Muscle hypertrophy and neuroplasticity in the small bowel in short bowel syndrome.

Short bowel syndrome (SBS) is a severe, life-threatening condition and one of the leading causes of intestinal failure in children. Here we were interested in changes in muscle layers and especially in the myenteric plexus of the enteric nervous system (ENS) of the small bowel in the context of intestinal adaptation. Twelve rats underwent a massive resection of the small intestine to induce SBS. Sham laparotomy without small bowel transection was performed in 10 rats. Two weeks after surgery, the remaining jejunum and ileum were harvested and studied. Samples of human small bowel were obtained from patients who underwent resection of small bowel segments due to a medical indication. Morphological changes in the muscle layers and the expression of nestin, a marker for neuronal plasticity, were studied. Following SBS, muscle tissue increases significantly in both parts of the small bowel, i.e., jejunum and ileum. The leading pathophysiological mechanism of these changes is hypertrophy. Additionally, we observed an increased nestin expression in the myenteric plexus in the remaining bowel with SBS. Our human data also showed that in patients with SBS, the proportion of stem cells in the myenteric plexus had risen by more than twofold. Our findings suggest that the ENS is tightly connected to changes in intestinal muscle layers and is critically involved in the process of intestinal adaptation to SBS.

Pediatric Intestinal Pseudo-Obstruction: An International Survey on Diagnostic and Management Strategies in the European Reference Network for Rare Inherited and Congenital Anomalies Intestinal Failure Teams.

OBJECTIVES: Pediatric intestinal pseudo-obstruction (PIPO) management is based on nutritional, medical, and surgical care while available evidence is scarce. The aim of this study was to outline the current diagnostic and management strategies in intestinal failure (IF) teams of the European Reference Network for rare Inherited and Congenital Anomalies (ERNICA) and to compare these practices to the latest PIPO international guidelines. METHODS: An online survey on institutional diagnostic and management strategies of PIPO was conducted among the ERNICA IF teams. RESULTS: In total, 11 of 21 ERNICA IF centers from 8 countries participated. On average, 64% of teams had ≥6 and 36% had 1-5 PIPO patients under active follow-up. In total, 80 of 102 PIPO patients were parenteral nutrition (PN) dependent while each IF team had median 4 (range 0-19) PN dependent PIPO patients under follow-up. On average, each center received 1-2 new PIPO patients per year. Diagnostics mostly followed current guidelines while medical and surgical management strategies were diverse. CONCLUSIONS: Numbers of PIPO patients are low and management strategies are diverse among ERNICA IF teams. To improve PIPO patient care, regional reference centers with specialized multidisciplinary IF teams and continuous collaboration across centers are needed.

Habitual physical activity in patients born with oesophageal atresia: a multicenter cross-sectional study and comparison to a healthy reference cohort matched for gender and age.

Oesophageal atresia (EA) is associated with life-long gastrointestinal and respiratory morbidity and other associated malformations. The aim of this study is to compare physical activity (PA) levels of children and adolescents with and without EA. A validated questionnaire (MoMo-PAQ) was used to evaluate PA in EA patients EA (4-17 years), who were randomly matched for gender and age (1:5) with a representative sample of the Motorik-Modul Longitudinal Study (n = 6233). Sports activity per week (sports index) and minutes of moderate to vigorous physical activity per week (MVPA minutes) were calculated. Correlations between PA and medical factors were analysed. In total, 104 patients and 520 controls were included. Children with EA were significantly less active at higher intensities (mean MPVA minutes 462; 95% confidence interval (CI): 370-554) compared to controls (626; 95% CI: 576-676), although there was no statistically significant difference in the sports index (187; 95% CI: 156-220 versus 220; 95% CI: 203-237). A lower mean weight-for-age and height-for-age, additional urogenital (r = - 0.20, p = 0.04) or anorectal malformation (r = - 0.24, p = 0.01) were associated with fewer MVPA minutes. For other medical factors (prematurity, type of repair, congenital heart disease, skeletal malformation or symptom load), no statistically significant association with PA was found.  Conclusion: EA patients participated in PA at a similar level but lower intensities compared to the reference cohort. PA in EA patients was largely independent of medical factors. TRIAL REGISTRATION: German Clinical Trials Register (ID: DRKS00025276) on September 6, 2021. WHAT IS KNOWN: • Oesophageal atresia is associated with a low body weight and height, delayed development of motor skills and impaired lung function and exercise capacity. WHAT IS NEW: • Patients with oesophageal atresia have a similar amount of sports activity per week but engage significantly less in moderate to vigorous physical activities compared to peers. • Physical activity was  associated with weight-for-age and height-for-age, but largely independent of symptom load and other medical factors.

