Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Exercise-Induced Pulmonary Hypertension in Long-Term Survivors of Congenital Diaphragmatic Hernia.

OBJECTIVE: To determine the prevalence of exercise-induced pulmonary hypertension (PH) among long-survivors of congenital diaphragmatic hernia repair. STUDY DESIGN: This is a single-center, retrospective cohort study of CDH survivors who underwent exercise stress echocardiography (ESE) at Boston Children's Hospital from January 2006 to June 2020. PH severity was assessed by echocardiogram at baseline and after exercise. Patients were categorized by right ventricular systolic pressure (RVSP) after exercise: Group 1 - no or mild PH; and Group 2 - moderate or severe PH (RVSP ≥ 60 mmHg or ≥ ½ systemic blood pressure). RESULTS: Eighty-four patients with CDH underwent 173 ESE with median age 8.1 (4.8 - 19.1) years at first ESE. Sixty-four patients were classified as Group 1, 11 as Group 2, and 9 had indeterminate RVSP with ESE. Moderate to severe PH after exercise was found in 8 (10%) patients with no or mild PH at rest. Exercise-induced PH was associated with larger CDH defect size, patch repair, use of ECMO, supplemental oxygen at discharge, and higher WHO functional class. Higher VE/VCO2 slope, lower peak oxygen saturation, and lower percent predicted FEV1, and FEV1/FVC ratio were associated with Group 2 classification. ESE changed management in 9/11 Group 2 patients. PH was confirmed in all 5 Group 2 patients undergoing cardiac catheterization after ESE. CONCLUSIONS: Among long-term CDH survivors, 10% had moderate-severe exercise-induced PH on ESE, indicating ongoing pulmonary vascular abnormalities. Further studies are needed to optimally define PH screening and treatment for patients with repaired CDH.

A Tracheal Aspirate-derived Airway Basal Cell Model Reveals a Proinflammatory Epithelial Defect in Congenital Diaphragmatic Hernia.

Rationale: Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm and lung hypoplasia. The pathophysiology of lung defects in CDH is poorly understood. Objectives: To establish a translational model of human airway epithelium in CDH for pathogenic investigation and therapeutic testing. Methods: We developed a robust methodology of epithelial progenitor derivation from tracheal aspirates of newborns. Basal stem cells (BSCs) from patients with CDH and preterm and term non-CDH control subjects were derived and analyzed by bulk RNA sequencing, assay for transposase accessible chromatin with sequencing, and air-liquid interface differentiation. Lung sections from fetal human CDH samples and the nitrofen rat model of CDH were subjected to histological assessment of epithelial defects. Therapeutics to restore epithelial differentiation were evaluated in human epithelial cell culture and the nitrofen rat model of CDH. Measurements and Main Results: Transcriptomic and epigenetic profiling of CDH and control BSCs reveals a proinflammatory signature that is manifested by hyperactive nuclear factor kappa B and independent of severity and hernia size. In addition, CDH BSCs exhibit defective epithelial differentiation in vitro that recapitulates epithelial phenotypes found in fetal human CDH lung samples and fetal tracheas of the nitrofen rat model of CDH. Furthermore, blockade of nuclear factor kappa B hyperactivity normalizes epithelial differentiation phenotypes of human CDH BSCs in vitro and in nitrofen rat tracheas in vivo. Conclusions: Our findings have identified an underlying proinflammatory signature and BSC differentiation defects as a potential therapeutic target for airway epithelial defects in CDH.

Efficacy and Safety of Tacrolimus or Infliximab Therapy in Children and Young Adults With Acute Severe Colitis.

