The Global Initiative for Children's Surgery: conception, gestation, and delivery.

More than two thirds of the global population lack access to safe, affordable surgical and anesthesia care. This inequity disproportionately affects children in low- and middle-income countries (LMIC). In 2016, a group of pediatric surgical care providers founded the Global Initiative for Children's Surgery (GICS). Their goal was to assemble a multidisciplinary team of specialists and advocates to improve surgical care for children, with a particular emphasis on those in low-resource settings. This review details the history of GICS, the process of its inception, the values guiding its work, its past achievements, and its current initiatives. The experience of GICS may serve as an effective model for global collaboration on other areas of public and global health.

Inclusion of Children's Surgery in National Surgical Plans and Child Health Programmes: the need and roadmap from Global Initiative for Children's Surgery.

About 1.7 billion children and adolescents, mostly in low- and middle-income countries (LMICs) lack access to surgical care. While some of these countries have developed surgical plans and others are in the process of developing theirs, children's surgery has not received the much-needed specific emphasis and focus in these plans. With the significant burden of children's surgical conditions especially in low- and middle-income countries, universal health coverage and the United Nations' (UN) Sustainable Development Goals (SDG) will not be achieved without deliberate efforts to scale up access to children's surgical care. Inclusion of children's surgery in National Surgical Obstetric and Anaesthesia Plans (NSOAPs) can be done using the Global Initiative for Children's Surgery (GICS)-modified Children's Surgical Assessment Tool (CSAT) tool for baseline assessment and the Optimal Resources for Children Surgical Care (OReCS) as a foundational tool for implementation.

COVID-19 pre-procedural testing strategy and early outcomes at a large tertiary care children's hospital.

PURPOSE: With the emergence of the coronavirus disease-2019 (COVID-19) pandemic, institutions were tasked with developing individualized pre-procedural testing strategies that allowed for re-initiation of elective procedures within national and state guidelines. This report describes the experience of a single US children's hospital (Children's Wisconsin, CW) in developing a universal pre-procedural COVID-19 testing protocol and reports early outcomes. METHODS: The CW pre-procedural COVID-19 response began with the creation of a multi-disciplinary taskforce that sought to develop a strategy for universal pre-procedural COVID-19 testing which (1) maximized patient safety, (2) prevented in-hospital viral transmission, (3) conserved resources, and (4) allowed for resumption of procedural care within institutional capacity. RESULTS: Of 11,209 general anesthetics performed at CW from March 16, 2020 to October 31, 2020, 11,150 patients (99.5%) underwent pre-procedural COVID-19 testing. Overall, 1.4% of pre-procedural patients tested positive for COVID-19. By June 2020, CW was operating at near-normal procedural volume and there were no documented cases of in-hospital viral transmission. Only 0.5% of procedures were performed under augmented COVID-19 precautions (negative pressure environment and highest-level personal protective equipment). CONCLUSION: CW successfully developed a multi-disciplinary pre-procedural COVID-19 testing protocol that enabled resumption of near-normal procedural volume within three months while limiting in-hospital viral transmission and resource use.

Long-term Quality of Life in Neonatal Surgical Disease.

