ERNICA Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis

Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis Anna L €of Granstr €om a, b, *, Willemijn Irvine c, Anders Telle Hoel d, Merit Tabbers e, Kristiina Kyrklund f, Francesco Fascetti-Leon g, h, Fabio Fusaro i, Nikhil Thapar j, k, l, m, Anne Dariel n, Cornelius E.J. Sloots o, Marc Miserez p, Annette Lemli q, Sabine Alexander q, Cecile Lambe r,C /C19elia Cr /C19etolle s, Niels Qvist t, Nagoud Schukfeh u, Martin Lacher v, Duccio Cavalieri w, Ernst van Heurn x, y, z, Rony Sfeir aa, Mikko P. Pakarinen a, f, Kristin Bjørnland d, Tomas Wester a, b a Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden b Unit of Pediatric Surgery, Karolinska University Hospital, Stockholm, Sweden c Department of Evidence Based Medicine and Methodology, Qualicura Healthcare Support Agency, Breda, the Netherlands d Department of Pediatric Surgery, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway e Emma Children's Hospital - Amsterdam University Medical Centers, Amsterdam, the Netherlands f Section of Pediatric Surgery, New Children's Hospital, University of Helsinki, Finland g University of Padua, Department of Women's and Children's Health, Padua, Italy h University Hospital, Unit of Pediatric Surgery, Division of Women's and Children's Health, Padua, Italy i Neonatal Surgery Unit, Bambino Gesù Children's Research Hospital, Rome, Italy j Stem Cell and Regenerative Medicine, Gos Institute of Child Health, University College London, London, UK k Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Australia l School of Medicine, University of Queensland, Brisbane, Australia m Woolworths Centre for Child Nutrition Research, Queensland University of Technology, Brisbane, Australia n Department of Pediatric Surgery, Assistance Publique Des H ^opitaux De Marseille, H ^opital Timone Enfants, Marseille, France o Department of Pediatric Surgery, Erasmus Mc e Sophia Children's Hospital, Rotterdam, the Netherlands p Department of Abdominal Surgery, University Hospital Gasthuisberg, Ku Leuven, Belgium q Soma, The German Patient Support Organization for Anorectal Malformations and Hirschsprung Disease, Munich, Germany r Service De Gastro-Ent /C19erologie Et Nutrition P /C19ediatrique, H ^opital Necker-Enfants Malades, Universit /C19e Paris Cit /C19e, Paris, France s Pediatric Surgery Department, National Reference Center for Ano Rectal Malformations and Rare Pelvic Anomalies Marep, Assistance Publique-H ^opitaux De Paris, Universit /C19e Paris Cit /C19e, Paris, France t Research Unit for Surgery, And Centre of Excellence in Gastrointestinal Diseases and Malformations in Infancy and Childhood (Gain), Odense Univers ity Hospital, Odense Denmark, University of Southern Denmark, Odense, Denmark u Hannover Medical School, Department of Pediatric Surgery, Carl-Neuberg-Straße 1, 30625, Hannover, Germany v Department of Pediatric Surgery, University of Leipzig, Germany w Department of Biology, University of Florence and Associazione Famiglie Pazienti Morbo Di Hirschprung (Amorhi), Italy x Department of Paediatric Surgery, Amsterdam University Medical Centres, the Netherlands y Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute, Amsterdam, the Netherlands z Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands aa Department of Pediatric Surgery, Jeanne De Flandre Hospital, Lille, France article info Article history: Received 21 February 2024 Received in revised form 17 April 2024 Accepted 23 April 2024 Keywords: Hirschsprung’s disease Total colonic aganglionosis Poor bowel function abstract Background: Hirschsprung disease is a congenital intestinal motility disorder characterized by an absence of enteric ganglion cells. Total colonic aganglionosis and near total or total intestinal agan- glionosis, defined as absence of ganglion cells in the entire colon and with variable length of small bowel involved, are life-threatening conditions which affect less than 10 % of all patients with Hirschsprung disease. The aim of this project was to develop clinical consensus statements within ERNICA, the Eu- ropean Reference Network for rare congenital digestive diseases, on four major topics: Surgical treatment of total colonic aganglionosis, surgical treatment of total intestinal aganglionosis, management of poor bowel function in total colonic and/or intestinal aganglionosis and long-term management in total colonic and or intestinal aganglionosis. * Corresponding author. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. E-mail address: anna.lof@ki.se (A.L. Granstr €om). Contents lists available at ScienceDirect Journal of Pediatric Surgery journal homepage: www.sciencedirect.com/journal/ journal-of-pediatric-surgery https://doi.org/10.1016/j.jpedsurg.2024.04.019 0022-3468/© 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/). Journal of Pediatric Surgery xxx (xxxx) xxx Please cite this article as: Granstr €om AL et al., Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2024.04.019 Surgical treatment Long-term management Methods: A multidisciplinary panel of representatives from ERNICA centers was invited to participate. Literature was searched, using speci fied search terms, in Medline (ALL), Embase and Google Scholar. Abstracts were screened and full text publications were selected. The panel was divided in four groups that extracted data from the full text publications and suggested draft statements for each of the major topics. A modi fied Delphi process was used to re fine and agree on the statements. Results: The consensus statement was conducted by a multidisciplinary panel of 24 participants from 10 European countries, 45 statements reached consensus after 3 Delphi-rounds. The availability of high- quality clinical evidence was limited, and most statements were based on expert opinion. Another 25 statements did not reach consensus. Conclusions: Total colonic and total intestinal aganglionosis are rare variants of Hirschsprung disease, with very limited availability of high-quality clinical evidence. This consensus statement provides statements on the surgical treatment, management of poor bowel function and long-term management