Peptic ulcer disease: clinical guidelines

List of Abbreviations

H₂ blockers – histamine H₂-receptor antagonists (ATC code: A02BA)

H. pylori – Helicobacter pylori

BP – blood pressure

APC – argon plasma coagulation

UAGT – upper alimentary gastrointestinal tract

GV – globular volume

CI – confidence interval

Du – duodenum

GIB - gastrointestinal bleeding

GI – gastrointestinal tract

IMV – invasive mechanical ventilation

PPI – proton pump inhibitors (ATC code: A02BC01)

CT – computed tomography

INR – international normalized ratio

HC – healthcare organization

NSAIDs – nonsteroidal anti-inflammatory and antirheumatic drugs (ATC code: A02BA)

RR – relative risk

ICU – intensive care unit

BV – blood volume

OR – odds ratio

PU – perforated peptic ulcer

ESR – erythrocyte sedimentation rate

TAE – transcatheter arterial embolization

LCE – level of confidence of evidence

US – ultrasound examination

GRS – grade of recommendation strength

NNT – number needed to treat

HR – heart rate

EGD – esophagogastroduodenoscopy

EVS – endovascular vessel embolization

PUD – peptic ulcer disease

UGIB – upper gastrointestinal bleeding

Terms and Definitions

Stopped ulcer-related gastroduodenal bleeding – bleeding from a gastric or duodenal ulcer that has stopped spontaneously by the time of endoscopic examination or surgical intervention.

Acute ulcer with perforation and bleeding – an acute surgical condition occurring in the area of an ulcer as a result of transmural destruction of the gastric or duodenal wall, with the penetration of contents into the free abdominal cavity and bleeding from an eroded vessel into the abdominal cavity or into the lumen of the organ.

Ulcer penetration – a deep defect affecting the wall of the stomach or duodenum, with penetration into adjacent organs, most commonly the liver or pancreas.

Prior (achieved) ulcer-related gastroduodenal bleeding – a clinical term reflecting the objectively confirmed fact that a patient has experienced intraluminal bleeding from a gastric or duodenal ulcer. The term is most commonly used to characterize bleeding that has stopped spontaneously by the time of diagnosis.

Covered ulcer perforation – an ulcer with a perforation opening, typically of small diameter (up to 0.3–0.5 cm), covered by food particles or fibrin, the inferior surface of the liver, an omental epiploon, or the colonic wall.

Ongoing ulcer-related gastroduodenal bleeding – bleeding from a gastric or duodenal ulcer characterized by active blood flow from the ulcer at the time of endoscopic examination or surgical intervention. A sign of ongoing bleeding during an endovascular intervention is the extravasation of contrast agents beyond the vascular bed.

Ulcer bleeding recurrence (recurrent ulcer-related gastroduodenal bleeding) – resumption of bleeding from the same gastric or duodenal ulcer that served as the source of primary bleeding, following its spontaneous or endoscopic cessation, or after surgical intervention. In most cases, bleeding recurrence develops while the patient is hospitalized.

Duodenal stenosis – complete or partial narrowing of the duodenal lumen resulting in intestinal obstruction.

Surgical intervention is an invasive procedure that may be used for diagnostic purposes and/or as a method of treating diseases.

Surgical treatment – a method of treating diseases by dividing and uniting tissues during a surgical operation.

Endovascular treatment – a surgical intervention performed on blood vessels via percutaneous access under image guidance.

Eradication – treatment aimed at eliminating Helicobacter pylori (H. pylori) infection

First-line eradication regimen – an H. pylori infection eradication regimen prescribed as the primary treatment.

Second-line eradication regimen is an eradication regimen prescribed when the first-line H. pylori regimen is ineffective.

Perforated gastric ulcer or perforated duodenal ulcer – an acute surgical condition occurring in the area of an ulcer as a result of transmural destruction of the gastric or duodenal wall, with the penetration of contents into the free abdominal cavity.

Ulcer-related gastroduodenal bleeding – bleeding into the lumen of the gastrointestinal tract originating from a gastric or duodenal ulcer.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Peptic ulcer disease (PUD) is a chronic, relapsing condition characterized by alternating periods of exacerbation and remission, with the primary manifestation being the formation of a defect (ulcer) in the wall of the stomach and duodenum.

Bleeding gastric or duodenal ulcer – an acute condition resulting from ongoing destructive processes in the ulcer crater, leading to the erosion of vessels in its base located within the gastric or duodenal wall, or beyond the organs in cases of ulcer penetration, with the development of bleeding into the gastrointestinal lumen.

Perforated gastric ulcer or perforated duodenal ulcer (PU) – an acute surgical condition occurring in the area of an ulcer as a result of transmural destruction of the gastric or duodenal wall, with the penetration of contents into the free abdominal cavity.

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

According to modern concepts, the pathogenesis of PUD generally boils down to an imbalance between aggressive acid-peptic factors of the gastric contents and the protective elements of the gastric and duodenal mucosa [1].

The aggressive component of ulcer formation includes an increase in parietal cell mass (often genetically determined), hypergastrinemia, impaired neural and humoral regulation of gastric acid secretion, increased pepsinogen and pepsin production, impaired gastroduodenal motility (delayed or accelerated gastric emptying), and colonization of the gastric mucosa by microorganisms Helicobacter pylori (H. pylori).

Impairment of the protective properties of the gastric and duodenal mucosa may result from decreased production and altered qualitative composition of gastric mucus, reduced bicarbonate secretion, lowered regenerative activity of epithelial cells, impaired blood supply to the gastric mucosa, and a reduced prostaglandin content in the gastric wall (e.g., when taking nonsteroidal anti-inflammatory and antirheumatic drugs [NSAIDs]).

A decisive role in the development of PUD is currently attributed to H. pylori microorganisms, discovered in 1983 by Australian scientists B. Marshall and J. Warren.

The spectrum of adverse effects of H. pylori on the gastric and duodenal mucosa is quite diverse. These bacteria produce a number of enzymes (urease, proteases, phospholipases) that damage the mucosal protective barrier, as well as various cytotoxins. The most pathogenic are the VacA strain of H. pylori, which produces vacuolating cytotoxin leading to cytoplasmic vacuolization and epithelial cell death, and the CagA strain, which expresses the cytotoxin-associated gene. H. pylori promote the release of interleukins, lysosomal enzymes, and tumor necrosis factor in the gastric mucosa, triggering inflammatory processes.

Colonization of the gastric mucosa by H. pylori is accompanied by the development of superficial antral gastritis and duodenitis, leading to elevated gastrin levels followed by enhanced hydrochloric acid secretion. Excessive amounts of hydrochloric acid entering the duodenal lumen, under conditions of relative pancreatic bicarbonate deficiency, promote the progression of duodenitis and cause the appearance of areas of gastric metaplasia in the duodenum (transformation of the duodenal mucosal epithelium to a gastric phenotype), which are rapidly colonized by H. pylori. Subsequently, in unfavorable courses—especially in the presence of additional etiological factors (genetic predisposition, blood group 0 [I], smoking, psychological stress, etc.)—an ulcer defect forms within the metaplastic mucosa. Approximately 80% of duodenal ulcers and 60% of gastric ulcers are H. pylori-associated [2]. H. pylori-negative ulcers are most often caused by the intake of nonsteroidal anti-inflammatory and antirheumatic drugs.

