Hirschsprung's Disease: Clinical Guidelines

List of Abbreviations

AChE — acetylcholinesterase

HD — Hirschsprung's disease

BF — biofeedback

HAEC — Hirschsprung-associated enterocolitis

IHC — immunohistochemical

GIT - gastrointestinal tract

ICD - International Statistical Classification of Diseases and Related Health Problems (10th Revision)

RAIR — rectoanal inhibitory reflex

Ultrasound - ultrasound examination

Terms and Definitions

Megacolon is dilation of the colon or the entire large intestine.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hirschsprung disease (HD) is a congenital bowel malformation characterized by the absence of ganglion cells in the neural plexuses of the bowel wall, the presence of abnormal nerve fibers, and impaired conductivity in the neuro-reflex arcs of the bowel wall, leading to impaired motor function [1].

Synonyms: agangliosis; congenital (aganglionic) megacolon.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The most popular theory of HD pathogenesis remains the hypothesis of impaired migration of nerve cells along the intestinal tube from the 6th to the 12th week of intrauterine development [2]. The direct cause of impaired neuroblast migration or their death may be the exposure to teratogenic factors during pregnancy, intrauterine bowel ischemia, severe hypoxia, or intrauterine infection [3]. In addition, there is a hypothesis that agangliosis develops due to impaired differentiation of nerve cells that have already reached the intestinal wall [4]. Various factors, such as hypoxia, exposure to chemical agents, increased radiation, and viral infection, can influence cell maturation. The development of genetics has played a significant role in explaining the origin of HD [5]. The conclusion about the role of heredity was initially made based on the high frequency of familial cases of the disease, reaching 20–30%. According to the literature, about 20 known genes play a role in HD pathogenesis, the main ones being the RET (tyrosine kinase receptor) gene, GDNF (glial cell line-derived neurotrophic factor), EDNRB (endothelin receptor type B gene), and EDN3 (endothelin-3) [4, 8]. HD is combined with other malformations and genetic syndromes in 30% of cases [6], with Down syndrome being the most frequent [8].

The absence of ganglion cells in the neural plexuses is a pathogenetic factor leading to the accumulation of acetylcholinesterase (AChE) in the mucosa, which, along with the lack of neurotransmitters, provides an inhibitory effect in the bowel wall [7, 8, 9]. The aganglionic segment does not participate in peristaltic activity and acts as a functional obstruction to the passage of intestinal contents; as a result, a chronic retention of fecal masses occurs in the proximal bowel, which dilates over time, forming a secondary megacolon [1].

1.3 Epidemiology of the Disease or Condition

The incidence of HD ranges from 1:2000 to 1:12000 newborns, averaging 1:5000 [10]. The disease is four times more common in boys than in girls [11]. In familial cases of HD, a higher frequency of associated anomalies has been described compared to isolated ones (39% vs. 21%) [5].

1.4 Features of Coding the Disease or Condition

Q43.1 - Hirschsprung disease

1.5 Classification of the disease or condition

The international classification [2, 11, 12, 13] distinguishes:

1) Short-segment HD (typical, rectosigmoid form) (S-HSCR, type 1) - agangliosis does not extend above the proximal third of the sigmoid colon;

2) Long-segment HD (L-HSCR, type 2) - agangliosis extends proximally to the sigmoid colon;

3) Total form of HD (total agangliosis) - agangliosis extends to the entire large intestine, often involving a segment of the ileum of varying length [14, 15].

For any form of HD, the clinical diagnosis must indicate the extent of agangliosis. The existence of an ultrashort form of HD has been described by some authors [16, 17], but distinguishing it as an independent nosological entity currently seems impractical. The segmental form of agangliosis is not recognized by all researchers, although isolated observations have been described in the literature [18].

1.6 Clinical presentation of the disease or condition

In most cases, HD manifests in the neonatal period [19, 20, 21].

The onset of the disease can present with acute intestinal obstruction, colonic perforation, or Hirschsprung-associated enterocolitis (HAEC) [22, 23].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria are established based on clinical and instrumental examination data and the results of pathomorphological (histological) examination (pathomorphological examination of biopsy (surgical) material of the large intestine) [1]:

1) complaints of delayed meconium passage, delayed spontaneous stool from an early age;

2) presence of a relative narrowing zone with suprastenotic dilation according to X-ray examination (irrigoscopy/irrigography);

3) absence of the rectoanal inhibitory reflex (RAIR) according to anorectal manometry (in older school-age children);

4) absence of ganglion cells in the myenteric and submucosal plexuses of the wall of the large intestine (and ileum) according to histological examination (pathomorphological examination of biopsy (surgical) material of the large, colon, and rectum).

Differential diagnosis is carried out with other malformations and diseases of the large and small intestine [1, 24, 25, 26, 27]:

- chronic functional constipation;

- other types of low intestinal obstruction;

- anorectal malformations;

- hypoperistaltic syndrome;

- intestinal neuronal dysplasia;

- chronic intestinal pseudo-obstruction syndrome (visceral myopathy, Alpers' disease, and other genetic diseases).

Principles of diagnosis formulation:

When formulating the diagnosis, it is recommended to indicate the length of the affected segment:

1. Hirschsprung disease, short segment (rectosigmoid form);

2. Hirschsprung disease, long segment (indicate the affected sections of the colon);

3. Hirschsprung disease, total form (total agangliosis of the colon).

2.1 Complaints and Anamnesis

Taking complaints (taking history and complaints in diseases of the large intestine) in patients begins with studying the family history to identify probands and siblings with HD. It is important to find out the time of meconium passage after birth, the age of constipation onset, and the character of the stool [1, 2, 20].

