Validation of the Clavien-Madadi Classification for Unexpected Events in Pediatric Surgery: A Collaborative ERNICA Project.

BACKGROUND: The Clavien-Madadi classification is a novel instrument for the assessment and grading of unexpected events in pediatric surgery, based on the Clavien-Dindo classification. The system has been adjusted to better fit the pediatric population in a prospective single-center study. There is a need now to validate the Clavien-Madadi classification within an international expert network. METHODS: A pediatric surgical working group created 19 case scenarios with unexpected events in a multi-staged process. Those were circulated within the European Reference Network of Inherited and Congenital Anomalies (ERNICA) and surgeons were instructed to rate the scenarios according to the Clavien-Madadi vs. Clavien-Dindo classification. RESULTS: 59 surgeons from 12 European countries completed the questionnaire. Based on ratings of the case scenarios, the Clavien-Madadi classification showed significantly superior agreement rates of the respondents (85.9% vs 76.2%; p < 0.05) and was less frequently considered inaccurate for rating the pediatric population compared to Clavien-Dindo (2.1% vs 11.1%; p = 0.05). Fleiss' kappa analysis showed slightly higher strength of agreement using the Clavien-Madadi classification (0.74 vs 0.69). Additionally, intraclass correlation coefficient was slightly higher for the Clavien-Madadi compared to the Clavien-Dindo classification (ICCjust 0.93 vs 0.89; ICCunjust 0.93 vs 0.89). More pediatric surgeons preferred the Clavien-Madadi classification for the case scenarios (43.0% vs 11.8%; p = 0.002) and advantages of the Clavien-Madadi were confirmed by 81.4% of the surgeons. CONCLUSION: The Clavien-Madadi classification is an accurate and reliable instrument for the grading of unexpected events in pediatric surgery. We therefore recommend its application in clinical and academic pediatric surgical practice. LEVEL OF EVIDENCE: III.

Benchmarks for Pediatric Surgical Registries: Recommendations for the Assessment and Grading of Complications.

Procedure-related registries in general surgical practice offer a platform for prospective trials, the pooling of data, and detailed outcome analysis. Recommendations by the Idea, Development, Exploration, Assessment, and Long-term follow-up (IDEAL) collaboration and Outcome4Medicine have further improved the uniform reporting of complications and adverse events.In the pediatric surgical network, disease-specific registries for rare and inherited congenital anomalies are gaining importance, fostering international collaborations on studies of low-incidence diseases. However, to date, reporting of complications in the pediatric surgical registries has been inconsistent. Therefore, the European Reference Network for Rare Inherited and Congenital Anomalies (ERNICA) recently endorsed the validation of the first severity grading system for children. The planned reform of the European Paediatric Surgical Audit (EPSA) registry, which includes the implementation of the Clavien-Madadi classification, represents a further effort to establish uniform outcome reporting.This article provides an overview of experiences with surgical registries and complication reporting, along with the potential application of this knowledge to future pediatric surgical practice.

Selection of Quality Indicators to Evaluate Quality of Care for Patients with Esophageal Atresia Using a Delphi Method.

OBJECTIVE: Survival of neonates with esophageal atresia (EA) is relatively high and stable, resulting in increased attention to optimizing care and longer-term morbidity. This study aimed to reach consensus on a quality indicator set for benchmarking EA care between hospitals, regions, or countries in a European clinical audit. METHODS: Using an online Delphi method, a panel of EA health care professionals and patient representatives rated potential outcome, structure, and process indicators for EA care identified through systematic literature and guideline review on a nine-point Likert scale in three questionnaires. Items were included based on predefined criteria. In rounds 2 and 3, participants were asked to select the five to ten most essential of the included indicators. RESULTS: An international panel of 14 patient representatives and 71 multidisciplinary health care professionals representing 41 European hospitals completed all questionnaires (response rate: 81%), eventually including 22 baseline characteristics and 32 indicators. After ranking, 10 indicators were prioritized by both stakeholder groups. In addition, each stakeholder group highly prioritized one additional indicator. Following an additional online vote by the other group, these were both added to the final set. CONCLUSION: This study established a core indicator set of twenty-two baseline characteristics, eight outcome indicators, one structure indicator, and three process indicators for evaluating (quality of) EA care in Europe. These indicators, covering various aspects of EA care, will be implemented in the European Pediatric Surgical Audit to enable recognition of practice variation and focus EA care improvement initiatives.