1.3 Epidemiology of the Disease or Condition

It has been shown that 11-14% of men and 8-11% of women may develop peptic ulcer disease (PUD) during their lifetime [3]. In the USA, 500,000 patients with newly diagnosed PUD and more than 4 million patients with disease relapses are identified annually [2, 4]. PUD localized in the duodenum occurs 4 times more frequently than gastric PUD. Among patients with duodenal ulcers, men predominate over women, whereas among patients with gastric ulcers, the male-to-female ratio is approximately equal [5].

In recent years, there has been a downward trend in the hospitalization of patients with uncomplicated PUD both in foreign countries [6] and in Russia. An analysis of the frequency and prevalence of PUD in the Russian Federation based on statistical data from the Russian Ministry of Health for the period from 2006 to 2017 showed that the incidence of PUD decreased from 128.7 to 79.5 per 100,000 population [7, 8]. At the same time, an increase in the frequency of PUD complications (bleeding, perforation) has been noted worldwide, driven by the growing use of NSAIDs [6]. In the UK, more than 2,000 patients die annually from complications of gastric and duodenal ulcer disease associated with NSAID use; in the USA, more than 16,500 patients [9].

In Europe, the incidence of perforated peptic ulcer (PPU) over the past 10-year period decreased from 9.7 to 5.6 per 100,000 population [103, 104, 105]. In Russia, over the same period, the incidence of PPU decreased from 26.9 to 17.1 per 100,000 population. In 2018, across the federal districts of the Russian Federation, the incidence of PPU ranged from 11.7 to 19.5 people per 100,000 population. In the city of Moscow, as of December 31, 2018, the incidence of PPU was 9.7 people per 100,000 population [106, 107, 108, 109].

The male-to-female ratio in PPU is 2:1. The majority of patients are young and middle-aged individuals [104, 105, 106, 108].

In the Russian Federation, the number of patients with bleeding from chronic gastric and duodenal ulcers is 90-160 people per 100,000 population and shows no clear downward trend [10, 11, 200]. Despite the fact that in recent years there has been a decrease in hospitalizations of patients with uncomplicated PUD both abroad [12] and in Russia, an increase in the frequency of PUD complications (bleeding and perforation) is noted, driven by the growing use of NSAIDs [10]. In 2022, 47,483 patients with bleeding peptic ulcer disease were hospitalized in the Russian Federation. Surgical intervention was performed in 5,746 patients (surgical activity rate of 12.1%). Overall mortality was 5.87%, and postoperative mortality was 16.92% [10]. In recent years, there has been a trend toward a decrease in overall mortality from bleeding peptic ulcers due to improvements in endoscopic and endovascular hemostasis methods, as well as the efficacy of modern medical anti-ulcer therapy regimens [13, 14, 15].

1.4 Features of Coding the Disease or Condition

Gastric ulcer (K25)

K25.0 – acute with hemorrhage

K25.1 – acute with perforation

K25.2 – acute with hemorrhage and perforation

K25.3 – acute without hemorrhage or perforation

K25.4 – chronic or unspecified with hemorrhage

K25.5 – chronic or unspecified with perforation

K25.6 – chronic or unspecified with hemorrhage and perforation

K25.7 – chronic without hemorrhage or perforation

K25.9 – unspecified as acute or chronic without hemorrhage or perforation

Duodenal ulcer (K26)

K26.0 – acute with hemorrhage

K26.1 – acute with perforation

K26.2 – acute with hemorrhage and perforation

K26.3 – acute without hemorrhage or perforation

K26.4 – chronic or unspecified with hemorrhage

K26.5 – chronic or unspecified with perforation

K26.6 – chronic or unspecified with hemorrhage and perforation

K26.7 – chronic without hemorrhage or perforation

K26.9 – unspecified as acute or chronic without hemorrhage or perforation

Peptic ulcer, site unspecified (K27)

K27.0 – acute with hemorrhage

K27.4 – chronic or unspecified with hemorrhage

Gastrojejunal ulcer (K28)

K28.0 – acute with hemorrhage

K28.4 – chronic or unspecified with hemorrhage

Other diseases of stomach and duodenum (K31)

K31.1 – adult hypertrophic pyloric stenosis

K31.2 – hour-glass stricture and stenosis of stomach

K31.6 – fistula of stomach and duodenum

K31.9 – disease of stomach and duodenum, unspecified

1.5 Classification of the disease or condition

There is no universally accepted classification of PUD.

First and foremost, depending on the presence or absence of H. pylori infection, peptic ulcer disease is classified as either associated or not associated with H. pylori infection. The latter form is sometimes called idiopathic. There is also a distinction between peptic ulcer disease as an independent condition (essential peptic ulcer disease) and symptomatic ulcers of the stomach and duodenum (drug-induced, stress ulcers, those associated with endocrine pathology, and those occurring with other chronic diseases of internal organs), which arise in the context of other diseases and are linked to specific etiological and pathogenetic factors in their development [17].

Depending on localization, gastric ulcers (cardiac and subcardiac regions, body of the stomach, antrum, pyloric channel) and duodenal ulcers (bulb, postbulbar region), as well as combined gastric and duodenal ulcers, are distinguished. Moreover, ulcers may be located on the lesser or greater curvature, and on the anterior and posterior walls of the stomach and duodenum.

According to the number of ulcer defects, single and multiple ulcers are distinguished, and depending on the size of the defect – small ulcers (up to 5 mm in diameter), medium (6-19 mm), large (20-30 mm in diameter), and giant ulcers (over 30 mm in diameter).

When formulating the diagnosis, the stage of the disease course (exacerbation, healing, remission (scarring)) is indicated, as well as any existing scar-ulcerative deformation of the stomach and/or duodenum and its severity; the presence of PUD complications (including history of): bleeding, perforation, penetration, scar-ulcerative stenosis, and the nature of surgical interventions, if performed, are also specified.

Endoscopic classification of ulcer healing stages according to Sakita-Miwa

A1	H1	S1
A2	H2	S2

Figure 1. Stages of gastric ulcer regression (healing) and their characteristic features:

A (Active). Active stage (exacerbation)

A1. The mucosa surrounding the ulcer appears swollen due to edema; epithelial regeneration is absent.

A2. Mucosal edema around the ulcer has decreased, the ulcer margin is clearly visible, and the first sprouts of regenerating epithelium have appeared at the margin. A red rim is often traced along the perimeter of the ulcer, and a circular white slough is seen directly at the edge. Usually, converging mucosal folds can be traced right up to the ulcer margin.

H (Healing). Healing stage

H1. The layer of white fibrin covering the ulcer becomes thin, and the regenerating epithelium extends directly onto the ulcer base. The gradient between the margin and the bottom of the ulcer smooths out. However, the ulcer crater is still evident, and the ulcer margin is clearly visible. The diameter of the ulcer defect is approximately half to two-thirds of the ulcer diameter in stage A1.

H2. The ulcer defect is smaller than in stage H1, and the regenerating epithelium covers most of the ulcer base. The area of the white fibrin layer is approximately one-quarter to one-third of the ulcer area in stage A1.

