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Despite ongoing efforts to decrease ionizing radiation exposure from computed tomography (CT) use in pediatric appendicitis, high CT utilization rates are still observed across many hospitals. This study aims to identify factors influencing CT use and facilitators and barriers to quality improvement efforts.The Pediatric Surgery Quality Collaborative is a voluntary consortium of 42 children's hospitals participating in the National Surgical Quality Improvement Project - Pediatric. Hospitals were compared based on CT utilization from January 1, 2019, to December 31, 2019. Semi-structured interviews were conducted with surgeons, radiologists, emergency medicine physicians, and clinical data abstractors from 7 hospitals with low CT use rates (high performers) and 6 hospitals with high CT use rates (low performers). A mixed deductive and inductive coding approach for analysis of the interview transcripts was used to develop a codebook based on the Theoretical Domains Framework and subsequently identify prominent barriers and facilitators to CT reduction.Thematic saturation was achieved after 13 interviews. We identified four factors that distinguish high-performing from low-performing hospitals: (1) consistent availability of resources such as ultrasound technicians, pediatric radiologists, and magnetic resonance imaging (MRI); (2) presence of and adherence to protocols guiding imaging modality decision making and imaging execution; (3) culture of inter-departmental collaboration; and (4) presence of a radiation reduction champion.Significant barriers to reducing the use of CT in pediatric appendicitis exist. Our findings highlight that future quality improvement efforts should target resource availability, protocol adherence, collaborative culture, and radiation reduction champions.Level III.

Background/Purpose Comprehensive opioid stewardship programs require collective stakeholder alignment and proficiency. We aimed to determine opioid-related prescribing practices, knowledge, and beliefs among providers who care for pediatric surgical patients. Methods A single-center, cross-sectional survey was conducted of attending physicians, residents, and advanced practice providers (APPs), who managed pediatric surgical patients. Results Of 110 providers surveyed, 75% completed the survey. Over half of respondents (n = 43, 52%) reported always/very often prescribing opioids at discharge, with residents reporting the highest rate (66%). Provider types had varying prescribing patterns, including what types of opioids and non-opioids they prescribed. There was a lack of formal training, particularly among residents, of which only 42% reported receiving formal opioid prescribing education. Finally, although only 28% of providers felt that the opioid epidemic affects children, 48% believed pediatric providers’ prescribing patterns contributed to the opioid epidemic as a whole, and 80% reported changing their prescribing practices in response. Conclusions Significant variability exists in opioid prescribing practices, knowledge, and beliefs among providers who care for pediatric surgical patients. Effective opioid stewardship requires comprehensive policies, pediatric specific guidelines, and education for all providers caring for children to align provider proficiency and optimize prescribing patterns.

Congenital diaphragmatic hernia (CDH) patients often have suspected isolated aortic arch anomalies (IAAA) on imaging. The purpose of this work was to describe the incidence and outcomes of CDH + IAAA patients.Cardiovascular data were collected for infants from the CDH Study Group born between 2007 and 2019. IAAA were defined as coarctation of aorta, hypoplastic aortic arch, interrupted aortic arch, and aortic aneurysmal disease on early, postnatal echocardiography. Patients with major cardiac malformations and/or chromosomal abnormalities were excluded. Primary outcomes included the rate of aortic intervention, rates of extracorporeal life support (ECLS) utilization, and mortality.Of 6357 CDH infants, 432 (7%) were diagnosed with a thoracic aortic anomaly. Of these, 165 were diagnosed with IAAA, most commonly coarctation of the aorta (n = 106; 64%) or hypoplastic aortic arch (n = 58; 35%). CDH + IAAA patients had lower birthweights (3 kg vs. 2.9 kg) and Apgar scores (7 vs. 6) than patients without IAAA (both χIAAA in CDH are associated with increased mortality. This often simply reflects severity of the defect and thoracic anatomic derangement, as opposed to unique aortic pathology, given few CDH + IAAA patients undergo aortic intervention.

To evaluate the impact of repeat extracorporeal life support (ECLS) on survival and in-hospital outcomes in congenital diaphragmatic hernia (CDH) neonates.Despite the widespread use of ECLS, investigations on multiple ECLS courses for CDH neonates are limited.This is a retrospective cohort study of all ECLS-eligible CDH neonates enrolled in the CDH Study Group registry between 1995 and 2019. CDH infants with estimated gestational age at birth32 weeks and a birth weight1.8 kg and/or with major cardiac or chromosomal anomalies were excluded. The primary outcomes were survival and morbidities during the index hospitalization.Of 10,089 ECLS-eligible CDH infants, 3025 (30%) received one ECLS course, and 160 (1.6%) received multiple courses. The overall survival rate for patients who underwent no ECLS, one ECLS course, and multi-course ECLS were 86.9%±0.8%, 53.8%±1.8%, and 43.1%±7.7%, respectively. Overall ECLS survival rate is increased by 5.1%±4.6% (P=0.03) for CDH neonates treated at centers that conduct repeat ECLS compared to those that do not offer repeat ECLS. This suggests that there would be an overall survival benefit from increased use of multiple ECLS courses. Infants who did not receive ECLS support had the lowest morbidity risk while survivors of multi-course ECLS had the highest rates of morbidities during the index hospitalization.Although survival is lower for repeat ECLS, the use of multiple ECLS courses has the potential to increase overall survival for CDH neonates. Increased use of repeat ECLS might be associated with improved survival. The potential survival advantage of repeat ECLS must be balanced against the increased risk of morbidities during the index hospitalization.

