Cincinnati Children's Hospital Medical Center

Background Our objective was to better understand the natural history and disease modifiers of Alpha-1-antitrypsin deficiency (AATD), a common genetic liver disease causing hepatitis and cirrhosis in adults and children. The clinical course is highly variable. Some infants present with neonatal cholestasis, which can resolve spontaneously or progress to cirrhosis; others are well in infancy, only to develop portal hypertension later in childhood. Methods The Childhood Liver Disease Research Network has been enrolling AATD participants into longitudinal, observational studies at North American tertiary centers since 2004. We examined the clinical courses of 2 subgroups of participants from the several hundred enrolled; first, those presenting with neonatal cholestasis captured by a unique study, enrolled because of neonatal cholestasis but before specific diagnosis, then followed longitudinally (n=46); second, separately, all participants who progressed to liver transplant (n=119). Results We found male predominance for neonatal cholestasis in AATD (65% male, p =0.04), an association of neonatal gamma-glutamyl transpeptidase elevation to more severe disease, and a higher rate of neonatal cholestasis progression to portal hypertension than previously reported (41%) occurring at median age of 5 months. Participants with and without preceding neonatal cholestasis were at risk of progression to transplant. Participants who progressed to liver transplant following neonatal cholestasis were significantly younger at transplant than those without neonatal cholestasis (4.1 vs. 7.8 years, p =0.04, overall range 0.3–17 years). Neonatal cholestasis had a negative impact on growth parameters. Coagulopathy and varices were common before transplant, but gastrointestinal bleeding was not. Conclusions Patients with AATD and neonatal cholestasis are at risk of early progression to severe liver disease, but the risk of severe disease extends throughout childhood. Careful attention to nutrition and growth is needed.

Background Pediatric metabolic-associated fatty liver disease (MAFLD) is a global health problem, with lifestyle modification as its major therapeutic strategy. Rigorous characterization of dietary content on MAFLD in children is lacking. We hypothesized an objectively measured healthier diet would positively modulate MAFLD. Methods Diet was assessed using the Nutrition Data System for Research in children enrolled from 10 tertiary clinical centers to determine the Healthy Eating Index (HEI, 0–100) and individual food components. Results In all, 119 children were included (13.3 ± 2.7 y), 80 (67%) male, 67 (18%) White, and 90 (76%) Hispanic, with an average body mass index Z-score of 2.2 ± 0.5. Diet was classified as low HEI < 47.94 (n = 39), mid HEI ≥ 47.94 and < 58.89 (n = 41), or high HEI ≥ 58.89 (n=39). Children with high HEI (healthier diet) had lower body weight ( p = 0.005) and more favorable lipids. Mean serum triglycerides for low, mid, and high HEI were 163, 148, and 120 mg/dL, respectively; p = 0.04 mid versus high, p = 0.01 low versus high. Mean HDL was 38, 41 and 43 mg/dL; p = 0.02 low vs high. Less severe steatosis was noted with added sugar ≤ 10% of calories ( p = 0.03). Higher lobular inflammation is associated with a higher percentage of calories from fat (OR (95% CI) = 0.95 (0.91–1.00), p = 0.04). Conclusions In children with MAFLD, high HEI is associated with lower body weight and more favorable lipids, while added sugar and fat intake has individual histologic features. Differential consumption of major dietary components may modify both metabolic risk factors and histologic liver injury, highlighting the importance of objective diet assessments in children with MAFLD.

