Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.

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.

Fluid Management in Critically Ill Children: Single-Center Retrospective Comparison of Trauma and Postoperative Patients, 2020-2022.

OBJECTIVE: Injury and surgery both represent well-defined starting points of a predictable inflammatory response, but the consequent response to IV fluids has not been studied. We aimed to review and compare our single-center fluid management strategies in these two populations. DESIGN: Retrospective cohort study from January 2020 to July 2022. The primary outcome was total IV fluid volume administered. Net fluid balances and select clinical outcomes were also evaluated. SETTING: Single tertiary academic center and level 1 pediatric trauma center in New York. PATIENTS: A dataset of critically ill trauma and surgical patients aged 0-18 years who were admitted to the PICU, 2020-2022. Trauma patients had at least moderate traumatic injuries (Injury Severity Score ≥ 9) and surgical patients had at least a 1-hour operation time. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 25 trauma and 115 surgical patients. During the first 5 days of hospitalization, we did not identify an association between grouping and total IV fluids administered and fluid balance in the prehospital, emergency department, and operating room (p = 0.90 and p = 0.79), even when adjusted for weight (p = 0.96). Time trend graphs of net fluid balance and IV fluid administered illustrated analogous fluid requirement and response with the transition from net positive to net negative fluid balance between 48 and 72 hours. There was an association between total IV fluid and ventilator requirement (p = 0.003). CONCLUSIONS: Critically ill pediatric trauma and postoperative patients seem to have similar fluid management and balance after injury or surgery. In our opinion, these two critically ill populations could be combined in large prospective studies on optimal fluid therapy in critically ill children.

Congenital Heart Disease with Congenital Diaphragmatic Hernia: Surgical Decision Making and Outcomes.

OBJECTIVE: To describe the types of congenital heart disease (CHD) in a congenital diaphragmatic hernia (CDH) cohort in a large volume center and evaluate surgical decision making and outcomes based on complexity of CHD and associated conditions. STUDY DESIGN: A retrospective review of patients with CHD and CDH diagnosed by echocardiogram between 01/01/2005 and 07/31/2021. The cohort was divided into 2 groups based on survival at discharge. RESULTS: Clinically important CHD was diagnosed in 19% (62/326) of CDH patients. There was 90% (18/20) survival in children undergoing surgery for both CHD and CDH as neonates, and 87.5 (22/24) in those undergoing repair initially for CDH alone. A genetic anomaly identified on clinical testing was noted in 16% with no significant association with survival. A higher frequency of other organ system anomalies was noted in nonsurvivors compared with survivors. Nonsurvivors were more likely to have unrepaired CDH (69% vs 0%, P < .001) and unrepaired CHD (88% vs 54%, P < .05), reflecting a decision not to offer surgery. CONCLUSIONS: Survival was excellent in patients who underwent repair of both CHD and CDH. Patients with univentricular physiology have poor survival and this finding should be incorporated into pre and postnatal counseling about eligibility for surgery. In contrast, patients with other complex lesions including transposition of the great arteries have excellent outcomes and survival at 5 years follow-up at a large pediatric and cardiothoracic surgical center.

Association of Economic Recession and Social Distancing With Pediatric Non-accidental Trauma During COVID-19.

INTRODUCTION: There has been concern that the incidence of non-accidental trauma (NAT) cases in children would rise during the COVID-19 pandemic due to the combination of social isolation and economic depression. Our goal was to evaluate NAT incidence and severity during the pandemic across multiple US cities. METHODS: Multi-institutional, retrospective cohort study comparing NAT rates in children <18 y old during the COVID-19 pandemic (March-August 2020) with a recent historical data (January 2015-February 2020) and during a previous economic recession (January 2007-December 2011) at level 1 Pediatric Trauma Centers. Comparisons were made in local and national macroeconomic indicators. RESULTS: Overall rates of NAT during March-August 2020 did not increase compared to historical data (P = 0.8). Severity of injuries did not increase during the pandemic as measured by Glasgow Coma Scale (GCS) (P = 0.97) or mortality (P = 0.7), but Injury Severity Score (ISS) slightly decreased (P = 0.018). Racial differences between time periods were seen, with increased proportions of NAT occurring in African-Americans during the pandemic (P < 0.001). NAT rates over time had low correlation (r = 0.32) with historical averages, suggesting a difference from previous years. Older children (≥3 y) had increased NAT rates during the pandemic. Overall NAT rates had low inverse correlation with unemployment (r = -0.37) and moderate inverse correlation with the stock market (r = -0.6). Significant variation between sites was observed. CONCLUSIONS: Overall NAT rates in children did not increase during the COVID-19 pandemic, but rates were highly variable by site and increases were seen in African-Americans and older children. Further studies are warranted to explore local influences on NAT rates.