[Recommendations of the S3 Guideline "Use of Extracorporeal Circulation (ECLS/ ECMO) for Cardiac and Circulatory Failure" of the Association of Scientific Medical Societies in Germany]. / Empfehlungen der S3-Leitlinie (AWMF) "Einsatz der extrakorporalen Zirkulation (ECLS/ECMO) bei Herz- und Kreislaufversagen".

In recent years, the use of mechanical support for patients with cardiac or circulatory failure has continuously increased, leading to 3,000 ECLS/ECMO (extracorporeal life support/extracorporeal membrane oxygenation) implantations annually in Germany. Due to the lack of guidelines, there is an urgent need for evidence-based recommendations addressing the central aspects of ECLS/ECMO therapy. In July 2015, the generation of a guideline level S3 according to the standards of the Association of the Scientific Medical Societies in Germany (AWMF) was announced by the German Society for Thoracic and Cardiovascular Surgery (GSTCVS). In a well-structured consensus process, involving experts from Germany, Austria and Switzerland, delegated by 16 scientific societies and the patients' representation, the guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" was created under guidance of the GSTCVS, and published in February 2021. The guideline focuses on clinical aspects of initiation, continuation, weaning and aftercare, herein also addressing structural and economic issues. This article presents an overview on the methodology as well as the final recommendations.

MR lung perfusion measurements in adolescents after congenital diaphragmatic hernia: correlation with spirometric lung function tests.

OBJECTIVES: To evaluate whether lung perfusion continues to be reduced in 10-year-old children after congenital diaphragmatic hernia (CDH) and whether lung perfusion values correlate with spirometric lung function measurements. METHODS: Fifty-four patients after CDH repair received dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI)-based lung perfusion measurements at the age of 10 years (10.2 ± 1.0 years). Additionally, a control group of 10 children has been examined according to the same protocol. Lung spirometry was additionally available in 43 patients of the CDH group. A comparison of ipsilateral and contralateral parameters was performed. RESULTS: Pulmonary blood flow (PBF) was reduced on the ipsilateral side in CDH patients (60.4 ± 23.8 vs. 93.3 ± 16.09 mL/100 mL/min; p < 0.0001). In comparison to the control group, especially the ratio of ipsilateral to contralateral, PBF was reduced in CDH patients (0.669 ± 0.152 vs. 0.975 ± 0.091; p < 0.0001). There is a positive correlation between ipsilateral pulmonary blood flow, and spirometric forced 1-s volume (r = 0.45; p = 0.0024). CONCLUSIONS: Pulmonary blood flow impairment persists during childhood and correlates with spirometric measurements. Without the need for ionizing radiation, MRI measurements seem promising as follow-up parameters after CDH. KEY POINTS: • Ten-year-old children after congenital diaphragmatic hernia continue to show reduced perfusion of ipsilateral lung. • Lung perfusion values correlate with lung function tests after congenital diaphragmatic hernia.

Neurocardiovascular coupling in congenital diaphragmatic hernia patients undergoing different types of surgical treatment.

BACKGROUND: The effect of peri-operative management on the neonatal brain is largely unknown. Triggers for perioperative brain injury might be revealed by studying changes in neonatal physiology peri-operatively. OBJECTIVE: To study neonatal pathophysiology and cerebral blood flow regulation peri-operatively using the neuro-cardiovascular graph. DESIGN: Observational, prospective cohort study on perioperative neuromonitoring. Neonates were included between July 2018 and April 2020. SETTING: Multicentre study in two high-volume tertiary university hospitals. PATIENTS: Neonates with congenital diaphragmatic hernia were eligible if they received surgical treatment within the first 28 days of life. Exclusion criteria were major cardiac or chromosomal anomalies, or syndromes associated with altered cerebral perfusion or major neurodevelopmental impairment. The neonates were stratified into different groups by type of peri-operative management. INTERVENTION: Each patient was monitored using near-infrared spectroscopy and EEG in addition to the routine peri-operative monitoring. Neurocardiovascular graphs were computed off-line. MAIN OUTCOME MEASURES: The primary endpoint was the difference in neurocardiovascular graph connectivity in the groups over time. RESULTS: Thirty-six patients were included. The intraoperative graph connectivity decreased in all patients operated upon in the operation room (OR) with sevoflurane-based anaesthesia ( P  < 0.001) but remained stable in all patients operated upon in the neonatal intensive care unit (NICU) with midazolam-based anaesthesia. Thoracoscopic surgery in the OR was associated with the largest median connectivity reduction (0.33 to 0.12, P  < 0.001) and a loss of baroreflex and neurovascular coupling. During open surgery in the OR, all regulation mechanisms remained intact. Open surgery in the NICU was associated with the highest neurovascular coupling values. CONCLUSION: Neurocardiovascular graphs provided more insight into the effect of the peri-operative management on the pathophysiology of neonates undergoing surgery. The neonate's clinical condition as well as the surgical and the anaesthesiological approach affected the neonatal physiology and CBF regulation mechanisms at different levels. TRIAL REGISTRATION: NL6972, URL: https://www.trialre-gister.nl/trial/6972 .