Titanium nitride coating of pectus bar increases metal contamination after minimally-invasive repair of pectus excavatum.

INTRODUCTION: Previous studies demonstrated a release of toxic metals, e.g. nickel and chromium, from stainless steel bars used for minimally invasive repair of pectus excavatum (MIRPE). In the present study, we investigated the impact of titanium nitride coating on the metal release and exposure of MIRPE patients. MATERIAL AND METHODS: We analyzed the courses of nickel and chromium levels in blood, urine and local tissue in patients undergoing MIRPE with a titanium nitride coated pectus bar between 03/2017 and 10/2018. Sample collection was scheduled prior to MIRPE, at defined postoperative time points and at bar removal. Additionally, we evaluated irritative symptoms. Results were compared to a control group who received uncoated stainless steel bars in a previous time period (03/2015-02/2017). RESULTS: 12 patients received coated pectus bars (mean age 15.7 years). The control group included 28 patients. After implantation of a titanium nitride coated bar, significant increase in systemic nickel and chromium levels after one, two and three years was noted. In an interim analysis one year after MIRPE, we observed patients with coated bars to have significantly elevated trace metal values compared to the control group. This elevation persisted throughout the observation period. Tissue metal values were also significantly increased. Irritative symptoms occurred significantly more often in study patients compared to controls (50.0% vs. 14.3%). CONCLUSIONS: Coating of pectus bars with titanium nitride failed to reduce metal contamination after MIRPE. Instead, it resulted in a significant increase of trace metal levels after MIRPE, compared to patients with stainless steel bars, which may be explained by wear of the coating and inter-component mobilization processes.

Impact of the COVID-19 Pandemic on Pediatric Surgical Scientific Formats: An ERNICA Survey on Challenges and Future Directions.

INTRODUCTION: The aims of this survey were to assess the experiences of the transition from in-person to virtual meetings among European pediatric surgeons since the beginning of the coronavirus disease 2019 (COVID-19) pandemic and to identify preferences for future formats. MATERIALS AND METHODS: An online questionnaire was circulated among members of the European Reference Network for rare Inherited and Congenital Anomalies Network (ERNICA) in 2022. Two time periods were compared (3 years before the COVID-19 pandemic vs. the year 2021). RESULTS: A total of 87 pediatric surgeons from 16 countries completed the survey. In addition, 27% of respondents were trainees/residents and 73% consultants/lead surgeons. Consultants participated in significantly more in-person congresses prior to the COVID-19 pandemic compared with trainees (5.2 vs. 1.9; p < 0.001). A significant increase in attendance of virtual meeting was reported during 2021 compared with pre-COVID-19 (1.4 vs. 6.7; p < 0.001). Consultants had experienced significantly less absenteeism thanks to virtual meetings compared with trainees (42/61 vs. 8/23; p < 0.05). Most surgeons considered virtual meetings more economic (82%), practical (78%), and family-friendly (66%). However, a majority reported missing social events (78%). The communication among attendees or between attendees and speakers or scientific faculty was deemed worse. A minority (14%) experienced equalized representation of trainees and consultants at virtual meetings. Most respondents (58%) agreed that future meeting strategies should focus on offering virtual formats. Regarding future congresses, respondents prefer hybrid (62%) over in-person (33%) or virtual (6%) formats. CONCLUSION: According to European pediatric surgeons, virtual learning formats hold multiple advantages and should be continued. Improved technology must meet the challenges, particularly to enhance communication, equal representation, and networking between attendees.

MUC-FIRE: Study protocol for a randomized multicenter open-label controlled trial to show that MUCous FIstula REfeeding reduces the time from enterostomy closure to full enteral feeds.