Cardiac surgery-associated acute kidney injury (CS-AKI) is common, but its impact on clinical outcomes is variable. Parsing AKI into sub-phenotype(s) and integrating pathologic positive cumulative fluid balance (CFB) may better inform prognosis. We sought to determine whether durational sub-phenotyping of CS-AKI with CFB strengthens association with outcomes among neonates undergoing the Norwood procedure. Multicenter, retrospective cohort study from the Neonatal and Pediatric Heart and Renal Outcomes Network. Transient CS-AKI: present only on post-operative day (POD) 1 and/or 2; persistent CS-AKI: continued after POD 2. CFB was evaluated per day and peak CFB during the first 7 postoperative days. Primary and secondary outcomes were mortality, respiratory support-free and hospital-free days (at 28, 60 days, respectively). The primary predictor was persistent CS-AKI, defined by modified neonatal Kidney Disease: Improving Global Outcomes criteria. CS-AKI occurred in 59% (205/347) neonates: 36.6% (127/347) transient and 22.5% (78/347) persistent; CFB > 10% occurred in 18.7% (65/347). Patients with either persistent CS-AKI or peak CFB > 10% had higher mortality. Combined persistent CS-AKI with peak CFB > 10% (n = 21) associated with increased mortality (aOR: 7.8, 95% CI: 1.4, 45.5; p = 0.02), decreased respiratory support-free (predicted mean 12 vs. 19; p < 0.001) and hospital-free days (17 vs. 29; p = 0.048) compared to those with neither. The combination of persistent CS-AKI and peak CFB > 10% after the Norwood procedure is associated with mortality and hospital resource utilization. Prospective studies targeting intra- and postoperative CS-AKI risk factors and reducing CFB have the potential to improve outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information

Background Pulmonary hypoplasia is the primary cause of perinatal death in lethal skeletal dysplasias. The antenatal ultrasound correlates for lethality are indirect, measuring the thorax (thoracic circumference, TC) or femur compared to the abdomen (TC/AC, FL/AC). A single study has correlated lethality with the observed-to-expected total lung volume (O/E-TFLV) on fetal MRI in 23 patients. Objective Our aim was to define a cutoff value to predict lethality more specifically using MRI-derived O/E-TFLV. Materials and methods Two large fetal center databases were searched for fetuses with skeletal dysplasia and MRI; O/E-TFLV was calculated. Ultrasound measures were included when available. Each was evaluated as a continuous variable against lethality (stillbirth or death in the first month of life). Logistic regression and receiver operating characteristic (ROC) curve analyses evaluated the prediction ability. AUC, sensitivity, and specificity were calculated. P < 0.05 was considered statistically significant. Results A total of 80 fetuses met inclusion criteria. O/E-TFLV < 0.49 was a significant risk factor in predicting lethality, with sensitivity and specificity of 0.63 and 0.93, respectively, and an AUC of 0.81 (P < 0.001). FL/AC < 0.129 was also a strong variable with sensitivity, specificity, and AUC of 0.73, 0.88, and 0.78, respectively (P < 0.001). TC/AC and TC percentile were not significant risk factors for lethality. An O/E-TFLV of < 0.38 defines a specificity for lethality at 1.00. Conclusion MRI-derived O/E-TFLV and US-derived FL/AC are significant predictors of lethality in fetuses with skeletal dysplasia. When prognosis is uncertain after ultrasound, calculation of MRI-derived O/E-TFLV may provide additional useful information for prognosis and delivery planning. Graphical abstract

Importance The utility of adenotonsillectomy in children who have habitual snoring without frequent obstructive breathing events (mild sleep-disordered breathing [SDB]) is unknown. Objectives To evaluate early adenotonsillectomy compared with watchful waiting and supportive care (watchful waiting) on neurodevelopmental, behavioral, health, and polysomnographic outcomes in children with mild SDB. Design, Setting, and Participants Randomized clinical trial enrolling 459 children aged 3 to 12.9 years with snoring and an obstructive apnea-hypopnea index (AHI) less than 3 enrolled at 7 US academic sleep centers from June 29, 2016, to February 1, 2021, and followed up for 12 months. Intervention Participants were randomized 1:1 to either early adenotonsillectomy (n = 231) or watchful waiting (n = 228). Main Outcomes and Measures The 2 primary outcomes were changes from baseline to 12 months for caregiver-reported Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite (GEC) T score, a measure of executive function; and a computerized test of attention, the Go/No-go (GNG) test d-prime signal detection score, reflecting the probability of response to target vs nontarget stimuli. Twenty-two secondary outcomes included 12-month changes in neurodevelopmental, behavioral, quality of life, sleep, and health outcomes. Results Of the 458 participants in the analyzed sample (231 adenotonsillectomy and 237 watchful waiting; mean age, 6.1 years; 230 female [50%]; 123 Black/African American [26.9%]; 75 Hispanic [16.3%]; median AHI, 0.5 [IQR, 0.2-1.1]), 394 children (86%) completed 12-month follow-up visits. There were no statistically significant differences in change from baseline between the 2 groups in executive function (BRIEF GEC T-scores: −3.1 for adenotonsillectomy vs −1.9 for watchful waiting; difference, −0.96 [95% CI, −2.66 to 0.74]) or attention (GNG d-prime scores: 0.2 for adenotonsillectomy vs 0.1 for watchful waiting; difference, 0.05 [95% CI, −0.18 to 0.27]) at 12 months. Behavioral problems, sleepiness, symptoms, and quality of life each improved more with adenotonsillectomy than with watchful waiting. Adenotonsillectomy was associated with a greater 12-month decline in systolic and diastolic blood pressure percentile levels (difference in changes, −9.02 [97% CI, −15.49 to −2.54] and −6.52 [97% CI, −11.59 to −1.45], respectively) and less progression of the AHI to greater than 3 events/h (1.3% of children in the adenotonsillectomy group compared with 13.2% in the watchful waiting group; difference, −11.2% [97% CI, −17.5% to −4.9%]). Six children (2.7%) experienced a serious adverse event associated with adenotonsillectomy. Conclusions In children with mild SDB, adenotonsillectomy, compared with watchful waiting, did not significantly improve executive function or attention at 12 months. However, children with adenotonsillectomy had improved secondary outcomes, including behavior, symptoms, and quality of life and decreased blood pressure, at 12-month follow-up. Trial Registration ClinicalTrials.gov Identifier: NCT02562040