OBJECTIVE: This prospective observational study was designed to assess Pediatric Quality of Life (PedsQL) after surgical treatment for congenital diaphragmatic hernia (CDH), esophageal atresia/tracheoesophageal fistula (EA/TEF), Hirschsprung disease (HD), gastroschisis (GAS), omphalocele (OMP), and necrotizing enterocolitis (NEC). SUMMARY OF BACKGROUND DATA: Improvements in neonatal and surgical care have led to increased survival for many newborn conditions. Quality of life in these patients is seldom explored in a longitudinal manner. We hypothesized that age-adjusted physical and psychosocial scores would improve over time, but with diagnosis-dependent variation. METHODS: Data were collected from 241 patients (CDH = 52; EA/TEF = 62; HD = 46; GAS = 32; OMP = 26; NEC = 23) in an institutional Clinical Outcomes Registry (COR) from 2012 to 2017. Aggregate physical, psychosocial, and overall PedsQL scores were determined for each diagnosis. Spline regression models were created to model scores as a function of age. RESULTS: Physical scores trended up for all diagnoses except CDH and NEC beyond age 10. Psychosocial scores trended up for all diagnoses except NEC and EA/TEF beyond age 10. Beyond age 12, CDH, GAS, and HD patients had overall scores within the normal range, while NEC, OMP, and EA/TEF patients had scores similar to children with chronic medical illness. CONCLUSION: Variation exists in long-term PedsQL scores after neonatal surgery for selected, complex disease. Beyond age 12, quality of life is significantly impaired in NEC, moderately impaired in OMP and EA/TEF, and within normal range for CDH, HD, and GAS patients at the population level. These data are relevant to prenatal and perioperative discussions with patients and families.

Clinical outcomes of splenectomy in children: report of the splenectomy in congenital hemolytic anemia registry.

The outcomes of children with congenital hemolytic anemia (CHA) undergoing total splenectomy (TS) or partial splenectomy (PS) remain unclear. In this study, we collected data from 100 children with CHA who underwent TS or PS from 2005 to 2013 at 16 sites in the Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium using a patient registry. We analyzed demographics and baseline clinical status, operative details, and outcomes at 4, 24, and 52 weeks after surgery. Results were summarized as hematologic outcomes, short-term adverse events (AEs) (≤30 days after surgery), and long-term AEs (31-365 days after surgery). For children with hereditary spherocytosis, after surgery there was an increase in hemoglobin (baseline 10.1 ± 1.8 g/dl, 52 week 12.8 ± 1.6 g/dl; mean ± SD), decrease in reticulocyte and bilirubin as well as control of symptoms. Children with sickle cell disease had control of clinical symptoms after surgery, but had no change in hematologic parameters. There was an 11% rate of short-term AEs and 11% rate of long-term AEs. As we accumulate more subjects and longer follow-up, use of a patient registry should enhance our capacity for clinical trials and engage all stakeholders in the decision-making process.

Inhibition of myeloperoxidase decreases vascular oxidative stress and increases vasodilatation in sickle cell disease mice.

Activated leukocytes and polymorphonuclear neutrophils (PMN) release myeloperoxidase (MPO), which binds to endothelial cells (EC), is translocated, and generates oxidants that scavenge nitric oxide (NO) and impair EC function. To determine whether MPO impairs EC function in sickle cell disease (SCD), control (AA) and SCD mice were treated with N-acetyl-lysyltyrosylcysteine-amide (KYC). SCD humans and mice have high plasma MPO and soluble L-selectin (sL-selectin). KYC had no effect on MPO but decreased plasma sL-selectin and malondialdehyde in SCD mice. MPO and 3-chlorotyrosine (3-ClTyr) were increased in SCD aortas. KYC decreased MPO and 3-ClTyr in SCD aortas to the levels in AA aortas. Vasodilatation in SCD mice was impaired. KYC increased vasodilatation in SCD mice more than 2-fold, to ∼60% of levels in AA mice. KYC inhibited MPO-dependent 3-ClTyr formation in EC proteins. SCD mice had high plasma alanine transaminase (ALT), which tended to decrease in KYC-treated SCD mice (P = 0.07). KYC increased MPO and XO/XDH and decreased 3-ClTyr and 3-nitrotyrosine (3-NO2Tyr) in SCD livers. These data support the hypothesis that SCD increases release of MPO, which generates oxidants that impair EC function and injure livers. Inhibiting MPO is an effective strategy for decreasing oxidative stress and liver injury and restoring EC function in SCD.

N-acetyl lysyltyrosylcysteine amide inhibits myeloperoxidase, a novel tripeptide inhibitor.

Myeloperoxidase (MPO) plays important roles in disease by increasing oxidative and nitrosative stress and oxidizing lipoproteins. Here we report N-acetyl lysyltyrosylcysteine amide (KYC) is an effective inhibitor of MPO activity. We show KYC inhibits MPO-mediated hypochlorous acid (HOCl) formation and nitration/oxidation of LDL. Disulfide is the major product of MPO-mediated KYC oxidation. KYC (≤4,000 µM) does not induce cytotoxicity in bovine aortic endothelial cells (BAECs). KYC inhibits HOCl generation by phorbol myristate acetate (PMA)-stimulated neutrophils and human promyelocytic leukemia (HL-60) cells but not superoxide generation by PMA-stimulated HL-60 cells. KYC inhibits MPO-mediated HOCl formation in BAEC culture and protects BAECs from MPO-induced injury. KYC inhibits MPO-mediated lipid peroxidation of LDL whereas tyrosine (Tyr) and tryptophan (Trp) enhance oxidation. KYC is unique as its isomers do not inhibit MPO activity, or are much less effective. Ultraviolet-visible spectral studies indicate KYC binds to the active site of MPO and reacts with compounds I and II. Docking studies show the Tyr of KYC rests just above the heme of MPO. Interestingly, KYC increases MPO-dependent H2O2 consumption. These data indicate KYC is a novel and specific inhibitor of MPO activity that is nontoxic to endothelial cell cultures. Accordingly, KYC may be useful for treating MPO-mediated vascular disease.

Intestinal alkaline phosphatase prevents the systemic inflammatory response associated with necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common surgical emergency in neonates, with an incidence of 0.5-2.4 cases per 1000 live births and a mortality rate between 10% and 50%. Neonates affected by NEC develop a septic injury that is associated with increased risk of neurological impairment due to intraventricular bleeding and chronic lung disease. Intestinal alkaline phosphatase (IAP) is an endogenous protein that has been shown to inactivate the endotoxin lipopolysaccharide (LPS), and has recently been used successfully as an adjunct to treat sepsis in adult patients. We tested the hypothesis that systemic, exogenous IAP will mitigate the inflammatory response as measured by serum levels of proinflammatory cytokines in a rat model of NEC. METHODS: Newborn Sprague-Dawley rats were divided into groups. Control pups were dam fed. NEC was induced by feeding formula containing LPS and exposure to intermittent hypoxia. NEC pups were given intraperitoneal injections of 4 or 40 glycine units (U) of IAP or placebo twice daily. Intestine and serum was collected for cytokine analysis as well as measurement of alkaline phosphatase activity. RESULTS: Systemic IAP administration significantly increased serum alkaline phosphatase activity in a dose- and time-dependent fashion. The proinflammatory cytokines tumor necrosis factor α, interleukin 6, and interleukin 1ß were significantly increased in NEC rats versus controls on days 2 and 3. Importantly, treatment with 40 U systemic IAP decreased these proinflammatory cytokines back to near-control levels. CONCLUSIONS: Systemic IAP administration appears effective in mitigating the systemic inflammatory response associated with NEC, and may prove to be a valuable adjunctive treatment for NEC.

Outcomes in pediatric surgery by hospital volume: a population-based comparison.

PURPOSE: The volume-outcome relationship has not been well-defined in pediatric surgery. Our aim was to determine the association between hospital-volume and outcomes for common procedures in children. METHODS: Retrospective population-based cohort study of patients <18 years of age hospitalized between 1989 and 2009 for common surgical procedures in Washington State. The association between annual hospital case volume and post-operative outcomes (readmission and reoperation within 30-days, post-operative complications) was assessed using multivariate logistic regression. RESULTS: The three most common procedures over the study period were appendectomy (n = 36,525), skin and soft tissue debridement (n = 9,813), and pyloromyotomy (n = 3,323). A greater proportion of patients with comorbidities were treated at higher-volume hospitals. After adjustment, outcomes did not differ significantly across hospital-volume quartiles except that debridement patients had lower odds of readmission (OR = 0.63, 95 % CI 0.46-0.88) and re-operation (OR = 0.53, 95 % CI 0.35-0.81) at medium-high-volume compared with high-volume centers. CONCLUSIONS: This work suggests that risks of readmission and post-operative complications for common procedures may be similar across hospital-volume categories, but appropriate risk-stratification is essential. In order to optimize safety, we must identify the resources required for low-, medium-, and high-risk surgical patients, and implement these standards into practice.

Trichobezoar: A Rare Cause of Protein-losing Enteropathy.

Protein-losing enteropathy (PLE) is caused by protein loss through the gastrointestinal tract which results in hypoalbuminemia. The most common causes of PLE in children include cow milk protein allergy, celiac disease, inflammatory bowel disease, hypertrophic gastritis, intestinal lymphangiectasia, and right-sided heart dysfunction. We present a case of a 12-year-old male with bilateral lower extremity edema, hypoalbuminemia, elevated stool alpha-1-antitrypsin, and microcytic anemia. He was found to have a trichobezoar in the stomach extending to the jejunum, an unusual cause of PLE. The patient underwent an open laparotomy and gastrostomy to remove the bezoar. Follow-up confirmed resolution of hypoalbuminemia.

Association of Rural Residence With Surgical Outcomes Among Infants at US Children's Hospitals.

OBJECTIVES: Disparities in pediatric health outcomes are widespread. It is unclear whether rurality negatively impacts outcomes of infants with surgical congenital diseases. This study compared outcomes of rural versus urban infants requiring complex surgical care at children's hospitals in the United States. METHODS: Rural and urban infants (aged <1 year) receiving surgical care at children's hospitals from 2016 to 2019 for esophageal atresia, gastroschisis, Hirschsprung's disease, anorectal malformation, and congenital diaphragmatic hernia were compared over a 1-year postoperative period using the Pediatric Health Information System. Generalized linear mixed effects models compared outcomes of rural and urban infants. RESULTS: Among 5732 infants, 20.2% lived in rural areas. Rural infants were more frequently white, lived farther from the hospital, and lived in areas with lower median household income compared with urban infants (all P < .001). Rural infants with anorectal malformation and gastroschisis had lower adjusted hospital days over 1 year; rural infants with esophageal atresia had higher adjusted odds of 30-day hospital readmission. Adjusted mortality, hospital days, and readmissions were otherwise similar between the 2 groups. Outcomes remained similar when comparing urban infants to rural infant subgroups with the longest hospital travel distance (≥60 miles) and lowest median household income (<$35 000). CONCLUSIONS: Despite longer travel distances and lower financial resources, rural infants with congenital anomalies have similar postoperative outcomes to urban infants when treated at children's hospitals. Future work is needed to examine outcomes for infants treated outside children's hospitals and to determine whether efforts are necessary to increase access to children's hospitals.

Evolution of the American College of Surgeons Children's Surgery Verification Program: Implications for optimizing multidisciplinary surgical care of the pediatric patient.

The Children's Surgery Verification Program of the American College of Surgeons began in 2016 based on the standards created by the Task Force for Children's Surgery. This program seeks to improve the surgical care of children by assuring the appropriate resources and robust performance improvement programs at participating centers. Three levels of centers with defined scopes of practice and matching resources are defined. Since its inception more than 50 center have been verified. A specialty hospital program was launched in 2019. The standards for all hospitals were revised in 2021 based on lessons learned. In this article the leaders of the program discuss the development, areas of greatest impact and future directions of the program.

Intestinal alkaline phosphatase administration in newborns decreases systemic inflammatory cytokine expression in a neonatal necrotizing enterocolitis rat model.