for these rare patients. The expert panel agreed that patients bene fit from multidisciplinary and personalized care, preferably in an expert center. Type of Study: Clinical consensus statement. Level of Evidence: 3a. © 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Background Hirschsprung disease (HSCR) is a congenital intestinal motility disorder characterized by an absence of enteric ganglion cells. It is a developmental defect of the enteric nervous system caused by incomplete migration, proliferation, differentiation, and survival of enteric nervous system progenitors. The birth prevalence is 1 in 5000 living newborns [ 1]. Total colonic aganglionosis (TCA) af- fects less than 10 % of all patients with HSCR and is de fined as the absence of ganglion cells in the entire colon extending into the distal ileum up to 50 cm from the ileocaecal valve [ 2,3]. The most severe form of aganglionosis is near total, with aganglionosis extending up to 50 e100 cm from the ileo-caecal valve or total intestinal aganglionosis (TIA) with less than 50 cm of ganglionic segment from the Treitz ligament [ 4,5]. TCA is a life-threatening condition with an overall mortality rate of 2 e20 % due to Hirschsprung-associated enterocolitis (HAEC), intestinal failure, or associated genetic syndromes [ 2,3,6]. TCA remains a chal- lenging surgical condition despite recent advances in surgical techniques and pre- and post-operative care. To address healthcare inequalities and ensure delivery of high- quality care for patients with rare and complex diseases, the Eu- ropean Union (EU) initiated European Reference Networks (ERNs) [7]. ERNICA is the ERN for rare inherited and congenital digestive disorders, including HSCR. ERNICA guidelines for management of rectosigmoid HSCR were recently published [ 8]. However, TCA and TIA require a different approach in various aspects of care as compared to HSCR and specific TCA and TIA clinical decision support is missing. For TCA and TIA, there is a lack of high-level evidence. Therefore, the aim of this paper was to develop clinical consensus statements on four major topics: Surgical treatment of TCA, surgical treatment of TIA, management of poor bowel function in TCA or TIA and long-term management in TCA or TIA. A clinical consensus statement re flects opinions, drafted by content experts, for which consensus is sought using explicit methodology to identify areas of agreement and disagreement. In contrast to clinical practice guidelines, which are based primarily on high-level evidence, clinical consensus statements are more applicable to situations where evidence is limited or lacking, yet there are still opportunities to reduce uncertainty and improve quality of care. 2. Materials and methods 2.1. Panel For this consensus statement, a multidisciplinary panel was sought amongst ERNICA members of the intestinal diseases work- ing group. In total, 24 participants originating from 10 European countries participated in the consensus panel. Amongst the 24 panel members were three pediatric gastroenterologists, three patient representatives (one of whom is also a microbiologist) and 17 pediatric surgeons. The panel was supported by a methodologist throughout the entire project. 2.2. Literature search and selection At the start of the project, a literature search was conducted by a professional information specialist. The aim of the search was identification of relevant literature on the (surgical) treatment and follow up of children with TCA or TIA published between 2006 and January 2022. Initially the main search terms were ‘total colonic aganglionosis’, ‘hirschsprung’ and related terms and combinations, later on ‘intestinal aganglionosis ’ was added. The search was con- ducted in databased Medline (ALL), Embase and Google Scholar. After removal of duplicates all publications (n ¼ 1004) were screened for title and abstract. The first screening was done by a pediatric surgeon (ALG) and a methodologist (WI). Both screened all results based on title and abstract using the systematic review app Rayyan © and identi fied useful publications according to the inclusion criteria displayed in Table 1. After completing the screening of all titles and abstracts decision discrepancies were discussed. After the first screening round, two pediatric surgeons (ALG, AHT) screened the included publications and categorized them to the four major topics: Surgical treatment of TCA, surgical treatment of TIA, investigation and management of poor bowel function in TCA or TIA and long-term follow up in TCA or TIA, including organization of care. Some publications could be categorized to more than one topic. Any results that did not match A.L. Granstr €om, W. Irvine, A.T. Hoel et al. / Journal of Pediatric Surgery xxx (xxxx) xxx2 Please cite this article as: Granstr €om AL et al., Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2024.04.019 one of these preselected topics were excluded in the second screening round. Prisma table over the literature search is shown in Fig. 1. 2.3. Data extraction The panel was divided into four subgroups, each covering one of the four topics. Each group received electronic full-text versions of each article that was included for their topic. Panel members used spreadsheets to summarize the included literature for their topic and registered study design, study aim and intervention, type of patients, summary of the outcomes, the level of evidence and a suggestion for a statement to enter the Delphi process based on the publication's conclusion [ 9]. Fig. 1. Prisma chart of the literature search. Table 1 Inclusion criteria of publications on treatment and follow up of children with TCA or TIA prior to the Delphi process of this consensus statement. Patients Patients with TCA or TIA Intervention Any surgical, non-surgical or pharmacological treatment Comparison Any comparison Outcome Any outcome Study design /C15 Randomized controlled trials /C15 Cohort studies /C15 Case-control studies /C15 Case series /C15 Meta-analyses /C15 Guidelines /C15 Reviews Timeline 2006 e2022 Language English A.L. Granstr €om, W. Irvine, A.T. Hoel et al. / Journal of Pediatric