Operative Volumes and Postoperative Outcomes After Elective Resection of Congenital Lung Malformations in Infants.

OBJECTIVE: To determine whether hospital- and surgeon-level operative volumes are associated with differences in postoperative outcomes among infants undergoing elective lung surgery for a congenital lung malformation (CLM). SUMMARY BACKGROUND DATA: Infant lung surgery is a relatively uncommon procedure performed by pediatric surgeons nationwide. The relationship between surgical volume and postoperative outcomes remains unknown. METHODS: A retrospective cohort study of asymptomatic infants who underwent elective lung resection of a CLM was conducted using the Pediatric Health Information System database (2016-2020). Multivariable linear and poisson regressions were performed based on annual lung resection tertiles. RESULTS: There were 1420 infants managed by 48 hospitals and 309 primary surgeons. Institutions that performed seven or fewer CLM resections per year (56%) were associated with significantly higher postoperative complication rates compared to medium- and high-volume hospitals (low: 134 [34%], medium: 110 [21%], high: 144 [29%]; P<0.001). Surgeons who performed one or fewer CLM resections per year (82%) were associated with significantly higher complication rates compared to medium- and high-volume surgeons (low: 171 [31%], medium: 75 [26%], high: 119 [24%]; P=0.02). Multivariable analyses confirmed that low-volume hospitals were associated with higher complications (OR 1.81, CI 1.38-2.37; P<0.001), and low-volume surgeons had an increased risk of complications (overall: OR 1.37, CI 1.01-1.84; P=0.04). CONCLUSIONS: In this cohort study of infants undergoing elective lung resection for a CLM, lower volume providers were associated with higher postoperative patient morbidity. These findings represent an opportunity to inform quality improvement initiatives on pediatric lung resection and the debate on surgical subspecialization for this unique patient population.

The impact of undergoing elective pediatric lung resection during respiratory syncytial virus peak season on patient outcomes: A nationwide retrospective analysis.

OBJECTIVES: Observational data to support delaying elective pediatric thoracic surgery during peak respiratory viral illness season is lacking. This study evaluated whether lung surgery during peak viral season is associated with differences in postoperative outcomes and resource utilization. METHODS: A retrospective observational cohort study was performed using the Pediatric Health Information System (PHIS). Patients with a congenital lung malformation (CLM) who underwent elective lung resection between 1 January 2016 and 29 February 2020 were included. Respiratory syncytial virus (RSV) incidence was used as a proxy for respiratory viral illness circulation. Monthly hospital-specific RSV incidence was calculated from PHIS data, and peak RSV season was defined by Centers for Disease Control data. Multivariable regression models were built to identify predictors of postoperative mechanical ventilation, which was the main outcome measure, as well as secondary outcomes including 30-day readmission after lung resection, postoperative length of stay (LOS) and hospital billing charges. RESULTS: Of 1542 CLM patients identified, 344 (22.3%) underwent lung resection during peak RSV season. 38% fewer operations were performed per month during peak RSV season than during off-peak months (p < .001). Children who underwent surgery during peak RSV season did not differ from the off-peak group in terms of age at operation, race, or comorbid conditions (i.e., congenital heart disease, newborn respiratory distress, and preoperative pneumonia). There was no association between hospital-specific RSV incidence at the time of surgery and postoperative mechanical ventilation, postoperative LOS, 30-day readmission rate or hospital billing charges. DISCUSSION: Performing elective lung surgery in children with CLMs during peak viral season is not associated with adverse surgical outcomes or increased utilization of healthcare resources.

The Burden of Congenital Heart Disease and Urogenital Lesions in a National Cohort of Hirschsprung Patients.