BACKGROUND: Supplementation of intestinal alkaline phosphatase (IAP), an endogenous protein expressed in the intestines, decreases the severity of necrotizing enterocolitis (NEC)-associated intestinal injury and permeability. We hypothesized that IAP administration is protective in a dose-dependent manner of the inflammatory response in a neonatal rat model. MATERIALS AND METHODS: Pre- and full-term newborn Sprague-Dawley rat pups were sacrificed on day of life 3. Control pups were vaginally delivered and dam fed. Preterm pups were delivered via cesarean section and exposed to intermittent hypoxia and formula feeds containing lipopolysaccharide (NEC) with and without IAP. Three different standardized doses were administered to a group of pups treated with 40, 4, and 0.4U/kg of bovine IAP (NEC+IAP40, IAP4, or IAP0.4U). Reverse transcription-real-time polymerase chain reaction (RT-PCR) for inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α on liver and lung tissues and serum cytokine analysis for interleukin (IL)-1ß, IL-6, IL-10, and TNF-α were performed. Data were analyzed by Kruskal-Wallis and Mann-Whitney tests, expressed as mean±standard error of the mean and P≤0.05 considered significant. RESULTS: Levels of cytokines IL-1ß, IL-6, and TNF-α increased significantly in NEC versus control, returning to control levels with increasing doses of supplemental enteral IAP. Hepatic and pulmonary TNF-α and iNOS messenger ribonucleic acid expressions increased in NEC, and the remaining elevated despite IAP supplementation. CONCLUSIONS: Proinflammatory cytokine expression is increased systemically with intestinal NEC injury. Administration of IAP significantly reduces systemic proinflammatory cytokine expression in a dose-dependent manner. Early supplemental enteral IAP may reduce NEC-related injury and be useful for reducing effects caused by a proinflammatory cascade.

Increasing severity of pectus excavatum is associated with reduced pulmonary function.

OBJECTIVE: To determine whether pulmonary function decreases as a function of severity of pectus excavatum, and whether reduced function is restrictive or obstructive in nature in a large multicenter study. STUDY DESIGN: We evaluated preoperative spirometry data in 310 patients and lung volumes in 218 patients aged 6 to 21 years at 11 North American centers. We modeled the impact of the severity of deformity (based on the Haller index) on pulmonary function. RESULTS: The percentages of patients with abnormal forced vital capacity (FVC), forced expiratory volume in 1 second (FEV(1)), forced expiratory flow from 25% exhalation to 75% exhalation, and total lung capacity findings increased with increasing Haller index score. Less than 2% of patients demonstrated an obstructive pattern (FEV(1)/FVC <67%), and 14.5% demonstrated a restrictive pattern (FVC and FEV(1) <80% predicted; FEV(1)/FVC >80%). Patients with a Haller index of 7 are >4 times more likely to have an FVC of ≤80% than those with a Haller index of 4, and are also 4 times more likely to exhibit a restrictive pulmonary pattern. CONCLUSIONS: Among patients presenting for surgical repair of pectus excavatum, those with more severe deformities have a much higher likelihood of decreased pulmonary function with a restrictive pulmonary pattern.

Endothelial microparticles induce inflammation in acute lung injury.

BACKGROUND: Previously, we have shown that endothelial microparticles (EMPs) injected into mice induce acute lung injury (ALI) [1]. In this study, we hypothesize that EMPs induce ALI by initiating cytokine release in the lung, leading to recruitment and activation of neutrophils. MATERIALS AND METHODS: C57BL/6J male mice (8-10 wk old) were intravenously injected with EMPs (200,000/mL), LPS (2 mg/kg), or both. Bronchoalveolar lavage (BAL) and serum levels of IL-1ß and TNF-α were analyzed by enzyme-linked immunoassay (ELISA). Morphometric analysis was performed on H and E stained lung sections. Myeloperoxidase (MPO) levels were determined via an enzymatic assay and immunofluorescence of stained sections. RESULTS: EMPs led to significantly increased pulmonary and systemic IL-1ß and TNF-α levels, which correlated with increased neutrophil recruitment to the lung. MPO levels in the lungs were increased significantly following injection of EMPs or LPS, compared to PBS. In mice treated with EMPs and LPS either simultaneously or successively, the cytokine and MPO levels were significantly increased over that of either treatment alone. CONCLUSION: EMPs contribute to lung injury through the initiation of a cytokine cascade that increases recruitment of neutrophils and subsequent release of MPO. Furthermore, treatment of mice with both EMPs and LPS induced greater lung injury than either treatment alone, suggesting that EMPs prime the lung for increased injury by other pathogens. Therapies aimed at reducing or blocking EMPs may be a useful strategy for attenuating lung injury.