Surgery xxx (xxxx) xxx 3 Please cite this article as: Granstr €om AL et al., Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2024.04.019 2.4. Delphi method For this clinical consensus statement, a modi fied Delphi method was used. The Delphi method is a systematic approach to identify consensus among a group of experts and is recommended by the European Reference Network methodology handbooks as a method for formal consensus in case of large ( >12 experts) panels that are geographically dispersed [10]. The panel composed an initial list of statements formulated as statements of fact, rather than state- ments of action. The initial list consisted of statements derived from the included literature, supplemented with statements based on expert opinion. Panel members were asked to complete 3 surveys each using a 9-point Likert scale to measure agreement, where 1 corresponds to ‘completely disagree ’ and 9 to ‘completely agree ’ [11]. For every statement there was the possibility to select ‘not voting’ if a panel member felt that the topic was outside their field of expertise. Consensus criteria as displayed in Table 2 were agreed upon before voting. After each round a group discussion was organized where statements with a near or no consensus were discussed to deter- mine whether they should be re fined and revoted or omitted completely. These discussions provided panel members with the opportunity to explain their vote to the rest of the panel and listen to the motivation of others. If a statement was refined and entered a new survey, the initial statement as well as the score from the previous round was added to the survey information. Each of the surveys contained comment boxes to allow panel members to provide an immediate rationale that enhanced the discussions. An overview of the process to create this clinical consensus statement is displayed in Fig. 2 . 3. Results 3.1. Delphi process After screening the 1004 publications for the title and abstract, 98 publications were included for full text evaluation. Based on the literature and a group discussion during the ERNICA meeting in Helsinki, 68 statements were created to enter the Delphi process. After the first round, consensus was reached for 34 statements. A total of 21 statements with no or near consensus were reworded or clarified, the remaining 13 were omitted. One statement was split into 3 more speci fic statements and statements 12 and 52 were added. 26 statements entered the second Delphi round, resulting in an additional 1 1 statements for which consensus could be reached. Four statements with a near-consensus score (1 1, 14, 37 and 48) were re-worded and entered a final third round. This resulted in consensus for only one of these statements. After 3 rounds the panel reached consensus on 45 statements, and the key informa- tion for these consensus statements is summarized below. An overview of the Delphi process is displayed in Fig. 3. 3.2. Key statements In total 45 statements reached consensus after the Delphi sur- veys (Table 3). They were subcategorized into the four major topics: Surgical treatment of TCA, surgical treatment of (near) TIA, poor bowel function and long-term follow up, including organization of care. 3.2.1. Surgical management of TCA and (near) TIA Since TCA is a rare disease, an expert center should be involved in the evaluation and management of a patient with TCA (State- ment 12). Due to differences between health care systems in Eu- ropean countries, the exact de finition of an expert center is problematic, but the panel agreed that an expert center should offer multidisciplinary care by a complete team including pediatric surgeon, pediatric gastroenterologist or specialized pediatrician, nurses, dietician, pathologist and psychologist, as previously described by Kyrklund et al. [ 8]. For patients with suspected or verified (near) TIA, the panel agreed that early referral to an expert intestinal rehabilitation center may prevent complications related to long-term parenteral nutrition dependence (Statement 16) [2,5,12e22], and promote timely listing for small bowel trans- plantation if needed [ 23]. At initial surgery, intraoperative representative mapping bi- opsies are needed to determine the level of aganglionosis and appropriate level to form a stoma. This may optimize positioning of a stoma and prevent stoma revisions (Statement 5 and 13) [14,15,24e28]. Representative histological intestinal mapping in- cludes multi-level biopsies starting from the rectum and continuing orally beyond the level where the pathologist reports ganglion cells. A 360-degree biopsy is recommended at the most distal part of the ganglionic bowel, usually at the level of the stoma. The mapping biopsies should be performed prior to pull-through surgery to con firm the diagnosis and allow for an adequately per- formed pull-through of normally gangliated bowel. Due to a lack of evidence no unambiguous expert opinion was reached regarding whether one speci fic pull-through procedure is preferable over others. The panel therefore concurred that the pull- through technique should be chosen based on the experience of the operating surgeon (Statement 3) [ 29,30]. It may be considered to leave a covering stoma after the reconstruction in selected patients (Statement 4), particularly patients undergoing ileo-anal J-pouch anastomosis, neonates, syndromic patients, or patients in subop- timal general condition [29]. The panel failed to reach consensus on timing for surgical reconstruction but agreed that the optimal timing of de finitive pull-through depends on the length of the aganglionic segment, stoma output, the patients' age, and the caregivers’ preferences (Statement 1 1). Remaining diverted bowel may increase the risk of enterocolitis and therefore timely removal can be bene ficial (Statement 17) [ 14]. 