Purpose Repetitive painful stimuli and early exposure to opioids places neonates at risk for neurocognitive delays. We aimed to understand opioid utilization for neonates with gastroschisis. Methods We performed a retrospective review of infants with gastroschisis at a tertiary children's hospital (2017–2019). Multivariate linear regression was performed to analyze variations in opioid use. Results Among 30 patients with gastroschisis, 33% were managed by primary suture-less closure, 7% by primary sutured closure, 40% by spring silo, and 20% by handsewn silo. The proportion of pain medication used was: morphine (89%), acetaminophen (8%), and fentanyl (3%). Opioids were used for a median of 6.5 days (range 0–20) per patient. Median total opioid administered across all patients was 2.2 morphine milligram equivalents (MME)/kg (IQR 0.7–3.3). Following definitive closure, median opioid use was 0.2 MME/kg (IQR 0.1–0.8). With multivariate regression, 45% of the variation in MME use was associated with the type of surgery after adjusting for weight, gestational age, and gender, p = 0.02. After definitive fascial closure, there was no significant variations in opioid use. Conclusion There is a significant variation in the utilization of opioid, primarily prior to fascial closure. Understanding pain needs and standardization may improve opioid stewardship in infants with gastroschisis. 197/200 Level of Evidence Level III

Cardiac dysfunction is a key determinant of outcome in congenital diaphragmatic hernia (CDH). Pro-b-type natriuretic peptide (proBNP) is used as a prognosticator in heart failure and cardiomyopathy. We hypothesized that proBNP levels would be associated with ventricular dysfunction and high-risk disease in CDH.Patients in the CDH Study Group (CDHSG) from 2015-2019 with at least one proBNP value were included. Ventricular function was determined using echocardiograms from the first 48 h of life.A total of 2,337 patients were identified, and 212 (9%) had at least one proBNP value. Of those, 3 (1.5%) patients had CDHSG stage A defects, 58 (29.6%) B, 111 (56.6%) C, and 24 (12.2%) D. Patients with high-risk defects (Stage C/D) had higher proBNP compared with low-risk defects (Stage A/B) (14,281 vs. 5,025, p = 0.007). ProBNP was significantly elevated in patients who died (median 14,100, IQR 4,377-22,900 vs 4,911, IQR 1,883-9,810) (p0.001). Ventricular dysfunction was associated with higher proBNP than normal ventricular function (8,379 vs. 4,778, p = 0.005). No proBNP value was both sensitive and specific for ventricular dysfunction (AUC=0.61).Among CDH patients, elevated proBNP was associated with high-risk defects, ventricular dysfunction, and mortality. ProBNP shows promise as a biomarker in CDH-associated cardiac dysfunction.

The purpose of this study was to analyze the clinical characteristics and outcomes of low birthweight (LBW) infants with congenital diaphragmatic hernia (CDH) compared to normal birthweight (NBW) infants with CDH. We hypothesized that LBW was associated with increased mortality, decreased extracorporeal life support (ECLS) utilization, and increased pulmonary morbidity in CDH patients. Patients in the CDH Study Group from 2007 to 2018 were included. LBW was defined as p = .03). LBW infants had longer durations of mechanical ventilation and were more likely to require supplemental oxygen at 30 days and at the time of discharge. LBW is a risk factor for mortality and pulmonary morbidity in CDH. Prolonged oxygen requirement and increased length of stay are important considerations when managing this population.

Ventilator management is a critical part of managing congenital diaphragmatic hernia (CDH). We aimed to use a murine model and patient data to study CDH-associated differences in oxygenation, airway resistance, and pulmonary mechanics by disease severity.We used the nitrofen model of CDH. For control and CDH rodents, data were collected within the first hour of life. Oxygen saturations (SpOControl rodents had a median SpONewborns with CDH have lower SpO

Objectives Given significant focus on improving survival for "high-risk" congenital diaphragmatic hernia, there is the potential to overlook the need to identify risk factors for suboptimal outcomes in "low-risk" congenital diaphragmatic hernia cases. We hypothesized that early cardiac dysfunction or severe pulmonary hypertension were predictors of adverse outcomes in this "low-risk" congenital diaphragmatic hernia population. Design This is a retrospective cohort study using data from the Congenital Diaphragmatic Hernia Study Group registry. "Low-risk" congenital diaphragmatic hernia was defined as Congenital Diaphragmatic Hernia Study Group defect size A/B without structural cardiac and chromosomal anomalies. Examined risk factors included left ventricular dysfunction, right ventricular dysfunction, and severe pulmonary hypertension on the first postnatal echocardiogram. The primary outcome was composite adverse events, defined as either death, extracorporeal membrane oxygenation utilization, oxygen requirement on day 30 of life, or hospitalization greater than or equal to 8 weeks. Multivariable adjustment was performed with logistic regression and inverse probability weighting. Setting Neonatal index hospitalization for congenital diaphragmatic hernia. Patients "Low-risk" congenital diaphragmatic hernia infants born between January 2015 and December 2018. Interventions First postnatal echocardiogram performed within 24 hours from birth. Measurements and main results Seven-hundred seventy-eight patients were identified as "low-risk" congenital diaphragmatic hernia. Left ventricular dysfunction, right ventricular dysfunction, and severe pulmonary hypertension were present in 10.8%, 20.5%, and 57.5%, respectively. The primary outcome occurred in 21.3%. Death occurred in 3.0% and 9.1% used extracorporeal membrane oxygenation. On unadjusted analysis, all three risk factors were associated with the primary outcome. On all multivariable adjustment methods, left ventricular dysfunction and severe pulmonary hypertension remained significant predictors of adverse outcomes while right ventricular dysfunction no longer demonstrated any effect. Conclusions Early left ventricular dysfunction and severe pulmonary hypertension are independent predictors of adverse outcomes among "low-risk" congenital diaphragmatic hernia infants. Early recognition may lead to interventions that can improve outcome in this at-risk cohort.

Rationale: Congenital diaphragmatic hernia (CDH) is an anomaly with a high morbidity and mortality. Cardiac dysfunction may be an important and underrecognized contributor to CDH pathophysiology an...