INTRODUCTION: One-third of children and young adults admitted for management of acute severe colitis (ASC) fail intravenous corticosteroids. Infliximab (IFX) or tacrolimus (TAC) is often used to prevent urgent colectomy in these patients. However, no prior studies have reviewed the outcome of pediatric patients with ASC who were treated with either IFX or TAC. METHODS: We retrospectively identified 170 pediatric patients with ASC admitted to our institution who did not respond to intravenous corticosteroids and were subsequently treated with either IFX or TAC. We compared 6-month colectomy rates, time to colectomy, improvement in disease activity indices, and adverse effects. RESULTS: The mean age of patients in the IFX (n = 84) and TAC (n = 86) groups were 14 and 13.8 years, respectively. The median study follow-up time was 23 months. The rate of colectomy 6 months from rescue therapy was similar whether patients received IFX or TAC (22.6% vs 26.7%, respectively, P = 0.53). The mean decline in Pediatric Ulcerative Colitis Activity Index scores from admission to discharge in those treated with IFX (31.9) or TAC (29.8) was similar (P = 0.63). Three patients treated with IFX experienced infusion reactions. Six patients treated with TAC experienced changes in renal function or electrolytes, and 4 patients reported neurologic symptoms. CONCLUSIONS: There were no significant differences in the likelihood of colectomy 6 months after initiating IFX or TAC rescue therapy. Efficacy of both agents was comparable. The types of adverse effects differed by therapy. These data support the use of either TAC or IFX in children with ASC refractory to intravenous corticosteroids.

Long-Term Functional Outcomes at 1-Year After Hospital Discharge in Critically Ill Neonates With Congenital Diaphragmatic Hernia.

OBJECTIVES: Congenital diaphragmatic hernia (CDH) is a birth defect associated with long-term morbidity. Our objective was to examine longitudinal change in Functional Status Scale (FSS) after hospital discharge in CDH survivors. DESIGN: Single-center retrospective cohort study. SETTING: Center for comprehensive CDH management at a quaternary, free-standing children's hospital. PATIENTS: Infants with Bochdalek CDH were admitted to the ICU between January 2009 and December 2019 and survived until hospital discharge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred forty-two infants (58% male, mean birth weight 3.08 kg, 80% left-sided defects) met inclusion criteria. Relevant clinical data were extracted from the medical record to calculate FSS (primary outcome) at hospital discharge and three subsequent outpatient follow-up time points. The median (interquartile range [IQR]) FSS score at hospital discharge was 8.0 (7.0-9.0); 39 patients (27.5%) had at least moderate impairment (FSS ≥ 9). Median (IQR) FSS at 0- to 6-month ( n = 141), 6- to 12-month ( n = 141), and over 12-month ( n = 140) follow-up visits were 7.0 (7.0-8.0), 7.0 (6.0-8.0), and 6.0 (6.0-7.0), respectively. Twenty-one patients (15%) had at least moderate impairment at over 12-month follow-up; median composite FSS scores in the over 12-month time point decreased by 2.0 points from hospital discharge. Median feeding domain scores improved by 1.0 (1.0-2.0), whereas other domain scores remained without impairment. Multivariable analysis demonstrated right-sided, C- or D-size defects, extracorporeal membrane oxygenation use, cardiopulmonary resuscitation, and chromosomal anomalies were associated with impairment. CONCLUSIONS: The majority of CDH survivors at our center had mild functional status impairment (FSS ≤ 8) at discharge and 1-year follow-up; however, nearly 15% of patients had moderate impairment during this time period. The feeding domain had the highest level of functional impairment. We observed unchanged or improving functional status longitudinally over 1-year follow-up after hospital discharge. Longitudinal outcomes will guide interdisciplinary management strategies in CDH survivors.

Supraventricular Tachycardia in Infants With Congenital Diaphragmatic Hernia: Prevalence, Associations, and Outcomes.