BACKGROUND: Hirschsprung's disease (HSCR) is often associated with other congenital and chromosomal defects. This study aimed to describe the prevalence of congenital heart disease (CHD) and congenital urogenital lesions in children with HSCR, with and without Trisomy 21 and other associated anomalies, to guide appropriate screening. METHODS: The Pediatric Health Information System was queried for patients with HSCR who underwent surgical treatment between 2016 and 2021. The prevalence of CHD, congenital urogenital lesions, Trisomy 21 and other congenital syndromes were calculated. Multivariable regression modeling was used to identify predictors of postoperative intensive care unit (ICU) admission and postoperative length of stay (LOS). RESULTS: Of 2021 HSCR patients at 47 children's hospitals, 264 (13.1%) had CHD, 244 (12.1%) had Trisomy 21, and 103 (5.1%) had a congenital urogenital lesion. The prevalence of CHD (49.6 vs. 8.1%, P < 0.001) and of undergoing a cardiac intervention with associated CHD (40.5 vs. 23.1%, P = 0.002) were higher in patients with Trisomy 21 compared to those without. CHD was associated with an increased likelihood of postoperative ICU admission (OR: 1.6, 95% CI: 1.1, 2.2) and greater postoperative LOS (IRR: 2.6, 95% CI: 2.6, 2.7), irrespective of Trisomy 21 diagnosis. CONCLUSIONS: The prevalence of CHD among HSCR patients (13.1%) was higher than previously reported, and CHD patients required more resource-intensive care after pull-through. While Trisomy 21 was associated with higher rates of CHD and cardiac intervention, 8.1% of HSCR patients without Trisomy 21 had CHD. Screening echocardiogram should be considered in all children diagnosed with HSCR, as CHD may influence perioperative risk stratification. However, screening renal ultrasound may have limited utility given the low prevalence of urogenital lesions in this population. LEVEL OF EVIDENCE: Level III.

Antibiotic-induced microbial depletion enhances murine small intestinal epithelial growth in a serotonin-dependent manner.

Regulation of small intestinal epithelial growth by endogenous and environmental factors is critical for intestinal homeostasis and recovery from insults. Depletion of the intestinal microbiome increases epithelial proliferation in small intestinal crypts, similar to the effects observed in animal models of serotonin potentiation. Based on prior evidence that the microbiome modulates serotonin activity, we hypothesized that microbial depletion-induced epithelial proliferation is dependent on host serotonin activity. A mouse model of antibiotic-induced microbial depletion (AIMD) was employed. Serotonin potentiation was achieved through either genetic knockout of the serotonin transporter (SERT) or pharmacological SERT inhibition, and inhibition of serotonin synthesis was achieved with para-chlorophenylalanine. AIMD and serotonin potentiation increased intestinal villus height and crypt proliferation in an additive manner, but the epithelial proliferation observed after AIMD was blocked in the absence of endogenous serotonin. Using Lgr5-EGFP-reporter mice, we evaluated intestinal stem cell (ISC) quantity and proliferation. AIMD increased the number of ISCs per crypt and ISC proliferation compared with controls, and changes in ISC number and proliferation were dependent on the presence of host serotonin. Furthermore, Western blotting demonstrated that AIMD reduced epithelial SERT protein expression compared with controls. In conclusion, host serotonin activity is necessary for microbial depletion-associated changes in villus height and ISC proliferation in crypts, and microbial depletion produces a functional serotonin-potentiated state through reduced SERT protein expression. These findings provide an understanding of how changes to the microbiome contribute to intestinal pathology and can be applied therapeutically.NEW & NOTEWORTHY Antibiotic-induced microbial depletion of the murine small intestine results in a state of potentiated serotonin activity through reduced epithelial expression of the serotonin transporter. Specifically, serotonin-dependent mechanisms lead to increased intestinal surface area and intestinal stem cell proliferation. Furthermore, the absence of endogenous serotonin leads to blunting of small intestinal villi, suggesting that serotonin signaling is required for epithelial homeostasis.

Racial and Ethnic Disparities in Outcomes Among Newborns with Congenital Diaphragmatic Hernia.