3.2.2. Poor bowel function after pull-through surgery To accurately treat patients with poor bowel function, the panel agreed that diagnosing the underlying cause of fecal incontinence and, or obstructive symptoms provides important information to guide the treatment strategy (Statement 24). In addition to clinical examination of a patient with fecal incontinence and, or, obstruc- tive symptoms, investigations should include imaging, examination under general anesthesia, re-biopsies as well as endoscopic ex- amination to exclude surgical complications (twisted pull-through, transition zone or stenosis) as appropriate. It may also be helpful to include a pediatric gastroenterologist or specialized pediatrician to rule out other gastro-intestinal causes. Patients with a damaged anal canal are at higher risk of fecal incontinence (Statement 23) [8,31]. The panel agreed that plain abdominal radiographs and contrast enema are appropriate to diagnose bowel dilation or twisted pull-through (Statement 19) but MRI could also be indi- cated in selected cases. In patients with dysmotility, full thickness small bowel biopsies may be indicated to exclude remaining Table 2 Consensus criteria of statements voted on during the Delphi process. Category Mean Score Outliers a Consensus /C21 7.00 and /C20 1 Near consensus /C21 6.50 and /C20 2 No consensus <6.50 or /C21 3 a >2 from the mean in each direction. A.L. Granstr €om, W. Irvine, A.T. Hoel et al. / Journal of Pediatric Surgery xxx (xxxx) xxx4 Please cite this article as: Granstr €om AL et al., Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2024.04.019 aganglionosis or other causes of dysmotility (Statement 22). Obtaining a second opinion by another experienced pathologist may be helpful. For patients with diarrhea, loperamide (Statement 28) and cholestyramine can be used (Statement 31) although there is little evidence for their ef ficacy, especially for patients without a colon. Treatment with loperamide should be evaluated every two weeks to weigh beneficial effect against side effects [8,32]. In patients with diarrhea, sodium chloride supplementation may be needed to prevent hyponatremia, based on the dosage of sodium/potassium ratio on a single micturition (which must be > 1) (Statement 33). If a patient does not pass stools for 24 h or has signs of HAEC, treat- ment with loperamide is no longer indicated and should be stopped (Statement 29). As per loperamide, the use of Cholestyramine should be evaluated every two weeks and may continue long-term if monitoring for any deficiencies of fat-soluble vitamins is ensured. By binding bile acids and reducing their osmotic effect, cholestyr- amine may also have a bene ficial effect on perineal rash. For suspected small bowel bacterial overgrowth, single courses or cyclic use of broad-spectrum antibiotics may be considered ensuring that HAEC has been excluded (Statement 38). This treat- ment is indicated in exceptional circumstances and after carefully considering other medical and surgical causes and treatment op- tions [ 33]. Patients with outlet obstruction and HAEC may bene fit from decompression with a transanal tube (Statement 43) [ 34]. Based on current evidence, the role of probiotics to prevent HAEC is unclear (Statement 39) [ 35,36]. For patients with poor bowel function and intractable fecal in- continence or diarrhea, an ileostomy can be considered (Statement 35). The panel agreed that it is necessary to involve patients and parents in discussions regarding this decision. In cases with persistent obstructive symptoms and recurrent HAEC, redo pull- through may be considered (Statement 46) [ 29]. Before proceeding with a redo procedure, a thorough investigation including a pa- thology review is needed, to rule out residual aganglionsis and other options (Statement 7). 3.2.3. Long-term follow up and organization of care The long-term management of TCA can be challenging. There- fore, the panel agreed that patients bene fit from long-term man- agement and follow-up by a multidisciplinary team (Statement 52). Like other ERNs, ERNICA also offers consultation of expert panels for such ultra-rare cases. Regular follow-up is an effective approach that may improve long-term outcomes (Statement 47) [ 3,34], as it can help to improve residual symptoms and identify complications early. Close monitoring with personalized management of growth- and bowel function is required (Statement 49) [ 37]. Treatment and follow-up in an expert center may reduce mortality and morbidity (Statement 51) [ 3,8]. The regular follow-up in an expert center is important for these patients, but the frequency needs to be personalized for each patient depending on the length and function of the remaining bowel, nutritional status, and comorbidities. To avoid delayed discovery of clinical issues that could have been addressed at an early stage, regular check-ups remain of great importance even if patients are doing well. More speci fically, monitoring of growth (Statement 53) as well as fluid and electrolytes in blood and urine provides important information regarding the intestinal nutrient uptake (Statement 54) [ 38]. Growth should be monitored with standardized growth charts (Statement 61). The monitoring of sodium in urine is espe- cially important in patients with TCA (Statement 55). Optimal so- dium balance is defined as UeNa >30 mmol/l and, or UeNa/UeK/C21 1 Fig. 2. Workflow for the development of this consensus statement. A.L. Granstr €om, W. Irvine, A.T. Hoel et al. / Journal of Pediatric Surgery xxx (xxxx) xxx 5 Please cite this article as: Granstr €om AL et al., Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2024.04.019 (Statement 56) [ 39]. The monitoring of vitamins also provides important information in the follow-up of patients as well (State- ment 57) and the panel agreed that patients bene fit from being regularly reviewed by a dietitian (Statement 60). Regular moni- toring was dif ficult for the panel to de fine, but they agreed that closer monitoring, is always indicated when a patient has signs or symptoms of fluid imbalance (Statement 59). Children with less than 80 cm of remaining small bowel may have a poorer chance to wean off parenteral nutrition (Statement 62). It is important to keep the balance between benefits and harms of parenteral nutrition and avoid excessive enteral feeding [ 14]. For patients with home parenteral nutrition, the panel agreed to recommend the ESPGHAN