Characteristic complaints:

1) for neonatal patients:

- abdominal distension;

- infant restlessness;

- bile-stained vomiting;

- fever (as the disease progresses);

- diarrhea.

2) for older patients:

- severe chronic constipation (absence of spontaneous stool from an early age and absence of the urge to defecate);

- poor weight and height gain;

- enlarged abdomen;

- abdominal distension;

- nausea, vomiting, abdominal pain (rarely);

- chronic anemia.

2.2 Physical Examination

Comment: The severity of the child's condition with HD is due to stool retention and abdominal distension. Clinical manifestations in newborns include the absence of meconium in the first 24–48 hours, against which abdominal distension and bile-stained vomiting occur. If HAEC develops, the general condition of the child progressively worsens, symptoms of intoxication appear, and body temperature rises. Visual inspection for large intestine diseases and sigmoid/rectal pathology reveals abdominal distension and visible intestinal loops through the anterior abdominal wall. Abdominal palpation for large intestine diseases and sigmoid/rectal pathology determines tenderness without a clear localization. Auscultation reveals increased peristalsis in certain areas of the abdominal cavity. In patients with a short segment of agangliosis, after inserting a gas-rectal tube into the anal canal, there is an "explosive," massive release of liquid stool, often with a foul odor. In patients with a long segment of agangliosis, such "anal stimulation" and cleansing enemas are ineffective—abdominal distension is not relieved, and stool does not pass. In patients with complicated HD in the form of bowel perforation, the clinical picture corresponds to peritonitis.

Visual inspection for sigmoid and rectal pathology and transrectal digital examination of the rectum are performed to identify concomitant rectal diseases [1].

2.3 Laboratory Diagnostics

There is no specific laboratory diagnostics for HD [1, 2]. Laboratory diagnostic tests can be performed on patients during the preparation and planning of surgical intervention to rule out concomitant diseases and complications, as well as if differential diagnosis is necessary [1, 2, 28, 29, 30, 31]. Monitoring of infectious status and pre- and postoperative evaluation include:

- complete blood count;

- complete blood count (CBC) with differential;

- general clinical blood biochemistry analysis;

- urinalysis;

- acid-base balance and blood gas analysis;

- blood procalcitonin level testing;

- determination of main ABO blood groups;

- determination of subgroups and other minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy;

- determination of Rhesus D antigen (Rh factor);

- microbiological (cultural) stool examination for aerobic and facultatively anaerobic microorganisms;

- microbiological (cultural) examination of feces / rectal swab for the causative agent of clostridial colitis (Clostridium difficile).

2.4 Instrumental Diagnostics

All patients with suspected Hirschsprung's disease require instrumental diagnostic methods (plain abdominal and pelvic X-ray, barium enema / irrigography) to diagnose the condition: radiological examinations allow assessment of the functional and anatomical state of the colon and detection of complicated courses, which significantly influences the choice of further diagnostic and therapeutic management.

Comment: radiological examination begins with a plain abdominal and pelvic X-ray to rule out complicated courses of the disease, such as hollow viscus perforation or low intestinal obstruction. A specific sign of hollow viscus perforation is the presence of free air under the diaphragm—the "crescent sign". For low intestinal obstruction, a specific sign is the presence of multiple fluid levels.

In an uncomplicated course of Hirschsprung's disease, dilation of intestinal loops is observed throughout the abdominal cavity. In newborns, an enlarged colon with an "air funnel" at the transition from the descending colon to the sigmoid colon and the absence of bowel gas pneumatization in the pelvic projection are typically visualized.

Comment:Contrast X-ray examination (barium enema / irrigography) is performed in real time under fluoroscopic guidance to visualize the affected segment (the aganglionic narrowed / "spastic" section of the colon), the transition zone (shaped like a "funnel"), and the normally formed section of the colon (having an increased diameter) [33]. Contraindications for contrast X-ray examination (barium enema / irrigography) include hollow viscus perforation and the presence of Hirschsprung's-associated enterocolitis (HAEC). Prior to the procedure, the bowel lumen must be cleansed by performing high colonic irrigation. Technique of contrast X-ray examination (barium enema / irrigography): a Foley catheter (No. 8 in newborns, No. 10–12 in infants under one year, No. 16–22 in older children) is inserted into the rectum to a depth of 2 cm; the balloon is not inflated. For the enema, barium sulfate** (V08BA02) is used as a contrast agent in patients older than the neonatal period, while iohexol** (V08AB02) is preferred in newborns at a dosage of 5–10 ml/kg of body weight, administered rectally and slowly using a syringe under fluoroscopic control of contrast progression through the colon. Barium enema should be initiated with the child in a lateral position (if the examination starts with an anteroposterior view, the transition zone may be missed). The administration of the contrast agent (barium sulfate** (V08BA02) or iohexol** (V08AB02)) into the colon is continued until the expanded colon is visualized; the colon must be filled up to the most proximal part—the cecum. Characteristic radiological signs of Hirschsprung's disease include: a colon that is dilated proximally and narrow distally, connected by a funnel-shaped transition zone. The diameter difference between the dilated and narrowed bowel segments is 2:1 or greater. If the entire colon has a narrow diameter, this may indicate total colonic aganglionosis. During the barium enema, the patient must be turned and radiograph images captured in the position where the transition zone is clearly visible. In doubtful cases or when visualization of the transition zone is unclear, delayed plain abdominal and pelvic X-rays should be performed at 12 and 24 hours post-enema, which increases the accuracy of fluoroscopic monitoring of contrast progression through the colon.