Background: After enterostomy creation, the distal bowel to the ostomy is excluded from the physiologic passage of stool, nutrient uptake, and growth of this intestinal section. Those infants frequently require long-term parenteral nutrition, continued after enterostomy reversal due to the notable diameter discrepancy of the proximal and distal bowel. Previous studies have shown that mucous fistula refeeding (MFR) results in faster weight gain in infants. The aim of the randomized multicenter open-label controlled MUCous FIstula REfeeding ("MUC-FIRE") trial is to demonstrate that MFR between enterostomy creation and reversal reduces the time to full enteral feeds after enterostomy closure compared to controls, resulting in shorter hospital stay and less adverse effects of parenteral nutrition. Methods/Design: A total of 120 infants will be included in the MUC-FIRE trial. Following enterostomy creation, infants will be randomized to either an intervention or a non-intervention group.In the intervention group, perioperative MFR between enterostomy creation and reversal will be performed. The control group receives standard care without MFR.The primary efficacy endpoint of the study is the time to full enteral feeds. Secondary endpoints include first postoperative bowel movement after stoma reversal, postoperative weight gain, and days of postoperative parenteral nutrition. In addition adverse events will be analyzed. Discussion: The MUC-FIRE trial will be the first prospective randomized trial to investigate the benefits and disadvantages of MFR in infants. The results of the trial are expected to provide an evidence-based foundation for guidelines in pediatric surgical centers worldwide. Trial registration: The trial has been registered at clinicaltrials.gov (number: NCT03469609, date of registration: March 19, 2018; last update: January 20, 2023, https://clinicaltrials.gov/ct2/show/NCT03469609?term=NCT03469609&draw=2&rank=1).

Implementation and validation of a novel instrument for the grading of unexpected events in paediatric surgery: Clavien-Madadi classification.

BACKGROUND: Inconsistent definitions of complications and unexpected events have limited accurate analysis of surgical outcomes. Perioperative outcome classifications currently used for adult patients have limitations when used for children. METHODS: A multidisciplinary group of experts modified the Clavien-Dindo classification to increase its utility and accuracy in paediatric surgery cohorts. Organizational and management errors were considered in the novel Clavien-Madadi classification, which focuses on procedural invasiveness rather than anaesthetic management. Unexpected events were prospectively documented in a paediatric surgery cohort. Results of the Clavien-Dindo and Clavien-Madadi classifications were compared and correlated with procedure complexity. RESULTS: Unexpected events were prospectively documented in a cohort of 17 502 children undergoing surgery between 2017 and 2021. The results of both classifications were highly correlated (ρ = 0.95), although the novel Clavien-Madadi classification identified 449 additional events (organizational and management errors) over the Clavien-Dindo classification, increasing the total number of events by 38 per cent (1605 versus 1158 events). The results of the novel system correlated significantly with the complexity of procedures in children (ρ = 0.756). Furthermore, grading of events > grade III according to the Clavien-Madadi classification showed a higher correlation with procedure complexity (ρ = 0.658) than the Clavien-Dindo classification (ρ = 0.198). CONCLUSION: The Clavien-Madadi classification is a tool for the detection of surgical and non-medical errors in paediatric surgery populations. Further validation in paediatric surgery populations is required before widespread use.

Variability in the Reporting of Baseline Characteristics, Treatment, and Outcomes in Esophageal Atresia Publications: A Systematic Review.

INTRODUCTION: As survival rates of infants born with esophageal atresia (EA) have improved considerably, research interests are shifting from viability to morbidity and longer-term outcomes. This review aims to identify all parameters studied in recent EA research and determine variability in their reporting, utilization, and definition. MATERIALS AND METHODS: Following PRISMA guidelines, we performed a systematic review of literature regarding the main EA care process, published between 2015 and 2021, combining the search term "esophageal atresia" with "morbidity," "mortality," "survival," "outcome," or "complication." Described outcomes were extracted from included publications, along with study and baseline characteristics. RESULTS: From 209 publications that met the inclusion criteria, 731 studied parameters were extracted and categorized into patient characteristics (n = 128), treatment and care process characteristics (n = 338), and outcomes (n = 265). Ninety-two of these were reported in more than 5% of included publications. Most frequently reported characteristics were sex (85%), EA type (74%), and repair type (60%). Most frequently reported outcomes were anastomotic stricture (72%), anastomotic leakage (68%), and mortality (66%). CONCLUSION: This study demonstrates considerable heterogeneity of studied parameters in EA research, emphasizing the need for standardized reporting to compare results of EA research. Additionally, the identified items may help develop an informed, evidence-based consensus on outcome measurement in esophageal atresia research and standardized data collection in registries or clinical audits, thereby enabling benchmarking and comparing care between centers, regions, and countries.