guidelines for monitoring (Statement 63) and that referral to a center with home parenteral nutrition team is warranted if patients still depend on parenteral nutrition by the age of transition of care (Statement 64) [ 23]. Panel members agreed that patients and parents should be offered referral for genetic consultation (Statement 66). RET gene mutation analysis is bene ficial for the exclusion of the rare possi- bility of MEN 2A associated mutations (Statement 65). Patients with associated syndromes may be referred for more speci fic ge- netic screening (Statement 67). Since genetic testing is evolving rapidly, genetic counseling is essential but only if approved by the family. The panel uniformly agreed that patients bene fit from a stan- dardized transition program from pediatric to adult care (State- ment 50). The positive impact of a structured transition to adult care has previously been shown for patients with HSCR and espe- cially for patients with TCA at risk of nutritional de ficiencies. The transition of care is important for future monitoring and treatment [3,8,40]. Overall, the assessment of the literature indicates that TCA is a drastically more severe condition with respect to short segment Fig. 3. Delphi process. A.L. Granstr €om, W. Irvine, A.T. Hoel et al. / Journal of Pediatric Surgery xxx (xxxx) xxx6 Please cite this article as: Granstr €om AL et al., Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2024.04.019 Table 3 Consented statements for TCA. Consensus statements on Surgical management of TCA Number Statement Mean Outliers Quality improvement opportunitya Evidence/Expert opinion 3 Choosing a pull-through technique, based on experience of the operating surgeon, may lead to better outcomes 7.73 1 Educating and empowering clinicians and patients Evidence 2b 4 A covering stoma may be considered in selected patients 7.75 0 Promoting appropriate care Evidence 4 5 Intraoperative frozen section biopsy may optimize the ostomy position and prevent stoma revisions 8.36 1 Educating and empowering clinicians and patients Evidence 4 9 Redo surgery may be bene ficial for patients with residual agangliosis AND long term functional problems resistant to conservative treatment or botox 7.85 1 Promoting appropriate care Expert 11 The timing of pull-through depends on length of aganglionosis, stoma output, the patients'age, and the caregivers' preferences 7.83 1 Promoting appropriate care Expert 12 An expert center should be involved in the evaluation and management of a patient with TCA 8.43 0 Improving access to care Expert 13 Representative multi-level mapping biopsies are appropriate to determine the level of aganglionosis and stoma 8.59 0 Reducing inappropriate or harmful care Evidence 4 Consensus statements on Surgical management of (near) total intestinal aganglionosis Number Statement Mean Outliers Quality improvement opportunity a Evidence/Expert opinion 16 Early referral to expert intestinal rehabilitation group may prevent complications related to long-term parenteral nutrition dependence 8.36 1 Promoting appropriate care Evidence 2a 17 Remaining diverted bowel may increase the risk of enterocolitis, therefore timely removal can be bene ficial 7.10 1 Promoting appropriate care Evidence 2a Consensus statements on poor bowel function investigation Number Statement Mean Outliers Quality improvement opportunitya Evidence/Expert opinion 7 A pathology review provides important information to guide the indication for a redo pull-though 8.40 0 Educating and empowering clinicians and patients Expert 19 Plain abdominal radiographs and contrast enema are appropriate to diagnose bowel dilatation or twisted pull through in patients with poor bowel function. 7.50 1 Promoting appropriate care Expert 22 In case of dysmotility in patients, full thickness small bowel biopsies may be a part of the investigation 7.85 0 Promoting appropriate care Expert 23 Patients with a damaged anal canal are at higher risk of fecal incontinence 8.41 0 Educating and empowering clinicians and patients Evidence 2a 24 Diagnosing the cause of fecal incontinence and/or obstructive symptoms provides important information to guide the treatment strategy 8.55 0 Promoting appropriate care Expert Consensus statements poor bowel function management Number Statement Mean Outliers Quality improvement opportunity a Evidence/Expert opinion 28 Loperamide can be used for the treatment of diarrhea if no clinical signs or symptoms of suffering from a gastrointestinal infection or small bowel bacterial overgrowth 7.70 1 Promoting appropriate care Expert 29 If patients pass no stool for 24 h or have signs of Hirshprung's associated entereocolitis, treatment with loperamide is no longer indicated 7.95 0 Reducing inappropriate or harmful care Expert 31 Cholestyramine can be helpful in the treatment of diarrhea and perineal rash 7.00 1 Promoting appropriate care Expert 33 Treatment with sodium chloride supplementation can be used in case of diarrhea or failure to thrive with a low sodium excretion in urine (Na <30 mmol/L and Na/K < 1) 8.63 0 Promoting appropriate care Expert 35 Ileostomy can be considered for patients with intractable fecal incontinence or intractable diarrhea 8.09 1 Educating and empowering clinicians and patients Expert 38 One single treatment period or cyclical use (1 week per month) of broad-spectrum antibiotics (e.g., metronidazole or cipro floxacin) may be considered in children with TCA and suspected small bowel bacterial overgrowth in exceptional circumstances and after re-considering other medical or surgical management options 7.40 1 Promoting appropriate care Evidence 4 39 Based on the current evidence, it is unclear what the role of probiotics is to prevent Hirschsprung-associated enteritis 7.80 0 Educating and empowering clinicians and patients Evidence 1b 43 Patients with obstructive symptoms and Hirschsprung- associated enteritis may bene fit from decompression with a transanal tube 7.60 1 Promoting appropriate care Evidence 4 (continued on next page ) A.L. Granstr €om, W. Irvine, A.T. Hoel et al. / Journal of Pediatric Surgery xxx (xxxx) xxx 7 Please cite this article as: Granstr €om AL et al., Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2024.04.019 Table 3 (continued ) Consensus statements poor bowel function management Number Statement Mean Outliers Quality improvement opportunitya Evidence/Expert opinion 46 Redo surgery may be considered in patients with persistent obstructive symptoms and recurrent Hirschsprung- associated enteritis 7,78 1 Promoting appropriate care Evidence 4 Consensus statements on organization of care Number Statement Mean Outliers Quality improvement opportunity a Evidence/Expert opinion 47 Regular follow-up is an effective approach that may improve long-term outcomes in patients 8.24 1 Promoting appropriate care Evidence 4 49 Close monitoring with personalized management of growth and bowel function is required in the follow-up 8.55 1 Promoting appropriate care Evidence 4 50 Patients bene fit from a transitional program from pediatric to adult care 8.64 0 Promoting appropriate care Evidence 4 51 Treatment and follow-up in an expert center reduces mortality and morbidity 8.55 1 Educating and empowering clinicians and patients Reducing inappropriate or harmful care Expert 52 Treatment and follow-up should be carried out in a multidisciplinary team 8.71 0 Promoting appropriate care Expert Consensus statements on Long-term management Number Statement Mean Outliers Quality improvement opportunitya Evidence/Expert opinion 53 Routinely monitoring growth during follow-up provides important information of the intestinal nutrient uptake 8.63 0 Promoting appropriate care Expert 54 Regular monitoring of fluid and electrolytes in blood and urine may provide important information on growth and nutrient uptake or loss 8.41 1 Promoting appropriate care Evidence 4 55 Monitoring of sodium in urine provides important information in the follow up of patients 8.30 1 Promoting appropriate care Evidence 4 56 A healthy fluid balance for patients is de fined as Na >30 mmol/l in urine and Na/K /C21 1. 7.94 1 Reducing regional variations in delivery of care Evidence 4 57 Monitoring of vitamins, including at least B12 and iron, provides important information in the follow-up of patients 7.95 1 Promoting appropriate care Expert 59 Closer monitoring is indicated when a patient has signs or symptoms of fluid imbalance 7.90 1 Promoting appropriate care Expert 60 Patients should be regularly reviewed by a dietitian, especially during childhood and growth 7.90 1 Promoting appropriate care Expert 61 Growth monitoring with standardized growth charts provides important information in the follow up of patients 8.41 0 Promoting appropriate care Expert 62 Children with less than 80 cm of remaining small bowel may have poorer chance to wean off parenteral nutrition 7.39 1 Educating and empowering clinicians and patients Expert 63 Recommendations in the ESPGHAN guideline for home parenteral nutrition are appropriate for the monitoring of TCA patients dependent on home parenteral nutrition 8.45 0 Educating and empowering clinicians and patients Expert 64 Referral to a center with a home parenteral nutrition team is warranted if patients still depend on parenteral nutrition by the age of transition of care 8.41 0 Facilitating coordination and continuity of care Expert 65 Genetic testing of RET is bene ficial as it allows a more accurate estimation of the risk of recurrence, and exclusion of the rare possibility of a MEN 2A-associated RET mutation 7.78 1 Promoting appropriate care Expert 66 Offering referral for genetic consultation is appropriate 8.36 1 Educating and empowering clinicians and patients Expert 67 Referral for genetic screening of the speci fic gene associated with the syndromic phenotype is appropriate for patients with an associated syndrome 8.17 1 Promoting appropriate care Expert 68 Routinely offering patients and their families psychological support is part of appropriate care 8.41 1 Promoting appropriate care Expert 69 Referral to a psychologist is appropriate if patients experience psychological problems 8.50 0 Promoting appropriate care Expert 70 Referral to an endocrinologist is appropriate for patients with pubertal delay 8.59 0 Promoting appropriate care Expert a Chosen between the following options. 1. Promoting appropriate care. 2. Reducing inappropriate or harmful care. 3. Reducing regional variations in delivery of care. 4. Improving access to care. 5. Educating and empowering clinicians and patients. 6. Facilitating coordination and continuity of care. 7. Facilitating ethical care. A.L. Granstr €om, W. Irvine, A.T. Hoel et al. / Journal of Pediatric Surgery xxx (xxxx) xxx8 Please cite this article as: Granstr €om AL et al., Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2024.04.019 HSCR, and that TCA patients and TCA families do require higher standards of care also during the transition to adulthood and potentially for the entire lifespan. In some patients with TCA, additional disciplines of care can be of great value. A chronic and complex disease such as TCA can place stress on families, therefore the panel agreed that psychological support should, at least, be offered to patients and their families (Statement 70) and that such support should preferably be avail- able within the regular multidisciplinary team. Referral to a psy- chologist is appropriate if the patients experience psychological problems (Statement 69). For patients with pubertal delay, a referral to an endocrinologist is appropriate (Statement 70). 4. Discussion The purpose of this paper was to re flect opinions drafted by con- tent experts for which consensus was sought using an explicit method. In doing so, areas of consensus were identified and areas of ambiguity that require further research were uncovered. The panel reviewed the current literature and could confirm that most studies were limited to retrospective reviews, small uncontrolled case series, and expert opinions with low levels of evidence. Therefore, some statements are based on expert opinion only. Important areas of disagreement or ambiguity and their research implications are dis- cussed below. The accompanying statements are summarized in Appendix 1. 