Syndromic congenital diaphragmatic hernia: Current incidence and outcome. Analysis from the congenital diaphragmatic hernia study group registry.

BACKGROUND: The aim of this study was to describe the incidence of Congenital Diaphragmatic Hernia, CDH, associated with known or clinically suspected syndromes, and the postnatal outcomes from a large database for CDH. METHODS: Data from the multicenter, multinational database on infants with CDH (Congenital Diaphragmatic Hernia Study Group Registry) born from 1996 to 2020 were analyzed. Patients with known or suspected syndromes were grouped and outcome data were analyzed and compared to those without syndromic features. RESULTS: A total of 12,553 patients were entered in the registry during the study period, and 421 had reported known syndromes, representing 3.4% of all CDH cases in the registry. A total of 50 different associated syndromes were reported. In addition to those with clinically suspected genetic conditions, a total rate of genetic syndromes with CDH was 8.2%. The overall survival to discharge for syndromic CDH was 34% and for non-syndromic CDH was 76.7%. The most common were syndromes Fryns syndrome (19.7% of all syndromes, 17% survival), trisomy 18 or Edward syndrome (17.5%, 9% survival), trisomy 21 or Down syndrome (9%, 47% survival), trisomy 13 or Patau syndrome (6.7%, 14% survival), Cornelia de Lange syndrome (6.4% of all syndromes, 22% survival) and Pallister-Killian syndrome (5.5% of all syndromes, 39.1% survival). In addition, 379 cases had reported chromosomal anomalies and 233 cases had clinically suspected syndromes, based on two more dysmorphic features or malformations in addition to CDH, but without molecular diagnosis. The syndromic CDH group had lower birth weight and gestational age at birth and increased incidence of bilateral CDH (2.9%) and rates of non-repair (53%). The length of hospital stay was longer, and larger number of patients needed O2 at 30 days. Extracorporeal life support was used only in 15% of the cases. Those who underwent surgical repair had survival to discharge rates of 73%. CONCLUSION: Syndromic CDH is rare and only 3.4% of the reported cases of CDH have a known syndrome or association, but, if including patients with two dysmorphic features malformations, in addition to CDH, altogether as many as 8.2% have a diagnosed or suspected genetic condition. These children have with lower survival rates. Given higher rates of non-repair and decreased extracorporeal life support use, along with a high early mortality, decision-making regarding goals of care clearly influences outcomes. Survival varies depending on the genetic cause. Early genetic diagnosis is important and may influence the decision-making.

Virtual Mentoring: A Novel Approach to Facilitate Medical Student Applications to General Surgery Residency.

OBJECTIVE: The COVID-19 pandemic rapidly altered the landscape of medical education, particularly disrupting the residency application process and highlighting the need for structured mentorship programs. This prompted our institution to develop a virtual mentoring program to provide tailored, one-on-one mentoring to medical students applying to general surgery residency. The aim of this study was to examine general surgery applicant perception of a pilot virtual mentoring curriculum. DESIGN: The mentorship program included student-tailored mentoring and advising in 5 domains: resume editing, personal statement composition, requesting letters of recommendation, interview skills, and residency program ranking. Electronic surveys were administered following ERAS application submission to participating applicants. The surveys were distributed and collected via a REDCap database. RESULTS: Eighteen out of 19 participants completed the survey. Confidence in a competitive resume (p = 0.006), interview skills (p < 0.001), obtaining letters of recommendation (p = 0.002), personal statement drafting (p < 0.001), and ranking residency programs (p < 0.001) were all significantly improved following completion of the program. Overall utility of the curriculum and likelihood to participate again and recommend the program to others was rated a median 5/5 on the Likert scale (5 [IQR 4-5]). Confidence in the matching carried a premedian 66.5 (50-65) and a postmedian 84 (75-91) (p = 0.004). CONCLUSION: Following the completion of the virtual mentoring program, participants were found to be more confident in all 5 targeted domains. In addition, they were more confident in their overall ability to match. General Surgery applicants find tailored virtual mentoring programs to be a useful tool allowing for continued program development and expansion.