2.5 Other Procedures

2.5.1 Pathomorphological examination of biopsy (surgical) material

Comment: there are two methods for obtaining rectal biopsy material: suction and full-thickness [35]. Suction biopsy is performed using a vacuum "gun" equipped with a specimen collection capsule at the tip [36]. Before the procedure, the rectal lumen must be thoroughly cleansed; then the gun is inserted into the rectum 3 cm from the dentate line so that the capsule openings face the posterior wall. Gentle pressure is applied to the rectal wall, and adequate negative pressure is generated for 10 seconds; then, by pressing the trigger, the blade is activated and the instrument is withdrawn from the rectum. This is recommended for children under 3 months of age. For diagnostic objectivity, obtaining 2–3 samples is recommended.

Transanal open full-thickness rectal biopsy is performed on an open anal canal using a retractor [37, 38]. After inspecting the anal canal, the first stay suture is placed on the posterior rectal wall 1 cm from the dentate line. The next suture is placed 2 cm from the dentate line—this will be the biopsy site itself. A third stay suture is placed 3 cm proximal to the dentate line. Then, by applying traction to the second stay suture, two vertical incisions are made between the first and second, and second and third sutures, to obtain an adequate specimen with sufficient tissue for examination. After extracting the biopsy material from the rectal lumen, the resulting defect is closed using the first and third stay suture ligatures.

For the pathomorphological examination of colonic biopsy (surgical) material, hematoxylin-eosin histological staining methods are used, along with pathomorphological examination of colonic biopsy (surgical) material for acetylcholinesterase (AChE) using histochemical methods, and pathomorphological examination of colonic biopsy (surgical) material using immunohistochemical (IHC) methods to detect calretinin [7].

The absence of ganglion cells on hematoxylin-eosin staining supports the diagnosis of Hirschsprung's disease. Ganglion cells can be detected using either frozen sections (obtained intraoperatively for urgent intraoperative pathomorphological examination of colonic biopsy (surgical) material) or formalin-fixed, 10% neutral buffered specimens embedded in histological paraffin blocks [39]. Hypertrophied nerve trunks may be detected during the examination; such a histological picture may correspond to the transition zone or "physiological" aganglionosis of the anal canal. In such cases, further pathomorphological examination of the colonic biopsy (surgical) material using immunohistochemical (IHC) calretinin staining or a repeated open full-thickness rectal biopsy is required.

Suspecting a diagnosis in patients with Hirschsprung's-like diseases due to pseudorectal aganglionosis involves two potential pitfalls: the first is that the biopsy sample is taken from the skin, anoderm, or dentate line, which are normally aganglionic segments; the second potential pitfall is obtaining a superficial biopsy sample without a sufficient submucosal layer.

When performing a pathomorphological examination of large intestine biopsy (surgical) material for acetylcholinesterase (AChE) using histochemical methods, the recommended thickness of the submucosal layer should be at least 1/3 of the biopsy specimen. If the submucosal layer is absent in the material, a repeat biopsy is required. Examination of the mucosa for hypertrophy of AChE-positive nerve fibers and increased AChE activity in the muscularis mucosae and lamina propria of the mucosa are indirect findings; therefore, pathomorphological examination of the intestinal mucosa alone (obtained, for example, during rectal biopsy) is inappropriate.

Performing a pathomorphological examination of large intestine biopsy (surgical) material using immunohistochemical (IHC) methods for calretinin in a patient with Hirschsprung's disease demonstrates its absence. Under normal conditions, calretinin is expressed by ganglion cells as well as nerve fibers throughout the submucosa, muscularis propria, and the intestinal mucosa itself. In the aganglionic intestine, all these structures remain negative for calretinin, resulting in a "black-and-white" staining pattern.

Other markers, such as S100, neuron-specific enolase, synaptophysin, etc., do not show high diagnostic accuracy, and the possibility of their use is currently being investigated [40]. In recent years, pilot studies have emerged using optical laser confocal microscopy [41, 42], studying the degree of maturity of ganglion cells [43, 44], and employing artificial intelligence for the pathomorphological verification of HD [45].

• In patients with suspected HD and a complicated disease course undergoing emergency surgery, it is recommended to obtain biopsy material for pathomorphological examination of biopsy (surgical) material from the large intestine, colon (sigmoid), and rectum to confirm the diagnosis and determine the extent of the aganglionosis zone [11, 12, 31, 46].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comment: when performing emergency surgery in the volume of ileostomy or colostomy in a patient with persistent symptoms of intestinal obstruction, hollow organ perforation, or severe enterocolitis, it is necessary to perform an intraoperative biopsy of the intestinal wall to exclude HD (operative colonic biopsy, large intestine biopsy, rectal biopsy). Biopsy sampling is recommended at multiple sites: the most distal point of the sigmoid colon, descending colon, transverse colon, ascending colon, and distal ileum. The collection of biopsy specimens (operative colonic biopsy, large intestine biopsy, rectal biopsy) is carried out depending on the level of intestinal perforation or the level of obstruction established intraoperatively. A full-thickness biopsy of the intestinal wall is mandatory. This method of biopsy sampling involves pathomorphological examination of the surgical (biopsy) material of the rectum/large intestine using both hematoxylin and eosin staining and acetylcholinesterase (AChE) testing and immunohistochemical (IHC) calretinin staining methods (pathomorphological examination of large intestine biopsy (surgical) material for acetylcholinesterase using histochemical methods, using immunohistochemical methods). After fixation, trimming, and processing, the specimens are embedded in histological paraffin. Paraffin blocks and histological slides are preserved to allow subsequent consultations of the biopsy material if necessary. In doubtful cases, it is recommended to consult the study results in higher-level institutions (evaluation, interpretation, and description of the results of a pathomorphological examination of biopsy (surgical) material of the first, second, third, fourth, fifth category of complexity, including through the use of telemedicine technologies).