Baseline assessment of inpatient burn care at Tenwek Hospital, Bomet, Kenya.

BACKGROUND: Burn injuries are a significant source of both death and disability in developing countries. The objective of this project was to create a database of baseline inpatient burn care data to facilitate improvement of preventive measures and clinical outcomes at Tenwek Hospital, Bomet, Kenya. METHODS: Both demographic and clinical data were obtained through a retrospective chart review conducted on inpatient burn patients admitted to Tenwek Hospital between January 1, 2006 and May 31, 2010. RESULTS: Of the 269 patients studied, 53 % were male and 47 % were female. More than half (59 %) of the burns occurred in children younger than age 5 years. All-cause mortality rate of inpatient burn patients was 12 %. Cardiac arrest, sepsis, and respiratory failure/pneumonia caused 81 % of the deaths. Scalds caused 55 % of the burns. Thirteen percent of the burns were seizure-related. Second degree burns accounted for 76 % of the burns. Forty-three percent of patients received at least one surgical debridement during their hospital stay. Thirty-seven percent of patients received at least one split-thickness skin graft. Antibiotic treatment was administered to 55 % of patients. Fifty-three percent of patients presented to Tenwek Hospital 1 day or more from the time of injury. CONCLUSIONS: We propose that prevention efforts focus on minimizing children's exposure to boiling liquids and open flames in homes, providing appropriate and consistent treatment to epileptics to prevent seizure-related burns, and stressing the importance of early presentation for treatment. A more selective approach to antibiotic use should be encouraged to decrease costs to the patient and hospital and lessen the risk of antibiotic resistance.

Pilot randomized controlled trial of restricted versus liberal crystalloid fluid management in pediatric post-operative and trauma patients.

BACKGROUND: Intravenous (IV) fluid therapy is essential in the treatment of critically ill pediatric surgery and trauma patients. Recent studies have suggested that aggressive fluids may be detrimental to patients. Prospective studies are needed to compare liberal to restricted fluid management in these patients. The primary objective of this pilot trial is to test study feasibility-recruitment and adherence to the study treatment algorithm. METHODS: We conducted a two-part pilot randomized controlled trial (RCT) comparing liberal to restricted crystalloid fluid management in 50 pediatric post-operative (1-18 years) and trauma (1-15 years) patients admitted to our pediatric intensive care unit (PICU). Patients were randomized to a high (liberal) volume or low (restricted) volume algorithm using unblinded, blocked randomization. A revised treatment algorithm was used after the 29th patient for the second part of the RCT. The goal of the trial was to determine the feasibility of conducting an RCT at a single site for recruitment and retention. We also collected data on the safety of study interventions and clinical outcomes, including pulmonary, infectious, renal, post-operative, and length of stay outcomes. RESULTS: Fifty patients were randomized to either liberal (n = 26) or restricted (n = 24) fluid management strategy. After data was obtained on 29 patients, a first study analysis was performed. The volume of fluid administered and triggers for intervention were adapted to optimize the treatment effect and clarity of outcomes. Updated and refined fluid management algorithms were created. These were used for the second part of the RCT on patients 30-50. During this second study period, 54% (21/39, 95% CI 37-70%) of patients approached were enrolled in the study. Of the patients enrolled, 71% (15/21, 95% CI 48-89%) completed the study. This met our a priori recruitment and retention criteria for success. A data safety monitoring committee concluded that no adverse events were related to study interventions. Although the study was not powered to detect differences in outcomes, after the algorithm was revised, we observed a non-significant trend towards improved pulmonary outcomes in patients on the restricted arm, including decreased need for and time on oxygen support and decreased need for mechanical ventilation. CONCLUSION: We demonstrated the feasibility and safety of conducting a single-site RCT comparing liberal to restricted crystalloid fluid management in critically ill pediatric post-operative and trauma patients. We observed trends in improved pulmonary outcomes in patients undergoing restricted fluid management. A definitive multicenter RCT comparing fluid management strategies in these patients is warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04201704 . Registered 17 December 2019-retrospectively registered.

