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

A Survey of Stated Physician Practices and Beliefs on the Use of Steroids in Pediatric Fluid and/or Vasoactive Infusion-Dependent Shock*

Objective: Limited evidence exists on the use of corticosteroids in pediatric shock. We sought to determine physicians&apos; practices and beliefs with regard to the management of pediatric shock. Design: Cross-sectional, Internet-based survey. Setting: Canada. Subjects: Physicians identified as practicing pediatric intensive care in any of 15 academic centers. Measurements and Main Results: Seventy of 97 physicians (72.2%) responded. Physicians stated that they were more likely to prescribe steroids for septic shock than for shock following cardiac surgery (odds ratio, 1.9 [95% CI, 0.9-4.3]) or trauma (odds ratio, 11.46 [95% CI, 2.5-51.2]), and 91.4% (64/70) would administer steroids to patients who had received 60 cc/ kg of fluid and two or more vasoactive medications. Thirty-five percent of respondents (25/70) reported that they rarely or never conducted adrenal axis testing before giving steroids to patients in shock. Eighty-seven percent of respondents Developing evidence-based guidelines for pediatric shock management has proven difficult given the conflicting adult evidence and the absence of pediatric trials. A large retrospectiv

Operationalizing Appropriate Sepsis Definitions in Children Worldwide: Considerations for the Pediatric Sepsis Definition Taskforce

Sepsis is a leading cause of global mortality in children, yet definitions for pediatric sepsis are outdated and lack global applicability and validity. In adults, the Sepsis-3 Definition Taskforce queried databases from high-income countries to develop and validate the criteria. The merit of this definition has been widely acknowledged; however, important considerations about less-resourced and more diverse settings pose challenges to its use globally. To improve applicability and relevance globally, the Pediatric Sepsis Definition Taskforce sought to develop a conceptual framework and rationale of the critical aspects and context-specific factors that must be considered for the optimal operationalization of future pediatric sepsis definitions. It is important to address challenges in developing a set of pediatric sepsis criteria which capture manifestations of illnesses with vastly different etiologies and underlying mechanisms. Ideal criteria need to be unambiguous, and capable of adapting to the different contexts in which children with suspected infections are present around the globe. Additionally, criteria need to facilitate early recognition and timely escalation of treatment to prevent progression and limit life-threatening organ dysfunction. To address these challenges, locally adaptable solutions are required, which permit individualized care based on available resources and the pretest probability of sepsis. This should facilitate affordable diagnostics which support risk stratification and prediction of likely treatment responses, and solutions for locally relevant outcome measures. For this purpose, global collaborative databases need to be established, using minimum variable datasets from routinely collected data. In summary, a "Think globally, act locally" approach is required

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock

ImportanceThe Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach.ObjectiveTo derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings.Design, Setting, and ParticipantsMulticenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged &amp;amp;lt;18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set.ExposureStacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock.Main Outcomes and MeasuresThe primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity.ResultsAmong the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings.Conclusions and RelevanceThe novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.</jats:sec

International Consensus Criteria for Pediatric Sepsis and Septic Shock.

ImportanceSepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children.ObjectiveTo update and evaluate criteria for sepsis and septic shock in children.Evidence reviewThe Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria.FindingsBased on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively.Conclusions and relevanceThe Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world

Melatonin and melatonin agonists to prevent and treat delirium in critical illness: a systematic review protocol

Abstract Background Delirium is a syndrome characterized by acute fluctuations and alterations in attention and arousal. Critically ill patients are at particularly high risk, and those that develop delirium are more likely to experience poor clinical outcomes such as prolonged duration of ICU and hospital length of stay, and increased mortality. Melatonin and melatonin agonists (MMA) have the potential to decrease the incidence and severity of delirium through their hypnotic and sedative-sparing effects, thus improving health-related outcomes. The objective of this review is to synthesize the available evidence pertaining to the efficacy and safety of MMA for the prevention and treatment of ICU delirium. Methods We will search Ovid MEDLINE, Web of Science, EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL to identify studies evaluating MMA in critically ill populations. We will also search http://apps.who.int/trialsearch for ongoing and unpublished studies and PROSPERO for registered reviews. We will not impose restrictions on language, date, or journal of publication. Authors will independently screen for eligible studies using pre-defined criteria; data extraction from eligible studies will be performed in duplicate. The Cochrane Risk of Bias Scale and the Newcastle-Ottawa Scale will be used to assess the risk of bias and quality of randomized and non-randomized studies, respectively. Our primary outcome of interest is delirium incidence, and secondary outcomes include duration of delirium, number of delirium- and coma-free days, use of physical and chemical (e.g., antipsychotics or benzodiazepines) restraints, duration of mechanical ventilation, ICU and hospital length of stay, mortality, long-term neurocognitive outcomes, hospital discharge disposition, and adverse events. We will use Review Manager (RevMan) to pool effect estimates from included studies. We will present results as relative risks with 95% confidence intervals for dichotomous outcomes and as mean differences, or standardized mean differences, for continuous outcomes. Discussion Current guidelines make no pharmacological recommendations for either the prevention or treatment of ICU delirium. This systematic review will synthesize the available evidence on the efficacy and safety of MMA for this purpose, thus potentially informing clinical decision-making and improving patient outcomes. Systematic review registration PROSPERO CRD4201502471

