Resilience Curriculum Improves Skills of Pediatric Fellows in Delivery of Difficult News.

BACKGROUND: Delivering difficult news to families is an essential but challenging skill. Pediatric trainees report limited confidence in this skill and perform poorly in simulation. We implemented the American Academy of Pediatrics (AAP) Resilience Curriculum and evaluated performance and self-efficacy in delivering difficult news. METHODS: The AAP Resilience Curriculum, using the SPIKES (Set-up, Perception, Invitation, Knowledge, Empathy, and Summary) framework, was taught to pediatric fellows. Fellows' performance during simulations with standardized patients before and after curriculum implementation was scored with a SPIKES checklist. Pre- and post-test surveys assessed self-efficacy in delivering difficult news. RESULTS: Fellows (n=19) significantly improved their performance in delivering difficult news, increasing the median SPIKES checklist scores from 78% to 90% completion (P<0.001). Pediatric fellows (n=35) reported improved confidence from 3.4/5 to 3.9 (P=0.01). CONCLUSIONS: Pediatric fellows demonstrated significant improvement in their ability to deliver difficult news during a simulated patient encounter and reported increased self-efficacy in delivering difficult news.

A quality improvement approach to integrating social determinants of health objectives into pediatric simulation.

Background: Health disparities and the unequal distribution of social resources impact health outcomes. By considering social determinants of health (SDH), clinicians can provide holistic and equitable care. However, barriers such as lack of time or understanding of the relevance of SDH to patient care prevent providers from addressing SDH. Simulation curricula may improve learners' ability to address SDH in practice. Objectives: The primary objective was to increase the percentage of pediatric emergency simulations that included SDH objectives from 5% to 50% in 12 months at one institution. As a balancing metric, we examined whether trainees approved the incorporation of SDH objectives. Methods: Using the Model for Improvement approach, we conducted interviews of residents and simulation facilitators to identify challenges to integrating SDH objectives into the simulation curriculum. Review of interviews and visual representation of the system helped identify key drivers in the process. A team of simulation leaders, residents, and fellows met regularly to develop simulation cases with embedded SDH objectives. Using a plan, do, study, act approach, we tested, refined, and implemented interventions including engaging residency program and SDH leadership, piloting cases, providing facilitators concise resources, inviting SDH-specific experts to co-debrief, and eliciting and incorporating learner and facilitator feedback to improve cases. SDH topics include homelessness, undocumented status, and racism. Results: Prior to the start of the quality improvement work, SDH were rarely incorporated into emergency simulations for pediatric residents. A p-chart was used to track the percentage of monthly cases that incorporated SDH topics. During the study period, the percentage of simulations including SDH topics increased to 57% per month. Most trainees (94%) welcomed incorporating SDH objectives. Conclusions: Using the Model for Improvement, we incorporated SDH objectives into pediatric resident emergency simulations. Next steps include examining effectiveness of the curriculum, dissemination to additional learners, and examining sustainability in practice.

Bundled Care to Reduce Sepsis Mortality: The Improving Pediatric Sepsis Outcomes (IPSO) Collaborative.

OBJECTIVES: We sought to improve utilization of a sepsis care bundle and decrease 3- and 30- day sepsis-attributable mortality, as well as determine which care elements of a sepsis bundle are associated with improved outcomes. METHODS: Children's Hospital Association formed a QI collaborative to Improve Pediatric Sepsis Outcomes (IPSO) (January 2017-March 2020 analyzed here). IPSO Suspected Sepsis (ISS) patients were those without organ dysfunction where the provider "intended to treat" sepsis. IPSO Critical Sepsis (ICS) patients approximated those with septic shock. Process (bundle adherence), outcome (mortality), and balancing measures were quantified over time using statistical process control. An original bundle (recognition method, fluid bolus < 20 min, antibiotics < 60 min) was retrospectively compared with varying bundle time-points, including a modified evidence-based care bundle, (recognition method, fluid bolus < 60 min, antibiotics < 180 min). We compared outcomes using Pearson χ-square and Kruskal Wallis tests and adjusted analysis. RESULTS: Reported are 24 518 ISS and 12 821 ICS cases from 40 children's hospitals (January 2017-March 2020). Modified bundle compliance demonstrated special cause variation (40.1% to 45.8% in ISS; 52.3% to 57.4% in ICS). The ISS cohort's 30-day, sepsis-attributable mortality dropped from 1.4% to 0.9%, a 35.7% relative reduction over time (P < .001). In the ICS cohort, compliance with the original bundle was not associated with a decrease in 30-day sepsis-attributable mortality, whereas compliance with the modified bundle decreased mortality from 4.75% to 2.4% (P < .01). CONCLUSIONS: Timely treatment of pediatric sepsis is associated with reduced mortality. A time-liberalized care bundle was associated with greater mortality reductions.

