelines for the management of bronchiectasis (BE) highlight the lack of evidence to recommend mucoactive agents, such as hypertonic saline (HTS) and carbocisteine, to aid sputum removal as part of standard care. We hypothesise that mucoactive agents (HTS or carbocisteine, or a combination) are effective in reducing exacerbations over a 52-week period, compared to usual care. Methods: This is a 52-week, 2 × 2 factorial, randomized, open-label trial to determine the clinical effectiveness and cost effectiveness of HTS 6% and carbocisteine for airway clearance versus usual care-the Clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care (CLEAR) trial. Patients will be randomised to (1) standard care and twice-daily nebulised HTS (6%), (2) standard care and carbocisteine (750 mg three times per day until visit 3, reducing to 750 mg twice per day), (3) standard care and combination of twice-daily nebulised HTS and carbocisteine, or (4) standard care. The primary outcome is the mean number of exacerbations over 52 weeks. Key inclusion criteria are as follows: Adults with a diagnosis of BE on computed tomography, BE as the primary respiratory diagnosis, and two or more pulmonary exacerbations in the last year requiring antibiotics and production of daily sputum. Discussion: This trial's pragmatic research design avoids the significant costs associated with double-blind trials whilst optimising rigour in other areas of trial delivery. The CLEAR trial will provide evidence as to whether HTS, carbocisteine or both are effective and cost effective for patients with BE. Trial registration: EudraCT number: 2017-000664-14 (first entered in the database on 20 October 2017). ISRCTN.com, ISRCTN89040295. Registered on 6 July/2018. Funder: National Institute for Health Research, Health Technology Assessment Programme (15/100/01). Sponsor: Belfast Health and Social Care Trust. Ethics Reference Number: 17/NE/0339. Protocol version: V3.0 Final_14052018

A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings

BackgroundA composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data.MethodsWe assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low-glucose and low-glucose hypoglycemia; very high-glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation.ResultsThe analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals.ConclusionThe GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments

Mapping child growth failure across low- and middle-income countries

Child growth failure (CGF), manifested as stunting, wasting, and underweight, is associated with high 5 mortality and increased risks of cognitive, physical, and metabolic impairments. Children in low- and middle-income countries (LMICs) face the highest levels of CGF globally. Here we illustrate national and subnational variation of under-5 CGF indicators across LMICs, providing 2000–2017 annual estimates mapped at a high spatial resolution and aggregated to policy-relevant administrative units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the World Health 10 Organization’s ambitious Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and rates of progress exist across regions, countries, and within countries; our maps identify areas where high prevalence persists even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where subnational disparities exist and the highest-need populations reside, these geospatial estimates can support policy-makers in planning locally 15 tailored interventions and efficient directing of resources to accelerate progress in reducing CGF and its health implications

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens