The promise and pitfalls of care standardization in congenital diaphragmatic hernia.

The aim of standardizing care is to enhance patient outcomes and optimize healthcare delivery by minimizing variations in care and ensuring the efficient allocation of healthcare resources. Despite these potential benefits to patients, healthcare providers and the healthcare system, standardization may also disadvantage these groups. With a specific focus on congenital diaphragmatic hernia, this article will review the promise and pitfalls of standardization, as well as a potential path forward that uses standardization to improve outcomes in this rare and complex disease process.

Critical elements of pediatrics sacrococcygeal germ cell tumor surgery.

Sacrococcygeal teratoma is the most common extragonadal germ cell tumor in the pediatric population, and accounts for approximately 70% of all teratomas in childhood.1,2 They present in two distinct phases, with most cases seen in neonates with large predominately exophytic tumors, often detected in utero on prenatal sonography or at birth. A smaller cohort presents in older infants and children with primarily hidden tumors in the pelvis which have a much higher rate of malignancy. The primary surgical objective is complete tumor resection without compromise to critical structures or function. Herein we outline the critical elements of tumor resection and management of sacrococcygeal germ cell tumors with a focus on the technical aspects of this tumor across a range of presentations.

Association Between Early Prostacyclin Therapy and Extracorporeal Life Support Use in Patients With Congenital Diaphragmatic Hernia.

Importance: Prostacyclin (PGI2) is a therapeutic option to treat congenital diaphragmatic hernia (CDH)-associated pulmonary hypertension in neonates. Its use may decrease the need for extracorporeal life support (ECLS). Objective: To evaluate the association of early PGI2 therapy with ECLS use and outcomes among patients with CDH. Design, Setting, and Participants: This was a cohort study from the CDH Study Group (CDHSG) registry of patients born from January 2007 to December 2019. Patients were from 88 different tertiary pediatric referral centers worldwide that contributed data to the CDHSG. Patients were included in the study if they were admitted within the first week of life. Propensity score matching was performed using estimated gestational age, birth weight, transfer status, 1-minute and 5-minute Apgar scores, highest and lowest partial pressure of arterial carbon dioxide in the first 24 hours of life, and degree of pulmonary hypertension as covariates to generate a matched cohort of exposed and unexposed patients. Data were analyzed from January 2021 to December 2022. Exposures: Early PGI2 therapy was defined as initiation of PGI2 within the first week of life. Patients who received ECLS were included in the early PGI2 group if PGI2 was started prior to ECLS. Main Outcomes and Measures: The primary outcome of the study was the proportion of patients receiving ECLS in the exposed and unexposed groups. Results: Of 6227 patients who met inclusion criteria (mean [SD] gestational age, 37.4 [2.36] weeks; 2618 [42%] female), 206 (3.3%) received early PGI2 therapy. ECLS was used in 46 of 206 patients who received PGI2 (22.2%) and 1682 of 6021 who did not (27.9%). After propensity score matching, there were 147 patients in the treatment and control groups. Thirty-four patients who received PGI2 (23.3%) and 63 who did not (42.9%) received ECLS. Those who received PGI2 were less likely to receive ECLS (adjusted odds ratio, 0.39; 95% CI, 0.22-0.68) and had shorter mean (SD) duration of ECLS (8.6 [3.73] days vs 12.6 [6.61] days; P < .001), although there was no significant difference in in-hospital mortality. Conclusions and Relevance: In this study, there was decreased use of ECLS and decreased ECLS duration among patients with CDH who started PGI2 therapy during the first week of life. These results identify a potential advantage of early prostacyclin therapy in this population.

Congenital pleuropulmonary blastoma in a newborn with a variant of uncertain significance in DICER1 evaluated by RNA-sequencing.

BACKGROUND: Pleuropulmonary blastoma (PPB) is a rare mesenchymal malignancy of the lung and is the most common pulmonary malignancy in infants and children. Cystic PPB, the earliest form of PPB occurring from birth to approximately two years of age, is often mistaken for a congenital pulmonary airway malformation, as the two entities can be difficult to distinguish on imaging and pathology. Diagnosis of PPB should prompt workup for DICER1 syndrome, an autosomal dominant tumor predisposition syndrome. We report a newborn with a congenital PPB presenting with tachypnea and hypoxia, who was found to have variant of uncertain clinical significance (VUS) in DICER1. CASE PRESENTATION: A term female infant developed respiratory distress shortly after birth. Initial imaging was concerning for a congenital pulmonary airway malformation versus congenital diaphragmatic hernia, and she was transferred to a quaternary neonatal intensive care unit for management and workup. Chest CT angiography demonstrated a macrocytic multicystic lesion within the right lower lobe without systemic arterial supply. The pediatric surgery team was consulted, and the neonate underwent right lower lobectomy. Pathology revealed a type I PPB. Oncology and genetics consultants recommended observation without chemotherapy and single gene sequencing of DICER1, which identified a germline VUS in DICER1 predicted to alter splicing. RNA-sequencing from blood demonstrated that the variant resulted in an in-frame deletion of 29 amino acids in a majority of transcripts from the affected allele. Due to the patient's young age at presentation and high clinical suspicion for DICER1 syndrome, tumor surveillance was initiated. Renal and pelvic ultrasonography were unremarkable. CONCLUSION: We present the case of a term neonate with respiratory distress and cystic lung mass, found to have a type I PPB with a germline VUS in DICER1 that likely increased her risk of DICER1-related tumors. Nearly 70% of patients with PPB demonstrate germline mutations in DICER1. Review of RNA sequencing data demonstrates the difficulty in classifying splice variants such as this. Penetrance is low, and many patients with pathogenic DICER1 variants do not develop a malignancy. Best practice surgical and oncologic recommendations include an individualized approach and tumor board discussion. This case highlights the importance of a multidisciplinary team approach and the utility of international registries for patients with rare diagnoses.

Gene-Environment Interactions in Repeat Expansion Diseases: Mechanisms of Environmentally Induced Repeat Instability.

Short tandem repeats (STRs) are units of 1-6 base pairs that occur in tandem repetition to form a repeat tract. STRs exhibit repeat instability, which generates expansions or contractions of the repeat tract. Over 50 diseases, primarily affecting the central nervous system and muscles, are characterized by repeat instability. Longer repeat tracts are typically associated with earlier age of onset and increased disease severity. Environmental exposures are suspected to play a role in the pathogenesis of repeat expansion diseases. Here, we review the current knowledge of mechanisms of environmentally induced repeat instability in repeat expansion diseases. The current evidence demonstrates that environmental factors modulate repeat instability via DNA damage and induction of DNA repair pathways, with distinct mechanisms for repeat expansion and contraction. Of particular note, oxidative stress is a key mediator of environmentally induced repeat instability. The preliminary evidence suggests epigenetic modifications as potential mediators of environmentally induced repeat instability. Future research incorporating an array of environmental exposures, new human cohorts, and improved model systems, with a continued focus on cell-types, tissues, and critical windows, will aid in identifying mechanisms of environmentally induced repeat instability. Identifying environmental modulators of repeat instability and their mechanisms of action will inform preventions, therapies, and public health measures.

Trends in use of prostacyclin analogs for management of CDH-associated pulmonary hypertension.

PURPOSE: Off-label use of prostacyclins to manage congenital diaphragmatic hernia-associated pulmonary hypertension (CDH-PHTN) has been described over recent years, but use is not standardized across institutions. This study aims to describe trends in use of these medications in the CDH Study Group (CDHSG) patients. METHODS: The CDHSG was queried for all patients born from 2007 to 2019. Records were reviewed to describe the number of patients receiving prostacyclins, the day of life on which the agent was started, start time relative to ECLS, the duration of medication use, and continuation of the medication at the time of discharge. Finally, trends in use by year of birth were evaluated to assess for changes in use over time. RESULTS: There were 6439 patients identified from the registry who were born during the study period. 4372 (68%) patients received medications to treat pulmonary hypertension. Of these, 604 (14%) received a prostacyclin at some point during their care. The median start time for prostacyclins was 7.5 days of life (mean 16.9 days, SD 32.5 days), and the median duration was 12.5 days (mean 25.1 days, SD 49.1 days). Among patients who received prostacyclins, 340 patients required ECLS during care, 53 (15.5%) of whom started the prostacyclin prior to ECLS, and 159 (46.8%) of whom started prostacyclin therapy during their ECLS run. Only a small cohort (26/604, 4.3%) required continuation of the prostacyclin at the time of discharge. The proportion of patients receiving a prostacyclin remained relatively stable over the study period. CONCLUSIONS: While the proportion of patients receiving a prostacyclin for management of CDH-PHTN has remained relatively stable over the last 13 years, there is significant variation in timing of initiation and duration of use especially in the pre-ECLS period that warrants further investigation to describe optimal use in these patients.

Characteristics of pediatric non-cardiac eCPR programs in United States and Canadian hospitals: A cross-sectional survey.

OBJECTIVE: To characterize practices surrounding pediatric eCPR in the U.S. and Canada. METHODS: Cross-sectional survey of U.S. and Canadian hospitals with non-cardiac eCPR programs. Variables included hospital and surgical group demographics, eCPR inclusion/exclusion criteria, cannulation approaches, and outcomes (survival to decannulation and survival to discharge). RESULTS: Surveys were completed by 40 hospitals in the United States (37) and Canada (3) among an estimated 49 programs (82% response rate). Respondents tended to work in >200 bed free-standing children's hospitals (27, 68%). Pediatric general surgeons respond to activations in 32 (80%) cases, with a median group size of 7 (IQR 5,9.5); 8 (20%) responding institutions take in-house call and 63% have a formal back-up system for eCPR. Dedicated simulation programs were reported by 22 (55%) respondents. Annual eCPR activations average approximately 6/year; approximately 39% of patients survived to decannulation, with 35% surviving to discharge. Cannulations occurred in a variety of settings and were mostly done through the neck at the purview of cannulating surgeon/proceduralist. Exclusion criteria used by hospitals included pre-hospital arrest (21, 53%), COVID+ (5, 13%), prolonged CPR (18, 45%), lethal chromosomal anomalies (15, 38%) and terminal underlying disease (14, 35%). CONCLUSIONS: While there are some similarities regarding inclusion/exclusion criteria, cannulation location and modality and follow-up in pediatric eCPR, these are not standard across multiple institutions. Survival to discharge after eCPR is modest but data on cost and long-term neurologic sequela are lacking. Codification of indications and surgical approaches may help clarify the utility and success of eCPR.

Similar frequency of atrial perforation between atrial and bicaval dual lumen veno-venous ECMO cannulas in a pediatric population.

PURPOSE: Complications associated with use of dual-lumen venovenous extracorporeal membrane oxygenation (VV-ECMO) cannulas are of concern in pediatric patients. While the risk of atrial perforation is believed to be higher with bicaval cannulas, direct comparison of complication rate between atrial and bicaval cannulas has not been conducted in this population. METHODS: A retrospective review was conducted at a free-standing children's hospital of all patients 0-18 years old, placed on VV-ECMO with a dual-lumen cannula from January 2009 to December 2018. Patients were grouped based on cannula type. Complications were assessed over the entire duration of the ECMO run. Logistic regression analyses were used to evaluate for an association between cannula type and risk of pericardial effusion or cannula-related complication requiring median sternotomy or pericardial drain placement. RESULTS: During the study period 119 patients were placed on VVECMO using a dual-lumen cannula. Eighty-two patients (69%) were <2 years old, 19 (16%) were 2-10 years old, and 18 (15%) were 11-18 years old. Seventy-three were cannulated with an atrial cannula and 46 patients received a bicaval cannula. Pericardial effusions were seen in 30% and 24% of these patients respectively while severe complications were seen in 9.6% and 8.7% of patients respectively. Compared to patients treated with a bicaval cannula, those who received an atrial cannula had similar odds of effusions (OR: 1.41, 95% CI: 0.62-3.36) and severe complications (OR 0.89, 95% CI: 0.27-3.18). After adjusting for age, weight, cannula and circuit manipulations, and use of echocardiography, the OR of effusion was 1.91 (95% CI: 0.65-6.42), and the adjusted OR of severe complication was 0.69 (95% CI: 0.16-3.33). CONCLUSIONS: There were no significant differences in frequency of pericardial effusions or severe cannula-related complications between the treatment groups across all pediatric patients and within the subgroup of patients under 2 years of age.

Epidemiology of swallow dysfunction in CDH patients.

PURPOSE: There is a growing body of literature regarding long-term pulmonary outcomes in children with congenital diaphragmatic hernia (CDH). Oral feeding skills in these children are often delayed. Chronic descending aspiration due to uncoordinated swallowing can further insult the already compromised lung parenchyma in these children. This study describes patterns of swallowing dysfunction and aspiration in patients with CDH. METHODS: Records of all children treated for CDH at our institution from January 2014 to December 2019 were reviewed. Concern for swallowing dysfunction was marked by performance of a video-fluoroscopic swallow study (VFSS). We determined the frequency of aspiration on VFSS and how frequently that finding changed patient management. We also evaluated for association between clinical suspicion of swallow dysfunction and descriptors of CDH severity. RESULTS: Sixty-nine patients were treated during this 6-year time period. Of those, 10 (14%) had a VFSS as an inpatient, and 25 (36%) had one as an outpatient. Eight (80%) inpatient and 17 (68%) outpatient studies identified aspiration. VFSS results changed management in 80% of patients, often by altering the consistency of oral feeds. There were no associations between CDH side, defect size or need for a patch and need for a VFSS. CONCLUSIONS: The frequency of aspiration in the CDH population is high. Identification of aspiration on VFSS leads to changes in treatment aimed at protecting the lungs. Additionally, the severity of the CDH was not associated with aspiration on VFSS.

Appendectomy Versus Observation for Appendicitis in Neutropenic Children With Cancer.

BACKGROUND: Optimal management of neutropenic appendicitis (NA) in children undergoing cancer therapy remains undefined. Management strategies include upfront appendectomy or initial nonoperative management. We aimed to characterize the effect of management strategy on complications and length of stay (LOS) and describe implications for chemotherapy delay or alteration. METHODS: Sites from the Pediatric Surgery Oncology Research Collaborative performed a retrospective review of children with NA over a 6-year period. RESULTS: Sixty-six children, with a median age of 11 years (range 1-17), were identified with NA while undergoing cancer treatment. The most common cancer diagnoses were leukemia (62%) and brain tumor (12%). Upfront appendectomy was performed in 41% of patients; the remainder had initial nonoperative management. Rates of abscess or perforation at diagnosis were equivalent in the groups (30% vs 24%; P = .23). Of patients who had initial nonoperative management, 46% (17 of 37) underwent delayed appendectomy during the same hospitalization. Delayed appendectomy was due to failure of initial nonoperative management in 65% (n = 11) and count recovery in 35% (n = 6). Cancer therapy was delayed in 35% (n = 23). Initial nonoperative management was associated with a delay in cancer treatment (46% vs. 22%, P = .05) and longer LOS (29 vs 12 days; P = .01). Patients who had initial nonoperative management and delayed appendectomy had a higher rate of postoperative complications (P < .01). CONCLUSIONS: In pediatric patients with NA from oncologic treatment, upfront appendectomy resulted in lower complication rates, reduced LOS, and fewer alterations in chemotherapy regimens compared to initial nonoperative management.

Induction of Short-Term Sensitization by an Aversive Chemical Stimulus in Zebrafish Larvae.

Larval zebrafish possess a number of molecular and genetic advantages for rigorous biological analyses of learning and memory. These advantages have motivated the search for novel forms of memory in these animals that can be exploited for understanding the cellular and molecular bases of vertebrate memory formation and consolidation. Here, we report a new form of behavioral sensitization in zebrafish larvae that is elicited by an aversive chemical stimulus [allyl isothiocyanate (AITC)] and that persists for ≥30 min. This form of sensitization is expressed as enhanced locomotion and thigmotaxis, as well as elevated heart rate. To characterize the neural basis of this nonassociative memory, we used transgenic zebrafish expressing the fluorescent calcium indicator GCaMP6 (Chen et al., 2013); because of the transparency of larval zebrafish, we could optically monitor neural activity in the brain of intact transgenic zebrafish before and after the induction of sensitization. We found a distinct brain area, previously linked to locomotion, that exhibited persistently enhanced neural activity following washout of AITC; this enhanced neural activity correlated with the behavioral sensitization. These results establish a novel form of memory in larval zebrafish and begin to unravel the neural basis of this memory.

Surgical management of pediatric rectal prolapse: A survey of the American Pediatric Surgical Association (APSA).

INTRODUCTION: Many management options exist for the treatment of refractory rectal prolapse (RP) in children. Our goal was to characterize current practice patterns among active members of APSA. METHODS: A 23-item questionnaire assessed the management of full-thickness RP for healthy children who have failed medical management. The survey was approved by our IRB and by the APSA Outcomes committee. RESULTS: 236 surgeons participated. The respondents were geographically dispersed (44 states, 5 provinces). 32% of respondents had twenty or more years of clinical experience. 71% evaluated 1-5 RP patients in the last 2 years, while 5% evaluated >10. 71% performed 0-1 procedure (operation or local therapy [LT]) for RP over 2 years. 59% would treat a 2-year-old patient differently than a 6-year-old with the same presentation, and were more likely to offer up-front surgery to a 6-year-old (26% vs 15%, p = 0.04), less likely to continue medical management indefinitely (2% vs 7%, p=0.01), and more likely to perform resection with rectopexy (30% vs. 15%, p=0.01). 71% perform LT as an initial intervention: injection sclerotherapy (59%), anal encirclement (8%), and sclerotherapy + anal encirclement (5%). 70% consider LT a failure after 1-3 attempts. If LT fails, surgical management consists of transabdominal rectopexy (46%), perineal proctectomy or proctosigmoidectomy (22%), transabdominal sigmoidectomy + rectopexy (22%), and posterior sagittal rectopexy (9%). CONCLUSIONS: There is wide variability in the surgical management of pediatric rectal prolapse. This suggests a need for development of processes to identify best practices and optimize outcomes for this condition.

Epidemiology of Hirschsprung disease in California from 1995 to 2013.

PURPOSE: This study seeks to update current epidemiology of Hirschsprung disease (HD) in California. METHODS: Using data from the California Office of Statewide Health Planning and Development Linked Birth (1995-2012) and Patient Discharge Databases (1995-2013), patients from either dataset with an ICD-9 diagnosis code of HD (751.3) or procedure code of Soave (48.41), Duhamel (48.65), or Swenson/other pull-through (48.49) were included. Patients > age 18 during their first admission were excluded. RESULTS: Of 9.3 million births, 2,464 patients were identified. Incidence was 2.2 cases/10,000 live births, with rates peaking at 2.9/10,000 births in 2002. Incidence was highest among African American (4.1/10,000) and Asian/Pacific Islander (2.5/10,000) births. Most were male (n = 1652, 67.1%). Sixty patients (2.4%) had Down syndrome. The median gestational age at birth was 38 weeks 6 days (interquartile range [IQR] 37 weeks 1 day-40 weeks 1 day). Mortality during the first year of life was 1.7%. Median age at death was 14.5 days (IQR 0-113 days). CONCLUSION: This is one of the largest population-based studies of HD. In California, the incidence of HD is stable, risk is highest among African American children, and the mortality rate is < 2%.

Epidemiology of gastroschisis: A population-based study in California from 1995 to 2012.

BACKGROUND: Although the incidence of gastroschisis is increasing, risk factors are not clearly identified. METHODS: Using the Linked Birth Database from the California Office of Statewide Health Planning and Development from 1995 to 2012, patients with gastroschisis were identified by ICD-9 diagnosis/procedure code or birth certificate designation. Logistic regressions examined demographics, birth factors, and maternal exposures on risk of gastroschisis. RESULTS: The prevalence of gastroschisis was 2.7 cases per 10,000 live births. Patients with gastroschisis had no difference in fetal exposure to alcohol (p = 0.609), narcotics (p = 0.072), hallucinogenics (p = 0.239), or cocaine (p = 0.777), but had higher exposure to unspecified/other noxious substances (OR 3.27, p = 0.040; OR 2.02, p = 0.002). Gastroschisis was associated with low/very low birthweight (OR 5.08-16.21, p < 0.001) and preterm birth (OR 3.26-10.0, p < 0.001). Multivariable analysis showed lower risk in black (OR 0.44, p < 0.001), Asian/Pacific Islander (OR 0.76, p = 0.003), and Hispanic patients (OR 0.72, p < 0.001) compared to white patients. Risk was higher in rural areas (OR 1.24-1.76, p = 0.001). Compared to women age < 20, risk decreased with advancing maternal age (OR 0.49-OR 0.03, p < 0.001). Patients with gastroschisis had increased total charges ($336,270 vs. $9012, p < 0.001) and length of stay (38.1 vs. 2.9 days, p < 0.001). Mortality was 4.6%. CONCLUSIONS: This is the largest population-based study summarizing current epidemiology of gastroschisis in California. TYPE OF STUDY: Retrospective comparative cohort study. LEVEL OF EVIDENCE: III.

