Ultrasound in Cardiopulmonary Arrest and Resuscitation: Constructing Comprehensive Implementation Frameworks in High-Risk Settings.

OBJECTIVES: Information obtained from point-of-care ultrasound during cardiopulmonary arrest and resuscitation (POCUS-CA) can be used to identify underlying pathophysiology and provide life-sustaining interventions. However, integration of POCUS-CA into resuscitation care is inconsistent. We used expert consensus building methodology to help identify discrete barriers to clinical integration. We subsequently applied implementation science frameworks to generate generalizable strategies to overcome these barriers. MEASURES AND MAIN RESULTS: Two multidisciplinary expert working groups used KJ Reverse-Merlin consensus building method to identify and characterize barriers contributing to failed POCUS-CA utilization in a hypothetical future state. Identified barriers were organized into affinity groups. The Center for Implementation Research (CFIR) framework and Expert Recommendations for Implementing Change (CFIR-ERIC) tool were used to identify strategies to guide POCUS-US implementation. RESULTS: Sixteen multidisciplinary resuscitation content experts participated in the working groups and identified individual barriers, consolidated into 19 unique affinity groups that mapped 12 separate CFIR constructs, representing all 5 CFIR domains. The CFIR-ERIC tool identified the following strategies as most impactful to address barriers described in the affinity groups: identify and prepare champions, conduct local needs assessment, conduct local consensus discussions, and conduct educational meetings. CONCLUSIONS: KJ Reverse-Merlin consensus building identified multiple barriers to implementing POCUS-CA. Implementation science methodologies identified and prioritized strategies to overcome barriers and guide POCUS-CA implementation across diverse clinical settings.

Safety and Efficacy of Ethanol for Catheter Salvage and Central Line-Associated Bloodstream Infection Prophylaxis in Polyurethane Catheters in the PICU.

OBJECTIVES: Ethanol lock therapy (ELT) is a potential method of central catheter salvage following central line-associated bloodstream infection (CLABSI) although there is potential risk of catheter damage in polyurethane catheters. Further, there is limited efficacy data across the spectrum of common pediatric catheters, and published ELT protocols describe dwell times that are not feasible for critically ill children. We sought to evaluate the safety and efficacy of ELT in polyurethane catheters using brief (30 min to 2 hr) dwell times in our PICU. DESIGN: Investigational pilot study using historical control data. SETTING: PICU in quaternary care, free-standing children's hospital. INTERVENTIONS: ELT in polyurethane central venous catheters for catheter salvage. RESULTS: ELT with brief dwell times was used in 25 patients, 22 of whom were bacteremic. Ultimately 11 patients, comprising 14 catheters, were diagnosed with a primary CLABSI. The catheter salvage rate in primary CLABSI patients receiving ELT was 92% (13/14) and significantly higher than the salvage rate in patients receiving antibiotics alone (non-ELT) (62%, 39/64; mean difference 0.32, 95% CI [0.14-0.50], p = 0.03). The rate of catheter fracture in all patients receiving ELT was 8% (2/25) while the rate of fracture in the non-ELT group was 13% (8/64; mean difference -0.05, 95% CI [-0.18 to 0.09], p = 0.72). The rate of tissue plasminogen activator (tPA) use in the ELT group was 8% (2/25), whereas the rate of tPA use in the non-ELT group was significantly higher at 42% (26/64; mean difference -0.34, 95% CI [-0.49 to -0.17], p = 0.002). CONCLUSIONS: The use of ELT for catheter salvage and prophylaxis in the PICU is safe in a variety of polyurethane catheters. Dwell times ranging from 30 minutes to 2 hours were effective in sterilizing the catheters while allowing other therapies to continue. This approach may decrease the need for frequent line changes in a medically fragile pediatric population.

Identification of MYCN non-amplified neuroblastoma subgroups points towards molecular signatures for precision prognosis and therapy stratification.

BACKGROUND: Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified cases. In particular, the extent of heterogeneity within the MYCN non-amplified population is unknown. METHODS: A total of 1566 samples from 16 datasets were identified in Gene Expression Omnibus (GEO) and ArrayExpress. Characterisation of the subtypes was analysed by ConsensusClusterPlus. Independent predictors for subgrouping were constructed from the single sample predictor based on the multiclassPairs package. Findings were verified using immunohistochemistry and CIBERSORTx analysis. RESULTS: We demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup_2 has the worst prognosis and this group shows a 'MYCN' signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup_3 is characterised by an 'inflamed' gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates a unique prognosis and vulnerability to investigational therapies. A total of 420 genes were identified as independent subgroup predictors with average balanced accuracy of 0.93 and 0.84 for train and test datasets, respectively. CONCLUSION: We propose that transcriptional subtyping may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.

A Survey of PICU Clinician Practices and Perceptions regarding Respiratory Cultures in the Evaluation of Ventilator-Associated Infections in the BrighT STAR Collaborative.

OBJECTIVES: To characterize respiratory culture practices for mechanically ventilated patients, and to identify drivers of culture use and potential barriers to changing practices across PICUs. DESIGN: Cross-sectional survey conducted May 2021-January 2022. SETTING: Sixteen academic pediatric hospitals across the United States participating in the BrighT STAR Collaborative. SUBJECTS: Pediatric critical care medicine physicians, advanced practice providers, respiratory therapists, and nurses. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We summarized the proportion of positive responses for each question within a hospital and calculated the median proportion and IQR across hospitals. We correlated responses with culture rates and compared responses by role. Sixteen invited institutions participated (100%). Five hundred sixty-eight of 1,301 (44%) e-mailed individuals completed the survey (median hospital response rate 60%). Saline lavage was common, but no PICUs had a standardized approach. There was the highest variability in perceived likelihood (median, IQR) to obtain cultures for isolated fever (49%, 38-61%), isolated laboratory changes (49%, 38-57%), fever and laboratory changes without respiratory symptoms (68%, 54-79%), isolated change in secretion characteristics (67%, 54-78%), and isolated increased secretions (55%, 40-65%). Respiratory cultures were likely to be obtained as a "pan culture" (75%, 70-86%). There was a significant correlation between higher culture rates and likelihood to obtain cultures for isolated fever, persistent fever, isolated hypotension, fever, and laboratory changes without respiratory symptoms, and "pan cultures." Respondents across hospitals would find clinical decision support (CDS) helpful (79%) and thought that CDS would help align ICU and/or consulting teams (82%). Anticipated barriers to change included reluctance to change (70%), opinion of consultants (64%), and concern for missing a diagnosis of ventilator-associated infections (62%). CONCLUSIONS: Respiratory culture collection and ordering practices were inconsistent, revealing opportunities for diagnostic stewardship. CDS would be generally well received; however, anticipated conceptual and psychologic barriers to change must be considered.

Lactate: an alternative pathway for the immunosuppressive properties of mesenchymal stem/stromal cells.

BACKGROUND: The metabolic reprogramming of mesenchymal stem/stromal cells (MSC) favoring glycolysis has recently emerged as a new approach to improve their immunotherapeutic abilities. This strategy is associated with greater lactate release, and interestingly, recent studies have proposed lactate as a functional suppressive molecule, changing the old paradigm of lactate as a waste product. Therefore, we evaluated the role of lactate as an alternative mediator of MSC immunosuppressive properties and its contribution to the enhanced immunoregulatory activity of glycolytic MSCs. MATERIALS AND METHODS: Murine CD4+ T cells from C57BL/6 male mice were differentiated into proinflammatory Th1 or Th17 cells and cultured with either L-lactate, MSCs pretreated or not with the glycolytic inductor, oligomycin, and MSCs pretreated or not with a chemical inhibitor of lactate dehydrogenase A (LDHA), galloflavin or LDH siRNA to prevent lactate production. Additionally, we validated our results using human umbilical cord-derived MSCs (UC-MSCs) in a murine model of delayed type 1 hypersensitivity (DTH). RESULTS: Our results showed that 50 mM of exogenous L-lactate inhibited the proliferation rate and phenotype of CD4+ T cell-derived Th1 or Th17 by 40% and 60%, respectively. Moreover, the suppressive activity of both glycolytic and basal MSCs was impaired when LDH activity was reduced. Likewise, in the DTH inflammation model, lactate production was required for MSC anti-inflammatory activity. This lactate dependent-immunosuppressive mechanism was confirmed in UC-MSCs through the inhibition of LDH, which significantly decreased their capacity to control proliferation of activated CD4+ and CD8+ human T cells by 30%. CONCLUSION: These findings identify a new MSC immunosuppressive pathway that is independent of the classical suppressive mechanism and demonstrated that the enhanced suppressive and therapeutic abilities of glycolytic MSCs depend at least in part on lactate production.

Implementation Science Research in Pediatric Critical Care Medicine.

OBJECTIVES: Delay or failure to consistently adopt evidence-based or consensus-based best practices into routine clinical care is common, including for patients in the PICU. PICU patients can fail to receive potentially beneficial diagnostic or therapeutic interventions, worsening the burden of illness and injury during critical illness. Implementation science (IS) has emerged to systematically address this problem, but its use of in the PICU has been limited to date. We therefore present a conceptual and methodologic overview of IS for the pediatric intensivist. DESIGN: The members of Excellence in Pediatric Implementation Science (ECLIPSE; part of the Pediatric Acute Lung Injury and Sepsis Investigators Network) represent multi-institutional expertise in the use of IS in the PICU. This narrative review reflects the collective knowledge and perspective of the ECLIPSE group about why IS can benefit PICU patients, how to distinguish IS from quality improvement (QI), and how to evaluate an IS article. RESULTS: IS requires a shift in one's thinking, away from questions and outcomes that define traditional clinical or translational research, including QI. Instead, in the IS rather than the QI literature, the terminology, definitions, and language differs by specifically focusing on relative importance of generalizable knowledge, as well as aspects of study design, scale, and timeframe over which the investigations occur. CONCLUSIONS: Research in pediatric critical care practice must acknowledge the limitations and potential for patient harm that may result from a failure to implement evidence-based or professionals' consensus-based practices. IS represents an innovative, pragmatic, and increasingly popular approach that our field must readily embrace in order to improve our ability to care for critically ill children.

A thematic analysis of staff perspectives on the impact of a mental health nurse (RMN) in a critical care unit.

Background: Recent guidelines in the UK have shaped Critical Care Units (CCUs) to bring the mental health needs of patients, and staff wellbeing to the forefront of service provision. A health board based in NHS Wales has trialled the secondment of a Mental Health Nurse (RMN) within a CCU to help service provision adhere to such guidelines. Methods: Critical care staff were invited to attend focus groups to share their experiences of how the RMN influenced service provision. Results: Thematic analysis identified five main themes; including 'smoother care pathways', 'a holistic approach to care', 'co-production', 'knowledge and confidence' and 'staff wellbeing'. Each of these themes reflected how the RMN had both direct and indirect benefits on patient and staff wellbeing. Conclusion: This qualitative exploration suggests that staff perceived value in the role of the RMN for both staff and patient outcomes, although further measures were considered necessary to improve staff-wellbeing within a critical care environment. This service evaluation supports recommendations for commissioning a RMN permanently in a CCU.

Predictors of recovery in a medium secure service: Influence of the Welsh Government's Mental Health (2010) Measure.

BACKGROUND: Research to date has failed to examine the effectiveness of MSUs in facilitating recovery, or the influence that mental health policy may have on this process. Examining predictors of short-term clinical outcomes during inpatient admission and the effects of policy changes may inform future policy, treatment planning and may improve service user outcomes. AIMS: To examine whether service user admission characteristics and length of stay predicted recovery status at discharge from medium secure care and whether a recovery-focused change in policy (introduction of the Mental Health (Wales) Measure (2010)) impacted either on recovery or the relationship between service user characteristics and recovery. METHODS: The study adopted a retrospective analysis of quantitative data obtained from healthcare records from a Welsh MSU between 2007 and 2017 (n = 198). The DUNDUM-4 scale assessed recovery whilst DUNDRUM-2 assessed security need at admission. Service user admission characteristics included HCR-20 subscale scores, previous security-level transitions, adverse childhood experiences, substance misuse histories. RESULTS: Shorter inpatient stays and higher scores on the dynamic HCR-20 clinical subscale were associated with poorer recovery outcomes. The relationship between admission characteristics and recovery endured despite changes in policy. Implementation of recovery focused legislation was associated with improved recovery. CONCLUSIONS: The findings suggest that treatment should focus on dynamic risk factors to improve service user outcomes and highlights the need for long-term medium-secure provision for some. Further research is needed to evaluate the success of MSUs and the validity of the DUNDRUM-4 across UK secure services.

Sustainability of the Bright STAR Diagnostic Stewardship Program to Reduce Blood Culture Rates Among Critically Ill Children.

This quality improvement study evaluates whether pediatric intensive care units sustained reduced blood culture rates after participation in the Bright STAR collaborative from 2017 to 2020.

Application of Participatory Ergonomics to the Dissemination of a Quality Improvement Program for Optimizing Blood Culture Use.

BACKGROUND: Blood cultures are overused in pediatric ICUs (PICUs), which may lead to unnecessary antibiotic use and antibiotic resistance. Using a participatory ergonomics (PE) approach, the authors disseminated a quality improvement (QI) program for optimizing blood culture use in PICUs to a national 14-hospital collaborative. The objective of this study was to evaluate the dissemination process and its impact on blood culture reduction. METHODS: The PE approach emphasized three key principles (stakeholder participation, application of human factors and ergonomics knowledge and tools, and cross-site collaboration) with a six-step dissemination process. Data on interactions between sites and the coordinating team and site experiences with the dissemination process were collected using site diaries and semiannual surveys with local QI teams, respectively, and correlated with the site-specific change in blood culture rates. RESULTS: Overall, participating sites were able to successfully implement the program and reduced their blood culture rates from 149.4 blood cultures per 1,000 patient-days/month before implementation to 100.5 blood cultures per 1,000 patient-days/month after implementation, corresponding to a 32.7% relative reduction (p < 0.001). Variations in the dissemination process, as well as in local interventions and implementation strategies, were observed across sites. Site-specific changes in blood culture rates were weakly negatively correlated with the number of preintervention interactions with the coordinating team (p = 0.057) but not correlated with their experiences with the six domains of the dissemination process or their interventions. CONCLUSIONS: The authors applied a PE approach to disseminate a QI program for optimizing PICU blood culture use to a multisite collaborative. Working with local stakeholders, participating sites tailored their interventions and implementation processes and achieved the goal of reducing blood culture use.

Comparison of Administrative Database-Derived and Hospital-Derived Data for Monitoring Blood Culture Use in the Pediatric Intensive Care Unit.

BACKGROUND: Optimizing blood culture practices requires monitoring of culture use. Collecting culture data from electronic medical records can be resource intensive. Our objective was to determine whether administrative data could serve as a data source to measure blood culture use in pediatric intensive care units (PICUs). METHODS: Using data from a national diagnostic stewardship collaborative to reduce blood culture use in PICUs, we compared the monthly number of blood cultures and patient-days collected from sites (site-derived) and the Pediatric Health Information System (PHIS, administrative-derived), an administrative data warehouse, for 11 participating sites. The collaborative's reduction in blood culture use was compared using administrative-derived and site-derived data. RESULTS: Across all sites and months, the median of the monthly relative blood culture rate (ratio of administrative- to site-derived data) was 0.96 (Q1: 0.77, Q3: 1.24). The administrative-derived data produced an estimate of blood culture reduction over time that was attenuated toward the null compared with site-derived data. CONCLUSIONS: Administrative data on blood culture use from the PHIS database correlates unpredictably with hospital-derived PICU data. The limitations of administrative billing data should be carefully considered before use for ICU-specific data.

Determinants of Blood Culture Use in Critically Ill Children: A Multicenter Qualitative Study.