Surgical management of large tracheoesophageal fistula in infants after button battery ingestion.

OBJECTIVES: In recent years, an increase in severe and even fatal outcomes related to oesophageal or airway button battery (BB) ingestion by infants and small children has been reported. Extensive tissue necrosis caused by lodged BB can lead to major complications, including tracheoesophageal fistula (TEF). In these instances, best treatment remains controversial. While small defects may warrant a conservative approach, surgery often remains inevitable in highly complex cases with large TEF. We present a series of small children that underwent successful surgical management by a multidisciplinary team in our institution. METHODS: This is a retrospective analysis of n = 4 patients <18 months undergoing TEF repair from 2018 to 2021. RESULTS: Surgical repair under extracorporeal membrane oxygenation (ECMO) support was feasible in n = 4 patients by reconstructing the trachea with decellularized aortic homografts that were buttressed with pedicled latissimus dorsi muscle flaps. While direct oesophageal repair was feasible in 1 patient, 3 required esophagogastrostomy and secondary repair. The procedure was completed successfully in all 4 children with no mortality and acceptable morbidity. CONCLUSIONS: Tracheo-oesophageal repair after BB ingestion remains challenging and is associated with major morbidity. Bioprosthetic materials in conjunction with the interposition of vascularized tissue flaps between trachea and oesophagus appear to be a valid approach to manage severe cases.

Definition, Documentation, and Classification of Complications in Pediatric Surgical Literature-A Plea for Standardization.

Severity grading systems for complications in surgical patients have been used since 1992. An increasing assessment of these instruments in pediatric surgery is also noticed, without their validation in children. To analyze the current practice, we performed a literature review with focus on the assessment and grading of complications. The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies reporting on postoperative complications as a primary or secondary endpoint using a severity grading system were included. Definition for simple adverse events, classification systems used, and the time horizon of postoperative documentation were analyzed. A total of 566 articles were screened, of which 36 met the inclusion criteria. About 86.1% of the papers were retrospective and 13.9% prospective analyses. None of the studies were prospective-randomized trials. Twenty (55.6%) studies did not include a definition of adverse events, whereas the remaining 16 (44.4%) showed variations in their definitions. All studies applied the Clavien-Dindo classification, whereas five (13.9%) additionally used the Comprehensive Complication Index. One study compared alternative grading instruments with the Clavien-Dindo classification, without demonstrating the superiority of any classification in pediatric surgery. Twenty-two studies (61.1%) did not report the time horizon of perioperative complication documentation, while 8 studies (22.2%) used 30 days and 6 studies (16.7%) used 3 months of postoperative documentation. Definition and classification of postoperative complications are inconsistent in the pediatric surgical literature. Establishment of a standardized protocol is mandatory to accurately compare outcome data.

Laparoscopic versus Open Inguinal Hernia Repair Is Feasible in Infants with Caudal Anesthesia and Spontaneous Respiration.

INTRODUCTION: Minimally invasive surgery (i.e., laparoscopy) and minimally invasive anesthesia (i.e., caudal anesthesia with spontaneous respiration) have separately shown benefits for inguinal hernia repair in infants, yet to what degree these techniques can be combined remains unknown. This study investigated whether laparoscopy impacts the feasibility of performing caudal anesthesia with spontaneous respiration in infants. METHODS: Prospectively collected data of all infants less than 12 months old and over 3 kg weight who underwent laparoscopic indirect hernia repair (LAP) at our department from 2019 to 2021 were compared with a historical control-matched group of infants who underwent open repair (OPEN) from 2017 to 2021. We assessed the patients' characteristics, anesthesia, and surgical data as well as intra- and postoperative complications. RESULTS: A total of 87 infants were included (LAP n = 29, OPEN n = 58). Caudal anesthesia with spontaneous respiration was feasible in 62.1% of cases (LAP n = 55.2%, OPEN n = 65.5%; nonsignificant). Neither group registered anesthetic intra- or postoperative complications. Sedatives were utilized in 97% of LAP patients versus 56.9% of OPEN patients (p < 0.00001). The airway was secured with a laryngeal mask in 89.7% of patients during LAP versus 41.4% during OPEN (p < 0.00001). No significant differences were found regarding the use frequency of opioids (48.3% LAP vs. 34.5% OPEN; nonsignificant) or neuromuscular blockers (6.9% LAP vs. 5.2% OPEN; nonsignificant). CONCLUSION: This is the first comparative study on caudal anesthesia and spontaneous respiration in infants undergoing laparoscopic versus open inguinal hernia surgery. Laparoscopy increased the need for ventilatory support and sedatives but did not significantly impair the feasibility of caudal anesthesia and spontaneous respiration.