4.1. Surgical management of TCA and (near) TIA The panel did not reach consensus on a preferable surgical method for patients with TCA. The statement “the current evidence indicates similar functional outcomes after different pull-through techniques” reached near consensus since a few panel members agree that J-pouch may result in better functional outcomes compared to other techniques [ 40]. There are several different techniques used for pull-through in TCA patients, with the largest series published on J-pouch and Duhamel, but the lack of comparative studies and ambiguous opinions in the panel left these statements without consensus ( Appendix 1, Statement 1,2) [ 3]. The best timing of reconstructive surgery and stoma closure did not reach consensus ( Appendix 1, Statement 10). In a small study from Reinshagen et al., including 12 TCA patients treated with J- pouch at 16 month of age and with stoma closure four months later, no postoperative complications were reported [ 39]. The panel was unable to reach consensus on a speci fic age that is optimal for pull- through, but could agree on the optimal patient clinical condition, which ended up in Statement 1 1. The statement concerning TIA that€Safest initial surgery involves formation of a jejunostomy at least 40 cm distal to the ligament of Treitz despite leaving a variable aganglionic segment of jejunum in continuitÿ only reached near consensus given several panel members thought that a stoma should be created more distally (Appendix 1, Statement 14). One of the reviewed studies indicated that it would be preferable to create a gastrostomy at the time for jejunostomy formation. The panel did not reach consensus since some panel members thought that enteral feeding is, usually, not a problem, and that enteral feeding should be encouraged since it decreases the risk of intestinal failure-associated liver disease (Appendix 1, Statement 15) [ 24]. 4.2. Poor bowel function For the investigation of a patient with poor bowel function after reconstructive surgery, the panel could not reach consensus regarding the role of anorectal manometry ( Appendix 1,S t a t e m e n t 20). Anorectal manometry is not available as a standard investigation at all expert centers and the panel concluded that further evaluation of anorectal manometry is needed before the method can be sug- gested as an appropriate investigation. For the same reason, state- ment for MRI as an appropriate investigation to exclude a twisted pull-through, also did not reach consensus with the panel suggesting that endoscopy should be the method of choice to exclude a twist until there is enough experience with MRI in these patients ( Ap- pendix 1, Statement 25). The statement“transanal neorectal biopsies are appropriate to provide insight into remaining aganglionosis and/ or transition zone in patients with poor bowel function ” reached near consensus (Appendix 1,S t a t e m e n t2 1 ) . There is a lack of knowledge and experience regarding pharma- cological management with proton pump inhibitors, histamine 2 re- ceptor antagonists, diosmectide and glucagon-like peptides 2 (GLP-2) (Appendix 1, Statement 26,27 ,30,34). These medications may be used to decrease stoma output or diarrhea and there were positive clinical experiences among the panel members for the use of GLP-2 for pa- tients with TIA, but none of these statements reached consensus. Normal daily intake of fiber is important for these patients, but the need for supplementalfibers was not universally agreed upon by the panel (Appendix 1, Statement 32), since it is unknown what effect, they have in individuals without a colon and given that a healthy daily fiber intake can also be reached through a patient's diet. For patients with TCA and fecal incontinence, compared to rectosigmoid HSCR, the panel suggested that trans-anal decom- pression could be used instead of irrigations ( Appendix 1 , State- ment 36). For patients with HAEC, several statements did not reach consensus. The panel did not agree that the management of HAEC in TCA patients is similar to HAEC in rectosigmoid HSCR patients [8]. Since TCA patients lack a colon, handling fluid and electrolyte balance in cases with HAEC is challenging. Therefore, the panel suggested a low threshold for hospital admission for treatment of confirmed or suspected HAEC in TCA patients. Reaching consensus about HAEC and indications for the use of antibiotics was dif ficult since the panel had differing opinions on when and what type of antibiotic should be used, which was the reason this statement only reached near consensus ( Appendix 1, Statement 37) [ 3,27]. Many panel members did agree that antibiotics should be reserved for confirmed HAEC with careful monitoring to avoid over prescrip- tion. The panel did not agree that patients with recurrent HAEC may benefit from a permanent ileostomy putting forward that the stoma does not necessarily need to be permanent ( Appendix 1 , Statement 40). The panel suggested that in dif ficult cases, where a stoma is discussed, the expert team should always consider the benefits and harms of life with and without a stoma. Intersphinteric botulinum toxin injections play a role in decreasing the risk for recurrent HAEC in patients with recto-sigmoid HSCR, however this statement reached only near consensus since obstructive symp- toms were considered less common in patients with TCA (Appendix 1, Statement 41). [ 8]. For the same reasons the statement “inter- sphincteric botulinum toxin injections may be bene ficial for pa- tients with persistent obstructive symptoms ” only reached near consensus. The quality of evidence for this intervention in TCA was very low and therefore this could not support the decision for many panel members. The larger part of the panel thought that botuli- num toxin injection could be an option, but that transitional zone pull-through, anastomotic stricture, rolled cuff and twisted pull- through should be ruled out first ( Appendix 1, Statement 48) [ 8]. The statement that rectal irrigations can be bene ficial to prevent recurrent enteritits reached near consensus since there was a dif- ference of opinion in the panel on the use of small bowel irrigations compared to transanal decompression (with a rectal tube) ( Ap- pendix 1, statement 45) [ 41,42]. A.L. Granstr €om, W. Irvine, A.T. Hoel et al. / Journal of Pediatric Surgery xxx (xxxx) xxx 9 Please cite this article as: Granstr €om AL et al., Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2024.04.019 4.3. Long-term follow up For long-term follow up, the panel tried to define an appropriate interval for follow up of patients with TCA, but this was dif ficult since the panel agreed that individualized care is warranted. Un- necessary testing should be avoided, hence why the intervals be- tween testing of blood and urine may be prolonged if a patient is stable ( Appendix 1, Statement 58). 