Characteristics and Outcomes of Sepsis Presenting in Inpatient Pediatric Settings.

OBJECTIVE: The pediatric sepsis literature lacks studies examining the inpatient setting, yet sepsis remains a leading cause of death in children's hospitals. More information is needed about sepsis arising in patients already hospitalized to improve morbidity and mortality outcomes. This study describes the clinical characteristics, process measures, and outcomes of inpatient sepsis cases compared with emergency department (ED) sepsis cases within the Improving Pediatric Sepsis Outcomes data registry from 46 hospitals that care for children. METHODS: This retrospective cohort study included Improving Pediatric Sepsis Outcomes sepsis cases from January 2017 to December 2019 with onset in inpatient or ED. We used descriptive statistics to compare inpatient and ED sepsis metrics and describe inpatient sepsis outcomes. RESULTS: The cohort included 26 855 cases; 8.4% were inpatient and 91.6% were ED. Inpatient cases had higher sepsis-attributable mortality (2.0% vs 1.4%, P = .025), longer length of stay after sepsis recognition (9 vs 5 days, P <.001), more intensive care admissions (57.6% vs 54.1%, P = .002), and greater average vasopressor use (18.0% vs 13.6%, P <.001) compared with ED. In the inpatient cohort, >40% of cases had a time from arrival to recognition within 12 hours. In 21% of cases, this time was >96 hours. Improved adherence to sepsis treatment bundles over time was associated with improved 30-day sepsis-attributable mortality for inpatients with sepsis. CONCLUSIONS: Inpatient sepsis cases had longer lengths of stay, more need for intensive care, and higher vasopressor use. Sepsis-attributable mortality was significantly higher in inpatient cases compared with ED cases and improved with improved sepsis bundle adherence.

Age-Dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-Associated Thrombosis in Critically Ill Children: A Post Hoc Analysis of a Bayesian Phase 2b Randomized Clinical Trial.

OBJECTIVES: We explored the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against central venous catheter-associated deep venous thrombosis in critically ill children. DESIGN: Post hoc analysis of a Bayesian phase 2b randomized clinical trial. SETTING: Seven PICUs. PATIENTS: Children less than 18 years old with newly inserted central venous catheter. INTERVENTIONS: Enoxaparin started less than 24 hours after insertion of central venous catheter and adjusted to anti-Xa level of 0.2-0.5 international units/mL versus usual care. MEASUREMENTS AND MAIN RESULTS: Of 51 children randomized, 24 were infants less than 1 year old. Risk ratios of central venous catheter-associated deep venous thrombosis with prophylaxis with enoxaparin were 0.98 (95% credible interval, 0.37-2.44) in infants and 0.24 (95% credible interval, 0.04-0.82) in older children greater than or equal to 1 year old. Infants and older children achieved anti-Xa level greater than or equal to 0.2 international units/mL at comparable times. While central venous catheter was in situ, endogenous thrombin potential, a measure of thrombin generation, was 223.21 nM.min (95% CI, 8.78-437.64 nM.min) lower in infants. Factor VIII activity, a driver of thrombin generation, was also lower in infants by 45.1% (95% CI, 15.7-74.4%). Median minimum platelet count while central venous catheter was in situ was higher in infants by 39 × 103/mm3 (interquartile range, 17-61 × 103/mm3). Central venous catheter:vein ratio was not statistically different. Prophylaxis with enoxaparin was less efficacious against central venous catheter-associated deep venous thrombosis at lower factor VIII activity and at higher platelet count. CONCLUSIONS: The relatively lesser contribution of thrombin generation on central venous catheter-associated thrombus formation in critically ill infants potentially explains the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin.

Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children: A Bayesian Phase 2b Randomized Clinical Trial.

OBJECTIVES: We obtained preliminary evidence on the efficacy of early prophylaxis on the risk of central venous catheter-associated deep venous thrombosis and its effect on thrombin generation in critically ill children. DESIGN: Bayesian phase 2b randomized clinical trial. SETTING: Seven PICUs. PATIENTS: Children less than 18 years old with a newly inserted central venous catheter and at low risk of bleeding. INTERVENTION: Enoxaparin adjusted to anti-Xa level of 0.2-0.5 international units/mL started at less than 24 hours after insertion of central venous catheter (enoxaparin arm) versus usual care without placebo (usual care arm). MEASUREMENTS AND MAIN RESULTS: At the interim analysis, the proportion of central venous catheter-associated deep venous thrombosis on ultrasonography in the usual care arm, which was 54.2% of 24 children, was significantly higher than that previously reported. This resulted in misspecification of the preapproved Bayesian analysis, reversal of direction of treatment effect, and early termination of the randomized clinical trial. Nevertheless, with 30.4% of 23 children with central venous catheter-associated deep venous thrombosis on ultrasonography in the enoxaparin arm, risk ratio of central venous catheter-associated deep venous thrombosis was 0.55 (95% credible interval, 0.24-1.11). Including children without ultrasonography, clinically relevant central venous catheter-associated deep venous thrombosis developed in one of 27 children (3.7%) in the enoxaparin arm and seven of 24 (29.2%) in the usual care arm (p = 0.02). Clinically relevant bleeding developed in one child randomized to the enoxaparin arm. Response profile of endogenous thrombin potential, a measure of thrombin generation, was not statistically different between trial arms. CONCLUSIONS: These findings suggest the efficacy and safety of early prophylaxis that should be validated in a pivotal randomized clinical trial.

Early Enteral Nutrition Is Associated With Improved Clinical Outcomes in Critically Ill Children: A Secondary Analysis of Nutrition Support in the Heart and Lung Failure-Pediatric Insulin Titration Trial.

OBJECTIVES: The impact of early enteral nutrition on clinical outcomes in critically ill children has not been adequately described. We hypothesized that early enteral nutrition is associated with improved clinical outcomes in critically ill children. DESIGN: Secondary analysis of the Heart and Lung Failure-Pediatric Insulin Titration randomized controlled trial. SETTING: Thirty-five PICUs. PATIENTS: Critically ill children with hyperglycemia requiring inotropic support and/or invasive mechanical ventilation who were enrolled for at least 48 hours with complete nutrition data. INTERVENTIONS: Subjects received nutrition via guidelines that emphasized enteral nutrition and were classified into early enteral nutrition (enteral nutrition within 48 hr of study randomization) and no early enteral nutrition (enteral nutrition after 48 hr of study randomization, or no enteral nutrition at any time). MEASUREMENTS AND MAIN RESULTS: Of 608 eligible subjects, 331 (54%) received early enteral nutrition. Both early enteral nutrition and no early enteral nutrition groups had similar daily caloric intake over the first 8 study days (median, 36 vs 36 kcal/kg/d; p = 0.93). After controlling for age, body mass index z scores, primary reason for ICU admission, severity of illness, and mean Vasopressor-Inotrope Score at the time of randomization, and adjusting for site, early enteral nutrition was associated with lower 90-day hospital mortality (8% vs 17%; p = 0.007), more ICU-free days (median, 20 vs 17 d; p = 0.02), more hospital-free days (median, 8 vs 0 d; p = 0.003), more ventilator-free days (median, 21 vs 19 d; p = 0.003), and less organ dysfunction (median maximum Pediatric Logistic Organ Dysfunction, 11 vs 12; p < 0.001). CONCLUSIONS: In critically ill children with hyperglycemia requiring inotropic support and/or mechanical ventilation, early enteral nutrition was independently associated with better clinical outcomes.

Online Learning and Residents' Acquisition of Mechanical Ventilation Knowledge: Sequencing Matters.

