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.

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.

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.

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.

Younger Age and Female Gender Are Associated With Delayed Antibiotics in Pediatric Sepsis.

Sepsis is a leading cause of pediatric mortality and timely antibiotic administration has been shown to improve outcomes. In this retrospective review of a single center sepsis dataset, we identified younger age and female sex as more likely to have delays in antibiotics.

Control of serum glucose concentration in critical illness.

PURPOSE OF REVIEW: Hyperglycemia is a significant problem for children in the ICU. Use of tight glycemic control (TGC) to manage hyperglycemia remains controversial, especially given the potential risk of insulin-induced hypoglycemia. This review will address the latest evidence regarding TGC in critically ill children. RECENT FINDINGS: Two randomized controlled trials (RCT) involving primarily postoperative cardiac surgery patients demonstrated the feasibility and safety of TGC in pediatric patients. The trials, however, had discrepant results with regards to the benefit of TGC. There is also uncertainty about the generalizability of these results to nonpostoperative cardiac patients. There is only one published study addressing the long-term safety of TGC in children. In this study, hypoglycemia was not associated with adverse effects on neurocognitive development. In contrast, articles from adult studies demonstrate increased risk of death with hypoglycemia. SUMMARY: Although the clinical benefit of TGC in critically ill children is still unclear, TGC can be done safely in this population.

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.

Transport disposition using the Transport Risk Assessment in Pediatrics (TRAP) score.

BACKGROUND: Determining appropriate disposition for referred pediatric patients is difficult, since it relies primarily on a telephone description of the patient. In this study, we evaluate the Transport Risk Assessment in Pediatrics (TRAP) score's ability to assist in appropriate placement of these patients. This novel tool is derived from physiologic variables. OBJECTIVES: To determine the feasibility of calculating a TRAP score and whether a higher score correlates with pediatric intensive care unit (PICU) admission. METHODS: We performed an observational study of pediatric patients transported by a specialized team to a tertiary care center and the feasibility of implementing the TRAP tool. Patients were eligible if transported by the pediatric specialty transport team for direct admission to the children's hospital. The TRAP score was obtained either through chart review of the transport team's initial assessment or in real time by the transport team. RESULTS: A total of 269 patients were identified, with 238 patients included in the study. Using logistic regression, higher TRAP scores were associated with PICU admission (odds ratio [OR] 1.40, p < 0.001). Patients with a higher score were also less likely to leave the PICU within 24 hours (OR 0.79, p < 0.001). CONCLUSION: The TRAP score is a novel objective pediatric transport assessment tool where an elevated score is associated with PICU admission for more than 24 hours. This score may assist with the triage decisions for transported pediatric patients.

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.

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.

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.

Retrospective outcomes of glucose control in critically ill children.

BACKGROUND: Hyperglycemia is a significant problem for critically ill children. Treatment for hyperglycemia remains controversial. This study explores the effect of controlling blood glucose (BG) in hyperglycemic critically ill children. METHODS: A retrospective cohort of nondiabetic critically ill children (defined as requiring mechanical ventilation and/or vasopressors) with BG persistently ≥ 150 mg/dl and treated with insulin (treatment group) were compared with a historical cohort of similar children who did not receive interventions to control hyperglycemia (baseline group). RESULTS: There were 130 children in the treatment group and 137 children in the baseline group. Mean BG in the treatment group was 140 ± 24 mg/dl compared with 179 ± 47 mg/dl in the baseline group (p < .001). After adjusting for patient characteristics, cointerventions, and glucose metrics, patients in the treatment group had 2.5 fewer intensive care unit (ICU)-free days (i.e., number of days alive and discharged from ICU within 28 days after inclusion) than the baseline group (p = .023). Glucose control was not independently associated with duration of ICU stay, ventilator-free days, vasopressor-free days, or mortality. CONCLUSIONS: Blood glucose control appears associated with worse outcomes in critically ill children. Our data combined with conflicting results in adults leads us to strongly advocate for the conduct of randomized trials on glucose control in critically ill children.