Importance: There is some data to suggest that racial and ethnic minority infants with congenital diaphragmatic hernia (CDH) have poorer clinical outcomes. Objective: To determine what patient- and institutional-level factors are associated with racial and ethnic differences in CDH mortality. Design, Setting, and Participants: Multicenter cohort study of 49 US children's hospitals using the Pediatric Health Information System database from January 1, 2015, to December 31, 2020. Participants were patients with CDH admitted on day of life 0 who underwent surgical repair. Patient race and ethnicity were guardian-reported vs hospital assigned as Black, Hispanic (White or Black), or White. Data were analyzed from August 2021 to March 2022. Exposures: Patient race and ethnicity: (1) White vs Black and (2) White vs Hispanic; and institutional-level diversity (as defined by the percentage of Black and Hispanic patients with CDH at each hospital): (1) 30% or less, (2) 31% to 40%, and (3) more than 40%. Main Outcomes and Measures: The primary outcomes were in-hospital and 60-day mortality. The study hypothesized that hospitals managing a more racially and ethnically diverse population of patients with CDH would be associated with lower mortality among Black and Hispanic infants. Results: Among 1565 infants, 188 (12%), 306 (20%), and 1071 (68%) were Black, Hispanic, and White, respectively. Compared with White infants, Black infants had significantly lower gestational ages (mean [SD], White: 37.6 [2] weeks vs Black: 36.6 [3] weeks; difference, 1 week; 95% CI for difference, 0.6-1.4; P < .001), lower birthweights (White: 3.0 [1.0] kg vs Black: 2.7 [1.0] kg; difference, 0.3 kg; 95% CI for difference, 0.2-0.4; P < .001), and higher extracorporeal life support use (White: 316 patients [30%] vs Black: 69 patients [37%]; χ21 = 3.9; P = .05). Black infants had higher 60-day (White: 99 patients [9%] vs Black: 29 patients [15%]; χ21 = 6.7; P = .01) and in-hospital (White: 133 patients [12%] vs Black: 40 patients [21%]; χ21 = 10.6; P = .001) mortality . There were no mortality differences in Hispanic patients compared with White patients. On regression analyses, institutional diversity of 31% to 40% in Black patients (hazard ratio [HR], 0.17; 95% CI, 0.04-0.78; P = .02) and diversity greater than 40% in Hispanic patients (HR, 0.37; 95% CI, 0.15-0.89; P = .03) were associated with lower mortality without altering outcomes in White patients. Conclusions and Relevance: In this cohort study of 1565 who underwent surgical repair patients with CDH, Black infants had higher 60-day and in-hospital mortality after adjusting for disease severity. Hospitals treating a more racially and ethnically diverse patient population were associated with lower mortality in Black and Hispanic patients.

Delayed primary repair in 100 infants with isolated long-gap esophageal atresia: A nationwide analysis of children's hospitals.

BACKGROUND: This study aimed to evaluate the contemporary surgical management of long-gap esophageal atresia, a rare and challenging problem managed by pediatric general surgeons. METHODS: A retrospective review of the Pediatric Health Information System database for infants who underwent neonatal gastrostomy, followed by surgical reconstruction for long-gap esophageal atresia (2014-2021). Patients with birthweight less than 1.5 kg and those who received neonatal cardiac surgery were excluded. Outcomes were analyzed, including the need for further procedures, length of stay, and mortality. RESULTS: Of 1,346 infants who underwent repair across 47 major children's hospitals, 100 (7%) met the inclusion criteria for long-gap esophageal atresia. Cardiac anomalies were identified in 43% of patients. The median age at repair was 87 days (interquartile range, 62-133). Ten percent of patients had a planned or unplanned reoperation ≤30 days after index surgery, and 4% underwent reoperation at >30 days. The median time to reoperation was 9 days (interquartile range, 7-60). Mortality during index admission was 5%, and the median hospital length of stay was 143 days (interquartile range, 101-192). Length of stay was significantly longer in patients with cardiac anomalies (cardiac: 179 days, non-cardiac: 125 days; P < .001), and 52% of patients required at least 1 postoperative dilation. The median time to the first dilation was 70 days (interquartile range, 42-173). CONCLUSION: This large multicenter study highlights the challenges of infants with long-gap esophageal atresia but suggests a high rate of successful delayed primary reconstruction. Hospitalizations are prolonged, and anastomotic stricture rates remain high. These data are useful for pediatric surgeons in counseling families on surgical repair strategy, timing, and postoperative outcomes.