To determine the association between prenatal ultrasound (US) and magnetic resonance imaging (MRI) characteristics in right congenital diaphragmatic hernia (RCDH) with postnatal outcome.CDH Study Group data were reviewed for all RCDH infants (n = 156) born between 2015 and 2019. Prenatal US and MRI lung size measurements were correlated with survival, extracorporeal life support (ECLS), and defect size.Overall survival was 64.1%. ECLS was required in 40.4%. US and MRI-based prenatal assessment of pulmonary hypoplasia does not predict survival. Prenatal measurement of lung size using either US or MRI correlates with ECLS use. Only MRI-based measures of lung size are associated with defect size.Image-based prenatal predictors of survival, ECLS, and defect size are of limited value in RCDH. Extrapolation of prenatal survival and morbidity indicators from left to right-sided CDH is not appropriate. There is an urgent need to develop RCDH prenatal prediction models.

To evaluate the association between prenatal imaging predictors of patients with left-sided congenital diaphragmatic hernia (LCDH) and postnatal outcomes.CDH study group data were reviewed for LCDH infants born 2015-2019. Prenatal ultrasound (US) and magnetic resonance imaging (MRI) data were collected and correlated with postnatal information including CDHSG defect size (A through D or non-repair (NR)).In total, 929 LCDH patients were included. Both US and MRI imaging predictors correlated with postnatal survival (72.2%) and ECLS use (29.6%). Logistic regression models confirmed increased survival and decreased ECLS use with larger values for all predictors. Importantly, all prenatal values evaluated showed no significant difference between defect size D and NR patients.This is the largest cohort of LCDH patients and demonstrates that prenatal imaging factors correlate with postnatal outcomes and confirms that patients in the non-repair group are prenatally similar to type D defects.

Randomized controlled trials (RCTs) are challenging, but are the studies most likely to change practice and benefit patients. RCTs investigating neonatal surgical therapies are rare. The Necrotizing Enterocolitis Surgery Trial (NEST) was the first surgical RCT conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN), and multiple lessons were learned. NEST was conducted over a 7.25-year enrollment period and the primary outcome was death or neurodevelopmental impairment (NDI) at 18-22 months corrected age. Surgical investigators designing clinical trials involving neonatal surgical treatments have many considerations to include, including how to study eligible but non-randomized patients, heterogeneity of treatment effect, use of frequentist and Bayesian analyses, assessment of generalizability, and anticipating criticisms during peer review. Surgeons are encouraged to embrace these challenges and seek innovative methods to acquire evidence that will be used to improve patient outcomes.

There is a known association between Cornelia de Lange syndrome (CdLS) and congenital diaphragmatic hernia (CDH), with CDH being the cause of death in 5%-20% of CdLS cases. We aimed to identify and describe patients with CDLS and CDH. We hypothesized that CdLS would be associated with high-risk CDH and poor outcomes.CDH Study Group patients from 1995 to 2019 were included. Those with CdLS were reviewed retrospectively. Rates of repair and outcomes were compared between patients with and without CdLS.We identified 9,251 CDH patients. Of those, 21 had confirmed CdLS. CdLS patients had a lower birth weight (2.2±0.57 kg) than non-CdLS patients (2.9±0.64 kg) (p0.001). 5-min Apgar scores were lower in CdLS patients (6, 4-7) than non-CdLS patients (7, 5-8) (p=0.014). Only 33% of CdLS patients underwent diaphragmatic repair compared to 84.2% of non-CdLS patients (p0.001). Mortality was 76% for CdLS patients compared with 29% for non-CdLS patients (p0.001). Of the 7 CdLS patients who underwent repair, 5 survived to hospital discharge.Infants with CdLS and CDH have a poor prognosis. However, CdLS patients who undergo repair can survive to discharge; therefore, the concomitant diagnosis of CdLS and CDH is not necessarily a contraindication to repair. Early recognition of these anomalies can assist with counseling and prognostication.Retrospective comparative study LEVEL OF EVIDENCE: III.

Intra-abdominal abscess, the most common complication after perforated appendicitis, is associated with considerable economic burden. However, costs of intra-abdominal abscesses in children are unknown. We aimed to evaluate resource utilization and costs attributable to intra-abdominal abscess in pediatric perforated appendicitis.A single-center retrospective analysis was performed of children (18 years) who underwent appendectomy for perforated appendicitis (2013-2019). Hospital costs incurred during the index admission and within 30 postoperative days were obtained from the hospital accounting system and inflated to 2019 USD. Generalized linear models were used to determine excess resource utilization and costs attributable to intra-abdominal abscess after adjusting for confounders.Of 763 patients, 153 (20%) developed intra-abdominal abscesses. Eighty-one patients with intra-abdominal abscesses (53%) underwent percutaneous abscess drainage. Intra-abdominal abscess was independently associated with a nearly 8-fold increased risk of 30-day readmission (adjusted risk ratio, 7.8 [95% confidence interval, 4.7-13.0]). Patients who developed an intra-abdominal abscess required 6.1 excess hospital bed days compared to patients without intra-abdominal abscess (95% confidence interval, 5.3-7.0). Adjusted mean hospital costs for patients with intra-abdominal abscess totaled $27,394 (95% confidence interval, $25,688-$29,101) versus $15,586 (95% confidence interval, $15,102-$16,069) for patients without intra-abdominal abscess. Intra-abdominal abscess was associated with an incremental cost of $11,809 (95% confidence interval, $10,029-$13,588). Hospital room costs accounted for 66% of excess costs.Postoperative intra-abdominal abscess nearly doubled pediatric perforated appendicitis costs, primarily due to more hospital bed days and associated room costs. Intra-abdominal abscesses resulted in estimated excess costs of $1.8 million during the study period. Even small reductions in intra-abdominal abscess rates or hospital bed days could yield substantial health care savings.