Mortality in Congenital Diaphragmatic Hernia: A Multicenter Registry Study of Over 5000 Patients Over 25 Years.

OBJECTIVE: To determine if risk-adjusted survival of patients with 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 5-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: 5203 patients from 23 centers with >22years 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.

Isolated aortic arch anomalies are associated with defect severity and outcome in patients with congenital diaphragmatic hernia.

PURPOSE: 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. METHODS: 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. RESULTS: 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 χ2 p < 0.001). CDH + IAAA were less likely to undergo diaphragm repair (72 vs. 87%, p < 0.001), and overall mortality was higher for CDH + IAAA infants (58 vs. 24%, p < 0.001). When controlling for defect size, birth weight, and Apgar, IAAA were significantly associated with mortality (OR 3.3, 95% CI 2.2-5.0; p < 0.01) but not associated with ECLS (OR 0.98, 95% CI 0.65-1.50; p = 0.90). Only 17% (n = 28) of CDH + IAAA patients underwent aortic intervention. CONCLUSIONS: IAAA 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.

Utilization of trauma nurse screening procedure for triage of the injured patient.

PURPOSE: The treatment of trauma patients requires significant hospital resources. Numerous protocols exist to triage the injured patient and determine the level of care they may require. The purpose of this work is to describe an institutional trauma nurse screening procedure and to evaluate its effectiveness in triaging injured patients. METHODS: This retrospective study was conducted at a large, tertiary trauma center from January to June 2021. Patients were assessed by trauma nurse clinicians (TNC) utilizing a standardized screening process to determine suitability for trauma activation. If the patient did not meet activation criteria, they were sent to the main Emergency Department for evaluation and treatment. Patients could be activated later by the emergency physician. The primary variables of interest were number of activations after initial "rule out," injury severity score (ISS) for patients who were activated, mechanism of injury, and disposition. RESULTS: A total of 1874 TNC screenings were performed. Of these, 1449 (77%) patients did not meet trauma activation criteria. Only 41 (2.8%) patients initially ruled out were later activated by the emergency physician and admitted for treatment of injuries. The average ISS of all activated patients was 9 ± 6. Thirty-six patients had an ISS ≤ 15, four between 16 and 25, and only one patient had an ISS > 25. Twenty-seven patients were admitted to the ward, five went to step-down units, and five required intensive care unit admission. Four patients required operative intervention for their injuries. CONCLUSION: These results suggest that nursing screening protocols can be safe, effective tools for triage of trauma patients.

Standardization of Pediatric Noncardiac Operating Room to Intensive Care Unit Handoffs Improves Communication and Patient Care.

OBJECTIVES: Handoffs are critical points in transitioning care between multidisciplinary teams, yet data regarding intensive care unit (ICU) handoffs in pediatric noncardiac surgical patients are lacking. We hypothesized that standardized handoffs from the pediatric operating room (OR) to the ICU would improve physician presence, communication, and patient care parameters. METHODS: This quality improvement initiative was performed at a tertiary children's hospital. Stakeholders (anesthesiologists, nurses, intensivists, and surgeons) developed a standardized OR to pediatric and neonatal ICU handoff process based on common goals and outcomes of interest. Baseline data were collected before intervention. Implementation was carried out in 2 phases, phase 1 with a written handoff and Phase 2 with a scripted handoff process. Data collected by trained observers included handoff attendance, distractions, and transfer of essential patient information. As a surrogate for outcomes, patient care parameter data were collected for 6 hours after transfer. RESULTS: After phase 1, surgery and ICU physician attendance increased significantly, distractions decreased, and communication of essential patient data improved. In phase 2 (scripted handoff), attendance continued to rise, distractions remained decreased, and transfer of essential information was still improved compared with baseline. Mean handoff duration did not significantly change throughout the study. Certain patient care parameters (escalation of respiratory support, additional laboratory studies, vasopressor administration, antibiotic administration and timing) remained unchanged compared with baseline. However, the need for resuscitative fluid bolus or blood products significantly decreased after implementation phase 2. CONCLUSIONS: Standardized handoffs for pediatric noncardiac surgical patients from the OR to the ICU can improve provider attendance and communication.