Morbidity and Mortality in Neonates with Symptomatic Congenital Lung Malformation.

BACKGROUND: Neonatal resection is the mainstay treatment of children presenting with symptomatic congenital lung malformation (CLM) at birth. The objective of this study was to evaluate risk factors for increased morbidity and mortality after neonatal CLM resection using a large multicenter database. STUDY DESIGN: Retrospective review of the Pediatric Health Information System database was performed. Children with a symptomatic CLM managed by lung resection before 30 days of age were included (2016 to 2021). Primary outcomes measures were postoperative respiratory complication and any complication, including death. RESULTS: Of 1,791 CLM patients identified, 256 (14%) underwent neonatal resection for symptomatic disease. Pathology included 123 (48%) congenital pulmonary airway malformation, 24 (10%) bronchopulmonary sequestration, 5 (2%) congenital lobar emphysema, 16 (6%) hybrid, and 88 (34%) unclassified lesion. Preoperative mechanical ventilation and extracorporeal membrane oxygenation (ECMO) were employed in 149 (58.2%) and 17 (6.7%) of cases, respectively. The median age at resection was 6.5 days (interquartile range 2 to 23). Postoperatively, 25 (10%) required mechanical ventilation for 48 hours or more, 3 (1%) continued ECMO, and 3 (1%) required ECMO rescue. The overall respiratory complication rate was 34% (87), rate of any complication was 51% (130), median postoperative length of stay was 20 days (interquartile range 9 to 52), and mortality rate was 14.5% (37). Birthweight was inversely correlated with complication risk (incidence rate ratio 0.55, 95% CI 0.36 to 0.83, p = 0.006). Cardiac structural anomaly was associated with a 21-day longer postoperative length of stay (95% CI 6 to 35, p = 0.006) and 2.2 times increased risk of any complication (95% CI 1.18 to 4.02, p = 0.014). CONCLUSIONS: In this large multicenter study, ECMO use and mortality are relatively uncommon among neonates undergoing lung resection for a symptomatic CLM. However, postoperative morbidity remains high, particularly in those with cardiac structural disease.

U.S. state policies on opioid prescribing during the peak of the prescription opioid crisis: Associations with opioid overdose mortality.

BACKGROUND: In response to the opioid overdose crisis in the United States, many states implemented policies to guide opioid prescribing, but their impact on overdose mortality (prescription and non-prescription) remains poorly understood. We examined the impact of U.S. state opioid-prescribing policies on opioid overdose mortality following implementation. METHODS: We calculated opioid overdose mortality rates from 1999-2016 by U.S. state using the CDC WONDER database, overall and separately for overdose deaths from prescription and non-prescription opioids. For each state, policies active on 1/1/2014 were reviewed for the presence and strength of six provisions recommending judicious opioid prescribing practices; "strong" provisions used the words "should," "shall," or "must". Interrupted time series (ITS) tested the association of each strong provision with overdose mortality, overall and separately for prescription and non-prescription opioids, in the two years following implementation. Sensitivity analyses compared between states, used time-lagged analyses, and excluded synthetic opioids from non-prescription opioid deaths. RESULTS: All six provisions had consistent direction of effect in ITS and sensitivity analyses. Strong provisions for prescriber training and limits on opioid dose reduced the slope of overall and prescription opioid overdose mortality in both ITS and sensitivity analyses. Reduced non-prescription opioid overdose mortality was only associated with strong provision for prescriber training. Some provisions had a negative impact. In ITS, strong provision for prescriber response to misuse increased the slope of non-prescription opioid overdose mortality. Strong provision for mandatory prescription drug monitoring program use had no relationship with overdose mortality in ITS and was associated with increased overall, prescription and non-prescription opioid overdose mortality in between-state sensitivity analysis. CONCLUSION: Opioid prescribing policies in U.S. states at the peak of the prescription opioid epidemic had modest mortality benefit, and did not reduce non-prescription opioid overdose mortality. A strong provision for prescriber training was the only provision associated with reduced prescription and non-prescription opioid overdose mortality. These findings can inform future efforts addressing prescription drug epidemics.