Blood cultures are fundamental in diagnosing and treating sepsis in the pediatric intensive care unit (PICU), but practices vary widely. Overuse can lead to false positive results and unnecessary antibiotics. Specific factors underlying decisions about blood culture use and overuse are unknown. Therefore, we aimed to identify perceived determinants of blood culture use in the PICU. Methods: We conducted semistructured interviews of clinicians (M.D., D.O., R.N., N.P., P.A.) from 6 PICUs who had participated in a quality improvement collaborative about blood culture practices. We developed interview questions by combining elements of the Consolidated Framework for Implementation Research and behavioral economics. We conducted telephone interviews, open-coded the transcripts, and used modified content analysis to determine key themes and mapped themes to elements of Consolidated Framework for Implementation Research and behavioral economics. Results: We reached thematic saturation in 24 interviews. Seven core themes emerged across 3 Consolidated Framework for Implementation Research domains: individual characteristics [personal belief in the importance of blood cultures, the perception that blood cultures are a low-risk test]; inner setting [adherence to site-specific usual practices, site-specific overall approach to PICU care (collaborative versus hierarchical), influence of non-PICU clinicians on blood culture decisions]; and outer setting [patient-specific risk factors, sepsis guidelines]. In addition, outcome bias, default bias, and loss aversion emerged as salient behavioral economics concepts. Conclusions: Determinants of blood culture use include individual clinician characteristics, inner setting, and outer setting, as well as default bias, outcome bias, and loss aversion. These determinants will now inform the development of candidate strategies to optimize culture practices.

Mixed-methods process evaluation of a respiratory-culture diagnostic stewardship intervention.

OBJECTIVE: To conduct a process evaluation of a respiratory culture diagnostic stewardship intervention. DESIGN: Mixed-methods study. SETTING: Tertiary-care pediatric intensive care unit (PICU). PARTICIPANTS: Critical care, infectious diseases, and pulmonary attending physicians and fellows; PICU nurse practitioners and hospitalist physicians; pediatric residents; and PICU nurses and respiratory therapists. METHODS: This mixed-methods study was conducted concurrently with a diagnostic stewardship intervention to reduce the inappropriate collection of respiratory cultures in mechanically ventilated children. We quantified baseline respiratory culture utilization and indications for ordering using quantitative methods. Semistructured interviews informed by these data and the Consolidated Framework for Implementation Research (CFIR) were then performed, recorded, transcribed, and coded to identify salient themes. Finally, themes identified in these interviews were used to create a cross-sectional survey. RESULTS: The number of cultures collected per day of service varied between attending physicians (range, 2.2-27 cultures per 100 days). In total, 14 interviews were performed, and 87 clinicians completed the survey (response rate, 47%) and 77 nurses or respiratory therapists completed the survey (response rate, 17%). Clinicians varied in their stated practices regarding culture ordering, and these differences both clustered by specialty and were associated with perceived utility of the respiratory culture. Furthermore, group "default" practices, fear, and hierarchy were drivers of culture orders. Barriers to standardization included fear of a missed diagnosis and tension between practice standardization and individual decision making. CONCLUSIONS: We identified significant variation in utilization and perceptions of respiratory cultures as well as several key barriers to implementation of this diagnostic test stewardship intervention.

Autophagy in pulmonary fibrosis: friend or foe?

Autophagy is an evolutionarily conserved process where long-lived and damaged or-ganelles are degraded. Autophagy has been widely associated with several ageing-process as well in diseases such as neurodegeneration, cancer and fibrosis, and is now being utilised as a target in these diseases. Idiopathic pulmonary fibrosis (IPF) is a progressive, interstitial lung disease with limited treatment options available. It is characterised by abnormal extracellular matrix (ECM) deposition by activated myofibroblasts. It is understood that repetitive micro-injuries to aged-alveolar epithelium combined with genetic factors drive the disease. Several groups have demonstrated that autophagy is altered in IPF although whether autophagy has a protective effect or not is yet to be determined. Autophagy has also been shown to influence many other processes including epithelial-mesenchymal transition (EMT) and endothelial-mesenchymal transition (EndMT) which are known to be key in the pathogenesis of IPF. In this review, we summarise the findings of evidence of altered autophagy in IPF lungs, as well as examine its roles within lung fibrosis. Given these findings, together with the growing use of autophagy manipulation in a clinical setting, this is an exciting area for further research in the study of lung fibrosis.