2.5.2 Anorectal manometry

Comment. Anorectal manometry is a useful screening method in which the presence of the rectoanal inhibitory reflex, consisting of the reflex relaxation of the internal anal sphincter in response to balloon distension of the rectum, essentially rules out HD [2, 48].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

General principles of treatment include surgical correction of the malformation, pharmacotherapy, diet therapy, treatment of complications and functional disorders in the postoperative period [1, 2, 11, 28, 30, 31, 49, 50].

3.1 Medical treatment

Medical treatment includes all types of treatment aimed at stabilizing the patient in the event of a complicated disease course, preoperative preparation, and the postoperative period [1, 2, 49, 51, 52].

Drug therapy includes:

- perioperative antibiotic prophylaxis;

- flushing of the large intestine (administration of an cleansing enema, siphon enema) with 0.9% sodium chloride solution** [29];

- infusion therapy;

- parenteral nutrition.

• cefazolin** with metronidazole**, or

• cefuroxime** with metronidazole**, or

• amoxicillin + [clavulanic acid]**, or

• ampicillin + [sulbactam]**, or

• #clindamycin** (in case of allergy to beta-lactam antibacterial drugs, penicillins; penicillin combinations, including combinations with beta-lactamase inhibitors; other beta-lactam antibacterial drugs), or

• #ertapenem** (in case of a high risk of complications and comorbidity, as well as the risk of colonization by antibiotic-resistant microorganisms as a result of previous systemic antibacterial drug use).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comment. Perioperative antibiotic prophylaxis is performed during elective surgical treatment. It is important to consider the patient's medical history, comorbid conditions, and previous episodes of Hirschsprung-associated enterocolitis (HAEC). The antibiotic (systemic antibacterial drug) is administered 30–60 minutes before the start of surgery. During prolonged surgery, it becomes necessary to re-administer the antibiotic intraoperatively.

When prescribing first-generation cephalosporins: cefazolin** (J01DB04) is administered preoperatively at a dose of 30 mg/kg intravenously; if the surgery lasts longer than 2 hours, the drug is additionally administered intraoperatively at a dose of 25–30 mg/kg intravenously, and postoperatively the drug is administered intravenously at the same dose throughout the day every 6–8 hours [101].

When prescribing second-generation cephalosporins: cefuroxime** (J01DC02) is administered preoperatively at a dose of 50 mg/kg intravenously, and postoperatively at 8 hours and 16 hours at the same dose intravenously; thereafter, the drug is administered intravenously at the same dose throughout the day every 6–8 hours [101].

Metronidazole** (J01XD01) is prescribed in combination with first- or second-generation cephalosporins as a single dose; the infusion must be completed 1 hour before surgery, with a dosage of 15 mg/kg for children over 12 years of age and 7.5 mg/kg intravenously for children under 12 years of age.

When prescribing amoxicillin + [clavulanic acid]** (J01CR02) preoperatively, the drug is administered by intravenous infusion (over 30–40 minutes) completing the infusion 30–60 minutes before surgery: for children under 3 months with a body weight of less than 4 kg: 25 mg of amoxicillin and 5 mg of clavulanic acid per 1 kg of body weight; for children under 3 months with a body weight of more than 4 kg: 25 mg of amoxicillin and 5 mg of clavulanic acid per 1 kg of body weight; for children aged 3 months to 12 years with a body weight of less than 40 kg: 25 mg of amoxicillin and 5 mg of clavulanic acid per 1 kg of body weight; for children over 12 years of age or with a body weight of more than 40 kg, usually 1000 mg + 200 mg is administered; postoperatively, it is administered at the same dosage depending on weight and age throughout the day every 6 hours.

When prescribing ampicillin + [sulbactam]** (J01CR01) preoperatively, it is administered intravenously (bolus or infusion) or intramuscularly, with infusion/administration completed 30–60 minutes prior, at a dosage of 50 mg/kg for children aged 7 days to 28 days, 50 mg/kg for children older than 1 month and up to 12 years with a body weight of less than 40 kg, and 1.5–3 g for children older than 12 years and weighing more than 40 kg; postoperatively, it is administered at the same dosage throughout the day every 6–8 hours.

When prescribing #clindamycin** (J01FF01) before surgery (in case of allergy to beta-lactam antibacterials, penicillins; or other beta-lactam antibacterials) in children over 3 years of age, the drug is administered intravenously by infusion at a dose of 10 mg/kg, 30–60 minutes before surgery, and postoperatively at the same dosage every 6 hours for 24 hours [101].

When prescribing #ertapenem** (J01DH03) before surgery, the drug is administered intravenously (or by intravenous infusion) with the infusion ending 30–60 minutes before surgery at a dosage for children aged 3 months to 13 years of 15 mg/kg once daily [101].

Postoperative antimicrobial therapy is prescribed taking into account the patient's medical history, intraoperative and postoperative complications, as well as the results of microbiological (culture) stool testing for aerobic and facultative anaerobic microorganisms and microbiological (culture) testing of feces/rectal swab for the causative agent of Clostridium difficile infection.