Subcutaneous local anesthetic infusion could eliminate use of epidural analgesia after the Nuss procedure.

AIM: To compare outcomes of continuous subcutaneous infusion of local anesthetic and epidural analgesia following the Nuss procedure. PATIENTS & METHODS: A retrospective chart review compared patients managed with subcutaneous local anesthetic infusion (n = 12) versus thoracic epidural (n = 19) following the Nuss procedure from March 2013 to June 2015. RESULTS: There was no difference in hospital length of stay or days on intravenous narcotics. Epidural catheter placement prolonged operating room time (146.58 ± 28.30 vs 121.42 ± 21.98 min, p = 0.01). Average pain scores were slightly higher in the subcutaneous infusion group (3.72 ± 1.62 vs 2.35 ± 0.95, p = 0.02), but of negligible clinical significance. CONCLUSION: Continuous subcutaneous infusion of local anesthetic could eliminate the need for thoracic epidural for pain management after the Nuss procedure.

Isolation of myogenic progenitor cell population from human placenta: A pilot study.

PURPOSE: The purpose of this study was to demonstrate a method of isolating myogenic progenitor cells from human placenta chorionic villi and to confirm the myogenic characteristics of the isolated cells. METHODS: Cells were isolated from chorionic villi of a second trimester male placenta via a combined enzymatic digestion and explant culture. A morphologically distinct subpopulation of elongated and multinucleated cells was identified. This subpopulation was manually passaged from the explant culture, expanded, and analyzed by fluorescence in situ hybridization (FISH) assay, immunocytochemistry, and flow cytometry. Myogenic characteristics including alignment and fusion were tested by growing these cells on aligned polylactic acid microfibrous scaffold in a fusion media composed of 2% horse serum in Dulbecco's modified Eagle medium/high glucose. RESULTS: The expanded subpopulation was uniformly positive for integrin α-7. Presence of Y-chromosome by FISH analysis confirmed chorionic villus origin rather than maternal cell contamination. Isolated cells grew, aligned, and fused on the microfibrous scaffold, and they expressed myogenin, desmin, and MHC confirming their myogenic identity. CONCLUSION: Myogenic progenitor cells can be isolated from human chorionic villi. This opens the possibility for translational and clinical applications using autologous myogenic cells for possible engraftment in treatment of chest and abdominal wall defects.

Outcomes of bedside sutureless umbilical closure without endotracheal intubation for gastroschisis repair in surgical infants.

INTRODUCTION: Newborns with gastroschisis have historically undergone surgical repair under general anesthesia. Our institution recently transitioned to the sutureless umbilical closure for gastroschisis. We sought to evaluate the feasibility of bedside gastroschisis repair without endotracheal intubation. METHODS: A retrospective review was performed of neonates with gastroschisis who underwent sutureless umbilical closure from 2011 to 2015. Clinical characteristics and outcomes between groups were compared. RESULTS: In total, 53 infants underwent sutureless umbilical closure. Closure without endotracheal intubation was attempted in 23 (43%) babies and was successful in 15 (65%) infants. Two of the 8 patients who required intubation needed a temporary silo. Neonates successfully repaired without intubation were more premature (p < 0.01), smaller at birth (p = 0.01), and repaired nearly an hour sooner (p < 0.01). There were no differences in time to full enteral nutrition, length of stay, bowel ischemia, or sepsis. CONCLUSION: Bedside sutureless umbilical closure without intubation is feasible and effective in newborns with gastroschisis. The procedure decreases time to gastroschisis closure. Smaller and more premature neonates were more likely to be successfully closed without intubation.