Methadone for Analgesia in Children with Life-Limiting Illness: Experience from a Tertiary Children\u27s Health Service.

Methadone has the potential to assist in the management of pain in children with life-limiting illness, but its use is limited by its complex pharmacokinetic profile and limited research on its use in children. This is a retrospective review of the use of methadone as an analgesic in 16 children with life-limiting illness. Efficacy, dosing and side effect profile were analysed. Fifteen (94%) patients had improvements in their analgesia with minimal observed adverse effects. Patients were either rapidly converted from a prior opioid in one change or received methadone as an adjunct medication. Conversions were calculated using ratios frequently in the range of 10:1 to 20:1 from the oral morphine equivalent total daily dose (MEDD). Adjunct initial dosing was a low dose trial, often beginning with 1 mg at night. Only two patients required a dose adjustment due to side effects attributed to methadone. This was despite the cohort having significant underlying illnesses, extensive concurrent medications, and high methadone dosing where needed. Analysis of dosing and ratios indicates that an individualised approach is required. Based on this and on the infrequency of methadone use in this population, specialist assistance with dosing is recommended. Further research, including prospective and pharmacokinetic studies, is recommended

Methadone for analgesia in children with life-limiting illness: experience from a tertiary children’s health service

Methadone has the potential to assist in the management of pain in children with life-limiting illness, but its use is limited by its complex pharmacokinetic profile and limited research on its use in children. This is a retrospective review of the use of methadone as an analgesic in 16 children with life-limiting illness. Efficacy, dosing and side effect profile were analysed. Fifteen (94%) patients had improvements in their analgesia with minimal observed adverse effects. Patients were either rapidly converted from a prior opioid in one change or received methadone as an adjunct medication. Conversions were calculated using ratios frequently in the range of 10:1 to 20:1 from the oral morphine equivalent total daily dose (MEDD). Adjunct initial dosing was a low dose trial, often beginning with 1 mg at night. Only two patients required a dose adjustment due to side effects attributed to methadone. This was despite the cohort having significant underlying illnesses, extensive concurrent medications, and high methadone dosing where needed. Analysis of dosing and ratios indicates that an individualised approach is required. Based on this and on the infrequency of methadone use in this population, specialist assistance with dosing is recommended. Further research, including prospective and pharmacokinetic studies, is recommended

Perceived potentially inappropriate treatment in the PICU: frequency, contributing factors and the distress it triggers

BackgroundPotentially inappropriate treatment in critically ill adults is associated with healthcare provider distress and burnout. Knowledge regarding perceived potentially inappropriate treatment amongst pediatric healthcare providers is limited.ObjectivesDetermine the frequency and factors associated with potentially inappropriate treatment in critically ill children as perceived by providers, and describe the factors that providers report contribute to the distress they experience when providing treatment perceived as potentially inappropriate.MethodsProspective observational mixed-methods study in a single tertiary level PICU conducted between March 2 and September 14, 2018. Patients 0–17 years inclusive with: (1) ≥1 organ system dysfunction (2) moderate to severe mental and physical disabilities, or (3) baseline dependence on medical technology were enrolled if they remained admitted to the PICU for ≥48 h, and were not medically fit for transfer/discharge. The frequency of perceived potentially inappropriate treatment was stratified into three groups based on degree of consensus (1, 2 or 3 providers) regarding the appropriateness of ongoing active treatment per enrolled patient. Distress was self-reported using a 100-point scale.ResultsOf 374 patients admitted during the study, 133 satisfied the inclusion-exclusion criteria. Eighteen patients (unanimous - 3 patients, 2 providers - 7 patients; single provider - 8 patients) were perceived as receiving potentially inappropriate treatment; unanimous consensus was associated with 100% mortality on 3-month follow up post PICU discharge. Fifty-three percent of providers experienced distress secondary to providing treatment perceived as potentially inappropriate. Qualitative thematic analysis revealed five themes regarding factors associated with provider distress: (1) suffering including a sense of causing harm, (2) conflict, (3) quality of life, (4) resource utilization, and (5) uncertainty.ConclusionsWhile treatment perceived as potentially inappropriate was infrequent, provider distress was commonly observed. By identifying specific factor(s) contributing to perceived potentially inappropriate treatment and any associated provider distress, organizations can design, implement and assess targeted interventions

Application of a gene modular approach for clinical phenotype genotype association and sepsis prediction using machine learning in meningococcal sepsis

Sepsis is a major global health concern causing high morbidity and mortality rates. Our study utilized a Meningococcal Septic Shock (MSS) temporal dataset to investigate the correlation between gene expression (GE) changes and clinical features. The research used Weighted Gene Co-expression Network Analysis (WGCNA) to establish links between gene expression and clinical parameters in infants admitted to the Pediatric Critical Care Unit with MSS. Additionally, various machine learning (ML) algorithms, including Support Vector Machine (SVM), Naive Bayes, K-Nearest Neighbors (KNN), Decision Tree, Random Forest, and Artificial Neural Network (ANN) were implemented to predict sepsis survival. The findings revealed a transition in gene function pathways from nuclear to cytoplasmic to extracellular, corresponding with Pediatric Logistic Organ Dysfunction score (PELOD) readings at 0, 24, and 48 h. ANN was the most accurate of the six ML models applied for survival prediction. This study successfully correlated PELOD with transcriptomic data, mapping enriched GE modules in acute sepsis. By integrating network analysis methods to identify key gene modules and using machine learning for sepsis prognosis, this study offers valuable insights for precision-based treatment strategies in future research. The observed temporal-spatial pattern of cellular recovery in sepsis could prove useful in guiding clinical management and therapeutic interventions