Evaluation of Murine Host Sex as a Biological Variable in Transplanted Human Intestinal Organoid Development.

BACKGROUND: Human intestinal organoids (HIOs), when transplanted into immunocompromised mice (tHIOs), demonstrate significant growth and maturation. While both male and female mice are reported to be viable hosts for these experiments, a direct comparison of sex-related differences in tHIO structure and development has not been performed. AIMS: We sought to identify host sex-related differences in tHIO engraftment, morphology, and epithelial and mesenchymal development. METHODS: HIOs were generated in vitro and transplanted beneath the kidney capsule of NSG male and female mice. tHIOs were harvested at 8-9 weeks. Anthropometric measurements were captured. tHIOs were divided in half and histology or RT-qPCR performed. Morphology was evaluated and epithelial architecture graded on a scale of 1 (absence of crypts/villi) to 4 (elongated crypt-villus axis). RT-qPCR and immunofluorescence microscopy were performed for epithelial and mesenchymal differentiation markers. RESULTS: Host survival and tHIO engraftment were equivalent in male and female hosts. tHIO weight and length were also equivalent between groups. The number of lumens per tHIOs from male and female hosts was similar, but the mean lumen circumference was larger for tHIOs from male hosts. tHIOs from male hosts were more likely to demonstrate higher grades of epithelial development. However, both groups showed similar differentiation into secretory and absorptive epithelial lineages. Markers for intestinal identity, mesenchymal development, and brush border enzymes were also expressed similarly between groups. CONCLUSIONS: While male host sex was associated with larger tHIO lumen size and mucosal maturation, tHIOs from both groups had similar engraftment, growth, and epithelial and mesenchymal cytodifferentiation.

Neonatal rodent ventilation and clinical correlation in congenital diaphragmatic hernia.

INTRODUCTION: 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. METHODS: We used the nitrofen model of CDH. For control and CDH rodents, data were collected within the first hour of life. Oxygen saturations (SpO2 ) were collected using MouseOx, and large airway resistance and inspiratory capacities were collected using flexiVent. A single-center, retrospective review of term CDH infants from 2014 to 2020 was performed. Tidal volumes were collected every 6 h for the first 48 h of life or until the patient was taken off conventional ventilation. Newborns that were mechanically ventilated but had no pulmonary pathology were used as controls. CDH severity was defined using the CDH Study Group (CDHSG) classification system. RESULTS: Control rodents had a median SpO2 of 94% (IQR: 88%-98%); CDH pups had a median SpO2 of 27.9% (IQR: 22%-30%) (p < 0.01). CDH rodents had lower inspiratory capacity than controls (median: 110 µl, IQR: 70-170 vs. median: 267 µl, IQR: 216-352; p < 0.01). CDH infants had a lower initial SpO2 than control infants. Overall, CDH infants had lower tidal volumes than control infants (median: 4.2 ml/kg, IQR: 3.3-5.0 vs. 5.4 ml/kg, IQR: 4.7-6.2; p = 0.03). Tidal volumes varied by CDHSG stage. CONCLUSION: Newborns with CDH have lower SpO2 and lower, CDHSG stage specific, tidal volumes than control infants. The nitrofen model of CDH reflects these differences. Rodent models may be useful in studying therapeutic ventilatory strategies for CDH infants.

Birth weight predicts patient outcomes in infants who undergo congenital diaphragmatic hernia repair.

PURPOSE: 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. METHODS: Patients in the CDH Study Group from 2007 to 2018 were included. LBW was defined as <2.5 kg. Clinical characteristics and outcomes for LBW patients were compared to normal birthweight (NBW) patients using univariate and multivariable analyses. RESULTS: Of 5,586 patients, 1,157 (21%) were LBW. LBW infants had more congenital anomalies and larger diaphragmatic defects than NBW infants. ECLS utilization was decreased, and overall mortality was increased among LBW infants compared to NBW infants. A 1 kg increase in birthweight was associated with 34% higher odds of survival after repair (adjusted Odds Ratio 1.34, 95% CI 1.03-1.76; 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. CONCLUSION: 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.