Pleural CD14+ monocytes/macrophages of healthy adolescents show a high expression of metallothionein family genes.

Nowadays laparoscopic interventions enable the collection of resident macrophage populations out of the human cavities. We employed this technique to isolate pleural monocytes/macrophages from healthy young adults who underwent a correction of pectus excavatum. High quality CD14+ monocytes/macrophages (plMo/Mφ) were used for RNA-sequencing (RNA-seq) in comparison with human monocyte-derived macrophages (MDM) natural (MDM-0) or IL-4-polarized (MDM-IL4). Transcriptome analysis revealed 7166 and 7076 differentially expressed genes (DEGs) in plMo/Mφ relative to natural MDM-0 and polarized MDM-IL4, respectively. The gene set enrichment analysis, which was used to compare RNA-seq data from plMo/Mφ with single-cell (scRNA-seq) data online from human bronchial lavage macrophages, showed that plMo/Mφs are characterized by a high expression of genes belonging to the metallothionein (MT) family, and that the expression of these genes is significantly higher in plMo/Mφ than in MDM-0 or MDM-IL4. Our results provide additional insights on high MTs-expressing macrophage subsets, which seem to be present not only in bronchial lavage of healthy adults or in pleural exudates of lung cancer patients but also in pleural fluid of healthy young adults. Macrophage subsets expressing high MTs may have specific roles in lung defense, repair, and homeostasis, and require further investigations.

Genome-wide identification of disease-causing copy number variations in 450 individuals with anorectal malformations.

Anorectal malformations (ARM) represent a spectrum of rare malformations originating from a perturbated development of the embryonic hindgut. Approximately 60% occur as a part of a defined genetic syndrome or within the spectrum of additional congenital anomalies. Rare copy number variations (CNVs) have been associated with both syndromic and non-syndromic forms. The present study represents the largest study to date to explore the contribution of CNVs to the expression of ARMs. SNP-array-based molecular karyotyping was applied in 450 individuals with ARM and 4392 healthy controls. CNVs were identified from raw intensity data using PennCNV. Overlapping CNVs between cases and controls were discarded. Remaining CNVs were filtered using a stringent filter algorithm of nine filter steps. Prioritized CNVs were confirmed using qPCR. Filtering prioritized and qPCR confirmed four microscopic chromosomal anomalies and nine submicroscopic CNVs comprising seven microdeletions (del2p13.2, del4p16.2, del7q31.33, del9p24.1, del16q12.1, del18q32, del22q11.21) and two microduplications (dup2p13.2, dup17q12) in 14 individuals (12 singletons and one affected sib-pair). Within these CNVs, based on their embryonic expression data and function, we suggest FOXK2, LPP, and SALL3 as putative candidate genes. Overall, our CNV analysis identified putative microscopic and submicroscopic chromosomal rearrangements in 3% of cases. Functional characterization and re-sequencing of suggested candidate genes is warranted.

Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes-Brocks syndrome 2.