S (Scarring). Scar stage

S1. The regenerating epithelium completely covers the ulcer base. The white fibrin layer has completely disappeared. Initially, the regeneration zone appears bright red. Upon targeted examination, a large number of capillaries can be seen. A "red scar" has formed.

S2. Within a period ranging from several months to several years, the initially red scar takes on the color of the surrounding mucosa. A "white scar" has formed.

Regarding the severity of bleeding, the most widespread classification in our country is A.I. Gorbashko's classification of 1982 (Appendix G1) [16], which uses a 3-grade scale distinguishing mild, moderate, and severe bleeding, taking into account both the volume of blood loss and the patient's general condition. The American College of Surgeons bleeding severity scale (Appendix G2) distinguishes 4 classes (degrees) of blood loss – mild, moderate, severe, and massive [19].

To characterize the ulcer – the source of bleeding peptic ulcer disease – based on the results of endoscopic examination, it is standard practice to use the J.F. Forrest classification (1974) (Appendix G5).

For classifying perforated peptic ulcers in Russia, the simplest and most convenient for practical use is the classification proposed by V.S. Saveliev in 2005 [110]. The main classification characteristics of PPU according to V.S. Saveliev, with 2015 additions, are:

1. By etiology: perforation of a chronic or acute ulcer (hormonal, stress-induced, etc.);

2. By localization:

a) gastric ulcers (indicating the anatomical region);

b) duodenal ulcers (indicating the anatomical region);

3. By clinical form:

a) perforation into the free abdominal cavity (typical, covered);

b) atypical perforation (into the omental bursa, lesser or greater omentum – between peritoneal leaves, into retroperitoneal tissue, into a cavity isolated by adhesions);

c) combination of perforation with other complications of the ulcerative process (bleeding, stenosis, penetration, malignant transformation);

4. Based on the severity of peritonitis (according to the current classification, see National Guidelines "Abdominal Surgical Infection", 2011).

1.6 Clinical presentation of the disease or condition

The leading symptom of PUD exacerbation is pain in the epigastric region, which may radiate to the left half of the chest and the left scapula, or to the thoracic or lumbar spine. Pain occurs immediately after eating (in ulcers of the cardiac and subcardiac parts of the stomach), or half an hour to an hour after eating (in ulcers of the gastric body). In ulcers of the pyloric channel and duodenal bulb, late pain is usually observed (2–3 hours after eating), as well as "hunger" pain occurring on an empty stomach and subsiding after eating, and night pain. Pain subsides after taking antisecretory and antacid drugs [5].

During a PUD exacerbation, acid eructation, nausea, and constipation are also common. Vomiting with acidic gastric contents, which brings relief and is therefore induced artificially by patients, has always been considered a sign of PUD, although nowadays it is relatively rare. Weight loss is often noted during an exacerbation of the disease because, despite a preserved and sometimes even increased appetite, patients restrict their food intake out of fear of increased pain.

Clinical symptoms observed during a peptic ulcer exacerbation are not pathognomonic and can occur in other diseases (e.g., chronic gastritis and duodenitis with functional dyspepsia syndrome); therefore, the diagnosis of PUD must be confirmed by instrumental diagnostic methods.

During the period of PUD exacerbation, physical examination often reveals tenderness in the epigastric region upon palpation, combined with moderate resistance of the anterior abdominal wall muscles. Local percussion tenderness in the same area (Mendel's sign) may also be detected. However, these signs are not strictly specific to a PUD exacerbation.

Seasonal periods (in spring and autumn) of increased pain and dyspeptic symptoms are typical for PUD.

In uncomplicated cases, PUD usually proceeds with alternating periods of exacerbation (lasting from 3–4 to 6–8 weeks) and remission (lasting from several weeks to many years). Under the influence of adverse factors (e.g., physical overexertion, use of NSAIDs and/or anticoagulants, alcohol abuse), complications may develop.

These include bleeding, ulcer perforation and penetration, formation of cicatricial ulcer stenosis, and malignant transformation of the ulcer.

Clinical manifestations of peptic gastroduodenal bleeding (PGDB) can be divided into two groups of symptoms: general signs of blood loss (weakness, dizziness, fainting, cold clammy sweat, decreased blood pressure, tachycardia) and symptoms caused by blood entering the lumen of the gastrointestinal tract. PGDB is typically characterized by its onset against the background of a peptic ulcer exacerbation with its inherent pain syndrome. As a rule, patients note a sudden disappearance of pain at the moment the bleeding develops. Vomiting of unaltered blood with clots or "coffee-ground" contents (hematemesis) is more characteristic of bleeding from a gastric ulcer, whereas black tarry stools (melena) are characteristic of bleeding from a duodenal ulcer, although the predominance of certain signs is largely related to the rate of blood loss. A blood loss of 100 ml can lead to the appearance of black, but formed stools. "True" melena (tarry, i.e., black and liquid stools) in an adult occurs with a blood loss of about 500 ml. Rapid and massive blood loss into the intestinal lumen may manifest as hematochezia—the passage of blood with clots through the anus.

Objective examination reveals: altered patient behavior (anxiety, fright or apathy, drowsiness; in severe bleeding – psychomotor agitation, delirium, hallucinations); pallor of the skin; pulse changes (rapid, low volume); blood pressure tends to decrease depending on the severity of blood loss; respiration is rapid. Digital rectal examination, which is mandatory when gastrointestinal bleeding is suspected, helps detect changes in stool color.

Characteristic clinical signs of perforated peptic ulcer (PPU) are:

1. Acute onset of the disease with "dagger-like" abdominal pain (Dieulafoy's sign).

2. Abdominal muscle rigidity ("board-like abdomen").

3. Abdominal tenderness upon palpation.

The patient assumes a forced position with bent knees; pain increases with movement, facial expression is anxious (facies Hippocratica), skin is pale, lips are cyanotic, mucous membranes of the mouth and lips are dry.

Blood pressure is reduced by 5–10%, pulse is slowed (Grekov's sign), breathing is frequent and shallow.

The anterior abdominal wall is tense ("board-like" rigidity), and in the first hour of the disease, sharp pain is noted in the epigastrium and mesogastrium—92% [111].

In the first hour of the disease, positive peritoneal irritation signs appear: Shchetkin-Blumberg, Voskresensky, Razdolsky—98%.

Percussion of the abdomen elicits sharp pain. Disappearance of liver dullness (Clark's sign) and high-pitched tympany over the liver (Spizharny's sign) can be established—37%. If fluid is present in the lower and lateral parts of the abdomen, dullness or flatness of the percussion sound is determined (De Quervain's sign).

Physical examination results may be contradictory, as peritonitis symptoms are observed in 35–50% of patients with PPU. This occurs more frequently with covered ulcer perforation or in patients with atypical localization of the process. Abdominal pain is less pronounced in perforation of ulcers of the posterior wall of the duodenum and the cardiac part of the stomach, when its contents enter the retroperitoneal tissue or omental bursa [112, 113, 114, 115, 181].

Penetration refers to the extension of a gastric or duodenal ulcer into surrounding tissues: the pancreas, lesser omentum, gallbladder, and common bile duct. Penetration of an ulcer causes persistent pain that loses its previous relationship with food intake, elevated body temperature, and an increased ESR in blood tests. The presence of ulcer penetration is confirmed radiologically and endoscopically.