How We Did It: Implementing a Trainee-Focused Surgical Research Curriculum and Infrastructure.

OBJECTIVE: To describe the implementation of a department-wide research curriculum and infrastructure created to promote academic collaboration and productivity, particularly amongst trainees and junior investigators involved in basic, translational, clinical, quality, or education research. DESIGN: Description of UT Southwestern Medical Center's (UTSW) surgical research resources and infrastructure and the development of a didactic curriculum focused on research methods, writing skills, and optimizing academic time and effort. SETTING: The collaboration was initiated by UTSW Department of Surgery residents who were on dedicated research time (DRT) and grew to include trainees and faculty at all levels of the institution. Guest lecturers from institutions around the country were incorporated via virtual meeting platforms. PARTICIPANTS: Medical students, residents, and clinical and research faculty from the Department of Surgery were invited to attend research meetings, didactics, and the guest-lecture series. Additionally, all groups were given access to shared resources and encouraged to share their own work. RESULTS: A robust set of resources including data analysis tools, manuscript and grant writing templates, funding opportunities, and a comprehensive list of surgical conferences was created and made accessible to UTSW Surgery team members. Moreover, a curriculum of lectures covering a broad variety of topics for all types of research was created and has thus far reached an audience of over 40 UTSW Surgery trainees and staff. CONCLUSIONS: A comprehensive set of lectures and resources targeted toward facilitating surgical research was designed and implemented at one of the largest surgical training programs in the country. This effort represents a low-cost, feasible, and accessible way to improve academic productivity and enhance the training of surgeon-scientists and can serve as a blueprint for other institutions around the country.

Extracorporeal Life Support for Respiratory Failure in Patients With Electronic Cigarette or Vaping Product Use-Associated Lung Injury.

OBJECTIVES: Electronic cigarette or vaping product use-associated lung injury is a clinical entity that can lead to respiratory failure and death. Despite the severity of electronic cigarette or vaping product use-associated lung injury, the role of extracorporeal life support in its management remains unclear. Our objective was to describe the clinical characteristics and outcomes of patients with electronic cigarette or vaping product use-associated lung injury who received extracorporeal life support. DESIGN: We performed a retrospective review of records of electronic cigarette or vaping product use-associated lung injury patients who received extracorporeal life support. Standardized data were collected via direct contact with extracorporeal life support centers. Data regarding presentation, ventilatory management, extracorporeal life support details, and outcome were analyzed. SETTING: This was a multi-institutional, international case series with patients from 10 different institutions in three different countries. PATIENTS: Patients who met criteria for confirmed electronic cigarette or vaping product use-associated lung injury (based on previously reported diagnostic criteria) and were placed on extracorporeal life support were included. Patients were identified via literature review and by direct contact with extracorporeal life support centers. MEASUREMENTS AND MAIN RESULTS: Data were collected for 14 patients ranging from 16 to 45 years old. All had confirmed vape use within 3 months of presentation. Nicotine was the most commonly used vaping product. All patients had respiratory symptoms and radiographic evidence of bilateral pulmonary opacities. IV antibiotics and corticosteroids were universally initiated. Patients were intubated for 1.9 days (range, 0-6) prior to extracorporeal life support initiation. Poor oxygenation and ventilation were the most common indications for extracorporeal life support. Five patients showed evidence of ventricular dysfunction on echocardiography. Thirteen patients (93%) were placed on venovenous extracorporeal life support, and one patient required multiple rounds of extracorporeal life support. Total extracorporeal life support duration ranged from 2 to 37 days. Thirteen patients survived to hospital discharge; one patient died of septic shock. CONCLUSIONS: Electronic cigarette or vaping product use-associated lung injury can cause refractory respiratory failure and hypoxemia. These data suggest that venovenous extracorporeal life support can be an effective treatment option for profound, refractory respiratory failure secondary to electronic cigarette or vaping product use-associated lung injury.