OBJECTIVES: To characterize the prevalence, associations, management, and outcomes of supraventricular tachycardia (SVT) in neonates with congenital diaphragmatic hernia (CDH). DESIGN: Retrospective chart and cardiology code review within a cohort of patients with CDH was used to define a subpopulation with atrial arrhythmia. SVT mechanisms were confirmed by electrocardiogram analysis. Cox proportional hazard regression identified risk factors for SVT and association with clinical outcomes. SETTING: Medical Surgical ICU in a single, tertiary center, Boston Children's Hospital. PATIENTS: Eligible patients included neonates presenting with classic Bochdalek posterolateral CDH between 2005 and 2017, excluding newborns with Morgagni hernia or late diagnoses of CDH (>28 d). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: SVT arose in 25 of 232 neonates with CDH, (11%); 14 of 25 infants (56%) had recurrent SVT; atrioventricular node-dependent tachycardia was the most frequent mechanism (32%). The majority (71%) of SVT episodes received intervention. Nine patients (36%) received preventative antiarrhythmic medications. SVT was associated with lower Apgar score at 1 min, structural heart disease, larger defect size, extracorporeal membrane oxygenation (ECMO) support, and prostaglandin therapy for ductal patency as well as hospital stay greater than or equal to 8 weeks and use of supplemental oxygen at discharge. CONCLUSIONS: SVT can occur in neonates with CDH and frequently requires treatment. Odds of occurrence are increased with greater CDH disease severity, ECMO, and prostaglandin use. In unadjusted logistic regression analysis, SVT was associated with adverse hospital outcomes, underscoring the importance of recognition and management in this vulnerable population.

The Role of Anesthetic Management in Surgical Site Infections After Pediatric Intestinal Surgery.

BACKGROUND: Although surgical site infections (SSIs) remain a significant health care issue, a limited number of studies have analyzed risk factors for SSIs in children, particularly the role of intraoperative anesthetic management. Pediatric patients are less likely to have major adult risk factors for SSIs such as smoking and diabetes. Thus children may be more suitable as a cohort for examining the role of intraoperative anesthetics in SSIs. AIM: We examined an association between SSI incidence and anesthetic management in children who underwent elective intestinal surgery in a single institution. METHODS: We performed a retrospective study of 621 patients who underwent elective intestinal surgery under general anesthesia between January 2017 and September 2019, with primary outcome as the incidence of SSIs. We compared patients who were dichotomized in accordance with the median of the sevoflurane dose. We used propensity score (PS) pairwise matching of these patients to avoid selection biases. PS matching yielded 204 pairs of patients. RESULTS: We found that higher doses of sevoflurane were associated with a higher incidence of SSIs (9.8% versus 3.9%, P = 0.019). We adjusted for intraoperative factors that were not included in the PS adjustment factors, and multivariate regression analysis after PS matching showed compatible results (odds ratio: 2.58, 95% confidence interval: 1.11-6.04, P = 0.028). CONCLUSIONS: Higher doses of sevoflurane are associated with increased odds of SSIs after pediatric elective intestinal surgery. A randomized controlled study of volatile anesthetic-based versus intravenous anesthetic-based anesthesia will be needed to further determine the role of anesthetic drugs in SSI risk.

Longitudinal Analysis of Ventilation Perfusion Mismatch in Congenital Diaphragmatic Hernia Survivors.

OBJECTIVE: To determine the natural history of pulmonary function for survivors of congenital diaphragmatic hernia (CDH). STUDY DESIGN: This was a retrospective cohort study of survivors of CDH born during 1991-2016 and followed at our institution. A generalized linear model was fitted to assess the longitudinal trends of ventilation (V), perfusion (Q), and V/Q mismatch. The association between V/Q ratio and body mass index percentile as well as functional status was also assessed with a generalized linear model. RESULTS: During the study period, 212 patients had at least one V/Q study. The average ipsilateral V/Q of the cohort increased over time (P < .01), an effect driven by progressive reduction in relative perfusion (P = .012). A higher V/Q ratio was correlated with lower body mass index percentile (P < .001) and higher probability of poor functional status (New York Heart Association class III or IV) (P = .045). CONCLUSIONS: In this cohort of survivors of CDH with more severe disease characteristics, V/Q mismatch worsens over time, primarily because of progressive perfusion deficit of the ipsilateral side. V/Q scans may be useful in identifying patients with CDH who are at risk for poor growth and functional status.