Digestive enzyme expression in the large intestine of children with short bowel syndrome in a late stage of adaptation.

BACKGROUND AND AIMS: Intestinal adaptation in short bowel syndrome (SBS) includes morphologic processes and functional mechanisms. This study investigated whether digestive enzyme expression in the duodenum and colon is upregulated in SBS patients. METHOD: Sucrase-isomaltase (SI), lactase-phlorizin hydrolase (LPH), and neutral Aminopeptidase N (ApN) were analyzed in duodenal and colonic biopsies from nine SBS patients in a late stage of adaptation as well as healthy and disease controls by immunoelectron microscopy (IEM), Western blots, and enzyme activities. Furthermore, proliferation rates and intestinal microbiota were analyzed in the mucosal specimen. RESULTS: We found significantly increased amounts of SI, LPH, and ApN in colonocytes in most SBS patients with large variation and strongest effect for SI and ApN. Digestive enzyme expression was only partially elevated in duodenal enterocytes due to a low proliferation level measured by Ki-67 staining. Microbiome analysis revealed high amounts of Lactobacillus resp. low amounts of Proteobacteria in SBS patients with preservation of colon and ileocecal valve. Colonic expression was associated with a better clinical course in single cases. CONCLUSION: In SBS patients disaccharidases and peptidases can be upregulated in the colon. Stimulation of this colonic intestinalization process by drugs, nutrients, and pre- or probiotics might offer better therapeutic approaches.

Parental risk factors for congenital diaphragmatic hernia - a large German case-control study.

BACKGROUND: Evidence for periconceptional or prenatal environmental risk factors for the development of congenital diaphragmatic hernia (CDH) is still scarce. Here, in a case-control study we investigated potential environmental risk factors in 199 CDH patients compared to 597 healthy control newborns. METHODS: The following data was collected: time of conception and birth, maternal BMI, parental risk factors such as smoking, alcohol or drug intake, use of hairspray, contact to animals and parental chronic diseases. CDH patients were born between 2001 and 2019, all healthy control newborns were born in 2011. Patients and control newborns were matched in the ratio of three to one. RESULTS: Presence of CDH was significantly associated with maternal periconceptional alcohol intake (odds ratio = 1.639, 95% confidence interval 1.101-2.440, p = 0.015) and maternal periconceptional use of hairspray (odds ratio = 2.072, 95% confidence interval 1.330-3.229, p = 0.001). CONCLUSION: Our study suggests an association between CDH and periconceptional maternal alcohol intake and periconceptional maternal use of hairspray. Besides the identification of novel and confirmation of previously described parental risk factors, our study underlines the multifactorial background of isolated CDH.

Case Report: 7-Year-Old Boy with Incarcerated Internal Hernia Leading to Extensive Intestinal Necrosis Due to a Large Congenital Mesenteric Defect.

We present a case of a 7-year-old boy with acute abdominal symptoms initially misdiagnosed as constipation. Delayed imaging diagnostics revealed an ileus with contorted small intestine, so laparotomy was indicated. An acute bowel obstruction was found based on an incarcerated internal hernia. Small and large bowel segments were incarcerated into a large mesenteric defect leading to extended intestinal necrosis. About 30 cm of necrotic small bowel and 15 cm of large intestine were resected, two primary anastomoses were performed. The mesenteric defect was closed with two running sutures. The boy's clinical outcome was very good. Two aspects are discussed: the initial clinical misdiagnosis of acute bowel obstruction in a child leading to a delay of diagnostics and therapy on the one hand and the origin of mesenteric defects on the other. In children with abdominal pain, ultrasound must be performed as soon as possible and pediatric surgeons have to be involved early. There should be an awareness of the fact, that mesenteric defects and other congenital malformations can occur more often than we suspect it. In the case of an internal hernia, a misjudgement of the clinical condition may be very harmful for the patient and can lead to a short bowel syndrome or even death.

[Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure : Short version of the S3 guideline]. / Einsatz der extrakorporalen Zirkulation (ECLS/ECMO) bei Herz- und Kreislaufversagen : Kurzversion der AWMF-S3-Leitlinie.