Pyloric stenosis usually develops after the scarring of ulcers located in the pyloric channel or the initial part of the duodenum. Often, this complication is promoted by surgery involving the closure of a perforated ulcer in this area. The most characteristic clinical symptoms of pyloric stenosis are vomiting of food eaten the day before, as well as eructation with the odor of hydrogen sulfide. Palpation of the abdomen in the epigastric region may reveal a "late succussion splash" (Vasilenko's sign); in thin patients, gastric peristalsis sometimes becomes visible. With decompensated pyloric stenosis, patient exhaustion may progress, accompanied by electrolyte disturbances.

Malignant transformation (malignancy) of a benign gastric ulcer is not as frequent a complication as previously believed. Cases of timely unrecognized infiltrative-ulcerative gastric cancer are often mistakenly perceived as ulcer malignancy. Diagnosing ulcer malignancy is not always straightforward. Clinically, it is sometimes possible to note a change in the course of PUD with the loss of periodicity and seasonality of exacerbations. Blood tests reveal anemia and an elevated ESR. The final conclusion is made based on the histological examination of biopsy specimens taken from various areas of the ulcer.

Certain features of the clinical picture are inherent in symptomatic ulcers that occur against the background of other diseases or when taking medications [17].

Thus, "stress" gastroduodenal ulcers refer to acute, usually multiple ulcers of the stomach and duodenum that occur in extensive burns (Curling's ulcers), after traumatic brain injuries and neurosurgical operations (Cushing's ulcers), after major abdominal surgeries, especially those associated with organ transplantation, in acute myocardial infarction, in patients with end-stage chronic renal and hepatic failure, and in other critical conditions. "Stress" ulcers are usually acute, multiple, often asymptomatic, prone to gastrointestinal bleeding, and characterized by high mortality rates, often due to the severe course of the underlying disease.

Among medicinal gastric and duodenal ulcers, acute erosive and ulcerative lesions associated with the use of NSAIDs (NSAID-gastropathy), which block the cyclooxygenase-1 enzyme responsible for prostaglandin synthesis in the gastric wall, are of the greatest importance. Gastroduodenal ulcers occur in 20–25% of patients taking NSAIDs long-term, and erosive lesions occur in more than 50% of patients. Risk factors for their development include older age, a history of PUD, concomitant cardiovascular and liver diseases, high doses of NSAIDs, and concomitant anticoagulant use.

Gastroduodenal ulcers and erosions caused by NSAID use are also frequently multiple, often asymptomatic, and manifest as sudden gastrointestinal bleeding (melena or coffee-ground vomiting). The risk of their development in such patients increases by 4–5 times [19].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of the disease/condition:

The diagnosis of peptic ulcer disease is established based on

1) anamnesic data (characteristic complaints, history of peptic ulcer disease)

2) physical examination (detection of abdominal wall muscle tenderness and resistance upon palpation)

3) instrumental examination (detection of an ulcer defect during endoscopic and radiological examination of the stomach and duodenum

The diagnostic program for bleeding peptic ulcer of the stomach and duodenum (PUGSD) should: 1) establish the fact of acute bleeding into the lumen of the upper gastrointestinal tract; 2) identify the source of bleeding; 3) determine the severity of blood loss. In life-threatening bleeding, diagnostic studies must be performed concurrently with emergency management measures.

Diagnostic criteria:

The diagnosis of acute PUGSD is established based on a combination of general clinical signs of blood loss; signs of bleeding into the gastrointestinal tract lumen; anamnestic and laboratory data confirmed by the results of EGD. Upon admission to the hospital, the patient must be immediately examined by a surgeon, and emergency laboratory diagnostics must be performed.

• In patients with PUGSD, to determine the severity of blood loss, it is recommended to use the A.I. Gorbashko classification, 1982 [16] (Appendix G1), and the ACS (American College of Surgeons) evaluation scale [1] (Appendix G2) [16, 19].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In patients with PUGSD, to determine the severity of blood loss, it is recommended to use the Shock Index (Appendix G7) [20].

GRL CLEL 4Recommendation Grade C (Level of Evidence – 4).

• In patients with PUGSD, it is recommended to assess the risk of rebleeding based on a combination of clinical and endoscopic data [11, 15, 21, 22].

GRL CLEL 4Recommendation Grade C (Level of Evidence – 4).

Comment. Criteria for a high risk of rebleeding include clinical signs (history of collapse, severe blood loss, severe concomitant comorbidities) and laboratory findings mainly reflecting the intensity of bleeding, as well as endoscopic signs (bleeding types FIA–B, FIIA–B, depth, size, and location of the ulcer) [11, 15, 21]. To assess the risk of PUGSD recurrence and determine further management tactics, the AIMS65 score (Appendix G3), Glasgow–Blatchford Bleeding Score (Appendix G4), and the repeatedly validated Rockall score (Appendix G6) can be used.

2.1 Complaints and Anamnesis

Complaints and anamnestic data characteristic of patients with peptic ulcer disease are described in subsection 1.6.

• In a patient with signs of upper gastrointestinal bleeding, it is recommended to evaluate complaints, history of the present illness, and personal history upon admission to the hospital, but this should not cause a delay in emergency diagnostic and therapeutic measures [12, 13, 14, 19, 21, 23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. It is important to find out how long ago the bleeding started; whether presyncope or loss of consciousness was noted; whether there were single or recurrent episodes of hematemesis, the volume and nature of the vomitus (bright red or dark blood, clots, "coffee-ground" material); and the frequency of melena episodes. Frequently (in 60–70% of patients), the history indicates the presence of "non-ulcer" conditions that can be complicated by upper gastrointestinal bleeding (gastric tumors, liver cirrhosis, Mallory–Weiss syndrome, etc.). In a significant number of patients with PUGSD, bleeding occurs against the background of an exacerbation of peptic ulcer disease, or a history of typical signs of this disease with characteristic "ulcer" pain and seasonal exacerbations can be elicited. In some patients, there may be indications of the ineffectiveness of prior surgical treatment, where the newly appeared pain syndrome should be attributed primarily to the formation of a peptic ulcer.

It is necessary to identify conditions that may cause the development of acute PUGSD: severe concomitant diseases (coronary artery disease, myocardial infarction, heart failure, cerebrovascular accident, renal and hepatic failure, oncological and hematological diseases); treatment with antithrombotic agents (ATX code: B01A).

• Upon admission to the emergency department of a patient with suspected perforated ulcer (PU), it is recommended to have an examination by a surgeon to rule out or confirm this diagnosis and determine further management [108, 110].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• When interviewing a patient with suspected PU, the physician is recommended to pay attention to the presence of Dieulafoy's symptom (acute "dagger-like" abdominal pain) and a history of ulcers [108, 110].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Sudden onset of intense "dagger-like" pain is associated with the rupture of gastric or duodenal contents into the abdominal cavity and peritoneal irritation.

2.2 Physical Examination

Physical examination data characteristic of patients with peptic ulcer disease are presented in subsection 1.6.

