Long-Term Evaluation of the Shape of the Reconstructed Diaphragm in Patients with Left-Sided Congenital Diaphragmatic Hernia Using Serial Chest Radiographs and Correlation to Further Complications.

Background: Defining risk factors for long-term comorbidities in patients after neonatal repair of congenital diaphragmatic hernia (CDH) is an important cornerstone of the implementation of targeted longitudinal follow-up programs. Methods: This study systematically assessed serial chest radiographs of 89 patients with left-sided CDH throughout a mean follow-up of 8.2 years. These geometrical variables for the left and right side were recorded: diaphragmatic angle (LDA, RDA), diaphragmatic diameter (LDD, RDD), diaphragmatic height (LDH, RDH), diaphragmatic curvature index (LDCI, RDCI), lower lung diameter (LLLD, RLLD) and thoracic area (LTA, RTA). Results: It was demonstrated that the shape of the diaphragm in patients with large defects systematically differs from that of patients with small defects. Characteristically, patients with large defects present with a smaller LDCI (5.1 vs. 8.4, p < 0.001) at 6 months of age, which increases over time (11.4 vs. 7.0 at the age of 15.5 years, p = 0.727), representing a flattening of the patch and the attached rudimentary diaphragm as the child grows. Conclusions: Multiple variables during early follow-up were significantly associated with comorbidities such as recurrence, scoliotic curves of the spine and a reduced thoracic area. Some geometrical variables may serve as surrogate parameters for disease severity, which is associated with long-term comorbidities.

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.

Impact of cryopreservation on viability, gene expression and function of enteric nervous system derived neurospheres.

Introduction: Impairment of both the central and peripheral nervous system is a major cause of mortality and disability. It varies from an affection of the brain to various types of enteric dysganglionosis. Congenital enteric dysganglionosis is characterized by the local absence of intrinsic innervation due to deficits in either migration, proliferation or differentiation of neural stem cells. Despite surgery, children's quality of life is reduced. Neural stem cell transplantation seems a promising therapeutic approach, requiring huge amounts of cells and multiple approaches to fully colonize the diseased areas completely. A combination of successful expansion and storage of neural stem cells is needed until a sufficient amount of cells is generated. This must be combined with suitable cell transplantation strategies, that cover all the area affected. Cryopreservation provides the possibility to store cells for long time, unfortunately with side effects, i.e., upon vitality. Methods: In this study we investigate the impact of different freezing and thawing protocols (M1-M4) upon enteric neural stem cell survival, protein and gene expression, and cell function. Results: Freezing enteric nervous system derived neurospheres (ENSdN) following slow-freezing protocols (M1-3) resulted in higher survival rates than flash-freezing (M4). RNA expression profiles were least affected by freezing protocols M1/2, whereas the protein expression of ENSdN remained unchanged after treatment with protocol M1 only. Cells treated with the most promising freezing protocol (M1, slow freezing in fetal calf serum plus 10% DMSO) were subsequently investigated using single-cell calcium imaging. Freezing of ENSdN did not alter the increase in intracellular calcium in response to a specific set of stimuli. Single cells could be assigned to functional subgroups according to response patterns and a significant shift towards cells responding to nicotine was observed after freezing. Discussion: The results demonstrate that cryopreservation of ENSdN is possible with reduced viability, only slight changes in protein/gene expression patterns and without an impact on the neuronal function of different enteric nervous system cell subtypes, with the exception of a subtle upregulation of cells expressing nicotinergic acetylcholine receptors. In summary, cryopreservation presents a good method to store sufficient amounts of enteric neural stem cells without neuronal impairment, in order to enable subsequent transplantation of cells into compromised tissues.

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.

Use of Temporary Double-J Stent Placement for Children With Congenital Hydronephrosis: A Long-Term Single-Center Cohort Study.