A Transcriptomic Appreciation of Childhood Meningococcal and Polymicrobial Sepsis from a Pro-Inflammatory and Trajectorial Perspective, a Role for Vascular Endothelial Growth Factor A and B Modulation?

This study investigated the temporal dynamics of childhood sepsis by analyzing gene expression changes associated with proinflammatory processes. Five datasets, including four meningococcal sepsis shock (MSS) datasets (two temporal and two longitudinal) and one polymicrobial sepsis dataset, were selected to track temporal changes in gene expression. Hierarchical clustering revealed three temporal phases: early, intermediate, and late, providing a framework for understanding sepsis progression. Principal component analysis supported the identification of gene expression trajectories. Differential gene analysis highlighted consistent upregulation of vascular endothelial growth factor A (VEGF-A) and nuclear factor κB1 (NFKB1), genes involved in inflammation, across the sepsis datasets. NFKB1 gene expression also showed temporal changes in the MSS datasets. In the postmortem dataset comparing MSS cases to controls, VEGF-A was upregulated and VEGF-B downregulated. Renal tissue exhibited higher VEGF-A expression compared with other tissues. Similar VEGF-A upregulation and VEGF-B downregulation patterns were observed in the cross-sectional MSS datasets and the polymicrobial sepsis dataset. Hexagonal plots confirmed VEGF-R (VEGF receptor)–VEGF-R2 signaling pathway enrichment in the MSS cross-sectional studies. The polymicrobial sepsis dataset also showed enrichment of the VEGF pathway in septic shock day 3 and sepsis day 3 samples compared with controls. These findings provide unique insights into the dynamic nature of sepsis from a transcriptomic perspective and suggest potential implications for biomarker development. Future research should focus on larger-scale temporal transcriptomic studies with appropriate control groups and validate the identified gene combination as a potential biomarker panel for sepsis

Advancing sepsis clinical research: harnessing transcriptomics for an omics-based strategy - a comprehensive scoping review

Sepsis continues to be recognized as a significant global health challenge across all ages and is characterized by a complex pathophysiology. In this scoping review, PRISMA-ScR guidelines were adhered to, and a transcriptomic methodology was adopted, with the protocol registered on the Open Science Framework. We hypothesized that gene expression analysis could provide a foundation for establishing a clinical research framework for sepsis. A comprehensive search of the PubMed database was conducted with a particular focus on original research and systematic reviews of transcriptomic sepsis studies published between 2012 and 2022. Both coding and non-coding gene expression studies have been included in this review. An effort was made to enhance the understanding of sepsis at the mRNA gene expression level by applying a systems biology approach through transcriptomic analysis. Seven crucial components related to sepsis research were addressed in this study: endotyping (n = 64), biomarker (n = 409), definition (n = 0), diagnosis (n = 1098), progression (n = 124), severity (n = 451), and benchmark (n = 62). These components were classified into two groups, with one focusing on Biomarkers and Endotypes and the other oriented towards clinical aspects. Our review of the selected studies revealed a compelling association between gene transcripts and clinical sepsis, reinforcing the proposed research framework. Nevertheless, challenges have arisen from the lack of consensus in the sepsis terminology employed in research studies and the absence of a comprehensive definition of sepsis. There is a gap in the alignment between the notion of sepsis as a clinical phenomenon and that of laboratory indicators. It is potentially responsible for the variable number of patients within each category. Ideally, future studies should incorporate a transcriptomic perspective. The integration of transcriptomic data with clinical endpoints holds significant potential for advancing sepsis research, facilitating a consensus-driven approach, and enabling the precision management of sepsis

Parental Presence at the Bedside of Critically Ill Children in a Unit With Unrestricted Visitation.