• A patient with signs of upper gastrointestinal bleeding is recommended to undergo an examination upon admission, including the assessment of all major body systems; transrectal digital examination (A01.19.004); and gastric tube placement when necessary [12, 13, 14, 15, 19, 21, 23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Objective examination data combined with complaints and history, already at the stage of patient admission, make it possible to judge the severity and suspected source of bleeding, as well as concomitant diseases. Confused consciousness, marked pallor of the skin and conjunctiva, rapid pulse of low volume and tension, decreased blood pressure and pulse pressure, the presence of a large amount of blood and clots in the stomach, and black liquid or blood-tinged contents upon rectal examination are signs of acute massive bleeding.

Inspection of the skin and visible mucous membranes may reveal their subicteric or yellowish tint, the presence of spider angiomas, dilation of the subcutaneous veins of the anterolateral abdomen, which typically occurs in liver diseases; intradermal or subcutaneous hemorrhages, and multiple telangiectasias in blood vessel diseases and blood coagulation disorders. Clinical observations have verified that blood pressure below 100 mm Hg and a heart rate of more than 100 beats per minute in a patient with normal baseline pressure correspond to a blood loss of about 20% of the circulating blood volume. Percussion (A01.16.004) and palpation (A01.16.003) in some cases allow the detection of a gastric tumor, hepatosplenomegaly, signs of ascites, and enlarged dense lymph nodes. The patient's examination must be completed with a digital rectal examination, followed by gastric sounding. The objective data thus obtained, regardless of the presence or absence of anamnestic indications of hematemesis and melena, are important signs supporting the clinical diagnosis.

2.3 Laboratory Diagnostics

• All patients with peptic ulcer disease are recommended to undergo a complete blood count (B03.016.002) to rule out anemia as a consequence of occult ulcer bleeding [19].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comments. The complete blood count in the uncomplicated course of peptic ulcer disease most often remains without significant changes, but anemia may also be detected, indicating overt or occult bleeding.

• All patients with peptic ulcer disease are recommended to undergo a fecal occult blood test to rule out occult ulcer bleeding [24].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comment. Fecal occult blood testing holds a specific place in the diagnosis of peptic ulcer exacerbations. When interpreting its results, it must be remembered that a positive fecal occult blood test is also found in many other diseases, which requires their mandatory exclusion.

• In patients with refractory peptic ulcer disease, serum gastrin level testing is recommended to rule out Zollinger–Ellison syndrome [25].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. The pathogenesis of gastroduodenal ulcers in Zollinger–Ellison syndrome is associated with extreme gastric acid hypersecretion resulting from a gastrin-producing tumor in patients (most commonly in the pancreas). These ulcers are usually multiple, localized not only in the stomach and duodenum but also in the jejunum and sometimes the esophagus, and present with severe pain and intractable diarrhea. Examination of such patients reveals sharply elevated gastric acid secretion (especially under basal conditions) and an increased serum gastrin level (3–4 times above normal). Provocative tests (with secretin, glucagon), pancreatic ultrasound and CT, and gastric endosonography assist in recognizing Zollinger–Ellison syndrome.

Laboratory tests in patients with gastrointestinal bleeding generally include urgent blood grouping (ABO system, Rhesus system, and Kell antigen), complete blood count (CBC), blood sodium, potassium, and chloride levels, blood gas analysis (acid-base balance), blood osmolality, blood urea and creatinine, prothrombin time (PT) in blood or plasma, international normalized ratio (INR), blood fibrinogen, blood glucose, total protein, albumin, total bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) [12, 13, 14, 15, 19, 21, 23].

A drop in hemoglobin, a decrease in red blood cell count, and a reduction in hematocrit clearly indicate the severity of blood loss. However, in the first hours following the onset of acute bleeding—even when severe—hemodilution has not yet developed, so these parameters may change insignificantly. In addition to anemia resulting from acute blood loss and the effect of blood spilled into the lumen of the digestive tract, there is often moderate leukocytosis and hyperbilirubinemia (due to the indirect fraction), along with elevated urea levels at normal creatinine values, which is associated with the syndrome of intestinal blood reabsorption.

The measurement of circulating blood volume (CBV) and its components using dyes and radioisotopes is currently practically obsolete. The severity of the patient's condition and their individual reactions to the sustained blood loss are quite accurately characterized by a number of parameters of central hemodynamics, oxygen transport, and metabolic disorders (blood urea, electrolytes, acid-base status, plasma osmolality, etc.).

Blood loss, especially severe, can lead to hypocoagulation with prolonged blood clotting time, decreased prothrombin and fibrinogen levels, up to the development of acute hyperfibrinolysis.

2.4 Instrumental Diagnostics

• In all patients with suspected peptic ulcer disease, in the absence of contraindications, esophagogastroduodenoscopy (EGD) (A.03.16.001) is recommended to confirm the diagnosis [2].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. Elective endoscopic examination confirms the presence of an ulcer defect, clarifies its location, shape, size, depth, and the condition of the ulcer base and edges, and allows for the detection of signs of penetration, scar deformity, and luminal stenosis. Elective endoscopic examination makes it possible to detect other concomitant changes in the mucous membrane and determine disorders of gastroduodenal motility. To assess the stage of the ulcer process (exacerbation, healing, scarring), it is advisable to use the internationally accepted Sakita-Miwa classification (Fig. 1).

When an ulcer is located in the stomach, multiple (at least 6 fragments) forceps biopsies must be performed in all cases from the most altered edges of the ulcer defect, followed by morphological examination of the biopsy material to rule out or confirm the malignant nature of the ulcerous lesion.

When an ulcer is located in the duodenum, there is usually no need to perform a biopsy from the edges of the ulcer defect, as such ulcers are extremely rarely malignant. Benign duodenal ulcers should be differentiated from ulcerated forms of neuroendocrine and subepithelial tumors, as well as from the invasion of adjacent organ tumors into the duodenum, most frequently the pancreas. In these cases, a biopsy is undoubtedly necessary.

Patients with gastric ulcers should undergo a follow-up endoscopic examination with repeat multiple (at least 6 fragments) forceps biopsies at the end of the course of conservative treatment. This primarily applies to patients who continue to experience symptoms of peptic ulcer disease despite an appropriate course of drug therapy, or if the etiology of the ulcer remains insufficiently clear.

Patients with duodenal ulcers should undergo a follow-up endoscopic examination in cases where distinct clinical symptoms persist despite the treatment provided, in order to rule out refractory peptic ulcer disease and non-peptic etiology of the ulcer.

• In patients with suspected peptic ulcer disease in whom an endoscopic examination cannot be performed, X-ray examination of the stomach and duodenum is recommended to confirm the diagnosis [26].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comment. X-ray examination reveals a direct sign of peptic ulcer disease—a "niche" on the contour or relief of the mucous membrane—and indirect signs of the disease (local circular spasm of muscle fibers on the stomach wall opposite the ulcer in the form of a "pointing finger," convergence of mucosal folds toward the "niche," scar-ulcerative deformation of the stomach and duodenal bulb, fasting hypersecretion, and gastroduodenal motility disorders).

Currently, X-ray examination for the diagnosis of peptic ulcer disease is resorted to much less frequently than before. It is used in cases where, for some reason (e.g., presence of contraindications), endoscopic examination cannot be performed; when it is necessary to evaluate the peristalsis of the stomach wall for differential diagnosis with infiltrative-ulcerative cancer; or when it is necessary to clarify the nature of gastric evacuation.