OBJECTIVE: To evaluate the utilization of double-J stents in children with congenital hydronephrosis in order to avoid or postpone more invasive surgical intervention. Numerous studies have demonstrated that congenital hydronephrosis caused by ureteropelvic junction obstruction (UPJO) or primary obstructive megaureter (POM) may require a surgical correction in up to 20% of cases. METHODS: All infants with severe hydronephrosis and/or an obstructive pattern on renal scintigraphy that received double-J stent placement between 2010 to 2015 in our center were analyzed. Children were followed regularly with ultrasound and received antibiotic metaphylaxis. Urinary tract infection (UTI) and double-J dislocation were defined as complications. Treatment success was defined as avoidance of surgery and reduction of hydronephrosis to grade 1 or 0 during the observation period. RESULTS: 29 children were included, in these, 34 (23 UPJO, 7 POM, 4 UPJO and POM) treatment attempts were performed. Stent implantation failed in six cases, resulting in 28 double-J stent treatments, of which 19 (69%) were successful within the follow-up period of 20 to 104 months. The most common complications were febrile UTI in 6 of29 cases and double-J dislocation in 3 of 29 cases. CONCLUSION: During the observation period, the success rate of temporary double-J in urodynamically relevant obstruction was relatively high. However, urinary tract infections and a complex disease course due to renal stent dislocation, as well as the need for repeated anesthesia and radiation exposure, should be taken into account. Hence, we do not recommend double-J stents placement in all children with congenital hydronephrosis; it may be useful in selected cases.

[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.

Long-Term Evaluation of Gastroesophageal Reflux in Neonates with and without Preventive Anti-reflux Surgery at the Time of Congenital Diaphragmatic Hernia Repair.

One potential comorbidity after congenital diaphragmatic hernia (CDH) is gastroesophageal reflux (GER), which can have a substantial effect on patients' quality of life, thriving, and complications later in life. Efforts have been made to reduce gastroesophageal reflux with a preventive anti-reflux procedure at the time of CDH repair. In this follow-up study of neonates participating in a primary RCT study on preventive anti-reflux surgery, symptoms of GER were assessed longitudinally. Long-term data with a median follow-up time of ten years was available in 66 patients. Thirty-one neonates received an initial fundoplication. Secondary anti-reflux surgery was necessary in 18% and only in patients with large defects. It was required significantly more often in patients with intrathoracic herniation of liver (p = 0.015) and stomach (p = 0.019) and patch repair (p = 0.03). Liver herniation was the only independent risk factor identified in multivariate regression analysis. Primary fundopexy and hemifundoplication did not reveal a protective effect regarding the occurrence of GER symptoms, the need for secondary antireflux surgery or the gain of body weight regardless of defect size neither in the short nor in the long term. Symptoms of GER must be assessed carefully especially in children with large defects, as these are prone to require secondary anti-reflux surgery in the long-term. Routine evaluation of GER including endoscopy and impedance measurement should be recommended especially for high-risk patients.

The Management of Asymptomatic Congenital Pulmonary Airway Malformation: Results of a European Delphi Survey.

Consensus on the optimal management of asymptomatic congenital pulmonary airway malformation (CPAM) is lacking, and comparison between studies remains difficult due to a large variety in outcome measures. We aimed to define a core outcome set (COS) for pediatric patients with an asymptomatic CPAM. An online, three-round Delphi survey was conducted in two stakeholder groups of specialized caregivers (surgeons and non-surgeons) in various European centers. Proposed outcome parameters were scored according to level of importance, and the final COS was established through consensus. A total of 55 participants (33 surgeons, 22 non-surgeons) from 28 centers in 13 European countries completed the three rounds and rated 43 outcome parameters. The final COS comprises seven outcome parameters: respiratory insufficiency, surgical complications, mass effect/mediastinal shift (at three time-points) and multifocal disease (at two time-points). The seven outcome parameters included in the final COS reflect the diversity in priorities among this large group of European participants. However, we recommend the incorporation of these outcome parameters in the design of future studies, as they describe measurable and validated outcomes as well as the accepted age at measurement.

Small Bowel Obstruction After Neonatal Repair of Congenital Diaphragmatic Hernia-Incidence and Risk-Factors Identified in a Large Longitudinal Cohort-Study.