Most patients with congenital anomalies of the kidney and urinary tract (CAKUT) remain genetically unexplained. In search of novel genes associated with CAKUT in humans, we applied whole-exome sequencing in a patient with kidney, anorectal, spinal, and brain anomalies, and identified a rare heterozygous missense variant in the DACT1 (dishevelled binding antagonist of beta catenin 1) gene encoding a cytoplasmic WNT signaling mediator. Our patient's features overlapped Townes-Brocks syndrome 2 (TBS2) previously described in a family carrying a DACT1 nonsense variant as well as those of Dact1-deficient mice. Therefore, we assessed the role of DACT1 in CAKUT pathogenesis. Taken together, very rare (minor allele frequency ≤ 0.0005) non-silent DACT1 variants were detected in eight of 209 (3.8%) CAKUT families, significantly more frequently than in controls (1.7%). All seven different DACT1 missense variants, predominantly likely pathogenic and exclusively maternally inherited, were located in the interaction region with DVL2 (dishevelled segment polarity protein 2), and biochemical characterization revealed reduced binding of mutant DACT1 to DVL2. Patients carrying DACT1 variants presented with kidney agenesis, duplex or (multi)cystic (hypo)dysplastic kidneys with hydronephrosis and TBS2 features. During murine development, Dact1 was expressed in organs affected by anomalies in patients with DACT1 variants, including the kidney, anal canal, vertebrae, and brain. In a branching morphogenesis assay, tubule formation was impaired in CRISPR/Cas9-induced Dact1-/- murine inner medullary collecting duct cells. In summary, we provide evidence that heterozygous hypomorphic DACT1 variants cause CAKUT and other features of TBS2, including anomalies of the skeleton, brain, distal digestive and genital tract.

Nickel contamination after minimally-invasive repair of pectus excavatum persists after bar removal.

BACKGROUND: Minimally-invasive repair of pectus excavatum (MIRPE) has been shown to be associated with high release of trace metals into patient's body. The aim of our study was to analyze the kinetics of metal contamination after MIRPE and after bar removal. METHODS: We prospectively assessed nickel and chromium changes in blood, urine, and local tissue in patients undergoing MIRPE with stainless-steel bar(s). Baseline samples were taken prior to surgery, further samples were taken at six defined time points until 30 months after bar removal. Clinical symptoms were evaluated at the time of every sample collection. RESULTS: 28 patients were included (mean age 16.4 years). At four weeks after MIRPE and persisting up to bar removal, we found significantly elevated trace metal levels in blood and urine. Tissue nickel and chromium levels were significantly elevated at the time of bar removal. After bar removal, the concentration of trace metal in urine and the concentration of chromium in plasma decreased gradually. In contrast, nickel levels in blood further increased. Five patients showed irritative symptoms after MIRPE, all symptomatic patients had elevated metal levels. CONCLUSIONS: Following MIRPE, we found a rapid systemic increase of nickel and chromium. Our data indicate that trace metal release could cause irritative symptoms. The prolonged elevated systemic nickel levels beyond bar removal necessitate further investigations of the long-term side effects of MIRPE.

The Role of Laparoscopic Treatment of Choledochal Malformation in Europe: A Single-Center Experience and Review of the Literature.

BACKGROUND: Numerous studies from Asian countries, including large collectives, have reported excellent results after laparoscopic resection of choledochal malformation (CM). However, the role of laparoscopic CM resection is still controversial outside Asia. We aimed to analyze the outcome of laparoscopic CM resection in our institution and to compare our outcome with the data reported in the literature. METHODS: All patients who underwent laparoscopic CM resection in our pediatric surgical department from 2002 to 2019 were retrospectively analyzed for surgical details and postoperative complications, which were graded according to the Clavien-Dindo classification. A systematic literature search identified all reports on over 10 cases of laparoscopic pediatric CM resection and surgical details, follow-up, and complication rates were extracted. RESULTS: Fifty-seven patients (72% female) with a mean age of 3.6 + 4.1 years underwent laparoscopic CM resection in our department. Conversion rate was 30%. Total complication rate was 28%. The rate of major complications (Clavien-Dindo grade III or more) was 16% and included stricture of the biliodigestive or enteric anastomosis (n = 4), adhesive ileus (n = 3), portal vein thrombosis (n = 1), and recurrent cholangitis with consecutive liver transplantation (n = 1). With increasing experience, complication rates decreased. The majority of publications on laparoscopic CM resections originated from Asia (n = 36) and reported on low complication rates. In contrast, publications originating from non-Asian countries (n = 5) reported on higher complications following laparoscopic CM resection. CONCLUSION: Our data indicate that laparoscopic CM resection can be safely performed. The learning curve in combination with the low incidence calls for a centralization of patients who undergo laparoscopic CM resection. There seems to be a discrepancy on complications rates reported from Asian and non-Asian countries following laparoscopic CM resection.