OBJECTIVE: Rapid advancements in medicine and changing standards in medical education require new, efficient educational strategies. We investigated whether an online intervention could increase residents' knowledge and improve knowledge retention in mechanical ventilation when compared with a clinical rotation and whether the timing of intervention had an impact on overall knowledge gains. DESIGN: A prospective, interventional crossover study conducted from October 2015 to December 2017. SETTING: Multicenter study conducted in 33 PICUs across eight countries. SUBJECTS: Pediatric categorical residents rotating through the PICU for the first time. We allocated 483 residents into two arms based on rotation date to use an online intervention either before or after the clinical rotation. INTERVENTIONS: Residents completed an online virtual mechanical ventilation simulator either before or after a 1-month clinical rotation with a 2-month period between interventions. MEASUREMENTS AND MAIN RESULTS: Performance on case-based, multiple-choice question tests before and after each intervention was used to quantify knowledge gains and knowledge retention. Initial knowledge gains in residents who completed the online intervention (average knowledge gain, 6.9%; SD, 18.2) were noninferior compared with those who completed 1 month of a clinical rotation (average knowledge gain, 6.1%; SD, 18.9; difference, 0.8%; 95% CI, -5.05 to 6.47; p = 0.81). Knowledge retention was greater following completion of the online intervention when compared with the clinical rotation when controlling for time (difference, 7.6%; 95% CI, 0.7-14.5; p = 0.03). When the online intervention was sequenced before (average knowledge gain, 14.6%; SD, 15.4) rather than after (average knowledge gain, 7.0%; SD, 19.1) the clinical rotation, residents had superior overall knowledge acquisition (difference, 7.6%; 95% CI, 2.01-12.97;p = 0.008). CONCLUSIONS: Incorporating an interactive online educational intervention prior to a clinical rotation may offer a strategy to prime learners for the upcoming rotation, augmenting clinical learning in graduate medical education.

Decreasing Time to Antibiotics for Patients with Sepsis in the Emergency Department.

BACKGROUND: Sepsis is a significant cause of morbidity and mortality. Patients may present in a spectrum, from nonsevere sepsis through septic shock. Literature supports improvement in patient outcomes with timely care. This project describes an effort to improve delays in antibiotic administration in patients with sepsis spectrum disease presenting to a pediatric emergency department (PED). OBJECTIVE: This project aimed to decrease time to antibiotics for patients with sepsis in the PED from 154 to <120 minutes within 2 years. METHODS: Following the collection of baseline data, we assembled a multidisciplinary team. Specific interventions included staff education, the institution of a best practice alert with order set and standardized huddle response, and local stocking of antibiotics. We included all patients with orders for intravenous antibiotics and blood culture. RESULTS: From April 2015 to April 2017, the PED demonstrated reduction in time to antibiotics from 154 to 114 minutes. The time from emergency department (ED) arrival to antibiotic order also improved, from 87 to 59 minutes. CONCLUSIONS: This initiative improved prioritization and efficiency of care of sepsis, and overall time to antibiotics in this population. The results of this project demonstrate the effectiveness of a multidisciplinary team working to improve an essential time-driven process.

Barriers to Communication in a PICU: A Qualitative Investigation of Family and Provider Perceptions.

OBJECTIVES: Family and medical provider perceptions of communication barriers within the PICU are poorly understood. We designed a qualitative study to characterize the perspective of families and medical providers of critically ill children regarding communication barriers. The identified barriers may be used to direct efforts to improve communication. DESIGN: Semi-structured interviews were conducted from August 2017 to January 2018. Interviews were audio recorded and professionally transcribed verbatim. SETTING: A PICU at a tertiary care academic center. PATIENTS: Forty-two families whose children were admitted to the PICU (excluding patients receiving end-of-life care or with protective services involvement) and 12 PICU staff members, including nurses, residents, fellows, and attending's. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An interprofessional team of a physician, nurse manager, and medical student coded the transcripts. Interviewing continued until thematic saturation was reached. Codes were organized into common themes using a modified constant comparative method. The families interviewed represented 16 previously healthy children, and 26 children with a chronic health condition. Staff interviewed included three residents, three fellows, three attending intensivists, and three nurses. Participants' perceptions and experiences of barriers to communication included the following: 1) Communication breakdowns related to coordination of care among several services, 2) Family-centered rounds are insufficient for effective communication, 3) Undervaluing the knowledge of families of children with chronic health conditions or special needs, and 4) Communication breakdowns occur across provider hand-offs. Theme 3 was identified by families, but not by providers. CONCLUSIONS: Families and medical providers both identified several barriers to communication. However, only families identified the barrier "Undervaluing the knowledge of families with chronically ill children." Future work should explore these barriers and the discrepancy in perception between providers and families to determine if there are interventions that improve both family satisfaction and patient care.