• All patients in the postoperative period are recommended to undergo pain management using epidural analgesia with ropivacaine**, and in children older than 12 months, intravenous analgesia with fentanyl** [54, 98].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: in the absence of contraindications, epidural blockade for analgesia (epidural analgesia) can be performed in the postoperative period. For pain management, a 0.2% solution of ropivacaine** (N01BB09) is used for patients aged 0 to 6 months at a dose of 0.2 mg/kg/hour, for patients aged 6 to 12 months at a dose of 0.4 mg/kg/hour, and for ages 1–12 years at 0.4 mg/kg/hour (2 mg/ml) by continuous infusion into the epidural space for up to 72 hours [55, 98].

Opioid intravenous analgesia is used for postoperative pain management. For intravenous analgesia in children older than 12 months, Fentanyl** 0.005% solution (N01AH01) is used. The duration of postoperative pain management is determined by persistent pain syndrome and intestinal paresis [54, 98].

• All patients with Hirschsprung's disease in the postoperative period are recommended to receive infusion therapy and parenteral nutrition according to standard methods [98]

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

3.2 Non-drug treatment

Comment. To perform and administer cleansing enemas, it is recommended to use a Foley catheter, which is inserted into the rectum for decompression. Using a single-use syringe, 0.9% #sodium chloride solution** (B05CB01) is administered, and the catheter is disconnected to allow gas and stool to escape. The procedure is repeated until clear effluent is obtained.

3.3 Dietary therapy

There is no special diet for patients with Hirschsprung's disease.

Comment: in the postoperative period following radical surgical treatment, an enteral pause for 48 hours is recommended. Enteral feeding is resumed upon the appearance of stool and the absence of complications.

In the event of severe HAEC, an enteral pause is recommended until inflammatory laboratory markers normalize and intestinal passage is restored [79, 80, 99].

Patients older than 1 year are prescribed a mechanically and chemically sparing diet [79, 80]. Infants are prescribed feeding with breast milk, infant formula for special medical purposes (therapeutic) for young children: lactose-free dry formula or dry formula based on extensively hydrolyzed whey proteins. Introduction of complementary foods is carried out after normalization of stool and relief of the inflammatory process, with a gradual expansion of the diet. Patients with loose stools and those recovering from HAEC are indicated for the restriction of milk and dairy products containing lactose. They should be replaced with infant formula for special medical purposes (therapeutic) for young children, specifically lactose-free dry formula or dry formula based on extensively hydrolyzed whey proteins, especially in patients following colectomy. Foods rich in simple sugars (jams, jellies, candies, cookies, puddings, ice cream), juices and sweet beverages with added sucrose, high-fructose corn syrup, and carbonated beverages should be excluded. Foods rich in soluble fiber (oat flakes, pumpkin, carrots, bananas, applesauce, peeled apple) should be restricted [79, 80].

3.4 Surgical treatment

Comment: the type and method of surgery depend on the length of the aganglionic segment, the presence of an intestinal stoma, and the preferences of the pediatric surgeon. In all cases, resection of the pathological segment of the large intestine (sigmoid, left hemicolon, subtotal, total) is performed down to a normally formed intestinal segment.

The most frequently performed operations are the Swenson, Duhamel, and Soave procedures.

In the Swenson procedure, the pulled-through segment is anastomosed with the distal rectum. The Duhamel procedure involves the creation of a retrorectal reservoir in which the mobilized colon, brought down presacral, is anastomosed with the posterior wall of the rectum while preserving its aganglionic part. In the Soave procedure, a seromuscular muscular cuff is left in the distal rectum, through which the mobilized normal colon is pulled down.

Colon mobilization can be performed via an abdominal approach (colectomy with abdominoperineal rectal resection), a laparoscopic approach (laparoscopically assisted colectomy with abdominoperineal rectal resection), or transanally [1, 2, 11, 13, 63, 66, 67, 68, 69]. The extent of colonic mobilization is determined by the results of pathomorphological examination of biopsy (surgical) material from the large intestine, colon, and rectum [38, 43]. In the presence of an intestinal stoma on the descending or sigmoid colon, preference is given to pulling down the segment of the large intestine leading to the stoma.

In the total form of Hirschsprung's disease, the ileum is pulled down with the formation of an ileorectal anastomosis (colectomy with ileorectal anastomosis) [13, 14, 70, 71, 72].

In the postoperative period on days 10–14, it is recommended to perform an examination of the patient under general anesthesia and calibration of the anastomotic zone (colonic bougienage), which is performed using Hegar dilators.

3.5 Treatment of complications

In the postoperative period, patients with Hirschsprung's disease may develop purulent-inflammatory complications, anastomotic leakage, bowel retraction, recurrent HAEC, and obstructive syndrome [73, 74, 75, 76].

Comment. HAEC manifests as abdominal distension, deterioration of the child's general condition, febrility, delayed stool or diarrhea [75]. Anastomotic leakage manifests as the accumulation of air in the free abdominal cavity (pneumoperitoneum). If a postoperative complication is suspected, an upright plain abdominal radiograph in the anteroposterior projection must be performed. The presence of free air under the diaphragm is an indication for emergency surgery. Treatment of bowel obstruction and HAEC begins with conservative measures (antibacterial therapy, cleansing enema, administration of medications via enema) [77]. In the absence of an effect from the treatment or upon clinical deterioration, emergency surgery—creation of an ileostomy (ileostomy)—is performed.

3.6 Management of obstructive syndrome

Obstructive syndrome arises as a result of anatomical and functional causes [78, 79].