OBJECTIVE To determine if risk-adjusted survival of patients with congenital diaphragmatic hernia (CDH) has improved over the last 25 years within centers that are long-term, consistent participants in the CDH Study Group (CDHSG). SUMMARY BACKGROUND DATA The CDHSG is a multicenter collaboration focused on evaluation of infants with CDH. Despite advances in pediatric surgical and intensive care, CDH mortality has appeared to plateau. Herein, we studied CDH mortality rates amongst long-term contributors to the CDHSG. METHODS We divided registry data into five-year intervals, with Era 1 (E1) beginning in 1995, and analyzed multiple variables (operative strategy, defect size, and mortality) to assess evolution of disease characteristics and severity over time. For mortality analyses, patients were risk stratified using a validated prediction score based on 5-minute Apgar (Apgar5) and birth weight. A risk-adjusted, observed to expected (O:E) mortality model was created using E1 as a reference. RESULTS 5,203 patients from 23 centers with ≥22 years of participation were included. Birth weight, Apgar5, diaphragmatic agenesis, and repair rate were unchanged over time (all p > 0.05). In E5 compared to E1, minimally invasive and patch repair were more prevalent, and timing of diaphragmatic repair was later (all p < 0.01). Overall mortality decreased over time: E1 (30.7%), E2 (30.3%), E3 (28.7%), E4 (26.0%), E5 (25.8%) (p = 0.03). Risk-adjusted mortality showed a significant improvement in E5 compared to E1 (OR 0.78, 95% CI 0.62-0.98; p = 0.03). O:E mortality improved over time, with the greatest improvement in E5. CONCLUSIONS Risk-adjusted and observed-to-expected CDH mortality have improved over time.

OBJECTIVE: To determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP). SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown. METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18–22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches. RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage (adjusted relative risk [aRR] = 1.0; 95% confidence interval [CI]: 0.87–1.14). A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (p = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR=0.81; 95% CI: 0.64 to 1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference

INTRODUCTION: Biliary dyskinesia (BD) is a common indication for pediatric cholecystectomy. While diagnosis is primarily based on diminished gallbladder ejection fraction (GB-EF), work-up and management in pediatrics is controversial. METHODS: We conducted a multi-institutional retrospective review of children undergoing cholecystectomy for BD to compare perioperative work-up and outcomes. RESULTS: Six hundred seventy-eight patients across 16 institutions were included. There was no significant difference in gender, age, or BMI between institutions. Most patients were white (86.3%), non-Hispanic (79.9%), and had private insurance (55.2%). Gallbladder ejection fraction (EF) was reported in 84.5% of patients, and 44.8% had an EF < 15%. 30.7% of patients were initially seen by pediatric surgeons, 31.3% by pediatric gastroenterologists, and 23.4% by the emergency department with significant variability between institutions (p < 0.001). Symptoms persisted in 35.3% of patients post-operatively with a median follow-up of 21 days (IQR 13, 34). On multivariate analysis, only non-white race and the presence of psychiatric comorbidities were associated with increased risk of post-operative symptoms. CONCLUSION: There is significant variability in evaluation and follow-up both before and after cholecystectomy for BD. Prospective research with standardized data collection and follow-up is needed to develop and validate optimal care pathways for pediatric patients with suspected BD. STUDY TYPE: Case Series, Retrospective Review. LEVEL OF EVIDENCE: Level IV.

Evidence-based guidelines recommend ultrasound (US) over computed tomography (CT) as the primary imaging modality for suspected pediatric appendicitis. Continued high rates of CT use may result in significant unnecessary radiation exposure in children. The purpose of this study was to evaluate variables associated with preoperative CT use in pediatric appendectomy patients.A retrospective cohort study of pediatric patients who underwent appendectomy for acute appendicitis in 2015-2016 at National Surgical Quality Improvement Program for Pediatrics (NSQIP-P) hospitals was conducted. Pediatric (18 years old) patients who underwent appendectomy for acute appendicitis in an NSQIP-P hospital from 2015 to 2016 were included. Patients were excluded if they underwent interval or incidental appendectomy or did not have a final diagnosis of appendicitis. Variables associated with imaging evaluation, including age, body mass index (BMI), race/ethnicity, gender and hospital of presentation (NSQIP-P vs. non-NSQIP-P hospital) were evaluated. The primary outcome was receipt of preoperative CT. Secondary outcomes include reimaging practices and trends over time.22,333 children underwent appendectomies, of which almost all were imaged preoperatively (96.5%) and 36% of whom presented initially to a non-NSQIP-P hospital. Overall, US only was the most common imaging modality (52%), followed by CT only (27%), US+CT (16%), no imaging (3%), MRI +/- CT/US (1%) and MRI only (1%). On regression, older age (11 years), obesity (BMI95th percentile for age), and female gender were associated with increased odds of receiving a CT scan. However, initial presentation to a non-NSQIP-P hospital was the strongest predictor of CT use (OR 9.4, 95% CI 8.1-10.8). Reimaging after transfer was common, especially after US and MRI at a non-NSQIP-P hospital. CT use decreased between 2015 and 2016 in non-NSQIP-P hospitals but remained the same (25%) in NSQIP-P facilities.Though patient characteristics were associated with different imaging practices, presentation at a referral, nonchildren's hospital is the strongest predictor of CT use in children with appendicitis. NSQIP-P hospitals frequently reimage transferred patients and have not reduced their CT use. Novel strategies are required for all hospital types in order to sustain reduction in CT use and mitigate unnecessary imaging.Level III.Retrospective comparative study.