Long-term outcomes of congenital diaphragmatic hernia: A single institution experience.

BACKGROUND/PURPOSE: As survival rates for patients with congenital diaphragmatic hernia (CDH) increase, long-term sequelae become increasingly prevalent. We present the outcomes of patients who underwent CDH repair at our institution and discuss standardization of follow-up care in our long-term multidisciplinary follow-up clinic. METHODS: A retrospective review of patients followed in multidisciplinary clinic after CDH repair at our institution from January 1, 2005 to December 1, 2020. RESULTS: A total of 193 patients met inclusion criteria, 73 females (37.8%) and 120 males (62.2%). Left-sided defects were most common (75.7%), followed by right-sided defects (20.7%). Median age at repair was 4 days (IQR 3-6) and 59.6% of all defects required patch repair. Median length of stay was 29 days (IQR 16.8-50.0). Median length of follow up was 49 months (IQR 17.8-95.3) with 25 patients followed for more than 12 years. Long-term outcomes included gastroesophageal reflux disease (42.0%), diaphragmatic hernia recurrence (10.9%), asthma (23.6%), neurodevelopmental delay (28.6%), attention deficit hyperactivity disorder (7.3%), autism (1.6%), chest wall deformity (15.5%), scoliosis (11.4%), and inguinal hernia (6.7%). CONCLUSION: As survival of patients with CDH improves, long-term care must be continuously studied and fine-tuned to ensure appropriate surveillance and optimization of long-term outcomes.

Extracorporeal Membrane Oxygenation (ECMO) and its complications in newborns with congenital diaphragmatic hernia.

BACKGROUND: Extracorporeal Membrane Oxygenation (ECMO) is offered to patients with congenital diaphragmatic hernia (CDH) who are in severe respiratory and cardiac failure. We aim to describe the types of complications among these patients and their impact on survival. METHODS: A single-center, retrospective review of CDH patients cannulated onto ECMO between January 2005 and November 2020 was conducted. ECMO complications, as categorized by the Extracorporeal Life Support Organization (ELSO), were correlated with survival status. Descriptive statistics were used to compare observed complications between survivors and non-survivors. RESULTS: In our cohort of CDH neonates, 21% (54/258) were supported with ECMO, of whom, 61% (33/54) survived. Survivors and non-survivors were similar in baseline characteristics except for birthweight z-score (p = 0.043). Seventy percent of CDH neonates experienced complications during their ECMO run, with the most common categories being metabolic (48.1%) and mechanical (38.9%), followed by hemorrhage (22.2%), neurological (18.5%), renal (11.1%), pulmonary (7.4%), and cardiovascular (7.4%). The median number of complications per patient was higher in the non-survivor group  (2 (IQR: 1-4) vs 1 (IQR: 0-2), p = 0.043). In addition, mechanical (57.1% vs 27.3%, p = 0.045) and renal (28.6% vs 0%, p = 0.002) complications were more common among non-survivors compared to survivors. CONCLUSION: Complications occur frequently among ECMO-treated newborns with CDH, some of which have serious long-term consequences. Survivors had higher birth weight z-scores, shorter ECMO runs, and fewer complications per patient. Mechanical and renal complications were independently associated with mortality, emphasizing the utility of more focused strategies to target fluid balance and renal protection and to prevent circuit and cannula complications.

Novel technique for a single-incision laparoscopic surgery (SILS) approach to cholecystectomy: single-institution case series.

BACKGROUND: Multiple case series managed by a single-incision laparoscopic surgery (SILS) approach to cholecystectomy have been published, reporting that this new procedure is easily reproducible and safe. Currently, variations on surgical technique are being tested. This report describes the largest series of single-skin- and single-fascial-incision cholecystectomies using a multichannel port. METHODS: Between July 2008 and December 2009, 55 patients underwent SILS cholecystectomy by two experienced general surgeons at a single institution. The operative time, surgical technique, conversion rate, specimen pathology, and postoperative complications were reported. RESULTS: The reported series consisted of 43 women (78%) and 12 men (22%) with a mean age of 44.2 years (range, 22-89 years). The body mass index (BMI) of the patients ranged from 16.1 to 46.8 kg/m2 (mean, 29.1 kg/m2). The mean operating room (OR) time was 66.5 min (range, 30-140 min). An improvement in OR time was observed over the course of the study. The first 19 cases were managed through a single incision but with two fascial defects for port placement. The last 36 cases were performed through a single skin incision with a single fascial incision. In five cases, an extra port had to be placed, and one case was converted to open surgery. To date, no port-site hernias, wound infections, small bowel obstructions, or other postoperative complications have been observed. CONCLUSION: The authors believe that the single-skin- and single-fascial-incision technique will prove superior to creation of multiple fascial defects in terms of future port-site hernias and will replace prior techniques using multiple fascial incisions.