Disparities in utilization of outpatient surgical care among children.

BACKGROUND: The purpose of this study was to quantify disparities in the utilization of outpatient pediatric surgical care and to examine the extent to which neighborhood-level socioeconomic disadvantage is associated with access to care among children. METHODS: Clinic "no-shows" were examined among children scheduled from 2017 to 2019 at seven pediatric surgery clinics associated with a tertiary care children's hospital. The association between Area Deprivation Index, a neighborhood-level measure of socioeconomic disadvantage, and other patient factors with clinic no-shows was examined using multivariable logistic regression models. Difficulties in accessing postoperative care in particular were explored in a subgroup analysis of postoperative (within 90 days) clinic visits after appendectomy or inguinal/umbilical hernia repairs. RESULTS: Among 10,162 patients, 16% had at least 1 no-show for a clinic appointment. Area Deprivation Index (most deprived decile adjusted odds ratio 3.17, 95% confidence interval 2.20-4.58, P < .001), Black race (adjusted odds ratio 3.30, 95% confidence interval 2.70-4.00, P < .001), and public insurance (adjusted odds ratio 2.75, 95% confidence interval 2.38-3.31, P < .001) were associated with having at least 1 no-show. Similar associations were identified among 2,399 children scheduled for postoperative clinic visits after undergoing appendectomy or inguinal/umbilical hernia repair, among whom 20% were a no-show. CONCLUSION: Race, insurance type, and neighborhood-level socioeconomic disadvantage are associated with disparities in utilization of outpatient pediatric surgical care. Challenges accessing routine outpatient care among disadvantaged children may be one mechanism through which disparate outcomes result among children requiring surgical care.

The protective role of intestinal alkaline phosphatase in necrotizing enterocolitis.

BACKGROUND: Enterocytes produce intestinal alkaline phosphatase (iAP), which detoxifies lipopolysaccharide (LPS), a mediator in necrotizing enterocolitis (NEC) pathogenesis. We hypothesize that aberrant expression or function of iAP contributes to the pathogenesis of NEC. MATERIALS AND METHODS: Newborn Sprague Dawley rat pups were divided into three main groups. Control pups were breast fed, while two groups were exposed to intermittent hypoxia, LPS, and formula feeding for 4 d to induce NEC. Bovine iAP, with and without the presence of LPS, was administered orally to one of the NEC groups. The intestine was harvested and used to detect alkaline phosphatase (AP) activity and protein expression. Terminal ileum sections were used to grade intestinal injury and stained for AP. Comparisons were made with adult rat duodenum. RESULTS: Compared with adult rats, control pups expressed significantly less AP protein but had 2-fold higher AP activity. NEC pup AP activity was significantly decreased compared to controls (P < or = 0.05), which paralleled both the AP protein expression and immunofluorescence assay results. Following iAP administration, immunofluorescence, protein expression, and activity of AP were significantly increased compared with NEC pups without iAP supplementation. All NEC pups had intestinal injury grades > or = 2 on a 4-point scale, while control and iAP-treated pups had grades < 0.25 (P < 0.001). CONCLUSIONS: Enteral administration of iAP to rat pups with experimental NEC increased AP activity levels to that of controls, and appears to protect the intestine. This opens up a new area of study in NEC pathophysiology as well as a potential novel treatment strategy to prevent the development of NEC.