Aim To compare outcomes between prenatally and postnatally diagnosed CDH in a large multicenter database of prospectively collected data and evaluate factors associated with poorer outcome for prenatally diagnosed CDH. Material and Methods We used information from the multicenter, multinational CDH Study Group database on patients born between 2007 and 2015. We compared differences between prenatally and postnatally diagnosed CDH with respect to survival, side, size, ECMO needs, associated major cardiac malformations and liver position. Results 3746 cases of CDH were entered in the registry between 2007 and 2015, with an overall survival of 71%. Of those, 68% had a prenatal diagnosis. Survival rates were significantly better in the postnatally diagnosed group, 83 vs 65%. There was a higher proportion of bigger defect sizes, C and D, in the prenatally diagnosed group, but the survival rates were similar when patients were stratified by defect size. The rate of ECMO utilization was higher overall in the prenatally diagnosed group, 33 vs 22%, but it was similar within similar defect sizes. Right-sided defects are more commonly missed at prenatal screening than left-sided CDH, 53 vs 35% (p Conclusions Prenatally diagnosed CDH is associated with larger defect sizes compared to those with a postnatal diagnosis, and consequently have higher morbidity and mortality. Right-sided CDH are more often missed at prenatal ultrasound. The increasing rate of prenatal detection requires a clear understanding of accurate risk stratification, in order to counsel families and to provide appropriate perinatal management. Level of Evidence I for a Prognosis Study – This is a high-quality, prospective cohort study with 99% of patients followed to the study end point (death or discharge).

Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Accurate data are essential for the validity of clinical registries. This study aimed to validate NSQIP-P data, assess representativeness, and evaluate risk-adjusted predictive ability at a single institution.A prospective appendectomy-specific pediatric surgery research database (RD) maintained by clinical researchers was compared to the NSQIP-P data for appendectomies performed in 2016 at a tertiary children's hospital. NSQIP-P sampled data collected by trained surgical clinical reviewers (SCRs) were compared to matched RD patients. Both datasets used NSQIP-P definitions. Using χ458 appendectomies for acute appendicitis were performed in 2016, of which 250 (55%) were abstracted by SCRs and matched to RD patients. Patient demographics were similar between datasets. Disease severity (NSQIP-P:50% complicated vs RD:31% complicated) and composite morbidity (NSQIP-P:6.0% vs RD:14.4%) were significantly different (both p 0.01). Demographics and outcomes were similar between matched (n = 250) and unsampled patients in the RD (n = 208). NSQIP-P's risk-adjusted predicted morbidity was significantly lower than morbidity observed in all (n = 458) RD patients (NSQIP-P:9.9% vs RD:14.2%, p 0.01).Though constituting a representative sample, NSQIP-P appendectomy data were inconsistent with department data. Discrepancies appear to be the result of underreporting of outcome variables and disease misclassification.Retrospective comparative review.Level III.

Background Opioid misuse is a public health crisis in the United States. This study aimed to evaluate the discharge opioid prescription practices for pediatric simple appendectomy patients. Methods A retrospective review of pediatric appendectomy patients at a tertiary children's hospital was conducted from October 2016 to January 2018. Only patients with simple appendicitis were included. Written opioid prescriptions were found in the electronic medical record (EMR) or through a statewide prescription monitoring database. All dosing data were converted to oral morphine equivalents (OMEs). Analysis of variance and logistic regression were used. Results During the study, 590 patients underwent appendectomy, of which 371 (62.9%) were diagnosed as having simple acute appendicitis. The majority of patients were prescribed an opioid analgesic (62.5%). Demographics were similar between those who received opioids and those who did not. The OME prescribed per day (range 0.2 to 3.4 mg/kg/day) was highly variable as was duration of prescription (1 to 30 days). Odds of emergency department visit were 3.3 times higher (95% CI 1.3–8.2) in those who received opioids. Conclusion Postdischarge prescription practices for pediatric appendectomy are highly variable. Two-thirds of patients who received narcotics had a higher rate of complications. Greater scrutiny is required to optimize opioid stewardship. Type of study Retrospective comparative study. Level of evidence Level III.

To evaluate the association between hypercarbia in the first 24 h of life and clinical outcomes in infants with congenital diaphragmatic hernia (CDH). Retrospective review of patients entered into the CDHSG registry between 2007–2014. Half of the identified patients were analyzed to identify the PaCO2 value most predictive of mortality. Prediction models for outcomes of death, ECMO, and respiratory support at 30 days of life (DOL) were developed using PaCO2. Remaining half of data was used for validation of study findings. 1878 and 1875 patients were analyzed in the testing and validation groups. Lowest PaCO2≥60 mmHg in the first DOL is highly predictive of death prior to discharge. Prediction models including this variable demonstrate good discrimination for outcomes of death, ECMO, and respiratory support (AUC 0.8808, 0.8279, 0.8065). Lowest PaCO2 in the first DOL is an independent risk factor of mortality and morbidity in CDH.

Introduction: Intra-abdominal abscess (IAA) after perforated appendicitis is associated with increased healthcare costs. In 2016, our center conducted a pilot randomized control trial (RCT) in which 100 children (age 2-17) with perforated appendicitis were randomized to intra-abdominal irrigation with povidone-iodine (PVI) during appendectomy or no irrigation. We observed an 89% probability that PVI irrigation reduced the rate of IAA (Bayesian Relative Risk: 0.72 [95% credible interval (CrI), 0.38-1.23]). We hypothesized …