Longitudinal Analysis of Pulmonary Function in Survivors of Congenital Diaphragmatic Hernia.

OBJECTIVE: To analyze longitudinal trends of pulmonary function testing in patients with congenital diaphragmatic hernia (CDH) followed in our multidisciplinary clinic. STUDY DESIGN: This was a retrospective cohort study of CDH patients born between 1991 and 2013. A linear mixed effects model was fitted to estimate the trends of percent predicted forced expiratory volume in 1 second (FEV1pp), percent predicted forced vital capacity (FVCpp), and FEV1/FVC over time. RESULTS: Of 268 patients with CDH who survived to discharge, 119 had at least 1 pulmonary function test study. The FEV1pp (P < .001), FVCpp (P = .017), and FEV1/FVC (P = .001) decreased with age. Compared with defect size A/B, those with defect size C/D had lower FEV1pp by an average of 11.5% (95% CI, 2.9%-20.1%; P = .010). A history of oxygen use at initial hospital discharge also correlated with decreased FEV1pp by an average of 8.0% (95% CI, 1.2%-15.0%; P = .023). CONCLUSIONS: In a select cohort of CDH survivors, average pulmonary function declines with age relative to expected population normative values. Those with severe CDH represent a population at risk for worsening pulmonary function test measurements who may benefit from recognition and monitoring for complications.

Mortality and Factors Associated With Hemorrhage During Pediatric Extracorporeal Membrane Oxygenation.

OBJECTIVES: To quantify and identify factors associated with bleeding events during pediatric extracorporeal membrane oxygenation. DESIGN: Retrospective cohort study with primary outcome of bleeding days on extracorporeal membrane oxygenation. SETTING: Single tertiary care children's hospital. SUBJECTS: One-hundred twenty-two children supported with extracorporeal membrane oxygenation for greater than 12 hours during January 2015 through December 2016. INTERVENTIONS: Bleeding days were identified if mediastinal or cannula site exploration, activated factor VII administration, gastrointestinal, pulmonary, or intracranial hemorrhages occurred. Logistic regression was used to assess factors associated with bleeding days. MEASUREMENTS AND MAIN RESULTS: Study population was identified from institutional extracorporeal membrane oxygenation database. Clinical, laboratory, and survival data were obtained from medical records. Only data from patients' first extracorporeal membrane oxygenation run were used. One-hundred twenty-two patients with median age of 17 weeks (interquartile range, 1-148 wk) were analyzed. Congenital heart disease (n = 56, 46%) was the most common diagnosis. Bleeding days comprised 179 (16%) of the 1,121 observed extracorporeal membrane oxygenation-patient-days. By extracorporeal membrane oxygenation day 4, 50% of users had experienced a bleeding day. Central rather than peripheral cannulation (odds ratio, 2.58; 95% CI, 1.47-4.52; p < 0.001), older age (odds ratio, 1.31 per increased week; 95% CI, 1.14-1.52; p < 0.001), higher lactate (odds ratio, 1.08 per 1 mmol/L increase; 95% CI, 1.05-1.12; p < 0.001), and lower platelets (odds ratio, 0.87 per 25,000 cell/µL increase; 95% CI, 0.77-0.99; p = 0.005) were associated with bleeding days. Patients who experienced more frequent bleeding (> 75th percentile) had fewer ventilator-free and hospital-free days in the 60 days after cannulation (0 vs 31; p = 0.002 and 0 vs 0; p = 0.008) and higher in-hospital mortality (68 vs 34%; p < 0.001). CONCLUSIONS: Central cannulation, older age, low platelets, and high lactate are associated with bleeding days during pediatric extracorporeal membrane oxygenation. Patients who bleed more frequently during extracorporeal membrane oxygenation have higher in-hospital mortality, longer technological dependence, and reduced hospital-free days.

Comparison of Military Health System Data Repository and American College of Surgeons National Surgical Quality Improvement Program-Pediatric.