Preoperative Transfusion and Surgical Outcomes for Children with Sickle Cell Disease.

BACKGROUND: Current guidelines recommending preoperative transfusion to a hemoglobin level of 9 to 10 g/dL for patients with sickle cell disease (SCD) are based on imperfect evidence. The benefit of preoperative transfusion in children specifically is not known. This study aimed to evaluate whether preoperative RBC transfusion is associated with different rates of sickle cell crisis and surgical complications, compared with no preoperative transfusion, among children with SCD undergoing common abdominal operations. STUDY DESIGN: The NSQIP-Pediatrics database (2013 to 2019) was queried. Patients who underwent cholecystectomy, splenectomy, or appendectomy with a preoperative Hct level of less than 30% were included. The primary outcome was 30-day readmission for sickle cell crisis. Secondary outcomes were 30-day surgical complications and hospital length of stay. Propensity score matching methods were used to obtain two statistically similar cohorts of patients comprised of those who were preoperatively transfused and those who were not. RESULTS: Among 357 SCD patients, 200 (56%) received preoperative transfusion. In the matched cohort of 278 patients (139 per group), there was no statistically significant difference in 30-day readmission for sickle cell crisis in the transfused and non-transfused groups (5.8% vs 7.2%, p = 0.80). The rate of 30-day surgical complications did not differ between matched groups (10.8% vs 9.4%, p = 0.84). Subgroups defined by presenting Hct levels of 27.3% or greater or less than 27.3%, American Society of Anesthesiologists classification, wound class, and index operation were not associated with an altered risk of sickle cell crisis or surgical complications after preoperative transfusion compared with no transfusion. CONCLUSIONS: Preoperative transfusion for children with SCD undergoing semi-elective abdominal operations was not associated with improved outcomes. Prospective investigation is warranted to strengthen guidelines and minimize unnecessary perioperative transfusions in this population.

Comparing Serum Matrix Metalloproteinase-7 in Parenteral Nutrition-Associated Liver Disease and Biliary Atresia.

In this cross-sectional study, serum matrix metalloproteinase-7 levels were significantly lower in infants with jaundice and parenteral nutrition-associated liver disease compared with those with confirmed biliary atresia. Serum metalloproteinase-7 may aid in excluding biliary atresia and thus may minimize invasive testing in infants with a history of parenteral nutrition.

Variability in pediatric appendectomy: The association between disposable supply cost and procedure duration.

BACKGROUND: Pediatric appendicitis accounts for a notable proportion of health care use and cost in the United States. To identify opportunities for cost savings during pediatric laparoscopic appendectomy, this study assessed whether surgeons' use of costlier disposable supplies correlated with procedure duration and patient outcomes. METHODS: This retrospective cross-sectional study assessed laparoscopic appendectomy for uncomplicated pediatric appendicitis at 2 tertiary-care academic hospitals. The cost of disposable surgical supplies, procedure duration, and patient outcomes were obtained from medical records. The correlation between average supply cost and procedure duration among surgeons was assessed using Pearson's correlation coefficient. Associations between use of specific disposable supplies and supply cost or procedure duration were assessed using Student's t tests. RESULTS: A total of 380 laparoscopic appendectomies were performed by 11 surgeons. Mean normalized supply cost varied between surgeons (range: 60.6%-151.1%) and was not correlated with procedure duration (R = 0.2951, P = .378). The use of energy-based sealing devices (76.7% increase, P < .001), staplers (38.4% increase, P < .001), endoscopic specimen pouches (45.3% increase, P < .001), and disposable ports (43.6% increase, P < .001) increased overall disposable supply cost. None of the disposable supplies in this analysis were associated with shorter procedures. Based on Medicaid reimbursement, the interquartile range of supply cost was 9.2% and 6.0% of hospital revenue at each site. CONCLUSION: Surgeons varied in their use of disposable supplies for pediatric laparoscopic appendectomy, but the cost of supplies used did not influence outcomes. Incentivizing more judicious supply use may reduce costs related to pediatric appendicitis.