In Germany, a remarkable increase regarding the usage of extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) systems has been observed in recent years with approximately 3000 ECLS/ECMO implantations annually since 2015. Despite the widespread use of ECLS/ECMO, evidence-based recommendations or guidelines are still lacking regarding indications, contraindications, limitations and management of ECMO/ECLS patients. Therefore in 2015, the German Society of Thoracic and Cardiovascular Surgery (GSTCVS) registered the multidisciplinary S3 guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" to develop evidence-based recommendations for ECMO/ECLS systems according to the requirements of the Association of the Scientific Medical Societies in Germany (AWMF). Although the clinical application of ECMO/ECLS represents the main focus, the presented guideline also addresses structural and economic issues. Experts from 17 German, Austrian and Swiss scientific societies and a patients' organization, guided by the GSTCVS, completed the project in February 2021. In this report, we present a summary of the methodological concept and tables displaying the recommendations for each chapter of the guideline.

Case report: Infant with a Fast-growing Soft Tissue Tumor on the Thumb, Revealing a PLAG1-positive Connatal Lipoblastoma.

At the age of 4 months, an infant was presented to us with a nodular subcutaneous tumor on the right thumb measuring 2cm, already seen prenatally via ultrasound. An MRI in sedation performed at the age of 4.5 months had no diagnostic specificity. By a biopsy at the age of 5 months malignancy could be excluded. Finally at the age of 16 months the tumor which had meanwhile grown to a monstrous size (5 cm of diameter) could be entirely removed by microsurgical technique maintaining the integrity of all intrinsic structures. The diagnosis of myxoid lipoblastoma was confirmed. According to literature, Lipoblastomas often present as connatal rapid growing soft tissue tumors and are benign. Total removal is essential for avoiding a local recurrence.

Experience with Fully Covered Self-Expandable Metal Stents for Esophageal Leakage in Children.

BACKGROUND: There is a lack of experience with fully covered self-expandable metal stents (SEMSs) for the treatment of esophageal leakage particularly in infants and neonates. METHODS: Eight patients (5M, 3F) with a median age of 17 months (range, 1-135 months) who underwent treatment with SEMSs for an anastomotic leakage or perforation of the esophagus were recruited to this retrospective study. Four children were born premature. In six patients the stents were placed primarily as an emergency procedure. RESULTS: Median duration of individual stent placement was 42 days (range, 13-72 days). Six out of eight patients (75%) were treated with one stent only. In three preterm infants who had their stents inserted within the first month relative weight gain was 17% compared with 2% in five patients who were treated later in life (p=0.0986). In four cases (50%) distal migration of the stent was observed. Seven out of eight patients (88%) had their leakage resolved after stent therapy. CONCLUSIONS: Insertion of fully covered SEMSs is an alternative tool for the treatment of esophageal leakage in children and preterm infants, and successful with only one single application in selected cases. It can be used either following previous therapy or as part of an emergency procedure. Because of the absence of manufactured, age-related devices SEMSs that are originally designed for other organs can be applied.

Defining outcomes following congenital diaphragmatic hernia using standardised clinical assessment and management plan (SCAMP) methodology within the CDH EURO consortium.

Treatment modalities for neonates born with congenital diaphragmatic hernia (CDH) have greatly improved in recent times with a concomitant increase in survival. In 2008, CDH EURO consortium, a collaboration of a large volume of CDH centers in Western Europe, was established with a goal to standardize management and facilitate multicenter research. However, limited knowledge on long-term outcomes restricts the identification of optimal care pathways for CDH survivors in adolescence and adulthood. This review aimed to evaluate the current practice of long-term follow-up within the CDH EURO consortium centers, and to review the literature on long-term outcomes published from 2000 onward. Apart from having disease-specific morbidities, children with CDH are at risk for impaired neurodevelopmental problems and failure of educational attainments which may affect participation in society and the quality of life in later years. Thus, there is every reason to offer them long-term multidisciplinary follow-up programs. We discuss a proposed collaborative project using standardized clinical assessment and management plan (SCAMP) methodology to obtain uniform and standardized follow-up of CDH patients at an international level.

Thoracoscopic versus open repair of CDH in cardiovascular stable neonates.