BACKGROUND: Given the rarity of pediatric surgical disease, it is important to consider available large-scale data resources as a means to better study and understand relevant disease-processes and their treatments. The Military Health System Data Repository (MDR) includes claims-based information for > 3 million pediatric patients who are dependents of members and retirees of the United States Armed Services, but has not been externally validated. We hypothesized that demographics and selected outcome metrics would be similar between MDR and the previously validated American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-P) for several common pediatric surgical operations. METHODS: We selected five commonly performed pediatric surgical operations: appendectomy, pyeloplasty, pyloromyotomy, spinal arthrodesis for scoliosis, and facial reconstruction for cleft palate. Among children who underwent these operations, we compared demographics (age, sex, and race) and clinical outcomes (length of hospital stay [LOS] and mortality) in the MDR and NSQIP-P, including all available overlapping years (2012-2014). RESULTS: Age, sex, and race were generally similar between the NSQIP-P and MDR. Specifically, these demographics were generally similar between the resources for appendectomy (NSQIP-P, n = 20,602 vs. MDR, n = 4363; median age 11 vs. 12 years; female 40% vs. 41%; white 75% vs. 84%), pyeloplasty (NSQIP-P, n = 786 vs. MDR, n = 112; median age 0.9 vs. 2 years; female 28% vs. 28%; white 71% vs. 80%), pyloromyotomy, (NSQIP-P, n = 3827 vs. MDR, n = 227; median age 34 vs. < 1 year, female 17% vs. 16%; white 76% vs. 89%), scoliosis surgery (NSQIP-P, n = 5743 vs. MDR, n = 95; median age 14.2 vs. 14 years; female 75% vs. 67%; white 72% vs. 75%), and cleft lip/palate repair (NSQIP-P, n = 6202 vs. MDR, n = 749; median age, 1 vs. 1 year; female 42% vs. 45%; white 69% vs. 84%). Length of stay and 30-day mortality were similar between resources. LOS and 30-day mortality were also similar between datasets. CONCLUSION: For the selected common pediatric surgical operations, patients included in the MDR were comparable to those included in the validated NSQIP-P. The MDR may comprise a valuable clinical outcomes research resource, especially for studying infrequent diseases with follow-up beyond the 30-day peri-operative period.

The association between high-volume intraoperative fluid administration and outcomes among pediatric patients undergoing large bowel resection.

BACKGROUND: Traditional intraoperative fluid administration practices have been challenged this century with data suggesting improved outcomes with restrictive or goal-directed fluid administration during adult bowel surgery. Minimal data on outcomes associated with differing intraoperative fluid administration practice exists for pediatric patients. AIMS: We assessed factors and outcomes associated with high-volume fluid administration in pediatric patients undergoing colectomy. We hypothesized that high-volume fluid administration is associated with impaired recovery and, thus, increased length of stay. METHODS: A database of perioperative practice and postoperative outcomes at a tertiary pediatric hospital was queried for colectomy encounters between July 2012 and March 2017. Data extracted included patient characteristics, perioperative clinical data, and postoperative outcomes. Encounters were stratified into two groups: greater than 90th percentile fluids administered (high-volume fluid administration group) vs less than 90th percentile fluids administered. Univariable tests, multivariable logistic regression, and propensity score matched group comparisons were used to asses outcomes associated with high-volume fluid administration. RESULTS: A total of 209 colectomy encounters were identified from which 12 were excluded based on predetermined criteria. High-volume fluid administration was associated with length of stay >6 days (AOR 8.14, CI 1.75-37.8, P = 0.007), time to first meal >4 days (AOR of 5.91, CI 1.30-27.17, P = 0.02), and supplemental oxygen requirement >24 hours (AOR 3.60, CI 1.25-10.39, P = 0.02) after adjusting for ASA status, blood loss, transfusion, and open surgery. Similarly, propensity score matched patients with high-volume fluid administration vs controls were more likely to have length of stay >6 days (93% vs 54%, P = 0.007), time to first meal >4 days (93% vs 57%, P = 0.009), and supplemental oxygen requirement >24 hours (36% vs 12%, P = 0.033). CONCLUSION: High-volume fluid administration during colectomy for pediatric patients is associated with worsened postoperative outcomes suggestive of impaired recovery.