Melatonin and melatonin agonists to prevent and treat delirium in critical illness: a systematic review protocol

Background: Delirium is a syndrome characterized by acute fluctuations and alterations in attention and arousal. Critically ill patients are at particularly high risk, and those that develop delirium are more likely to experience poor clinical outcomes such as prolonged duration of ICU and hospital length of stay, and increased mortality. Melatonin and melatonin agonists (MMA) have the potential to decrease the incidence and severity of delirium through their hypnotic and sedative-sparing effects, thus improving health-related outcomes. The objective of this review is to synthesize the available evidence pertaining to the efficacy and safety of MMA for the prevention and treatment of ICU delirium. Methods: We will search Ovid MEDLINE, Web of Science, EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL to identify studies evaluating MMA in critically ill populations. We will also search http://apps.who.int/trialsearch for ongoing and unpublished studies and PROSPERO for registered reviews. We will not impose restrictions on language, date, or journal of publication. Authors will independently screen for eligible studies using pre-defined criteria; data extraction from eligible studies will be performed in duplicate. The Cochrane Risk of Bias Scale and the Newcastle-Ottawa Scale will be used to assess the risk of bias and quality of randomized and non-randomized studies, respectively. Our primary outcome of interest is delirium incidence, and secondary outcomes include duration of delirium, number of delirium- and coma-free days, use of physical and chemical (e.g., antipsychotics or benzodiazepines) restraints, duration of mechanical ventilation, ICU and hospital length of stay, mortality, long-term neurocognitive outcomes, hospital discharge disposition, and adverse events. We will use Review Manager (RevMan) to pool effect estimates from included studies. We will present results as relative risks with 95% confidence intervals for dichotomous outcomes and as mean differences, or standardized mean differences, for continuous outcomes. Discussion: Current guidelines make no pharmacological recommendations for either the prevention or treatment of ICU delirium. This systematic review will synthesize the available evidence on the efficacy and safety of MMA for this purpose, thus potentially informing clinical decision-making and improving patient outcomes. Systematic review registration:PROSPERO CRD42015024713

A systematic review of pediatric clinical trials of high dose vitamin D

Background. Due to inadequate UV exposure, intake of small quantities of vitamin D is recommended to prevent musculoskeletal disease. Both basic science and observational literature strongly suggest that higher doses may benefit specific populations and have non-musculoskeletal roles. Evaluating the evidence surrounding high dose supplementation can be challenging given a relatively large and growing body of clinical trial evidence spanning time, geography, populations and dosing regimens. Study objectives were to identify and summarize the clinical trial literature, recognize areas with high quality evidence, and develop a resource database that makes the literature more immediately accessible to end users. Methods. Medline (1946 to January 2015), Embase (1974 to January 2015), and Cochrane databases (January 2015), were searched for trials. All pediatric (0–18 years) trials administering doses higher than 400 IU (<1 year) or 600 IU (≥1 year) were included. Data was extracted independently by two of the authors. An online searchable database of trials was developed containing relevant extracted information (http://www.cheori.org/en/pedvitaminddatabaseOverview). Sensitivity and utility were assessed by comparing the trials in the database with those from systematic reviews of vitamin D supplementation including children. Results. A total of 2,579 candidate papers were identified, yielding 169 trials having one or more arms meeting eligibility criteria. The publication rate has increased significantly from 1 per year (1970–1979) to 14 per year (2010–2015). Although 84% of the total trials focused on healthy children or known high risk populations (e.g., renal, prematurity), this proportion has declined in recent years due to the rise in trials evaluating populations and outcomes not directly related to the musculoskeletal actions of vitamin D (27% in 2010s). Beyond healthy children, the only pediatric populations with more than 50 participants from low risk of bias trials evaluating a clinically relevant outcome were prematurity and respiratory illness. Finally, we created and validated the online searchable database using 13 recent systematic reviews. Of the 38 high dose trials identified by the systematic review, 36 (94.7%) could be found within the database. When compared with the search strategy reported in each systematic review, use of the database reduced the number of full papers to assess for eligibility by 85.2% (±13.4%). Conclusion. The pediatric vitamin D field is highly active, with a significant increase in trials evaluating non-classical diseases and outcomes. Despite the large overall number there are few high quality trials of sufficient size to provide answers on clinical efficacy of high-dose vitamin D. An open access online searchable data should assist end users in the rapid and comprehensive identification and evaluation of trials relevant to their population or question of interest

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

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. 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. 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). 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