Background Congenital diaphragmatic hernia (CDH) is, depending of the severity, a birth defect associated with significant mortality and morbidity. Prenatal screening by ultrasound may detect this condition and comprehensive assessment of severity is possible, allowing for in utero referral to an experienced centre for planned delivery. In an effort to improve outcomes, prenatal interventions to stimulate lung development were proposed. Along the same lines, new postnatal management strategies are being developed. In order to enable proper comparison of novel perinatal interventions as well as outcomes, a set of uniform and relevant outcome measures is required. Core outcome sets (COS) are agreed, clearly defined sets of outcomes to be measured in a standardised manner and reported consistently. Herein we aim to describe the methodology we will use to define a COS for perinatal and neonatal outcomes of foetuses and newborns with congenital diaphragmatic hernia and to draft a dissemination and implementation plan. Methods We will use the methodology described in the Core Outcome Measures in Effectiveness Trials (COMET) Initiative Handbook. An international steering group will be created to guide the development of the COS. We are systematically reviewing the literature to identify all potential relevant pre- and neonatal outcomes previously used in studies on perinatal interventions for CDH. We will build a consensus on these core outcomes in a stakeholder group using the Delphi method. After completion, a stakeholder meeting will decide on a final COS, using a modified Nominal Group Technique. Thereafter, we will review potential definitions and measurements of these outcomes, and again a consensus meeting will be organised, to finalise the COS before dissemination. Discussion We have started a procedure to develop a COS for studies on perinatal interventions for congenital diaphragmatic hernia, with the purpose of improving the quality of research, guide clinical practice and improve patient care and eventual use in future clinical trials, systematic reviews and clinical practice guidelines. Trial registration We prospectively registered this study in the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD42019124399) and The Core Outcome Measures in Effectiveness Trials (COMET) Initiative (registration number:1296).

Background Bronchopulmonary sequestration (BPS) has long been identified in patients with congenital diaphragmatic hernia (CDH), however the reported incidence in the literature varies widely and is not based on large series. Methods Version 4 of the Congenital Diaphragmatic Hernia Study Group (CDHSG) included questions specifically identifying BPS-associated cases. The data were prospectively collected between 2015 and 2020. Clinical characteristics and outcomes for CDH+BPS patients were compared to patients without BPS using univariate and multiple regression analyses. Results Out of 2118 total patients, 72 had a pulmonary sequestration (3.4%). The amount of CDH+BPS with high-risk (CDHSG type C and D) defects was significantly greater than those without BPS (68.0% vs 49.3%, respectively; p = 0.001). The need for ECLS (35/72, 48.6%) and overall mortality (21/72, 29.2%) was significantly higher in CDH+BPS. When corrected for hernia size, cardiac and chromosomal anomalies, the need for ECLS (OR 2.2, p = 0.004) and mortality (OR 2.0, p = 0.015) was significantly greater in CDH+BPS. Conclusions This is the largest series to look at the incidence of BPS in children with CDH. They are associated with larger defect sizes, a greater need for ECLS and higher mortality than those patients without BPS.

Introduction: Pulmonary hypertension (PH) is the major pathophysiologic consequence of congenital diaphragmatic hernia (CDH). We aimed to evaluate the association between early CDH-associated PH (CDH-PH) and inpatient outcomes. Methods: The CDH Study Group registry was queried for infants born 2015–2019 with echocardiograms before 48h of life. PH was categorized using echocardiographic findings: none, mild (right ventricular systolic pressure Results: Of 1,472 patients, 86.5% had CDH-PH: 13.9% mild (n = 193), 44.4% moderate (n = 631), and 33.2% severe (n = 468). On adjusted analysis, the primary outcome of mortality or oxygen support at 30 days occurred more frequently in infants with moderate (incidence rate ratio [IRR] 1.8, 95% confidence interval [CI], 1.2–2.6) and severe CDH-PH (IRR 2.0, 95% CI, 1.3–2.9). Extracorporeal life support (ECLS) utilization was associated only with severe CDH-PH after adjustment (IRR 1.8, 95% CI, 1.0–3.3). Discussion/Conclusion: Early, postnatal CDH-PH is independently associated with increased risk for mortality or oxygen support at 30 days and utilization of ECLS. Early echocardiogram is a valuable prognostic tool for early, inpatient outcomes in neonates with CDH.

Congenital diaphragmatic hernia (CDH) leads to pathophysiologic pulmonary vasoreactivity. Previous studies show that mesenchymal stromal cell-derived extracellular vesicles (MSCEv) inhibit lung inflammation and vascular remodeling. We characterize MSCEv and human pulmonary artery endothelial cell (HPAEC) interaction, as well as the pulmonary artery (PA) response to MSCEv treatment. HPAECs were cultured with and without exposure to nitrofen (2,4-dichloro-phenyl-p-nitrophenylether) and treated with MSCEv. HPAEC viability, architecture, production of reactive oxygen species (ROS), endothelial dysfunction-associated protein levels (PPARγ, LOX-1, LOX-2, nuclear factor-κB [NF-κB], endothelial NO synthase [eNOS], ET-1 [endothelin 1]), and the nature of MSCEv-cellular interaction were assessed. Newborn rodents with and without CDH (nitrofen model and Sprague-Dawley) were treated with intravascular MSCEv or vehicle control, and their PAs were isolated. Contractility was assessed by wire myography. The contractile (KCL and ET-1) and relaxation (fasudil) responses were evaluated. HPAEC viability correlated inversely with nitrofen dose, while architectural compromise was directly proportional. There was a 2.1 × increase in ROS levels in nitrofen HPAECs (

Prophylactic, intraabdominal drains have been used to prevent intraabdominal abscess (IAA) after perforated appendicitis. We hypothesized that routine drain placement would reduce the IAA rate in pediatric perforated appendicitis.A 27-month quality improvement (QI) initiative was conducted: closed-suction, intraabdominal drains were placed intraoperatively in pediatric (age 18) perforated appendicitis patients. QI patients were compared to controls admitted during the preceding 8 months and following 4 months. The primary outcome was 30-day IAA rate. Univariate and multivariate analyses were performed.Two hundred seventy QI patients were compared to 109 controls. There was 100% compliance during 21 of 27 months of the QI initiative; only 7 QI patients did not receive drains. IAA occurred in 20.0% of QI patients and 22.9% of control (p = 0.52). After adjustment, the QI initiative was not associated with reduced odds of IAA (OR 0.83, 95% CI 0.48-1.44). Median length of stay was longer in QI patients during the index admission (p = 0.03) and over 30 postoperative days (p = 0.03), but these relationships did not persist after adjustment.A QI initiative investigating prophylactic, intraabdominal drain placement in perforated appendicitis did not reduce the IAA rate. We recommend against routine drain placement in pediatric perforated appendicitis.Level III.