3.6.1 Anatomical causes of obstruction

include anastomotic stricture, twist of the pulled-through bowel, impaired transit through the formed reservoir after the Duhamel procedure, an extended seromuscular sleeve after the Soave procedure, and a residual zone of colonic aganglionosis, which is confirmed based on pathomorphological examination of rectal/colonic biopsy (surgical) material [80, 81, 82, 83].

Comment: if anatomical causes of obstruction are identified—rigid anastomotic stricture, residual aganglionosis zone, twist of the pulled-through bowel—repeat resection of the pathological section of the colon with abdominoperineal resection of the rectum and creation of a colorectal anastomosis 1–2 cm proximal to the dentate line should be considered [76, 79, 80]. Reoperation and correction of postoperative complications should be performed only in reference centers, given that reoperation is technically complex and does not always lead to the restoration of bowel and sphincter function.

3.6.2 Functional cause of obstruction

is caused by hypertonicity of the internal anal sphincter [2, 79, 84].

Comment: administration of other peripherally acting muscle relaxants (ATC code: M03AX) is indicated in case of detected increased anal sphincter tone. To treat anal sphincter hypertonicity and prevent the development of Hirschsprung-associated enterocolitis, it is recommended to inject #botulinum toxin type A – hemagglutinin complex** solution (M03AX01) into the muscle of the internal anal sphincter. According to various authors, the dosage of the drug ranges from 40 to 120 IU [84, 86].

Unsatisfactory functional outcomes in patients with Hirschsprung's disease after radical surgical treatment may manifest as fecal incontinence. Postoperative anal sphincter insufficiency with fecal incontinence occurs when the dentate line is destroyed during rectal mobilization. Another cause of fecal incontinence can be rectal distension against the background of chronic constipation with anal sphincter hypertonicity (retention incontinence, pseudoincontinence, or paradoxical fecal incontinence) [88, 89, 93].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

There are no specific rehabilitation methods for patients with Hirschsprung's disease.

5. Prevention and Dispensary Observation

Prevention.

There are no specific preventive measures for Hirschsprung's disease.

Prevention methods should aim to prevent the development of Hirschsprung-associated enterocolitis, anastomotic stricture, and functional bowel disorders [37, 80].

Follow-up care.

Comment. Follow-up care for the patient is provided by a pediatric surgeon, pediatrician, and gastroenterologist (follow-up appointment (examination, consultation) with a pediatric surgeon, pediatric gastroenterologist, and pediatrician) [1, 2, 90, 79].

6. Organization of Medical Care

Treatment of patients with Hirschsprung's disease is carried out in a multidisciplinary pediatric hospital. Care for patients with Hirschsprung's disease is provided by pediatric surgeons and anesthesiologists-resuscitators experienced in treating children with Hirschsprung's disease. The staff of the children's hospital must include pathologists experienced in interpreting biopsy and surgical material (pathomorphological examination of rectal/colonic biopsy [surgical] material). For scheduled surgical interventions, patient hospitalization is planned; in case of a complicated course of the disease, patients are hospitalized on an emergency basis.

Comment. Examination of children is carried out in pediatric surgery departments [33, 39, 111, 142].

Indications for planned hospitalization:

- confirmed diagnosis of Hirschsprung's disease,

- suspected Hirschsprung's disease.

Indications for emergency hospitalization:

- intestinal obstruction,

- Hirschsprung-associated enterocolitis,

- bowel perforation and other conditions requiring urgent surgical intervention.

Indications for patient discharge:

- sustained improvement, when the patient can stay outside the hospital without detriment to health,

- need to transfer the patient to another medical institution,

- at the request of the patient or their legal representative.

7. Additional Information

The prognosis for children operated on for Hirschsprung's disease is favorable in the absence of complications involving the colorectal anastomosis and with preservation of the anatomical integrity of the anal canal [1, 93, 94, 95, 96].

Factors negatively affecting treatment outcomes:

- development of infectious complications,

- extended and total forms of Hirschsprung's disease,

- chromosomal abnormalities and genetic pathology,

- repeated surgical interventions.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Alexander Yu. Razumovsky – MD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Pediatric Surgery named after Yu.F. Isakov, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief Pediatric Surgeon of the Moscow Healthcare Department, Chief Pediatric Surgeon of the Central Federal District of the Russian Federation, Head of the Department of Thoracic Surgery and Surgical Gastroenterology, Filatov Children's City Clinical Hospital of the Moscow Healthcare Department (Moscow). Chairman of the Presidium of the Russian Association of Pediatric Surgeons, Board Member of the Moscow Society of Surgeons, Board Member of the Society of Endoscopic Surgeons, Board Member of the Russian Society of Surgeons-Gastroenterologists, Member of the European Association of Pediatric Surgeons, Member of the Russian Association of Hepatobiliary Surgeons.

2. Yury A. Shelygin – MD, Professor, Academician of the Russian Academy of Sciences, Scientific Advisor of the A.N. Ryzhikh National Medical Research Center of Coloproctology of the Russian Ministry of Health, President of the Association of Coloproctologists of Russia.

3. Sergey I. Achkasov – MD, Professor, Corresponding Member of the Russian Academy of Sciences, Director of the A.N. Ryzhikh National Medical Research Center of Coloproctology of the Russian Ministry of Health, Board Member of the Association of Coloproctologists of Russia.

