Clinical Research Directory

Effects of Butyrate Enemas on Postoperative Intestinal Motility Disorders in Hirschsprung's Disease

Hirschsprung's disease (HD) is a rare congenital disorder (1/5000) defined by the absence of ganglion cells in the submucosal and myenteric plexuses along a variable length of the digestive tract. This abnormality most often leads to distal bowel obstruction in newborns with delayed passage of meconium. Treatment is surgical and consists in the resection of the aganglionic and transitional segments. However, the postoperative outcomes remain unpredictable. Despite complete curative surgery, intestinal functional disorders persist in 40-50% of children, mainly obstructive symptoms, and 15-25% of children will also develop postoperative enterocolitis, which remains the leading cause of mortality in HD. There is currently no preventive treatment of these intestinal functional disorders and enterocolitis. Recent preclinical studies have identified butyrate, a short-chain fatty acid, as a regulator of intestinal homeostasis in newborns and adults, particularly involved in maintaining epithelial integrity, regulating the immune response, and regulating the phenotype of the digestive tract and its functions. Butyrate regulates intestinal epithelial barrier functions by strengthening intestinal permeability, and regulates the functions of the enteric nervous system and its phenotype. In newborn rats, butyrate enemas increase the proportion of nitrergic (and also cholinergic) neurons, leading to improved nitrergic neurotransmission and, ultimately, improved colonic transit time. Our main hypothesis is that recto-colonic butyrate enemas administered preoperatively in newborns and infants with HD should reduce postoperative functional intestinal motility disorders and enterocolitis in the short, medium, and long terms. The BUTYHIRSCH project is a phase III, multicenter, national (24 pediatric surgery departments), controlled, randomized, open-label, prospective clinical drug trial. Fifty-eight patients will be included over a period of two years. The primary objective is to determine the short-term efficacy of preoperative butyrate enemas in reducing the time to postoperative bowel recovery. The secondary objectives are to determine the medium- and long-term efficacy of preoperative butyrate enemas on 1) the incidence of postoperative obstructive functional symptoms, 2) the stool consistency, 3) the total postoperative intestinal transit time, 4) the incidence and severity of postoperative enterocolitis, and 5) the intestinal inflammation. Patients will be randomized into 2 groups: the experimental group (29 patients) receiving a sodium butyrate recto-colic enema for 24 days before curative surgery and the control group (29 patients). Postoperative clinical follow-up will be prospective over 3 years in order to collect data on complications such as intestinal motility disorders and enterocolitis. No invasive or radiation-based examinations will be performed postoperatively. Additional investigative procedures will include assessment of total postoperative intestinal transit time using carmine red transit and assessment of intestinal inflammation by measuring fecal calprotectin. examinations will be performed postoperatively. Additional investigative procedures will include assessment of total postoperative intestinal transit time using carmine red transit and assessment of intestinal inflammation by measuring fecal calprotectin.

Prospective Evaluation of the Efficacy and Safety of Submucosal Endoscopy

To test the idea that submucosal endoscopy is effective and safe for endoscopic myotomy, endoscopic submucosal dissection, and access for tissue acquisition and resection. Submucosal endoscopy is a recent innovative addition to gastrointestinal endoscopy. This involves endoscopic maneuvers in the gut wall, by dissection of the submucosal layer of GI tract, thereby allowing endoscopic myotomy (incision of the muscle), endoscopic access for tissue acquisition and therapy, and resection of precancerous and cancerous gastrointestinal tissue. This approach has been a dramatic game-changer for minimally invasive management of various gastrointestinal conditions such as Zenker's diverticulum, Achalasia, Spastic Esophageal Disorders, Gastroparesis, esophageal obstruction, Hirschsprung's Disease, and Gastrointestinal neoplasia. The aim of the proposed study is to prospectively assess technical success, clinical success, and adverse events after submucosal endoscopy. Technical success will be defined as ability to successfully complete the submucosal endoscopic procedure. Clinical success will be defined as symptom relief and objective evaluation which will be assessed with radiologic imaging, repeat endoscopy, gastrointestinal motility studies, and pathology results routinely performed post-procedure for clinical care, as indicated. Adverse events will be recorded per published ASGE criteria. A database/ registry of patients undergoing submucosal endoscopic procedures will be created to demonstrate this.