Jejunoileal mucosal growth in mice with a limited microbiome.

Previous work demonstrated enhanced enterocyte proliferation and mucosal growth in gnotobiotic mice, suggesting that intestinal flora participate in mucosal homeostasis. Furthermore, broad-spectrum enteral antibiotics are known to induce near germ-free (GF) conditions in mice with conventional flora (CONV). We hypothesized that inducing near GF conditions with broad-spectrum enteral antibiotics would cause ordered small intestinal mucosal growth in CONV mice but would have no effect in GF mice with no inherent microbiome. C57BL/6J CONV and GF mice received either an antibiotic solution (Ampicillin, Ciprofloxacin, Metronidazole, Vancomycin, Meropenem) or a vehicle alone. After treatment, small intestinal villus height (VH), crypt depth (CD), mucosal surface area (MSA), crypt proliferation index (CPI), apoptosis, and villus and crypt cell types were assessed. Antibiotic-treated CONV (Abx-CONV) mice had taller villi, deeper crypts, increased CPI, increased apoptosis, and greater MSA compared to vehicle-treated CONV mice. Minor differences were noted in enterocyte and enterochromaffin cell proportions between groups, but goblet and Paneth cell proportions were unchanged in Abx-CONV mice compared to vehicle-treated CONV mice (p>0.05). Antibiotics caused no significant changes in VH or MSA in GF mice when compared to vehicle-treated GF mice (p>0.05). Enteral administration of broad-spectrum antibiotics to mice with a conventional microbiome stimulates ordered small intestinal mucosal growth. Mucosal growth was not seen in germ-free mice treated with antibiotics, implying that intestinal mucosal growth is associated with change in the microbiome in this model.

Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease.

The microbial metabolite butyrate serves as a link between the intestinal microbiome and epithelium. The monocarboxylate transporters MCT1 and SMCT1 are the predominant means of butyrate transport from the intestinal lumen to epithelial cytoplasm, where the molecule undergoes rapid ß-oxidation to generate cellular fuel. However, not all epithelial cells metabolize butyrate equally. Undifferentiated colonocytes, including neoplastic cells and intestinal stem cells at the epithelial crypt base preferentially utilize glucose over butyrate for cellular fuel. This divergent metabolic conditioning is central to the phenomenon known as "butyrate paradox", in which butyrate induces contradictory effects on epithelial proliferation in undifferentiated and differentiated colonocytes. There is evidence that accumulation of butyrate in epithelial cells results in histone modification and altered transcriptional activation that halts cell cycle progression. This manifests in the apparent protective effect of butyrate against colonic neoplasia. A corollary to this process is butyrate-induced inhibition of intestinal stem cells. Yet, emerging research has illustrated that the evolution of the crypt, along with butyrate-producing bacteria in the intestine, serve to protect crypt base stem cells from butyrate's anti-proliferative effects. Butyrate also regulates epithelial inflammation and tolerance to antigens, through production of anti-inflammatory cytokines and induction of tolerogenic dendritic cells. The role of butyrate in the pathogenesis and treatment of intestinal neoplasia, inflammatory bowel disease and malabsorptive states is evolving, and holds promise for the potential translation of butyrate's cellular function into clinical therapies.