4. Dmitry A. Morozov – MD, Professor, Director of the Research Clinical Institute of Pediatrics and Pediatric Surgery named after Academician Yu.E. Veltischev, Head of the Department of Pediatric Surgery and Urology-Andrology named after L.P. Alexandrov, I.M. Sechenov First Moscow State Medical University (Sechenov University), Chief freelance specialist pediatric surgeon of the Ministry of Health of the Russian Federation, Deputy Chairman of the Presidium of the Russian Association of Pediatric Surgeons, Vice President of the National Medical Chamber, Member of the Association of Coloproctologists of Russia, Member of the European Association of Pediatric Surgeons.

5. Vladimir A. Novozhilov – MD, Associate Professor, Head of the Department of Pediatric Surgery at Irkutsk State Medical University, Chief Physician of the City Yino-Matreninsky Children's Clinical Hospital, Member of the Russian Association of Pediatric Surgeons, Chairman of the Problem Commission on Coloproctology of the Russian Association of Pediatric Surgeons, Member of the Association of Coloproctologists of Russia.

6. Olga G. Mokrushina – MD, Professor of the Department of Pediatric Surgery named after Yu.F. Isakov at the Institute of Maternity and Childhood of Pirogov Russian National Research Medical University, Deputy Chief Physician for Surgery at the Filatov Children's City Clinical Hospital of the Moscow Healthcare Department (Moscow), Member of the Presidium of the Russian Association of Pediatric Surgeons, Member of the Problem Commission on Coloproctology of the Russian Association of Pediatric Surgeons, Member of the Association of Coloproctologists of Russia.

7. Olga V. Shcherbakova – MD, Head of the Surgical Department at the Federal Scientific and Clinical Center of Children and Adolescents of the Federal Medical-Biological Agency of Russia, Member of the Russian Association of Pediatric Surgeons, Member of the Problem Commission on Coloproctology of the Russian Association of Pediatric Surgeons, Member of the Association of Coloproctologists of Russia.

8. Svetlana A. Karavaeva – MD, Associate Professor, Head of the Department of Pediatric Surgery at the North-Western State Medical University named after I.I. Mechnikov, Member of the Presidium of the Russian Association of Pediatric Surgeons, Chairman of the Problem Commission on Neonatal Surgery, Member of the Problem Commission on Coloproctology of the Russian Association of Pediatric Surgeons.

9. Aleksey N. Kotin – PhD in Medicine, Associate Professor of the Department of Pediatric Surgery with a Course of Anesthesiology and Intensive Care at Pavlov First Saint Petersburg State Medical University, Leading Operating Surgeon of the Neonatal Surgery Service of the Children's City Multidisciplinary Clinical Center for High Medical Technologies (Saint Petersburg), Member of the Russian Association of Pediatric Surgeons, Member of the Problem Commission on Coloproctology of the Russian Association of Pediatric Surgeons, Member of the Association of Coloproctologists of Russia.

10. Mikhail A. Akselrov – MD, Associate Professor, Head of the Department of Pediatric Surgery with a Course of Urology and Andrology at the Institute of Maternity and Childhood, Tyumen State Medical University of the Russian Ministry of Health, Head of Pediatric Surgical Department No. 1 at Regional Clinical Hospital No. 2 (Tyumen), Chief freelance pediatric surgeon of the Tyumen Region, Member of the Association of Surgeons of Russia, Member of the Russian Association of Pediatric Surgeons, Member of the Problem Commission on Coloproctology of the Russian Association of Pediatric Surgeons, Member of the Association of Coloproctologists of Russia, Chairman of the Association of Pediatric Surgeons of the Tyumen Region.

11. Vyacheslav G. Svarich – MD, Professor of the Department of Pediatric Surgical Diseases named after G.A. Bairov at Saint Petersburg State Pediatric Medical University (Saint Petersburg), Associate Professor, Honored Doctor of the Russian Federation, Member of the Russian Association of Pediatric Surgeons, Member of the Problem Commission on Coloproctology of the Russian Association of Pediatric Surgeons, Member of the Association of Coloproctologists of Russia.

12. Natalya M. Stepanova – PhD in Medicine, Associate Professor of the Department of Pediatric Surgery at Irkutsk State Medical University, Head of the Center for the Treatment of Anorectal Malformations and Pediatric Colorectal Surgery at the City Yino-Matreninsky Children's Clinical Hospital (Irkutsk), Member of the Russian Association of Pediatric Surgeons, Member of the Problem Commission on Coloproctology of the Russian Association of Pediatric Surgeons, Member of the Association of Coloproctologists of Russia.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of the clinical guidelines:

1. Pediatric surgeons;

2. Anesthesiologists-intensivists;

3. Neonatologists;

4. Pediatricians;

5. Functional diagnostics physicians;

6. Medical geneticists;

7. Bedside nurse (ward nurse);

8. Healthcare organizers (methodologist physician);

9. Medical students, residents, postgraduate students.

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grading of recommendations assessment, development and evaluation (GRADE) for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The clinical guideline update mechanism provides for systematic revision at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or when justified additions/comments to previously approved clinical guidelines arise, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Related documents

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Federal Law of the Russian Federation No. 323-FZ dated November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation";

2. Federal Law No. 326-FZ dated November 29, 2010, "On Compulsory Medical Insurance in the Russian Federation";

3. Order of the Russian Ministry of Health No. 203n dated April 14, 2025, "On Approval of Criteria for Assessing the Quality of Medical Care";

4. Order of the Ministry of Labor of Russia No. 374n dated July 26, 2024, "On Approval of Classifications and Criteria Used in Carrying out Medical and Social Expertise of Citizens by Federal Medical and Social Expertise Institutions";

5. Federal Law No. 178-FZ dated July 17, 1999, "On State Social Assistance".

Appendix B. Physician Action Algorithms

Appendix B1. Examination of infants (from 0 to 3 months of age) with suspected Hirschsprung's disease