Objective: In patients with a congenital diaphragmatic hernia (CDH), postoperative small bowel obstruction (SBO) is a life-threatening event. Literature reports an incidence of SBO of 20% and an association with patch repair and ECMO treatment. Adhesions develop due to peritoneal damage and underly various biochemical and cellular processes. This longitudinal cohort study is aimed at identifying the incidence of SBO and the risk factors of surgical, pre-, and postoperative treatment. Methods: We evaluated all consecutive CDH survivors born between January 2009 and December 2017 participating in our prospective long-term follow-up program with a standardized protocol. Results: A total of 337 patients were included, with a median follow-up of 4 years. SBO with various underlying causes was observed in 38 patients (11.3%) and significantly more often after open surgery (OS). The majority of SBOs required surgical intervention (92%). Adhesive SBO (ASBO) was detected as the leading cause in 17 of 28 patients, in whom surgical reports were available. Duration of chest tube insertion [odds ratio (OR) 1.22; 95% CI 1.01-1.46, p = 0.04] was identified as an independent predictor for ASBO in multivariate analysis. Beyond the cut-off value of 16 days, the incidence of serous effusion and chylothorax was higher in patients with ASBO (ASBO/non-SBO: 2/10 vs. 3/139 serous effusion, p = 0.04; 2/10 vs. 13/139 chylothorax, p = 0.27). Type of diaphragmatic reconstruction, abdominal wall closure, or ECMO treatment showed no significant association with ASBO. A protective effect of one or more re-operations has been detected (RR 0.16; 95% CI 0.02-1.17; p = 0.049). Conclusion: Thoracoscopic CDH repair significantly lowers the risk of SBO; however, not every patient is suitable for this approach. GoreTex®-patches do not seem to affect the development of ASBO, while median laparotomy might be more favorable than a subcostal incision. Neonates produce more proinflammatory cytokines and have a reduced anti-inflammatory capacity, which may contribute to the higher incidence of ASBO in patients with a longer duration of chest tube insertion, serous effusion, chylothorax, and to the protective effect of re-operations. In the future, novel therapeutic strategies based on a better understanding of the biochemical and cellular processes involved in the pathophysiology of adhesion formation might contribute to a reduction of peritoneal adhesions and their associated morbidity and mortality.

Relationship between volume and outcome for gastroschisis: A systematic review.

BACKGROUND: Newborns with gastroschisis need surgery to reduce intestines into the abdominal cavity and to close the abdominal wall. Due to an existing volume-outcome relationship for other high-risk, low-volume procedures, we aimed at examining the relationship between hospital or surgeon volume and outcomes for gastroschisis. METHODS: We conducted a systematic literature search in Medline, Embase, CENTRAL, CINAHL and Biosis Previews in June 2021 and searched for additional literature. We included (cluster-) randomized controlled trials (RCTs) and prospective or retrospective cohort studies analyzing the relationship between hospital or surgeon volume and mortality, morbidity or quality of life. We assessed risk of bias of included studies using ROBINS-I and performed a systematic synthesis without meta-analysis and used GRADE for assessing the certainty of the evidence. RESULTS: We included 12 cohort studies on hospital volume. Higher hospital volume may reduce in-hospital mortality of neonates with gastroschisis, while the evidence is very uncertain for other outcomes. Findings are based on a low certainty of the evidence for in-hospital mortality and a very low certainty of the evidence for all other analyzed outcomes, mainly due to risk of bias and imprecision. We did not identify any study on surgeon volume. CONCLUSION: The evidence suggests that higher hospital volume reduces in-hospital mortality of newborns with gastroschisis. However, the magnitude of this effect seems to be heterogeneous and results should be interpreted with caution. There is no evidence on the relationship between surgeon volume and outcomes.

Recurrence of Congenital Diaphragmatic Hernia: Risk Factors, Management, and Future Perspectives.

Recurrence is one of the most common surgical complications in Congenital Diaphragmatic Hernia (CDH). It could remain clinically silent for a long time or present as an acute complication week, months, or even years after the primary surgery. Several risk factors have been identified so far. An extended diaphragmatic defect represents one of the leading independent risk factors, together with indirect signs of large defect such as the liver position related to the diaphragm and the use of the prosthetic patch and with the use of a minimally invasive surgical (MIS) approach. However, the exact contribution of each factor and the overall risk of recurrence during the life span still need to be fully understood. This mini-review aims to give an overview of the current knowledge regarding CDH recurrence, focusing on predisposing factors, clinical presentation, management and follow-up of high-risk patients, and future perspectives.

Operative Volume of Newborn Surgery in German University Hospitals: High Volume Versus Low Volume Centers.