Telemedicine as a component of forward triage in a pandemic.

OBJECTIVE(S): Coronavirus disease 2019 (COVID-19) presents an enormous challenge to healthcare systems globally. Optimizing access to healthcare while minimizing face-to-face patient encounters is critical to limiting exposures, conserving resources, and preserving health. We aimed to evaluate the utility of a COVID-focused telehealth program in avoiding potential in-person visits while maintaining high patient satisfaction. METHODS: All patients with COVID-related virtual visits at our center between March and May 2020 were included. Demographic, satisfaction, and clinical information were gathered using a modified, validated telehealth satisfaction questionnaire disseminated via email or telephone. Data were analyzed using Stata. RESULTS: Of 581 eligible patients, 180 (31%) responded to the survey. Symptoms (73%) and possible exposure (22%) were the main reasons cited for pursuing a virtual visit; cough (44%) and fever (36%) were the most common presenting symptoms. Regarding patient satisfaction, most patients rated the experience as "very good" or "excellent", and 94% of respondents said they would recommend COVID-focused triage through telehealth to others. Over 81% of patients indicated that, if telehealth was not an option, they would have sought an in-person encounter. Ultimately, only 27% of patients reported pursuing a face-to-face encounter after participating in the virtual visit. CONCLUSION: Based on patient self-reporting, telemedicine potentially prevented face-to-face COVID-related encounters. Patients expressed satisfaction with the virtual process and were less likely to pursue in-person consultation. Leveraging a telehealth strategy for forward triage has the potential to reduce exposures while conserving healthcare resources.

Early, Postnatal Pulmonary Hypertension Severity Predicts Inpatient Outcomes in Congenital Diaphragmatic Hernia.

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 <2/3 systemic), moderate (between 2/3 systemic and systemic), or severe (supra-systemic). Univariate and multivariate analyses were performed. Adjusted Poisson regression was used to assess the primary composite outcome of mortality or oxygen support at 30 days. 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.

Injury Severity, Arrival Physiology, Coagulopathy, and Outcomes Among the Youngest Trauma Patients.

BACKGROUND: Although physiologic differences exist between younger and older children, pediatric trauma analyses are weighted toward older patients. Trauma-induced coagulopathy, determined by rapid thrombelastography (rTEG), is a predictor of outcome in trauma patients, but the significance of rTEG values among very young trauma patients remains unknown. Our objective was to identify the prehospital or physiologic factors, including rTEG values, that were associated with mortality in trauma patients younger than 5 y old. MATERIALS AND METHODS: Patients younger than 5 y old that met the highest-level trauma activation criteria at an academic children's hospital from 2010-2016 were included. Data regarding demographics, pre-hospital management, laboratory values, injury severity, and outcome were queried. Univariate and multivariate analyses were performed comparing survivors and non-survivors. RESULTS: A total of 356 patients were included. 60% were male, and the median age was 3 y (IQR 1-4). Overall mortality was 13% (n = 45); brain injury (91%) and hemorrhage (9%) were the causes of death. Compared to survivors, rTEG values in nonsurvivors showed longer activated clotting time and slower speed of clot formation. Clot strength was also decreased in nonsurvivors. On stepwise regression modeling, rTEG values were not significant predictors of mortality. Admission base deficit, arrival temperature, and head injury severity were identified as independent predictors of mortality. CONCLUSIONS: While rTEG identified coagulopathy in trauma patients < 5 y old, it was not an independent predictor of mortality. Our findings suggest that trauma providers should pay close attention to admission base deficit, arrival temperature, and head injury severity when managing the youngest trauma patients.

Elevated proBNP levels are associated with disease severity, cardiac dysfunction, and mortality in congenital diaphragmatic hernia.

BACKGROUND: 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. METHODS: 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. RESULTS: 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) (p<0.001). 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). CONCLUSION: 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.

Incidence and outcomes of patients with congenital diaphragmatic hernia and pulmonary sequestration.

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.

Cornelia de Lange syndrome and congenital diaphragmatic hernia.