Short-Term Adverse Outcomes Associated With Hypoglycemia in Critically Ill Children.

OBJECTIVES: Previous studies report worse short-term outcomes with hypoglycemia in critically ill children. These studies relied on intermittent blood glucose measurements, which may have introduced detection bias. We analyzed data from the Heart And Lung Failure-Pediatric INsulin Titration trial to determine the association of hypoglycemia with adverse short-term outcomes in critically ill children. DESIGN: Nested case-control study. SETTING: Thirty-five PICUs. A computerized algorithm that guided the timing of blood glucose measurements and titration of insulin infusion, continuous glucose monitors, and standardized glucose infusion rates were used to minimize hypoglycemia. PATIENTS: Nondiabetic children with cardiovascular and/or respiratory failure and hyperglycemia. Cases were children with any hypoglycemia (blood glucose < 60 mg/dL), whereas controls were children without hypoglycemia. Each case was matched with up to four unique controls according to age group, study day, and severity of illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 112 (16.0%) of 698 children who received the Heart And Lung Failure-Pediatric INsulin Titration protocol developed hypoglycemia, including 25 (3.6%) who developed severe hypoglycemia (blood glucose < 40 mg/dL). Of these, 110 cases were matched to 427 controls. Hypoglycemia was associated with fewer ICU-free days (median, 15.3 vs 20.2 d; p = 0.04) and fewer hospital-free days (0 vs 7 d; p = 0.01) through day 28. Ventilator-free days through day 28 and mortality at 28 and 90 days did not differ between groups. More children with insulin-induced versus noninsulin-induced hypoglycemia had zero ICU-free days (35.8% vs 20.9%; p = 0.008). Outcomes did not differ between children with severe versus nonsevere hypoglycemia or those with recurrent versus isolated hypoglycemia. CONCLUSIONS: When a computerized algorithm, continuous glucose monitors and standardized glucose infusion rates were used to manage hyperglycemia in critically ill children with cardiovascular and/or respiratory failure, severe hypoglycemia (blood glucose < 40 mg/dL) was uncommon, but any hypoglycemia (blood glucose < 60 mg/dL) remained common and was associated with worse short-term outcomes.

Sera From Children After Cardiopulmonary Bypass Reduces Permeability of Capillary Endothelial Cell Barriers.

OBJECTIVES: Children undergoing cardiopulmonary bypass develop clinically impactful capillary leak of unclear etiology. A widely held hypothesis that exposure of circulating cells to the cardiopulmonary bypass circuit induces the release of inflammatory mediators that act to disrupt intercellular junctions of capillary endothelial cells inducing paracellular capillary leak either directly or through new gene expression. DESIGN: Cohort study. SETTING: Tertiary pediatric hospital. PATIENTS: Twenty children undergoing surgery with cardiopulmonary bypass for congenital heart disease. Serum was collected before cardiopulmonary bypass, 2 hours after cardiopulmonary bypass, and 18 hours after cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed the effects of 10% patient sera on the "function, structure, and gene expression" of cultured human dermal and pulmonary microvascular endothelial cells. Changes in barrier "function" were measured using transendothelial electrical resistance. Associations between changes in transendothelial electrical resistance and subject characteristics were analyzed using linear mixed effects model with area under the resistance curve as outcome. Changes in junctional "structure" were assessed by analyzing the organization of the endothelial cell junctional proteins claudin-5 and VE-cadherin using immunofluorescence microscopy. Changes in inflammatory "gene expression" were measured using real-time quantitative reverse transcription-polymerase chain reaction. All serum samples induced a transient, 120-minute increase in transendothelial electrical resistance followed by persistent loss of barrier function. Unexpectedly, sera collected postcardiopulmonary bypass-induced significantly less loss of barrier function in both dermal and pulmonary capillary endothelial cell compared with precardiopulmonary bypass sera. Consistent with the transendothelial electrical resistance results, claudin-5 and vascular endothelial-cadherin junctional staining showed less disruption in cultures treated with postcardiopulmonary bypass sera. Expression of genes commonly associated with inflammation was largely unaffected by patient sera. CONCLUSIONS: Contrary to the hypothesis, sera taken from children after cardiopulmonary bypass induces less capillary barrier disruption relative to sera taken from children before cardiopulmonary bypass, and none of the sera induced significant changes in expression of inflammatory genes.