To determine in-hospital morbidities for neonates with right-sided congenital diaphragmatic hernia (R-CDH) compared with those with left-sided defects (L-CDH) and to examine the differential effect of laterality and defect size on morbidities.This retrospective, multicenter, cohort study from the international Congenital Diaphragmatic Hernia Study Group registry collected data from neonates with CDH surviving until hospital discharge from 90 neonatal intensive care units between January 1, 2007, and July 31, 2020. Major pulmonary, cardiac, neurologic, and gastrointestinal morbidities were compared between neonates with L-CDH and R-CDH, adjusted for prenatal and postnatal factors using logistic regression.Of 4123 survivors with CDH, those with R-CDH (n = 598 [15%]) compared with those with L-CDH (n = 3525 [85%]) had an increased odds of pulmonary (1.7; 95% CI, 1.4-2.2, P .0001), cardiac (1.4; 95% CI, 1.1-1.8; P = .01), gastrointestinal (1.3; 95% CI, 1.1-1.6; P = .01), and multiple (1.6; 95% CI, 1.2-2.0; P .001) in-hospital morbidities, with a greater likelihood of morbidity with increasing defect size. There was no difference in neurologic morbidities between the groups.Neonates with R-CDH and a larger defect size are at an increased risk for in-hospital morbidities. Counseling and clinical strategies should incorporate knowledge of these risks, and approach to neonatal R-CDH should be distinct from current practices targeted to L-CDH.

The role of home antibiotics (HA) at discharge in children after perforated appendicitis is unclear. This study evaluates the outcomes of complicated appendicitis in patients being discharged with or without HA after initial operation and inpatient treatment.The 2015 and 2016 NSQIP-Pediatric database was queried for patients younger than 18 years of age with complicated appendicitis. Home antibiotics were prescribed or not (no home antibiotics [NHA]). Patients were stratified based on presence or absence of predischarge surgical site infection (SSI) and postoperative day of discharge (≤5 days or5 days). The primary end point was 30-day postdischarge composite morbidity, including emergency department visit, readmission, postdischarge reoperation, and SSI. Multivariable logistic regression was used to adjust for baseline covariables.Of 6,412 patients with complicated appendicitis, the majority were discharged with HA (HA 56.4%; NHA 43.6%). Patients receiving HA had higher preoperative leukocytosis, longer procedures, higher incidence of sepsis, more predischarge SSIs, and longer length of stay than the NHA cohort (all p0.01), suggesting greater severity of illness. In adjusted multivariable models, HA patients without a predischarge SSI had higher postdischarge morbidity (adjusted odds ratio [aOR] 1.22; 95% CI 1.04 to 1.44), as did HA patients discharged ≤5 days post operation (aOR 1.28; 95% CI 1.04 to 1.57) compared with NHA patients. Composite morbidity was similar between NHA and HA patients with predischarge SSIs (aOR 1.06; 95% CI 0.56 to 2.00) or who were discharged5 days post operation (aOR 1.14; 95% CI 0.89 to 1.46).Although the majority of pediatric patients with complicated appendicitis are discharged with HA, NSQIP-Pediatric data suggest there is no evidence of a significant benefit. There might be a cohort of patients with more severe disease who require continued antibiotics.

Wolf–Hirschhorn syndrome (WHS) is caused by partial deletion of the short arm of chromosome 4 and is characterized by dysmorphic facies, congenital heart defects, intellectual/developmental disability, and increased risk for congenital diaphragmatic hernia (CDH). In this report, we describe a stillborn girl with WHS and a large CDH. A literature review revealed 15 cases of WHS with CDH, which overlap a 2.3-Mb CDH critical region. We applied a machine-learning algorithm that integrates large-scale genomic knowledge to genes within the 4p16.3 CDH critical region and identified FGFRL1, CTBP1, NSD2, FGFR3, CPLX1, MAEA, CTBP1-AS2, and ZNF141 as genes whose haploinsufficiency may contribute to the development of CDH.

Congenital diaphragmatic hernia (CDH) has been reported twice in individuals with a clinical diagnosis of Fraser syndrome, a genetic disorder that can be caused by recessive mutations affecting FREM2 and FRAS1. In the extracellular matrix, FREM2 and FRAS1 form a self-stabilizing complex with FREM1, a protein whose deficiency causes sac CDH in humans and mice. By sequencing FREM2 and FRAS1 in a CDH cohort, and searching online databases, we identified five individuals who carried recessive or double heterozygous, putatively deleterious variants in these genes which may represent susceptibility alleles. Three of these alleles were significantly enriched in our CDH cohort compared with ethnically matched controls. We subsequently demonstrated that 8% of Frem2(ne/ne) and 1% of Fras1(Q1263*/Q1263*) mice develop the same type of anterior sac CDH seen in FREM1-deficient mice. We went on to show that development of sac hernias in FREM1-deficient mice is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. Based on these data, we conclude that deficiency of FREM2, and possibly FRAS1, are associated with an increased risk of developing CDH and that loss of the FREM1/FREM2/FRAS1 complex, or its function, leads to anterior sac CDH development through its effects on mesothelial fold progression.