Delayed presentation and sub-optimal outcomes of pediatric patients with acute appendicitis during the COVID-19 pandemic.

OBJECTIVE: Early presentation and prompt diagnosis of acute appendicitis are necessary to prevent progression of disease leading to complicated appendicitis. We hypothesize that patients had a delayed presentation of acute appendicitis during the COVID-19 pandemic, which affected severity of disease on presentation and outcomes. PATIENTS AND METHODS: We conducted a retrospective review of all patients who were treated for acute appendicitis at Morgan Stanley Children's Hospital (MSCH) between March 1, 2020 and May 31, 2020 when the COVID-19 pandemic was at its peak in New York City (NYC). For comparison, we reviewed patients treated from March 1, 2019 to May 31, 2019, prior to the pandemic. Demographics and baseline patient characteristics were analyzed for potential confounding variables. Outcomes were collected and grouped into those quantifying severity of illness on presentation to our ED, type of treatment, and associated post-treatment outcomes. Fisher's Exact Test and Kruskal-Wallis Test were used for univariate analysis while cox regression with calculation of hazard ratios was used for multivariate analysis. RESULTS: A total of 89 patients were included in this study, 41 patients were treated for appendicitis from March 1 to May 31 of 2019 (non-pandemic) and 48 were treated during the same time period in 2020 (pandemic). Duration of symptoms prior to presentation to the ED was significantly longer in patients treated in 2020, with a median of 2 days compared to 1 day (p = 0.003). Additionally, these patients were more likely to present with reported fever (52.1% vs 24.4%, p = 0.009) and had a higher heart rate on presentation with a median of 101 beats per minute (bpm) compared to 91 bpm (p = 0.040). Findings of complicated appendicitis on radiographic imaging including suspicion of perforation (41.7% vs 9.8%, p < 0.001) and intra-abdominal abscess (27.1% vs 7.3%, p = 0.025) were higher in patients presenting in 2020. Patients treated during the pandemic had higher rates of non-operative treatment (25.0% vs 7.3%, p = 0.044) requiring increased antibiotic use and image-guided percutaneous drain placement. They also had longer hospital length of stay by a median of 1 day (p = 0.001) and longer duration until symptom resolution by a median of 1 day (p = 0.004). Type of treatment was not a predictor of LOS (HR = 0.565, 95% CI = 0.357-0.894, p = 0.015) or duration until symptom resolution (HR = 0.630, 95% CI = 0.405-0.979, p = 0.040). CONCLUSION: Patients treated for acute appendicitis at our children's hospital during the peak of the COVID-19 pandemic presented with more severe disease and experienced suboptimal outcomes compared to those who presented during the same time period in 2019. LEVEL OF EVIDENCE: III.

Maintaining low transfusion and angioembolization rates in the age of nonoperative management of pediatric blunt splenic injury.

Nonoperative management of hemodynamically stable blunt splenic injury (BSI) is the gold standard in children. Recent studies from nonpediatric surgery-specialized trauma centers have demonstrated a rise in transfusion and angioembolization associated with decreased splenectomy rates. We investigate the rate of splenectomy and nonsurgical interventions (angioembolization, blood transfusion) for BSI in a pediatric surgery-specialized trauma center. We conducted a retrospective review of children (0 to 18 years) treated between September 2001 and September 2011 at a children's hospital. Analyzed data included presenting vital signs, nadir hemoglobin, splenic injury grade, Revised Trauma Score, and Injury Severity Score (ISS). Measured outcomes included transfusion, angioembolization, and splenectomy rates. The study period was divided into three time periods to identify possible trends and compared with national averages. There were 180 patients, 91 with multiple injuries (50.6%) and 89 (49.4%) with isolated BSI. Seventy-six per cent of patients were male, average age was 12.8 years, and average ISS was 14.7. The overall splenectomy rate was 1.7 per cent (1.1% for isolated splenic injury). Our angioembolization rate was 0.6 per cent compared with 7.4 to 16 per cent nationally. Our transfusion rate was 14.4 per cent overall and 5.6 per cent for isolated splenic injury compared with 9.5 to 24.9 per cent nationally. Intervention rates remained unchanged over the study period. Splenectomy rates have remained low at our institution without an increase in angioembolization or transfusion. Children with splenic injuries treated at dedicated pediatric hospitals can be successfully managed nonoperatively without angioembolization or blood transfusion.