Association of Diagnostic Stewardship for Blood Cultures in Critically Ill Children With Culture Rates, Antibiotic Use, and Patient Outcomes: Results of the Bright STAR Collaborative.

Importance: Blood culture overuse in the pediatric intensive care unit (PICU) can lead to unnecessary antibiotic use and contribute to antibiotic resistance. Optimizing blood culture practices through diagnostic stewardship may reduce unnecessary blood cultures and antibiotics. Objective: To evaluate the association of a 14-site multidisciplinary PICU blood culture collaborative with culture rates, antibiotic use, and patient outcomes. Design, Setting, and Participants: This prospective quality improvement (QI) collaborative involved 14 PICUs across the United States from 2017 to 2020 for the Bright STAR (Testing Stewardship for Antibiotic Reduction) collaborative. Data were collected from each participating PICU and from the Children's Hospital Association Pediatric Health Information System for prespecified primary and secondary outcomes. Exposures: A local QI program focusing on blood culture practices in the PICU (facilitated by a larger QI collaborative). Main Outcomes and Measures: The primary outcome was blood culture rates (per 1000 patient-days/mo). Secondary outcomes included broad-spectrum antibiotic use (total days of therapy and new initiations of broad-spectrum antibiotics ≥3 days after PICU admission) and PICU rates of central line-associated bloodstream infection (CLABSI), Clostridioides difficile infection, mortality, readmission, length of stay, sepsis, and severe sepsis/septic shock. Results: Across the 14 PICUs, the blood culture rate was 149.4 per 1000 patient-days/mo preimplementation and 100.5 per 1000 patient-days/mo postimplementation, for a 33% relative reduction (95% CI, 26%-39%). Comparing the periods before and after implementation, the rate of broad-spectrum antibiotic use decreased from 506 days to 440 days per 1000 patient-days/mo, respectively, a 13% relative reduction (95% CI, 7%-19%). The broad-spectrum antibiotic initiation rate decreased from 58.1 to 53.6 initiations/1000 patient-days/mo, an 8% relative reduction (95% CI, 4%-11%). Rates of CLABSI decreased from 1.8 to 1.1 per 1000 central venous line days/mo, a 36% relative reduction (95% CI, 20%-49%). Mortality, length of stay, readmission, sepsis, and severe sepsis/septic shock were similar before and after implementation. Conclusions and Relevance: Multidisciplinary diagnostic stewardship interventions can reduce blood culture and antibiotic use in the PICU. Future work will determine optimal strategies for wider-scale dissemination of diagnostic stewardship in this setting while monitoring patient safety and balancing measures.

Improving Vancomycin Stewardship in Critically Ill Children.

BACKGROUND AND OBJECTIVES: Inappropriate vancomycin use is common in children's hospitals. We report a quality improvement (QI) intervention to reduce vancomycin use in our tertiary care PICU. METHODS: We retrospectively quantified the prevalence of infections caused by organisms requiring vancomycin therapy, including methicillin-resistant Staphylococcus aureus (MRSA), among patients with suspected bacterial infections. Guided by these data, we performed 3 QI interventions over a 3-year period, including (1) stakeholder education, (2) generation of a consensus-based guideline for empiric vancomycin use, and (3) implementation of this guideline through clinical decision support. Vancomycin use in days of therapy (DOT) per 1000 patient days was measured by using statistical process control charts. Balancing measures included frequency of bacteremia due to an organism requiring vancomycin not covered with empiric therapy, 30-day mortality, and cardiovascular, respiratory, and renal organ dysfunction. RESULTS: Among 1276 episodes of suspected bacterial infection, a total of 19 cases of bacteremia (1.5%) due to organisms requiring vancomycin therapy were identified, including 6 MRSA bacteremias (0.5%). During the 3-year QI project, overall vancomycin DOT per 1000 patient days in the PICU decreased from a baseline mean of 182 DOT per 1000 patient days to 109 DOT per 1000 patient days (a 40% reduction). All balancing measures were unchanged, and all cases of MRSA bacteremia were treated empirically with vancomycin. CONCLUSION: Our interventions reduced overall vancomycin use in the PICU without evidence of harm. Provider education and consensus building surrounding indications for empiric vancomycin use were key strategies.