Objectives To determine the percentage of time that critically ill children have a parent at the bedside and to identify extrinsic factors that are associated with percent of time with parental presence at the bedside. Design Prospective cohort study. Setting PICU in a single tertiary care children\u27s hospital. Subjects Primary two parents of all children admitted to the PICU on 12 preselected days during a 1-year period from 2014 to 2015. Interventions None. Measurement and Main Results A total of 111 observations of 108 unique PICU admissions and families were performed. Children had at least one parent present a mean of 58.2% (SD, 34.6%) of the time. Mothers spent more time at the bedside (56.3% [SD, 31.0%]) than fathers (37.3% [SD, 29.5%]) (p = 0.0001). Percent of time with parental presence at the bedside was positively correlated with age (rs = 0.23; p = 0.02) and negatively associated with Pediatric Risk of Mortality III score (rs = -0.26; p = 0.01). Percent of time with parental presence at the bedside was lower for children who were mechanically ventilated (42.8% [SD, 35.5%]) than not (64.5% [SD, 32.2%]) (p = 0.01) and whose parent(s) were single (45.5% [SD, 27.5%]) or cohabitating/common-law (35.7% [SD, 26.4%]) compared with parents who were married (64.2% [SD, 34.2%]) or separated/divorced (68.3% [SD, 28.8%]) (p = 0.02). Percent of time with parental presence at the bedside was higher for children with chronic illnesses (63.4% [SD, 32.9%] vs 50.1% [SD, 35.8%] without; p = 0.04), when there was a bed in the patient room (61.4% [SD, 34.0%] vs 32.5% [SD, 28.3%] without; p = 0.01), and when parents slept in the patient room (90.3% [SD, 11.2%]) compared with their own home (37.6% [SD, 34.4%]) (p \u3c 0.0001). Percent of time with parental presence at the bedside was not correlated with day of PICU stay, number of siblings, previous PICU admission, isolation status, or nursing ratio. Conclusions Children had a parent present at the bedside approximately 60% of the time. The parents of younger, sicker children may benefit from supportive interventions during PICU admission. Further research is needed to examine both extrinsic and intrinsic factors affecting parental presence at the bedside

Datasheet1_Perceived potentially inappropriate treatment in the PICU: frequency, contributing factors and the distress it triggers.docx

BackgroundPotentially inappropriate treatment in critically ill adults is associated with healthcare provider distress and burnout. Knowledge regarding perceived potentially inappropriate treatment amongst pediatric healthcare providers is limited.ObjectivesDetermine the frequency and factors associated with potentially inappropriate treatment in critically ill children as perceived by providers, and describe the factors that providers report contribute to the distress they experience when providing treatment perceived as potentially inappropriate.MethodsProspective observational mixed-methods study in a single tertiary level PICU conducted between March 2 and September 14, 2018. Patients 0–17 years inclusive with: (1) ≥1 organ system dysfunction (2) moderate to severe mental and physical disabilities, or (3) baseline dependence on medical technology were enrolled if they remained admitted to the PICU for ≥48 h, and were not medically fit for transfer/discharge. The frequency of perceived potentially inappropriate treatment was stratified into three groups based on degree of consensus (1, 2 or 3 providers) regarding the appropriateness of ongoing active treatment per enrolled patient. Distress was self-reported using a 100-point scale.ResultsOf 374 patients admitted during the study, 133 satisfied the inclusion-exclusion criteria. Eighteen patients (unanimous - 3 patients, 2 providers - 7 patients; single provider - 8 patients) were perceived as receiving potentially inappropriate treatment; unanimous consensus was associated with 100% mortality on 3-month follow up post PICU discharge. Fifty-three percent of providers experienced distress secondary to providing treatment perceived as potentially inappropriate. Qualitative thematic analysis revealed five themes regarding factors associated with provider distress: (1) suffering including a sense of causing harm, (2) conflict, (3) quality of life, (4) resource utilization, and (5) uncertainty.ConclusionsWhile treatment perceived as potentially inappropriate was infrequent, provider distress was commonly observed. By identifying specific factor(s) contributing to perceived potentially inappropriate treatment and any associated provider distress, organizations can design, implement and assess targeted interventions.</p

Is Serum Bicarbonate Level Associated With Negative Outcomes in Pediatric Patients?: A Retrospective Cohort Study

OBJECTIVES: Early identification of children at risk for adverse outcomes is important. Serum bicarbonate is easily collected and widely available. We described the relationship between bicarbonate and adverse outcomes in children presenting to the emergency department (ED). METHODS: We conducted a retrospective cohort study of children aged 0 to 17 years from January 1, 2007, to December 31, 2011, who had a serum bicarbonate measured in the ED. Primary outcome was the predictive ability of bicarbonate for the individual components of the composite outcome that included at least one of the following: intensive care unit admission, assisted ventilation, inotropic support, cardiopulmonary resuscitation, or death. Secondary outcome was the relationship between bicarbonate level of greater and less than 13 mEq/L and the composite outcome. RESULTS: We reviewed 16,989 charts, of which 432 had an adverse outcome. Receiver operating characteristic curve analysis showed that a bicarbonate level of less than 18.5 mEq/L predicted inotropic support with an area under the curve of 0.69 (95% confidence interval [CI], 0.60-0.77; P \u3c 0.001) and death with an area under the curve of 0.75 (CI, 0.66-0.85; P \u3c 0.001). Significantly more patients with bicarbonate level of less than 13 mEq/L had at least 1 adverse outcome compared with those with bicarbonate level of greater than 13 mEq/L (4.4% vs 2.5%, P = 0.001), odds ratio 1.96 (95% CI, 1.3-2.97). CONCLUSIONS: Among children presenting to the ED, bicarbonate level of 18.5 mEq/L had fair specificity in predicting inotropic support and death. Negative outcomes are significantly associated with bicarbonate level of less than 13 mEq/L. Bicarbonate should routinely be measured in children at risk of clinical deterioration