Background Purposeful completion (fidelity) more than simple adherence to items in the surgical safety checklist may improve operating room efficiency and patient safety. The purpose of this study was to evaluate intraoperative delays and correlate them with adherence and fidelity to the preincision surgical safety checklist. Methods Trained observers evaluated surgical safety checklist compliance during 3 observation periods from 2014–2016. Degree of adherence, checkpoint verbalization, fidelity, and meaningful completion were assessed. Delays were categorized as missing or malfunctioning equipment, staff error, and medication issues. Descriptive statistics, analysis of variance, logistic regression, χ2 and Student t test were used to analyze results. Results Of the 591 cases observed, 19% (n = 110) had at least one documented, intraoperative delay. The majority of delays were related to missing (50%) or malfunctioning (30%) equipment. Compared with cases without delays, cases with delays did not have a different mean degree of adherence (96.3 ± 7.6% vs 95.6 ± 5.8%, P = .36). Degree of fidelity was different between cases with and without delays (mean fidelity 77.1 ± 14.9% vs 80.5 ± 7.14.2%, P = .03). Conclusion The preincision SSC is a communication tool offering an opportunity to discuss potential concerns and anticipated intraoperative needs. Fidelity rather than adherence to the surgical safety checklist seems to diminish intraoperative delays.

Objective: The objectives of this study were (i) to evaluate infants with congenital diaphragmatic hernia (CDH) that do not undergo repair, (ii) to identify nonrepair rate by institution, and (iii) to compare institutional outcomes based on nonrepair rate. Background: Approximately 20% of infants with CDH go unrepaired and the threshold to offer surgical repair is variable. Methods: Data were abstracted from a multicenter, prospectively collected database. Standard clinical variables, including repair (or nonrepair), and outcome were analyzed. Institutions were grouped based on volume and rate of nonrepair. Preoperative mortality predictors were identified using logistic regression, expected mortality for each center was calculated, and observed /expected (O/E) ratios were computed for center groups and compared by Kruskal-Wallis ANOVA. Results: A total of 3965 infants with CDH were identified and 691 infants (17.5%) were not repaired. Nonrepaired patients had lower Apgar scores (P < 0.05) and increased incidence of anomalies (P < 0.0001). Low-volume centers ("Lo", n=44 total, < 10 CDH pts/yr) and high-volume centers ("Hi", n = 21) had median nonrepair rates of 19.8% (range 0%-66.7%) and 16.7% (5.1%-38.5%), respectively. High-volume centers were further dichotomized by rate of nonrepair (HiLo = 5.1-16.7% and HiHi = 17.6-38.5%), leaving 3 groups: HiLo, HiHi, and Lo. Predictors of mortality were lower birth weight, lower Apgar scores, prenatal diagnosis, and presence of congenital anomalies. O/E ratios for mortality in the HiLo, HiHi, and Lo groups were 0.81, 0.94, and 1.21, respectively (P < 0.0001). For every 100 CDH patients, HiLo centers have 2.73 (2.4-3.1, 95% confidence interval) survivors beyond expectation. Conclusions: There are significant differences between repaired and nonrepaired CDH infants and significant center variation in rate of nonrepair exists. Aggressive surgical management, leading to a low rate of nonrepair, is associated with improved risk-adjusted mortality.

The purpose of our study was to evaluate surgical enteric access in pediatric cancer patients to determine factors associated with postoperative complications. We performed a single institution retrospective review of all patients

Background Institutional protocols for preincisional antibiotic prophylaxis can standardize care and improve outcomes. However, challenges remain in compliance with such protocols for urgent or emergent operations. We hypothesized that compliance with an institutional protocol for antibiotic prophylaxis for appendectomy for appendicitis in pediatric patients results in reduced surgical site infections (SSIs) after simple appendectomy. Methods This retrospective study assessed all pediatric patients (≤18 y) who underwent appendectomy for confirmed simple appendicitis at a tertiary children's hospital between 2012 and 2015. Demographic, admission, and outcome data were recorded. Compliance with the protocol was assessed. Univariate analyses were performed to identify factors associated with any SSI and protocol noncompliance. Results Overall compliance with antibiotic prophylaxis occurred in 590 of 697 patients (85%). Compliance was high with timing (91%), spectrum (95%), and protocol-recommended drug (87%). Admission antibiotics alone were administered in 65 patients (9%), preincisional antibiotics alone in 254 patients (36%), and both in 378 patients (55%). Patients included in the analysis received a median of 2 (range 1-6) doses of antibiotics preoperatively. Ten patients (1.4%) developed an SSI. Only receipt of any antibiotics within an hour of incision was associated with decreased odds of SSI (odds ratio 0.22, 95% confidence interval 0.06-0.87). No factors were associated with noncompliance. Conclusions An institutional appendicitis protocol yields high compliance with prophylactic antibiotic administration and associated low SSI rates, but at a cost of antibiotic over-administration. Further efforts are necessary to sustain compliance while also practicing appropriate antibiotic stewardship.

Surgical site infection (SSI) rate in pediatric appendicitis is a commonly used hospital quality metric. We hypothesized that surveillance of organ-space SSI (OSI) using cultures alone would fail to capture many clinically-important events.A prospective, multidisciplinary surveillance program recorded 30-day SSI and hospital length of stay (LOS) for patients18years undergoing appendectomy for perforated appendicitis from 2012 to 2015. Standardized treatment pathways were utilized, and OSI was identified by imaging and/or bacterial cultures.Four hundred ten appendectomies for perforated appendicitis were performed, and a total of 84 OSIs (20.5%) were diagnosed with imaging. Positive cultures were obtained for 39 (46%) OSIs, whereas 45 (54%) had imaging only. Compared to the mean LOS for patients without OSI (5.2±2.9days), LOS for patients with OSI and positive cultures (13.7±5.4days) or with OSI without cultures (10.4±3.7days) was significantly longer (both p0.001). The OSI rate identified by positive cultures alone was 9.5%, whereas the clinically-relevant OSI rate was 20.5%.Using positive cultures alone to capture OSI would have identified less than half of clinically-important infections. Utilizing clinically-relevant SSI is an appropriate metric for comparing hospital quality but requires agreed upon standards for diagnosis and reporting.II.Diagnostic study.