Background Informed consent for surgery is a complex process particularly in paediatrics. Complexity increases with procedures such as CHD surgery. Regulatory agencies outline informed consent contents for surgery. We assessed and described CHD surgical informed consent contents through survey dissemination to paediatric CHD centres across United States of America. Methods Publicly available email addresses for 125 paediatric cardiac clinicians at 70 CHD surgical centres were obtained. Nine-item de-identified survey assessing adherence to The Joint Commission informed consent standards was created and distributed via RedCap® 14 March, 2023. A follow-up email was sent 29 March, 2023. Survey link was closed 18 April, 2023. Results Thirty-seven surveys were completed. Results showed informed consent documents were available in both paper (25, 68%) and electronic (3, 8%) format. When both (9, 24%) formats were available, decision on which format to use was based on centre protocols (1, 11%), clinician personal preference (3, 33%), procedure being performed (1, 11%), or other (4, 45%). Five (13%) centres’ informed consent documents were available only in English, with 32 (87%) centres also having a Spanish version. Review of informed consent documents demonstrated missing The Joint Commission elements including procedure specific risks, benefits, treatment alternatives, and expected outcomes. Conclusions Informed consent for CHD surgery is a complex process with multiple factors involved. Majority of paediatric CHD surgical centres in the United States of America used a generic informed consent document which did not uniformly contain The Joint Commission specified information nor reflect time spent in discussion with families. Further research is needed on parental comprehension during the informed consent process.

Background Increasingly, efforts to advance health and well-being across whole organization, health systems, and communities include many related initiatives aligned to a common mission or goal. Too often, the work across a system suffers from ‘project-itis,’ lacking rigor in consistent design and learning systems to set up the work for real-time learning in support of success towards ultimate aims. To evaluate the work of QI implementation at project and organizational levels, we require systematic approaches to answer key learning questions and accelerate progress to our aims. Objectives and Methods To identify and apply approaches to organizational learning we used in 2 case studies, one at the organization and one at the community level, to learn from for system-wide impact. The Cincinnati, Ohio All Children Thrive (ACT) Learning Network uses guiding principles to support system alignment. These include: focus on unassailable goals, amplify the voices of those with lived experience and apply rigorous improvement science across the many sectors that influence health. The Institute for Healthcare Improvement (IHI) organization-based learning system is guided by 3 key evaluation questions. We developed or deployed a set of tools, and drawn from established Improvement and Implementation Science frameworks, to undertake a regular review of project progress, learn from and act on the programmatic and contextual factors that were enabling or impeding progress towards the project goals, and understand the causal pathway for the results we observed. Results and Conclusions We report on system design principles drawn from the two case examples. ACT’s learning system is applied at the neighborhood, city, and county level and has closed disparity gaps in a number of outcomes including preterm births, hospitalizations, and educational outcomes. IHI applied a novel framework for improvement research and evaluation across its portfolio of project work (more than 40 projects spanning a variety of content areas, project designs, and geographic settings). Systematic learning approach can be applied at organizational or community level to evaluate and learn from initiatives that are underway and to accelerate the path to achievement of organizational and community improvement goals.