Appendix B2. Evaluation of children over 3 months with suspected Hirschsprung disease

Appendix C. Patient Information

Hirschsprung's disease, or congenital agangliosis of the large bowel wall, is a congenital malformation developing in early pregnancy, which consists in the absence of nerve ganglia (clusters of nerve cells) in the bowel wall, leading to impaired bowel function. The aganglionic segment reacts with spasm to the passage of intestinal contents and contributes to the dilatation of the proximal section and the accumulation of fecal masses within it. Migration of nerve cells in the embryo proceeds from the stomach to the rectum. Most commonly, the aganglionic segment is located in the rectum and the upper third of the sigmoid colon (rectosigmoid form), but it can extend to the entire large bowel (total colonic agangliosis) and even the entire intestine. The causes of such impaired nerve cell migration are not fully understood. Factors complicating the course of early pregnancy, such as fetal hypoxia and infection, are considered as possible causes. In recent years, considerable attention has been paid to studying genetic features in children with Hirschsprung's disease. It is known that the number of familial cases of the disease reaches 20-30%.

Hirschsprung's disease does not always manifest from the neonatal period. The earliest symptom requiring attention after birth is delayed passage of the first stool (meconium) for more than 24 hours. If a gas rectal tube is inserted and the bowel is emptied, a "lucid" interval may occur during which liquid stool passes spontaneously in small portions, and the infant may be discharged from the maternity hospital without suspicion of surgical pathology. In a typical case, on the 2nd–3rd day, the baby develops clinical signs of intestinal obstruction: abdominal distension, absence of stool, regurgitation, or bilious vomiting. The severity of clinical manifestations depends on the length of the aganglionic bowel segment and the development of Hirschsprung-associated enterocolitis specific to this disease (lethargy, pallor in the infant, fever, liquid and scant stool, sometimes with blood). The longer the aganglionic part of the intestine, the more frequently the clinical picture of intestinal obstruction develops. Another manifestation of Hirschsprung's disease is chronic constipation. Most often, constipation progresses against the background of introducing complementary foods. This requires dietary regulation, laxatives (ATC code A06A), and bowel emptying depending on age using a gas rectal tube or cleansing enema. Ultimately, these measures prove ineffective, fecaliths form, or an episode of intestinal obstruction occurs.

The diagnosis of Hirschsprung's disease is established during inpatient examination. It includes radiological methods (plain abdominal radiography, contrast enema study of the colon – irrigography) and rectal biopsy. When emergency operations are performed in children with clinical signs of intestinal obstruction in the absence of anatomical causes and with suspected Hirschsprung's disease, a biopsy of various sections of the large and small intestine is performed (surgical colon biopsy).

Treatment for Hirschsprung's disease is exclusively surgical. Confirmation of the diagnosis is an indication for surgery regardless of the child's age. Radical surgery (resection of the pathological section of the colon and creation of a colorectal anastomosis 1–2 cm proximal to the dentate line) is always elective. Preparation for it consists of cleansing or siphon enemas (performing a cleansing enema, performing a siphon enema), and treatment of Hirschsprung-associated enterocolitis (with systemic antibacterial drugs and administration of medications via enemas). If it is not technically feasible to adequately empty the colon or if the child's severe condition does not allow it, a decompressive procedure may be performed, consisting of creating a temporary intestinal stoma (preventive colostomy A16.18.007.001).

Surgical treatment consists of resection of the pathological section of the large intestine with abdominoperineal resection of the rectum and creation of a colorectal anastomosis proximal to the dentate line. The surgery can be performed in various ways. The choice of method is determined by the operating pediatric surgeon. Currently, it is advisable to use minimally invasive resection techniques. Such methods include laparoscopically assisted colectomy with abdominoperineal resection of the rectum or transanal resection of the large intestine with abdominoperineal resection of the rectum. The intestinal stoma (if present) is usually closed at the time of the radical surgery. It is advisable to perform the surgery in a specialized medical institution with experience in treating such patients.

After the surgery, the child will be in the intensive care unit. Transfer to the ward is planned after stabilization of the condition and the initiation of enteral feeding. Children are usually fed after the appearance of spontaneous stool, most often on the 2nd–3rd day after surgical treatment. The duration of hospital stay depends on the course of the postoperative period and the possibility of increasing the feeding volume to the physiological level (according to age). On the 10th–14th day after surgical treatment, an examination of the anastomotic zone (under anesthesia) or its calibration with metal bougies may be required to rule out anastomotic stricture (anal dilation A16.19.040).

After discharge from the hospital, the child should be followed up by the operating pediatric surgeon. Initially, examination (digital rectal examination) is performed weekly, then monthly, and further as needed, but at least once a year. Possible postoperative complications include anastomotic stenosis and the onset of enterocolitis. They are most frequently diagnosed during the first year of life. Restoration of bowel emptying function takes time. In some cases, the absence of spontaneous stool is possible for 3–6 months or even longer after surgery. In this case, there is a need to use cleansing enemas (performing a cleansing enema) and laxatives (ATC code A06A). This requires constant contact with the attending physician (pediatric surgeon) and gastroenterologist. Most children lead a normal lifestyle after surgical treatment for Hirschsprung's disease, but some of them have specific features that come down to an existing tendency to constipation or fecal incontinence. With age, there is a tendency toward improvement in functional outcomes. Success in treatment depends on the interaction between the parents and the pediatric surgeon, regular implementation of recommendations, and dynamic follow-up.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

None provided.