INTRODUCTION: Adequate patient volume is essential for the maintenance of quality, meaningful research, and training of the next generation of pediatric surgeons. The role of university hospitals is to fulfill these tasks at the highest possible level. Due to decentralization of pediatric surgical care during the last decades, there is a trend toward reduction of operative caseloads. The aim of this study was to assess the operative volume of the most relevant congenital malformations at German academic pediatric surgical institutions over the past years. METHODS: Nineteen chairpersons representing university-chairs in pediatric surgery in Germany submitted data on 10 index procedures regarding congenital malformations or neonatal abdominal emergencies over a 3-year period (2015 through 2017). All institutions were categorized according to the total number of respective cases into "high," "medium," and "low" volume centers by terciles. Some operative numbers were verified using data from health insurance companies, when available. Finally, the ratio of cumulative case load versus prevalence of the particular malformation was calculated for the study period. RESULTS: From 2015 through 2017, a total 2,162 newborns underwent surgery for congenital malformations and neonatal abdominal emergencies at German academic medical centers, representing 51% of all expected newborn cases nationwide. The median of cases per center within the study period was 101 (range 18-258). Four institutions (21%) were classified as "high volume" centers, four (21%) as "medium volume" centers, and 11 (58%) as "low volume" centers. The proportion of patients operated on in high-volume centers varied per disease category: esophageal atresia/tracheoesophageal fistula: 40%, duodenal atresia: 40%, small and large bowel atresia: 39%, anorectal malformations: 40%, congenital diaphragmatic hernia: 56%, gastroschisis: 39%, omphalocele: 41%, Hirschsprung disease: 45%, posterior urethral valves: 39%, and necrotizing enterocolitis (NEC)/focal intestinal perforation (FIP)/gastric perforation (GP): 45%. CONCLUSION: This study provides a national benchmark for neonatal surgery performed in German university hospitals. The rarity of these cases highlights the difficulties for individual pediatric surgeons to gain adequate clinical and surgical experience and research capabilities. Therefore, a discussion on the centralization of care for these rare entities is necessary.

Application of bacterial nanocellulose-based wound dressings in the management of thermal injuries: Experience in 92 children.

BACKGROUND: Management of pediatric thermal injuries involves a high standard of care in a multidisciplinary setting. To avoid physical and psychological sequelae, wound dressings should minimize hospitalization time and anesthesia while maximizing patient comfort. PATIENTS AND METHODS: 190 children with thermal injuries of the torso, arms and legs were treated with polyurethane foam dressings or bacterial nanocellulose sheets. Data were analyzed retrospectively regarding hospitalization, procedures with general anesthesia, scar formation, rate of infection and need for skin grafting. RESULTS: The groups did not differ significantly concerning age, gender distribution or percentage of injured total body surface area. Statistical analysis showed that length of hospitalized care and procedures undergoing anesthesia were significantly reduced in the nanocellulose group (each p < 0.0001). There was no significant difference in rate of complications, wound healing and rate of skin grafting between the two subgroups. DISCUSSION: Acting as a temporary epidermal substitute, bacterial nanocellulose enables undisturbed reepithelialization without further wound dressing changes. In children, no additional topical antimicrobial agents are indicated for unimpaired wound healing. CONCLUSIONS: Bacterial nanocellulose is superior to polyurethane foam regarding length of hospitalization and number of interventions under anesthesia. It offers a safe, cost-effective treatment option and provides excellent comfort in pediatric patients.

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.

Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure -A clinical practice Guideline Level 3.

Aims Worldwide applications of extracorporeal circulation for mechanical support in cardiac and circulatory failure, which are referred to as extracorporeal life support (ECLS) or veno-arterial extracorporeal membrane oxygenation (va-ECMO), have dramatically increased over the past decade. In spite of the expanding use and the immense medical as well as socio-economic impact of this therapeutic approach, there has been a lack of interdisciplinary recommendations considering the best available evidence for ECLS treatment. Methods and Results In a multiprofessional, interdisciplinary scientific effort of all scientific societies involved in the treatment of patients with acute cardiac and circulatory failure, the first evidence- and expert consensus-based guideline (level S3) on ECLS/ECMO therapy was developed in a structured approach under regulations of the AWMF (Association of the Scientific Medical Societies in Germany) and under use of GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. This article presents all recommendations created by the expert panel, addressing a multitude of aspects for ECLS initiation, continuation, weaning and aftercare as well as structural and personnel requirements. Conclusions This first evidence- and expert consensus-based guideline (level S3) on ECLS/ECMO therapy should be used to apply the best available care nationwide. Beyond clinical practice advice, remaining important research aspects for future scientific efforts are formulated.

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 .