Diagnosis of perforated peptic ulcer. Instrumental examination methods allow for the detection of characteristic signs of a perforated ulcer: free gas in the abdominal cavity, free fluid in the abdominal cavity, the presence and location of the ulcer, and the perforation site.

• All patients with suspected perforated peptic ulcer are recommended to undergo a plain abdominal X-ray to detect free gas [103, 112, 113, 114, 115, 116, 117, 119, 181].

GCR BLOCE 2Level of recommendation validity B (Level of evidence – 2).

Comment. The diagnostic accuracy of plain radiography ranges from 30% to 85%. The examination is performed in the upright position. Gas in the free abdominal cavity is detected on the radiograph as a crescent-shaped layer between the diaphragm and the liver, and the diaphragm and the stomach. In severe conditions, the examination can be performed in the lateral decubitus position. However, a negative X-ray does not rule out a possible perforation. Therefore, some authors believe that in the case of overt signs of peritonitis, abdominal computed tomography should be the primary imaging modality.

• In all patients with suspected perforated peptic ulcer when other diagnostic methods are uninformative and technical facilities are available at the medical institution, abdominal computed tomography (CT) is recommended [112, 113, 115, 118, 119, 120].

GCR BLOCE 2Level of recommendation validity B (Level of evidence – 2).

Comment. Abdominal CT for perforated peptic ulcer has a high diagnostic accuracy of 98% [112, 115, 118, 119]. CT allows for the detection of: free gas in the abdominal cavity, free fluid in the abdominal cavity, thickening of the gastric or duodenal walls in the ulcer zone, and identification of the ulcer and perforation site [112, 115, 118, 119, 120, 121, 181].

• In patients with suspected perforated peptic ulcer with no signs of free gas in the abdominal cavity according to imaging methods, oral administration or administration via a nasogastric tube of a water-soluble contrast agent (V08A Iodine-containing X-ray contrast media) with an X-ray examination (plain abdominal X-ray or abdominal CT) is recommended to detect contrast leakage outside the gastrointestinal tract [113, 115, 118, 120].

GRL CLEL 4Recommendation Grade C (Level of Evidence – 4).

• In all patients with suspected perforated peptic ulcer who have a negative X-ray or where CT is not feasible, an ultrasound examination (complex) of the abdominal organs is recommended to detect free gas and free fluid in the abdominal cavity [121, 122, 123, 124].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Complex abdominal ultrasound has a high cumulative diagnostic accuracy for perforated peptic ulcer of 91%. Ultrasound can detect a thickened (hypoechoic) area of the organ wall containing the perforation. The ultrasound sign of ulcer perforation is a disruption of the outer contour of the organ wall in the area of the ulcer defect, which is filled with highly echogenic contents and is located precisely within the thickened zone. On ultrasound, the ulcer defect most commonly appears as a cone or an irregular cone-shaped "fish-eye" formation (according to T. Yoshizumi) [125]. When walled-off perforation is suspected, the cumulative value of ultrasound is: diagnostic accuracy 80.0%, specificity 85.7%, sensitivity 66.7%. However, the role of ultrasound in the diagnosis of perforated peptic ulcers requires further clarification [115].

• Esophagogastroduodenoscopy (EGD) is recommended for patients with suspected perforated peptic ulcer in ambiguous clinical and instrumental presentations (absence of peritoneal signs, absence of radiological signs of pneumoperitoneum) and for diagnosing other complications of peptic ulcer disease (bleeding, pyloroduodenal stenosis) [130, 215].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. EGD makes it possible to establish the presence of a perforated peptic ulcer in 90% of cases [130]. In cases of sealed perforation, in the absence of free air in the abdominal cavity according to diagnostic imaging, EGD can reveal an ulcer defect with perforation, while a repeat radiological examination after EGD may show signs of free air in the abdominal cavity. In addition, endoscopy also allows for a biopsy and helps rule out pyloroduodenal stenosis.

• Diagnostic laparoscopy is recommended for patients with suspected perforated peptic ulcer when there is no free gas in the abdominal cavity, but suspicion of hollow viscus perforation persists [110, 115, 127, 129].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Laparoscopy can reveal typical peritoneal exudate mixed with gastric contents or bile, identify the perforation site, determine its location, dimensions, severity of the ulcer infiltrate, and assess the presence, extent, and severity of peritonitis. Diagnostic laparoscopy can be converted into a therapeutic surgery.

• All patients with perforated peptic ulcer are recommended to undergo bacteriological examination of peritoneal fluid for aerobic and facultatively anaerobic opportunistic microorganisms, microbiological (cultural) examination of peritoneal fluid for anaerobic non-spore-forming microorganisms, and microbiological (cultural) examination of peritoneal fluid for fungi (yeast and mold) with determination of antimicrobial susceptibility during surgery [115, 131, 142].

GPR CLOC 4Grade of Recommendation C (Level of Evidence – 4).

Comment. Abdominal contamination with GI contents in perforated peptic ulcer naturally leads to infectious complications, with a frequency ranging from 17% to 63%. The most common bacterial complications are wound and respiratory infections. Fungal infection in patients with perforated peptic ulcer increases the risk of severe infectious complications and is associated with a longer hospital stay [131].

• Emergency endoscopic examination – esophagogastroduodenoscopy (EGD) (A03.16.001) is recommended for all patients with acute upper gastrointestinal bleeding, under procedural sedation with monitoring of vital signs during anesthesia (B03.003.006), concurrently with infusion-transfusion therapy [15, 27, 28].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. EGD must be performed within 2 hours of patient admission. The endoscopic method is of decisive importance for identifying the source and nature of bleeding, assessing the need and possibility of endoscopic hemostasis/bleeding prophylaxis, and predicting the risk of recurrent bleeding

• Before performing EGD, patients with suspected gastroduodenal ulcer bleeding are recommended to undergo gastric tubing (A11.16.009) followed by gastric lavage (A11.16.008) [15].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. The European Society of Gastrointestinal Endoscopy (ESGE) considers it acceptable for this purpose to also use gastrointestinal motility stimulants (ATC code: A03F) or #erythromycin (ATC code: J01FA01) (100–200 mg IV twice daily). ESGE also notes the necessity of tracheal intubation prior to EGD in patients with ongoing active bloody vomiting, encephalopathy, or agitation to protect the patient's airway from potential aspiration of gastric contents [12, 216].

• If a large amount of blood, blood clots, or food masses is detected in the gastric lumen during EGD, it is recommended to withdraw the flexible medical endoscope for gastrointestinal examination and evacuate the contents via a gastric tube [15].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In patients with bleeding peptic ulcer, it is recommended to stratify the source of ulcer bleeding according to the J.F. Forrest classification (1974) (see Appendix G) [13, 23].

GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).