BACKGROUND: Thoracoscopic surgery is an increasingly popular surgical technique to repair congenital diaphragmatic hernia (CDH). However, acidosis during surgery and the higher recurrence rate are considerable risk factors. The aim of this retrospective study is to compare the outcome of open versus thoracoscopic repair of the diaphragm in neonates with CDH with the same degree of cardiovascular and pulmonary illness who meet the criteria for thoracoscopic repair. METHODS: Retrospective analysis of all patients of two large national reference centers for CDH born in the years 2008 through 2012, and meeting the criteria for surgical repair on cardiopulmonary and physiological criteria according to the CDH EURO consortium consensus and meeting the criteria for thoracoscopic repair according to the review by Vijfhuize et al. The surgical technical aspects were comparable in both centers. RESULTS: 108 patients were included, of whom 75 underwent thoracoscopic repair and 34 underwent open repair. The gestational age and lung-to-head ratio were significantly lower and stay on the ICU significantly longer in the open-repair group. The operation time was longer (178 vs. 150 min, p = .012) and the recurrence rate higher (18.9 vs. 5.9 %, p = .036) in the thoracoscopic-repair group. The arterial pH, pO2, pCO2 and base excess before and after thoracoscopic repair were all significantly different. CONCLUSION: After critical selection for thoracoscopic repair of left-sided CDH based on the patient's preoperative condition, the outcomes of open repair were almost identical to those of thoracoscopic repair. A notable exception is the recurrence rate, which was significantly higher in the thoracoscopic-repair group. For the time being, thoracoscopic primary closure seems a safe and effective procedure, but efficacy of thoracoscopic patch repair has not been established.

The effect of intermittent intraabdominal pressure elevations and low cardiac output on the femoral to carotid arterial blood pressure difference in piglets.

BACKGROUND: Our previous work in a laparoscopic setting in piglets revealed that the systolic femoral artery pressure was approximately 5 % higher than its carotid counterpart, whereas the mean and diastolic values showed no significant difference. This remained idem when the intraabdominal pressure (IAP) was gradually increased. In this study, we aimed to investigate the effect of (1) intermittent IAP elevations and (2) a low cardiac output (CO) on the blood pressure (BP) difference cranially (carotid artery) and caudally (femoral artery) of a capnoperitoneum (ΔP = P a fem-P a carot). METHODS: A total of twenty-two piglets (mean body weight 11.0 kg; range 8.9-13.3 kg) were studied. Of these, 14 underwent intermittent IAP elevations at 8 and 16 mmHg, and ΔP was measured. In another 8 piglets, a model of reduced CO was created by introducing an air embolism (2 ml/kg over 30 s) in the inferior caval vein (VCI) at 12 mmHg IAP to further assess the influence of this variable on ΔP. RESULTS: Systolic ΔP remained at a mean of 5.6 mmHg and was not significantly affected by insufflation or exsufflation up to an IAP of 16 mmHg. Diastolic and mean values showed no differences between P a carot and P a fem. P a fem, systol remained higher than its carotid counterpart as long as the cardiac index (CI) was above 1.5 l/min/m2, but fell significantly below P a carot, systol at a low CI. There was no CO-dependent effect on diastolic and mean ΔP. Repeated IAP elevations do not significantly influence ΔP. CONCLUSIONS: Intermittent IAP elevations do not significantly influence ΔP. Despite of a CO-dependent inversion of systolic ΔP, mean BP measurements at the leg during laparoscopy remain representative even at low CO values.

The Surgical Treatment of Toxic Megacolon in Hirschsprung Disease.

OBJECTIVES: Enterocolitis remains the most significant cause of morbidity and mortality in Hirschsprung disease (HD). It could progress into toxic megacolon (TM)-acute dilatation of the colon as accompanying toxic complication of Hirschsprung enterocolitis. It is a devastating complication, especially in infants with so far undiagnosed HD. METHODS: A retrospective analysis of medical records of 4 infants with TM was performed. The diagnosis TM was determined on the basis of clinical information (abdominal pain or tenderness, abdominal distension, diarrhea, bloody diarrhea, and constipation), plain x-rays of the abdomen (segmental or total colonic dilation), and the presence of such criteria (fever, high heart rate, increased white blood cell count, C reactive protein, anemia, dehydration, electrolyte disturbances, hypotension). Surgical management and outcome was evaluated by retrospective chart review. RESULTS: The median duration of symptoms characteristic for TM was 3 days. Toxic megacolon was seen as the first manifestation of previously unknown HD in 3 patients; in 1 newborn, the contrast radiograph was suggestive of HD. In all patients, conservative treatment was failed. Three patients were treated with surgical decompression and ileostomy only. In all these cases, severe complications occurred, consequently 2 of them died. In 1 patient, a resection of the transverse dilated colon additionally was performed. This patient had no complications in postoperative period and survived. CONCLUSIONS: Because of the high mortality in patients with TM that were treated medically or with colonic decompression, a resection of massively distended part of the colon should be performed.