Factors Associated With Mortality in Children Who Successfully Wean From Extracorporeal Membrane Oxygenation.

OBJECTIVES: Extracorporeal membrane oxygenation is an established therapy for cardiac and respiratory failure unresponsive to usual care. Extracorporeal membrane oxygenation mortality remains high, with ongoing risk of death even after successful decannulation. We describe occurrence and factors associated with mortality in children weaned from extracorporeal membrane oxygenation. DESIGN: Retrospective cohort study. SETTING: Two hundred five extracorporeal membrane oxygenation centers reporting to the Extracorporeal Life Support Organization. SUBJECTS: Eleven thousand ninety-six patients, less than 18 years, supported with extracorporeal membrane oxygenation during 2007-2013, who achieved organ recovery before decannulation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was hospital mortality less than or equal to 30 days post extracorporeal membrane oxygenation decannulation. Among 11,096 patients, indication for extracorporeal membrane oxygenation cannulation was respiratory (6,206; 56%), cardiac (3,663; 33%), or cardiac arrest (extracorporeal cardiopulmonary resuscitation, 1,227; 11%); the majority were supported with venoarterial extracorporeal membrane oxygenation at some stage in their course (8,576 patients; 77%). Mortality was 13%. Factors associated with mortality included younger age (all < 1 yr categories compared with older, p < 0.05), lower weight among neonates (≤ 3 vs > 3 kg; p < 0.001), mode of extracorporeal membrane oxygenation support (venoarterial extracorporeal membrane oxygenation compared with venovenous extracorporeal membrane oxygenation, p < 0.001), longer admission to extracorporeal membrane oxygenation cannulation time (≥ 28 vs < 28 hr; p < 0.001), cardiac and extracorporeal cardiopulmonary resuscitation compared with respiratory extracorporeal membrane oxygenation (both p < 0.001), extracorporeal membrane oxygenation duration greater than or equal to 135 hours (p < 0.001), preextracorporeal membrane oxygenation hypoxemia (PO2 ≤ 43 vs > 43 mm Hg; p < 0.001), preextracorporeal membrane oxygenation acidemia (p < 0.001), and extracorporeal membrane oxygenation complications, particularly cerebral or renal (both p < 0.001). CONCLUSIONS: Despite extracorporeal membrane oxygenation decannulation for organ recovery, 13% of patients die in hospital. Mortality is associated with patient factors, preextracorporeal membrane oxygenation illness severity, and extracorporeal membrane oxygenation management. Evidence-based strategies to optimize readiness for extracorporeal membrane oxygenation decannulation and postextracorporeal membrane oxygenation decannulation care are needed.

RBC Exposure in Pediatric Extracorporeal Membrane Oxygenation: Epidemiology and Factors Associated With Large Blood Transfusion Volume.