Comment. Urgent endoscopic examination makes it possible to determine the location of the ulcer defect (the bleeding source), its size, depth, condition of the base and edges, reveal signs of ulcer penetration or sealed perforation, scarring and stenosis, and detect additional erosive and ulcerative lesions of the stomach and duodenum. In a patient with bleeding peptic ulcer and gastric localization of the ulcer, it is necessary to consider multiple gastric biopsies via endoscopy (A11.16.002) followed by pathomorphological examination of the gastric biopsy (surgical) material to rule out malignancy of the ulcer lesion. If biopsy during initial endoscopy poses a risk of re-bleeding, its performance should be deferred and carried out during follow-up EGD. In a patient with bleeding peptic ulcer and duodenal localization of the ulcer, routine biopsy from the edges of the ulcer defect is impractical. Benign duodenal ulcers should be differentiated from ulcerated forms of neuroendocrine and subepithelial tumors, as well as from invasion into the duodenum by tumors of adjacent organs, most commonly the pancreas. In such cases, biopsy is justified [12, 13, 14, 19, 21, 23].

• Emergency endoscopic examination/intervention (within 24 hours of bleeding onset and within the first two hours of admission) is recommended for all patients with acute upper gastrointestinal bleeding [199, 200].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. The endoscopic method is of decisive importance for identifying the source and nature of bleeding, assessing the need and feasibility of endoscopic hemostasis/bleeding prophylaxis, and predicting the risk of recurrent bleeding. That is why all patients with upper GI bleeding are indicated for emergency EGD. Endoscopy should preferably be performed using a therapeutic endoscope with forward-viewing optics and a wide instrument channel, featuring the ability to deliver a directed jet of fluid to wash away blood and clots and to aspirate contents through the biopsy channel parallel to the instrument inserted into it, on a functional table that allows changing the patient's position. In necessary cases (when it is impossible to fully visualize the bleeding source and properly guide the respective instrument to the bleeding site), wide-channel therapeutic duodenoscopes are used. Modern video endoscopic systems providing high-quality imaging of the bleeding source on a monitor screen provide invaluable assistance for the coordinated work of the operating team.

Declining emergency endoscopic diagnostics in exceptional cases may be justified in ongoing profuse bleeding, especially if history data and available medical records suggest its ulcerous etiology. However, if a round-the-clock endoscopic service is available, emergency esophagogastroduodenoscopy can also be performed in such patients; it is carried out directly on the operating table and is considered part of pre- or intraoperative revision.

Endoscopic diagnostics is not indicated for patients in agonal condition requiring resuscitation measures. The decision on the impossibility of performing EGD is made jointly by the attending surgeon, anesthesiologist-resuscitologist, and endoscopist.

• To increase the diagnostic and therapeutic value of EGD, it is recommended to clear the stomach of blood, clots, and food residues upon hospital admission by placing a large-bore gastric tube, washing, and evacuating the gastric contents [11, 199, 200].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. This purpose can also be achieved using drugs that accelerate gastric evacuation, in particular, slow intravenous bolus or drip administration of 200 mg of #erythromycin [216]. If medical history and clinical presentation strongly suggest that the upper gastrointestinal tract is free of contents, EGD may be undertaken without placing a gastric tube and without administering prokinetics. This decision is made jointly by the attending surgeon and the endoscopist.

Comment. Performing EGD in extremely severe patients with decompensated comorbid conditions is advisable only in situations where an "endoscopic intervention of despair" is undertaken concurrently with intensive care, directly to stop ongoing bleeding.

• If a large amount of blood, clots, or food debris—which cannot be displaced or removed through the instrument channel of the endoscope, thereby preventing a complete examination and hemostatic intervention on the bleeding source—is detected in the stomach lumen during diagnostic EGD, it is recommended to withdraw the endoscope and wash out/evacuate the contents via a large-bore gastric tube [6, 202].

GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).

Comment. At the very beginning of the endoscopic examination, blood, clots, and residual lavage fluid are completely removed from the lumen and mucous membrane through the biopsy channel of the device whenever possible. If blood and clots cannot be removed completely, bringing the bleeding source into a position accessible for examination and convenient for manipulation is achieved by changing the patient's position on the endoscopic table, breaking up and displacing clots with instruments (polypectomy snare, Dormia basket), targeted washing of the bleeding source by intensive jet irrigation through a separate endoscope channel (preferred) or through a catheter. Under conditions of ongoing bleeding, it is advisable to perform emergency additional preparation of the upper digestive tract for EGD directly on the endoscopic table, including the use of a fast-acting prokinetic (#erythromycin) [216].

• During urgent diagnostic EGD, the source of peptic ulcer bleeding is recommended to be evaluated according to the J.F. Forrest classification (1974) (see Appendix G) [203].

GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).

Comment. When performing an urgent endoscopic examination in a patient with gastroduodenal bleeding, it is necessary to examine all parts of the gastrointestinal tract accessible to this type of examination, regardless of the number of bleeding sources found in the esophagus or proximal stomach. To avoid diagnostic errors, the examination should be conducted with particular care in patients with anemia, as well as in patients with distinct clinical signs of massive bleeding but "minimal" endoscopic manifestations ("discrepancy between clinical presentation and findings"). In doubtful cases, if the facility has the technical capabilities, the video recording of the examination should be reviewed in a medical panel (consilium) with more experienced specialists, or repeated.

Urgent endoscopic examination confirms the presence and clarifies the localization of the ulcer defect that served as the source of bleeding, its size, depth, and the state of its base and edges. EGD allows for the detection of signs of penetration or covered perforation of the ulcer, scarring deformity and stenosis of the organ lumen, as well as additional erosive and ulcerative lesions of the stomach and duodenum.

• When a bleeding ulcer is localized in the stomach, it is recommended to perform multiple forceps biopsies from the edges of the ulcer defect followed by morphological examination to rule out malignant transformation of the ulceration [204].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

Comment. In cases where biopsy during initial EGD is hazardous in terms of rebleeding or technically difficult, performing a biopsy during follow-up EGD is justified. The number of biopsy specimens taken along the perimeter of the ulcer should be at least 6.

• When an ulcer is localized in the duodenum, routine biopsy from the edges of the ulcer defect is not recommended, as such ulcers are extremely rarely malignant [204].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

Comment. Benign duodenal ulcers should be differentiated from ulcerated forms of neuroendocrine and subepithelial tumors, as well as from invasion into the duodenum by tumors of adjacent organs, most commonly the pancreas. In these cases, biopsy is unquestionably necessary.

2.5 Other Procedures

• In all patients with peptic ulcer disease, to determine indications for eradication therapy, it is recommended to test for Helicobacter pylori infection using a 13C-urea breath test or stool antigen test, and—if EGD is performed concurrently—using a rapid urease test [29, 30].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comment. In accordance with the recommendations of the Maastricht VI consensus conference (2022) [29], the most optimal tests for initial diagnosis of H. pylori infection are the ¹³C-urea breath test and H. pylori stool antigen test. Thus, according to the latest Cochrane review and meta-analysis, the sensitivity of the ¹³C-urea breath test is 94% (95% CI: 0.89-0.97), and that of the H. pylori stool antigen test is 83% (95% CI: 0.73-0.90) at a fixed specificity of 90% [30].

If EGD is performed concurrently, the rapid urease test may be used as the primary diagnostic method. When using endoscopic diagnostic methods for H. pylori, at least 2 biopsy specimens from the gastric body and 1 biopsy specimen from the antrum are taken. The serological method for detecting antibodies against H. pylori can be used for the initial diagnosis of H. pylori infection, however, only if the detected antibodies belong to the IgG class. The microbiological (bacteriological) method is currently used to determine individual susceptibility of H. pylori to systemic antibacterial drugs in cases of treatment failure.