Undiagnosed medical comorbidities in the uninsured: a significant predictor of mortality following trauma.

BACKGROUND: Lack of health care insurance has been correlated with increased mortality after trauma. Medical comorbidities significantly affect trauma outcomes. Access to health care and thereby being diagnosed with a pretrauma comorbidity is highly dependent on insurance status. The objective of this study was to determine whether rates of diagnosed or undiagnosed preexisting comorbidities significantly contribute to disparities in mortality rates observed between insured and uninsured trauma patients. METHODS: Review of trauma patients admitted to a Level I trauma center during a 5-year period. Data extracted from the registry included age, sex, Injury Severity Score (ISS), comorbidities, mortality, and insurance status. Multivariate logistic regression analysis was performed using age, sex, and insurance status to predict comorbidities and age, sex, ISS, and insurance status to predict mortality. RESULTS: Insured patients were older (54 years vs. 38, p < 0.001) and more likely female (41.3% vs. 22.5%, p < 0.001). When adjusting for age and sex, insured patients were more likely to have a pretrauma diagnosis of coronary artery disease (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.54-2.83), diabetes mellitus (OR, 2.09; 95% CI, 1.61-2.72), hypertension (OR, 1.97; 95% CI, 1.65-2.35), asthma/emphysema (OR, 1.64; 95% CI, 1.32-2.04), neurologic problems (OR, 1.79; 95% CI, 1.31-2.44), and gastroesophageal reflux disease (OR, 2.03; 95% CI, 1.33-3.11), compared with patients without insurance. In the analysis to predict mortality, having insurance was protective (OR, 0.57; 95% CI, 0.45-0.71). Among patients with no diagnosed comorbidities, insured patients had the lowest mortality risk (OR, 0.5; 95% CI, 0.38-0.67). When analyzing only patients with diagnosed comorbidities, insurance status had no impact on mortality risk (OR, 0.81; 95% CI, 0.53-1.22). CONCLUSION: Undiagnosed preexisting comorbidities play a crucial role in determining outcomes following trauma. Diagnosis of medical comorbidities may be a marker of access to health care and may be associated with treatment, which may explain the gap in mortality rates between insured and uninsured trauma patients. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III.

Computed tomographic diagnosis of pneumatosis intestinalis: clinical measures predictive of the need for surgical intervention.

OBJECTIVE: To determine which clinical, laboratory, and radiographic parameters predict positive operative findings in patients with pneumatosis intestinalis on computed tomography (CT). DESIGN: Retrospective record review. SETTING: Tertiary care hospital and affiliated community hospital. PATIENTS: One hundred fifty consecutive patients diagnosed as having pneumatosis intestinalis on CT. MAIN OUTCOME MEASURES: Presence or absence of abdominal pathological findings at laparotomy and mortality rates. RESULTS: Of the 150 patients studied, 54 (36%) were managed nonoperatively, 72 (48%) were managed operatively, and 24 (16%) were considered unsalvageable and given comfort measures only. Sixty patients (47%) improved with nonoperative management or had negative intraoperative findings. In the nonoperative group, 50 (93%) improved (n = 50) and 3 (5%) crossed over to surgery. One patient (2%) died. In the operative group, 63 patients (87%) had operative findings requiring intervention and 9 (13%) had negative results on exploration. Twenty-one patients (28%) died. Univariate analysis identified numerous predictors of positive intraoperative findings, including history of coronary artery disease, tachycardia, tachypnea, hypotension, peritonitis, abdominal distention, and lactic acidemia. The significant radiographic findings included dilated loops of bowel, portal venous gas, and atherosclerosis on CT. On multivariate analysis, only abdominal distention (odds ratio = 13.19; P = .001), peritonitis (odds ratio = 9.35; P = .007), and lactic acidemia (odds ratio = 2.29; P = .02) were predictive of positive intraoperative findings. CONCLUSIONS: Many patients with pneumatosis intestinalis on CT can be successfully treated nonoperatively. In determining a management strategy, abnormal physical examination findings were more predictive of the need for surgical intervention than laboratory values or radiographic findings.