OBJECTIVES: To quantify and identify factors associated with large RBC exposure in children supported with extracorporeal membrane oxygenation. DESIGN: Retrospective cohort study. SETTING: Single tertiary care children's hospital. PATIENTS: One-hundred twenty-two children supported with extracorporeal membrane oxygenation for greater than 12 hours during January 1, 2015, to December 31, 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical, laboratory, and survival data were obtained from medical records. Only data from patients' first extracorporeal membrane oxygenation run were used. The primary outcome was RBC volume exposure during extracorporeal membrane oxygenation (mL/kg/d). Patients with RBC exposure volume greater than 75th percentile were categorized as "high RBC use" patients. A "bleeding day" was identified if mediastinum or cannula sites were explored and/or Factor VIIa administration, gastrointestinal, pulmonary, or intracranial hemorrhages occurred. Median age was 0.3 years (interquartile range, 0-3 yr). Congenital heart disease (n = 56; 46%) was the most common diagnosis. Median RBC volume transfused during extracorporeal membrane oxygenation was 39 mL/kg/d (interquartile range, 21-66 mL/kg/d). High RBC use patients were more likely be supported by venoarterial extracorporeal membrane oxygenation (100 vs 76%; p = 0.006), have congenital heart disease (68 vs 39%; p = 0.02), and experience bleeding (33 vs 11% d; p < 0.001). High RBC use patients showed a trend toward higher in-hospital mortality (58 vs 37%; p = 0.07). In the multivariable analysis, younger age (-9% per year; 95% CI, -10% to -7%; p < 0.001), more blood draws per day (+8%; 95% CI, 6-11%; p < 0.001), and higher proportion of bleeding days (+22% per 10% increase; 95% CI, 16-29%; p < 0.001) were associated with larger RBC exposure (model R = 0.66). CONCLUSIONS: Bleeding during extracorporeal membrane oxygenation, frequent laboratory draws, and younger age were associated with increased RBC exposure during extracorporeal membrane oxygenation. Higher transfusion volume was associated with increased mortality.

Technique and perioperative management of left pneumonectomy in neonatal piglets.

BACKGROUND: Although commonly performed in adult swine, unilateral pneumonectomy in piglets requires significant modifications in the surgical approach and perioperative care because of their smaller size and limited physiological reserve. METHODS: Nineteen neonatal piglets underwent a left pneumonectomy. They were allowed 5-7 d of preoperative acclimation and nutritional optimization. Preoperative weight gain and laboratory values were obtained before the time of surgery. A "ventro-cranial" approach is adopted where components of the pulmonary hilum were sequentially identified and ligated, starting from the most ventral and cranial structure, the superior pulmonary vein. The principle of gentle ventilation was followed throughout the entire operation. RESULTS: The median age of the piglets at the time of surgery was 12 (10-12) d. The median preoperative weight gain and albumin level were 20% (16-26%) and 2.3 (2.1-2.4) g/dL, respectively. The median operative time was 59 (50-70) min. Five of the first nine piglets died from complications, two from poor preoperative nutritional optimization (both with <10% weight gain and 2 g/dL for albumin), one from an intubation complication, one from intra-operative bleeding, and one in the postoperative period from a ruptured bulla. No mortality occurred for the next 10 cases. CONCLUSIONS: Successful outcomes for unilateral pneumonectomy in piglets require special attention to preoperative nutritional optimization, gentle ventilation, and meticulous surgical dissection. Preoperative weight gain and albumin levels should be used to identify appropriate surgical candidates. The "ventro-cranial" approach allows for a technically straightforward completion of the procedure.

Disparities in Healthcare Utilization: An Analysis of Disease Specific and Patient Level Factors in a Congenital Diaphragmatic Hernia Clinic.

OBJECTIVES: Our study examines if the disease severity profile of our Congenital Diaphragmatic Hernia (CDH) patient cohort adherent to long-term follow-up differs from patients lost to follow-up after discharge and examines factors associated with health care utilization. METHODS: Retrospective review identified CDH survivors born 2005-2019 with index repair at our institution. Primary outcome was long-term follow-up status: "active" or "inactive" according to clinic guidelines. Markers of CDH disease severity including CDH defect classification, oxygen use, tube feeds at discharge, and sociodemographic factors were examined as exposures. RESULTS: Of the 222 included patients, median age [IQR] was 10.2 years [6.7-14.3], 61% male, and 57 (26%) were insured by Medicaid. Sixty-three percent (139/222) of patients were adherent to follow-up. Seventy-six percent of patients discharged on tube feeds had active follow-up compared to 55% of patients who were not, with similar findings for oxygen at discharge (76% vs. 55%). Kaplan-Meier analysis showed patients with smaller defect size had earlier attrition compared to patients with larger defect size. Other race (Hispanic, Asian, Middle Eastern) patients had 2.87 higher odds of attrition compared to white patients (95% CI 1.18-7.0). Medicaid patients had 2.64 higher odds of attrition compared to private insurance (95% CI 1.23-5.66). CONCLUSION: Loss to follow-up was associated with race and insurance type. Disease severity was similar between the active and inactive clinic cohorts. Long-term CDH clinic publications should examine attrition to ensure reported outcomes reflect the discharged population. This study identified important factors to inform targeted interventions for follow-up adherence. LEVEL OF EVIDENCE: Level III.