Reducing Unplanned Extubations Across a Children's Hospital Using Quality Improvement Methods.

INTRODUCTION: Children who require an endotracheal (ET) tube for care during critical illness are at risk of unplanned extubations (UE), or the unintended dislodgement or removal of an ET tube that can lead to significant patient harm. A proposed national benchmark is 1 UE per 100 ventilator days. We aimed to reduce the rate of UEs in our intensive care units (ICUs) from 1.20 per 100 ventilator days to below the national benchmark within 2 years. METHODS: We identified several key drivers including ET securement standardization, safety culture, and strategies for high-risk situations. We employed quality improvement methodologies including apparent cause analysis and plan-do-study-act cycles to improve our processes and outcomes. RESULTS: Over 2 years, we reduced the rate of UEs hospital-wide by 75% from 1.2 to 0.3 per 100 ventilator days. We eliminated UEs in the pediatric ICU during the study period, while the UE rate in the neonatal ICU also decreased from 1.2 to 0.3 per 100 ventilator days. CONCLUSION: We demonstrated that by using quality improvement methodology, we successfully reduced our rate of UE by 75% to a level well below the proposed national benchmark.

Vitamin D Status After Cardiopulmonary Bypass in Children With Congenital Heart Disease.

Deficiency in 25-hydroxyvitamin D (25OHD) is associated with increased morbidity and mortality in the critically ill. Children who underwent surgery for congenital heart disease under cardiopulmonary bypass (CPB) are typically deficient in 25OHD. It is unclear whether this deficiency is due to CPB. We hypothesized that CPB reduces the levels of 25OHD in children with congenital heart disease. We conducted a prospective observational study on children aged 2 months to 17 years who underwent CPB. Serum was collected at 3 time points: immediately before, immediately after surgery, and 24 hours after surgery. 25-Hydroxyvitamin D, 1,25-dihydroxyvitamin D, 1,25(OH)2D, vitamin D binding protein, and albumin levels were measured. Levels were compared using repeated measures analysis of variance. We enrolled 20 patients, 40% were deficient in 25OHD with levels <20 ng/mL prior to surgery. Mean (±standard deviation) of 25OHD at the 3 time points was 21.3 ± 8 ng/mL, 19 ± 5.8 ng/mL, and 19.5 ± 6.6 ng/mL, respectively ( P = .02). The decrease in 25OHD was observed primarily in children with sufficient levels of 25OHD, with mean levels at the 3 time points: 26.8 ± 4.2 ng/mL, 21.5 ± 5.7 ng/mL, and 23.0 ± 4.9 ng/mL, respectively ( P < .001). Calculated means of free fraction of 25OHD at the 3 time points were 6.2 ± 2.8 pg/mL, 5.8 ± 2.2 pg/mL, and 5.5 ± 2.4 pg/mL, respectively, ( P = .04). Mean levels of 1,25(OH)2D were 63.7 ± 34.9 ng/mL, 53.2 ± 30.6 ng/mL, and 67.7 ± 23.5 ng/mL ( P = .04). Vitamin D binding protein and albumin levels did not significantly change. Cardiopulmonary bypass decreases 25OHD by reducing the free fraction. Current investigations are geared to establish whether vitamin D deficiency is associated with outcomes and if treatment is appropriate.

Risk Factors for Delayed Enteral Nutrition in Critically Ill Children.