4.4. Strengths and limitations In rare diseases where large cohorts and randomized clinical trials are uncommon and almost impossible, clinical consensus statements are suf ficient to re flect uncertainties and gaps in knowledge. Through a consensus development process, many of the uncertainties can be overcome, a consensual opinion reached, and statements formed. The strength of this study is the diverse and relevant panel of experts, representing several specialties with surgical and medical expertise in TCA care as well as patient rep- resentatives. In the process, we also chose an anonymized Delphi voting process, to decrease the risk of a single individual domi- nating the discussion and decisions. The whole process strictly followed the well-established, structured, systematic approaches recommended to the development of consensus [ 11,43]. There are several limitations that need to be recognized, including the limited published literature. This is due to disease characteristics of TCA and the clinical heterogeneity among TCA patients, which mean that either trials are dif ficult to interpret or that they may only be directly applicable to a subset of patients. This project was initiated before the Covid-19 pandemic and during the worst outbreak, there were no other possibilities than online meetings. For this kind of project, although many steps of the process of developing clinical consensus, can be done online, it has been obvious how important in person meetings are for dynamic and productive group discussions The project was fortunately able to restore such meetings for the finalization of this consensus. Also, to be able to progress with a project like this, strict de finitions for TCA and near TIA were needed and decided on by the experts. Although, there are also other de finitions used in the literature for both TCA and near TIA. 5. Future perspectives This consensus statement has shown that there are knowledge or research gaps regarding several aspects of treatment and follow up of patients with TCA or TIA. The preferred surgical methods and timing of de finitive surgery are two important aspects that will need further research. The role of using a J-pouch for the pull- through procedure needs to be de fined. Furthermore, the role of diagnostic modalities such as anorectal manometry and MRI as tools to investigate for poor bowel function is still unclear. The ef- ficacy or effectiveness of botulinum toxin injection treatment in patients with TCA or TIA has been insuf ficiently addressed both to treat outlet obstruction and prevent HAEC. The de finitions, causes and predisposing factors for HAEC and bowel dysmotility in the remaining ganglionic bowel remain incompletely understood. Also, the composition of intestinal microbiota and the role of probiotics is a topic of current research interest in HAEC. The prevalence of small bowel in flammation and its impact on long term functional outcomes is unclear. Monitoring and medical treatment of TCA patients has barely been studied and more research should be focused also on this area. Most of these research questions need well designed, prospective, controlled, multicenter studies to answer. The research gaps that have been listed here are highly prioritized by the patient's representatives. 6. Conclusions In this consensus statement, conducted by a multidisciplinary panel of 23 participants originating from 10 European countries, 45 statements reached consensus after 3 Delphi-rounds. Most state- ments were based on expert opinion. For treatment and follow-up of individuals with a rare disease as TCA, there is limited availability of high-quality clinical evidence. However, the expert panel agreed these patients require highly specialized, multidisciplinary, and personalized care, preferably in an expert center from infancy up to adulthood. Most statements were based on expert opinion. Further prospective and multicenter studies are needed for more clinical evidence. Overall, the assessment of the literature indicates that TCA is a drastically more severe condition with respect to short segment HSCR, and that TCA patients and TCA families do require higher standards of care also during the transition to adulthood and potentially for the entire lifespan. Therefore, patients and parents should be informed about the availability of current guidelines and consensus statements and could bene fit from information on the availability of patient and parent support groups as early as possible. These networks are active in many countries for infor- mation and peer support on lived experience of the disease. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Funding Ernica. Declaration of competing interest All contributing authors have submitted a declaration of interest form. No competing interests were noticed, all declarations are available on request. Acknowledgements This clinical consensus statement is generated within the Eu- ropean Reference Network for rare Inherited and Congenital Anomalies (ERNICA). ERNICA is funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily re flect those of the European Union or the Health and Digital Executive Agency (HaDEA). Neither the European Union nor the granting authority can be held responsible for them. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jpedsurg.2024.04.019. A.L. Granstr €om, W. Irvine, A.T. 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