Impact of bowel rotation and fixation on obstructive complications in congenital diaphragmatic hernia.

AIM OF THE STUDY: Small bowel obstruction (SBO) is a known complication after congenital diaphragmatic hernia (CDH) repair, which can require surgery and even extensive bowel resection causing short bowel syndrome (SBS). We investigate whether specific bowel rotation and fixation can be used as a predictor for SBO including volvulus. METHODS: A retrospective review of 256 CDH survivors following repair from 2003 to 2020 was performed. Operative notes and upper gastrointestinal series (UGI) were screened to determine the rotation and fixation of the bowel. Primary outcomes included SBO occurrence, SBO treated surgically, and volvulus. For statistical analysis Fisher's exact test was utilized. RESULTS: Twenty-two (9%) patients presented with SBO and majority, 19 (86%), required surgery. Adhesion were observed in 10 (45%), recurrence in 5 (23%), and extensive volvulus leading to SBS in 3 (14%). Both rotation and fixation were recorded in 117 (46%). Presence of left CDH with malrotation and nonfixation was a significant predictor for SBO requiring surgery (P<0.05 vs all other groups). All 3 patients with extensive volvulus had left CDH with nonfixed bowel (100%), however only 1 had malrotation (33%). CONCLUSIONS: Malrotation and nonfixation are associated with increased SBO in CDH. Normal rotation is not protective and patients are still at risk for volvulus resulting in SBS. SBO requiring surgical intervention is common in CDH. Bowel rotation and fixation are important determinants that, should be routinely documented and education about the risk of SBO should be included in family counseling. LEVEL OF EVIDENCE: Level IV - Case Series.

The Timing of Congenital Diaphragmatic Hernia Repair on Extracorporeal Membrane Oxygenation Impacts Surgical Bleeding Risk.

BACKGROUND: The optimal timing of surgical repair for infants with congenital diaphragmatic hernia (CDH) treated with extracorporeal membrane oxygenation (ECMO) support remains controversial. The risk of surgical bleeding is considered by many centers as a primary factor in determining the preferred timing of CDH repair for infants requiring ECMO support. This study compares surgical bleeding following CDH repair on ECMO in early versus delayed fashion. METHODS: A retrospective review of 146 infants who underwent CDH repair while on ECMO support from 1995 to 2021. Early repair occurred during the first 48 h after ECMO cannulation (ER) and delayed repair after 48 h (DR). Surgical bleeding was defined by the requirement of reoperative intervention for hemostasis or decompression. RESULTS: 102 infants had ER and 44 infants DR. Surgical bleeding was more frequent in the DR group (36% vs 5%, p < 0.001) with an odds ratio of 11.7 (95% CI: 3.48-39.3, p < 0.001). Blood urea nitrogen level on the day of repair was significantly elevated among those who bled (median 63 mg/dL, IQR 20-85) vs. those who did not (median 9 mg/dL, IQR 7-13) (p < 0.0001). Duration of ECMO support was shorter in the ER group (median 13 vs 18 days, p = 0.005). Survival was not statistically different between the two groups (ER 60% vs. DR 57%, p = 0.737). CONCLUSION: We demonstrate a significantly lower incidence of bleeding and shorter duration of ECMO with early CDH repair. Azotemia was a strong risk factor for surgical bleeding associated with delayed CDH repair on ECMO. LEVEL OF EVIDENCE: Level III cohort study.