OBJECTIVE: Delayed enteral nutrition, defined as enteral nutrition started 48 hours or more after admission to the PICU, is associated with an inability to achieve full enteral nutrition and worse outcomes in critically ill children. We reviewed nutritional practices in six medical-surgical PICUs and determined risk factors associated with delayed enteral nutrition in critically ill children. DESIGN: Retrospective cross-sectional study using medical records as source of data. SETTING: Six medical-surgical PICUs in northeastern United States. PATIENTS: Children less than 21 years old admitted to the PICU for 72 hours or more excluding those awaiting or recovering from abdominal surgery. MEASUREMENTS AND MAIN RESULTS: A total of 444 children with a median age of 4.0 years were included in the study. Enteral nutrition was started at a median time of 20 hours after admission to the PICU. There was no significant difference in time to start enteral nutrition among the PICUs. Of those included, 88 children (19.8%) had delayed enteral nutrition. Risk factors associated with delayed enteral nutrition were noninvasive (odds ratio, 3.37; 95% CI, 1.69-6.72) and invasive positive-pressure ventilation (odds ratio, 2.06; 95% CI, 1.15-3.69), severity of illness (odds ratio for every 0.1 increase in pediatric index of mortality 2 score, 1.39; 95% CI, 1.14-1.71), procedures (odds ratio, 3.33; 95% CI, 1.67-6.64), and gastrointestinal disturbances (odds ratio, 2.05; 95% CI, 1.14-3.68) within 48 hours after admission to the PICU. Delayed enteral nutrition was associated with failure to reach full enteral nutrition while in the PICU (odds ratio, 4.09; 95% CI, 1.97-8.53). Nutrition consults were obtained in less than half of the cases, and none of the PICUs used tools to assure the adequacy of energy and protein nutrition. CONCLUSIONS: Institutions in this study initiated enteral nutrition for a high percentage of patients by 48 hours of admission. Noninvasive positive-pressure ventilation was most strongly associated with delay enteral nutrition. A better understanding of these risk factors and assessments of nutritional requirements should be explored in future prospective studies.

Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells.

BACKGROUND: Many cancers show aberrant silencing of gene expression and overexpression of histone methyltransferases. The histone methyltransferases (HKMT) EZH2 and EHMT2 maintain the repressive chromatin histone methylation marks H3K27me and H3K9me, respectively, which are associated with transcriptional silencing. Although selective HKMT inhibitors reduce levels of individual repressive marks, removal of H3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducing the expression of genes with multiple repressive marks. RESULTS: We report that gene expression and inhibition of triple negative breast cancer cell growth (MDA-MB-231) are markedly increased when targeting both EZH2 and EHMT2, either by siRNA knockdown or pharmacological inhibition, rather than either enzyme independently. Indeed, expression of certain genes is only induced upon dual inhibition. We sought to identify compounds which showed evidence of dual EZH2 and EHMT2 inhibition. Using a cell-based assay, based on the substrate competitive EHMT2 inhibitor BIX01294, we have identified proof-of-concept compounds that induce re-expression of a subset of genes consistent with dual HKMT inhibition. Chromatin immunoprecipitation verified a decrease in silencing marks and an increase in permissive marks at the promoter and transcription start site of re-expressed genes, while Western analysis showed reduction in global levels of H3K27me3 and H3K9me3. The compounds inhibit growth in a panel of breast cancer and lymphoma cell lines with low to sub-micromolar IC50s. Biochemically, the compounds are substrate competitive inhibitors against both EZH2 and EHMT1/2. CONCLUSIONS: We have demonstrated that dual inhibition of EZH2 and EHMT2 is more effective at eliciting biological responses of gene transcription and cancer cell growth inhibition compared to inhibition of single HKMTs, and we report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells.

A pediatric critical care perspective on vitamin D.

The mechanisms of action of vitamin D are the subject of intense investigation. Evidence now suggests vitamin D affects immune function and cell proliferation, prompting interest in its role in critical illness and cardiac disease. Multiple studies demonstrate strong associations between vitamin D deficiency and severity of illness including need for higher inotrope support, more fluid resuscitation, and longer intensive care unit stay. The pediatric cardiac population may be at even more risk and nearly twice as likely to be deficient compared to the noncardiac population. Low vitamin D levels have been found in postoperative cardiac patients, where investigators speculate cardiopulmonary bypass alters levels directly or indirectly. Patients with congestive heart failure who are deficient also seem to benefit from vitamin D supplementation. This review summarizes recent studies in children that investigate the relation between vitamin D status and clinical outcomes in the critically ill including those with cardiac disease.