Importance Pediatric ventilator-associated events (PedVAEs, defined as a sustained worsening in oxygenation after a baseline period of stability or improvement) are useful for surveillance of complications from mechanical ventilation. It is unclear whether interventions to mitigate known risk factors can reduce PedVAE rates. Objective To assess whether adherence to 1 or more test factors in a quality improvement bundle was associated with a reduction in PedVAE rates. Design, Setting, and Participants This multicenter quality improvement study obtained data from 2017 to 2020 for patients who were mechanically ventilated and cared for in neonatal, pediatric, and cardiac intensive care units (ICUs). These ICUs were located in 95 hospitals participating in the Children’s Hospitals’ Solutions for Patient Safety (SPS) network in North America. Data analyses were performed between September 2021 and April 2023. Intervention A quality improvement bundle consisted of 3 test factors: multidisciplinary apparent cause analysis, daily discussion of extubation readiness, and daily discussion of fluid balance goals. This bundle was distributed to a subgroup of hospitals that volunteered to participate in a collaborative PedVAE prevention initiative under the SPS network guidance in July 2018. Main Outcomes and Measures Each SPS network hospital submitted monthly PedVAE rates from January 1, 2017, to May 31, 2020, and test factor data were submitted from July 1, 2018, to May 31, 2020. Analyses focused on hospitals that reliably submitted PedVAE rate data, defined as outcomes data submission through May 31, 2020, for at least 80% of the baseline and postbaseline periods. Results Of the 95 hospitals in the SPS network that reported PedVAE data, 21 were grouped in the Pioneer cohort and 74 in the non-Pioneer cohort. Only 12 hospitals (57%) from the 21 Pioneer hospitals and 33 (45%) from the 74 non-Pioneer hospitals were considered to be reliable reporters of outcome data. Among the 12 hospitals, the PedVAE rate decreased from 1.9 to 1.4 events per 1000 ventilator days (absolute rate difference, −0.6; 95% CI, −0.5 to −0.7; P < .001). No significant change in the PedVAE rate was seen among the 33 hospitals that reliably submitted PedVAE rates but did not implement the bundle. Of the 12 hospitals, 3 that reliably performed daily discussion of extubation readiness had a decrease in PedVAE rate from 2.6 to 1.2 events per 1000 ventilator days (absolute rate difference, −1.4; 95% CI, −1.0 to −1.7; P < .001), whereas the other 9 hospitals that did not implement this discussion did not have a decrease. Conclusions and Relevance This study found that a multicenter quality improvement intervention targeting PedVAE risk factors was associated with a substantial reduction in the rate of PedVAEs in hospital ICUs. The findings suggest that ICU teams seeking to reduce PedVAEs incorporate daily discussion of extubation readiness during morning rounds.

Background Neurocognitive impairment and quality of life are two important long-term challenges for patients with complex CHD. The impact of re-interventions during adolescence and young adulthood on neurocognition and quality of life is not well understood. Methods In this prospective longitudinal multi-institutional study, patients 13–30 years old with severe CHD referred for surgical or transcatheter pulmonary valve replacement were enrolled. Clinical characteristics were collected, and executive function and quality of life were assessed prior to the planned pulmonary re-intervention. These results were compared to normative data and were compared between treatment strategies. Results Among 68 patients enrolled from 2016 to 2020, a nearly equal proportion were referred for surgical and transcatheter pulmonary valve replacement (53% versus 47%). Tetralogy of Fallot was the most common diagnosis (59%) and pulmonary re-intervention indications included stenosis (25%), insufficiency (40%), and mixed disease (35%). There were no substantial differences between patients referred for surgical and transcatheter therapy. Executive functioning deficits were evident in 19–31% of patients and quality of life was universally lower compared to normative sample data. However, measures of executive function and quality of life did not differ between the surgical and transcatheter patients. Conclusion In this patient group, impairments in neurocognitive function and quality of life are common and can be significant. Given similar baseline characteristics, comparing changes in neurocognitive outcomes and quality of life after surgical versus transcatheter pulmonary valve replacement will offer unique insights into how treatment approaches impact these important long-term patient outcomes.