PURPOSE: 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. METHODS: 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. RESULTS: 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) (p<0.001). 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 (p<0.001). Mortality was 76% for CdLS patients compared with 29% for non-CdLS patients (p<0.001). Of the 7 CdLS patients who underwent repair, 5 survived to hospital discharge. CONCLUSIONS: 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. TYPE OF STUDY: Retrospective comparative study LEVEL OF EVIDENCE: III.

Extracellular vesicles influence the pulmonary arterial extracellular matrix in congenital diaphragmatic hernia.

OBJECTIVE: Abnormal pulmonary vasculature directly affects the development and progression of congenital diaphragmatic hernia (CDH)-associated pulmonary hypertension (PH). Though overarching structural and cellular changes in CDH-affected pulmonary arteries have been documented, the precise role of the extracellular matrix (ECM) in the pulmonary artery (PA) pathophysiology remains undefined. Here, we quantify the structural, compositional, and mechanical CDH-induced changes in the main and distal PA ECM and investigate the efficacy of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as a therapy to ameliorate pathological vascular ECM changes. METHODS: Pregnant Sprague-Dawley rodents were administered nitrofen to induce CDH-affected pulmonary vasculature in the offspring. A portion of CDH-affected pups was treated with intravenous infusion of MSC-EVs (1 × 1010 /mL) upon birth. A suite of histological, mechanical, and transmission electron microscopic analyses were utilized to characterize the PA ECM. RESULTS: The CDH model main PA presented significantly altered characteristics-including greater vessel thickness, greater lysyl oxidase (LOX) expression, and a relatively lower ultimate tensile strength of 13.6 MPa compared to control tissue (25.1 MPa), suggesting that CDH incurs ECM structural disorganization. MSC-EV treatment demonstrated the potential to reverse CDH-related changes, particularly through rapid inhibition of ECM remodeling enzymes (LOX and MMP-9). Additionally, MSC-EV treatment bolstered structural aspects of the PA ECM and mitigated pathological disorganization as exhibited by increased medial wall thickness and stiffness that, while not significantly altered, trends away from CDH-affected tissue. CONCLUSIONS: These data demonstrate notable ECM remodeling in the CDH pulmonary vasculature, along with the capacity of MSC-EVs to attenuate pathological ECM remodeling, identifying MSC-EVs as a potentially efficacious therapeutic for CDH-associated pulmonary hypertension.

Extracellular Vesicles Attenuate Nitrofen-Mediated Human Pulmonary Artery Endothelial Dysfunction: Implications for Congenital Diaphragmatic Hernia.

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 (P < 0.001), and MSCEv treatment attenuated ROS levels by 1.5 × versus nitrofen HPAECs (P < 0.01). Nitrofen-induced alterations in endothelial dysfunction-associated proteins are shown, and exposure to MSCEv restored more physiologic expression. Nitrofen HPAEC displayed greater MSCEv uptake (80% increase, P < 0.05). Adenosine, a clathrin-mediated endocytosis inhibitor, decreased uptake by 46% (P < 0.05). CDH PA contraction was impaired with KCL (108.6% ± 1.4% vs. 112.0% ± 1.4%, P = 0.092) and ET-1 (121.7% ± 3.0% vs. 131.2% ± 1.8%, P < 0.01). CDH PA relaxation was impaired with fasudil (32.2% ± 1.9% vs. 42.1% ± 2.2%, P < 0.001). After MSCEv treatment, CDH PA contraction improved (125.9% ± 3.4% vs. 116.4 ± 3.5, P = 0.06), and relaxation was unchanged (32.5% ± 3.2% vs. 29.4% ± 3.1%, P = 0.496). HPAEC exposure to nitrofen led to changes consistent with vasculopathy in CDH, and MSCEv treatment led to a more physiologic cellular response. MSCEv were preferentially taken up by nitrofen-treated cells by clathrin-dependent endocytosis. In vivo, MSCEv exposure improved PA contractile response. These data reveal mechanisms of cellular and signaling alterations that characterize MSCEv-mediated attenuation of pulmonary vascular dysfunction in CDH-associated pulmonary hypertension.