To monitor eradication, which is performed 4–6 weeks after the end of eradication therapy, it is best to use the ¹³C-urea breath test or the H. pylori stool antigen test. During this period, patients must not take systemic antibacterial drugs or bismuth preparations (A02BX Other drugs for peptic ulcer disease and GERD). To avoid false-negative results, the intake of proton pump inhibitors (PPIs) must be discontinued 2 weeks prior to the scheduled follow-up test. In addition, a negative test result for H. pylori infection must be confirmed by another diagnostic method.

• In all patients with peptic ulcer bleeding, to determine indications for eradication therapy, it is recommended to consider performing the ¹³C-urea breath test for H. pylori (A07.16.006) [12, 13, 14, 19, 21, 23, 31, 32].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. In accordance with the recommendations of the Maastricht V consensus conference (2016) [33], the optimal tests for initial diagnosis of H. pylori infection are the ¹³C-urea breath test for H. pylori (A07.16.006) and the H. pylori stool antigen test (A26.19.020). The rapid urease test may also be used as a primary diagnostic method [32]. If an urgently performed H. pylori test turns out negative, it must be repeated.

• In all patients with peptic ulcer bleeding, it is recommended to consider monitoring H. pylori eradication to determine the further treatment program [31, 32].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment. To monitor eradication 4–6 weeks after the end of eradication therapy, it is advisable to use the ¹³C-urea breath test for H. pylori (A07.16.006) and/or the H. pylori stool antigen test (A26.19.020). Intake of PPIs must be discontinued 2 weeks prior to the scheduled follow-up test. A negative result must be confirmed by two diagnostic methods [31, 32].

Differential diagnosis of peptic ulcer gastrointestinal bleeding is performed with bleeding from the upper respiratory tract, nasopharynx, and lungs, where blood swallowed by the patient can simulate gastrointestinal bleeding. A carefully taken medical history, patient examination, and instrumental diagnostic methods (targeted chest X-ray, computed tomography of the thoracic cavity, bronchoscopy) make it possible to suspect pulmonary hemorrhage, which is characterized by the bright red color of foamy blood, usually released during a cough or in separate spits.

It should also be remembered that black stools can be observed after taking certain medications (iron supplements, bismuth preparations (A07BB), activated charcoal, etc.). In doubtful cases, laboratory testing of stool for occult blood (A09.19.001) is advisable.

Bleeding from mucosal tears of the esophagogastric junction should be suspected if young patients who abuse alcohol experience multiple bouts of vomiting ending in the appearance of bright red blood in the vomitus.

The presence of vague gastric complaints, weight loss, and deterioration of the patient's general condition (the so-called "small signs" syndrome) suggests a gastric tumor as the cause of bleeding. In such cases, the vomitus most often has a coffee-ground appearance.

Bleeding from esophageal varices is characterized by recurrent vomiting of dark blood; melena usually appears within 1-2 days. Among past medical conditions, liver and biliary tract diseases (primarily liver cirrhosis), as well as recurrent severe attacks of acute pancreatitis, are important to note.

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

Treatment of peptic ulcer disease must be comprehensive and include not only the prescribing of medications, but also a wide range of various measures: dietary nutrition, smoking cessation and discontinuation of alcohol abuse, avoidance of ulcerogenic medications, normalization of work and rest regimens, and spa-resort treatment.

Patients with uncomplicated peptic ulcer disease are candidates for conservative treatment. In most cases, it is carried out on an outpatient basis. However, in the presence of severe pain syndrome, a high risk of complications (e.g., large and giant ulcers), the need for further evaluation to verify the diagnosis (e.g., in case of an unclear nature of the gastric ulcerous lesion), or severe comorbidities, hospitalization of patients is advisable.

3.1. Diet therapy

• In all patients with peptic ulcer disease, diet therapy is recommended to accelerate ulcer healing [34].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Commentary. The fundamental principles of dietary therapy for patients with peptic ulcer disease, developed many years ago, remain relevant today. The recommendations for frequent (5–6 times a day), fractional meals adhering to the rule "six small meals are better than three large ones," along with mechanical, thermal, and chemical sparing of the mucosa, remain valid. The diet must exclude foods that irritate the gastric mucosa and stimulate hydrochloric acid secretion: strong meat and fish broths, fried and heavily peppered foods, smoked and canned goods, condiments and spices (onions, garlic, pepper, mustard), pickles and marinades, carbonated fruit drinks, beer, dry white wine, champagne, coffee, and citrus fruits.

Preference should be given to foods with pronounced buffering properties (i.e., the ability to bind and neutralize hydrochloric acid). These include meat and fish (boiled or steamed), eggs, milk, and dairy products. Pasta, stale white bread, dry sponge cake, and dry biscuits, as well as milk and vegetarian soups, are also permitted. Vegetables (potatoes, carrots, zucchini, cauliflower) can be prepared stewed or in the form of purees and steamed soufflés. Porridges, sweet berry kissels, mousses, jellies, raw grated and baked apples, cocoa with milk, and weak tea can be included in the diet.

One should also remember such simple yet important recommendations as the need to eat in a calm atmosphere, without rushing, while sitting, and chewing food thoroughly. This promotes better impregnation of food with saliva, the buffering capacity of which is quite pronounced.

3.2. Conservative treatment

• In patients with an exacerbation of peptic ulcer disease, antisecretory therapy with proton pump inhibitors (PPIs) for 4-6 weeks is recommended to achieve ulcer healing [2, 3].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. Currently, only antacids, H₂-histamine receptor blockers (H₂-blockers), and PPIs can be considered as baseline anti-ulcer therapy. In 1990, W. Burget et al. [35] published data from a meta-analysis of 300 studies, concluding that gastric and duodenal ulcers scar in almost all cases if intragastric pH >3 can be maintained for about 18 hours per day (the Burget rule). According to one of the latest meta-analyses, H₂-blockers and PPIs are significantly more effective than placebo in achieving ulcer scar formation (OR = 3.49, 95% CI: 3.28-3.72; p <0.0001) and reducing the risk of rebleeding in complicated disease (OR = 0.68, 95% CI: 0.60-0.78; p <0.0001) [36].

Only PPIs can fulfill the requirement of maintaining the necessary duration of increased gastric pH after administration, which is required for the healing of gastroduodenal ulcers. Currently, PPIs are the mainstay of therapy for peptic ulcer disease exacerbations. They are prescribed to relieve pain and dyspeptic symptoms, as well as to achieve scarring of the ulcer defect in the shortest possible time. Numerous randomized comparative studies (including meta-analyses) have demonstrated a significantly higher efficacy of PPIs compared to H₂ blockers in resolving clinical symptoms and achieving ulcer scarring [37, 38]. A recent meta-analysis demonstrated that PPIs are nearly 1.5 times more effective than H₂ blockers regarding epithelialization of the ulcer defect (OR = 5.22, 95% CI: 4.00-6.80 vs. OR = 3.80, 95% CI: 3.44-4.20; p < 0.0001) [36].

Currently, there is a pharmacotherapy protocol for peptic ulcer disease that prescribes the administration of a selected drug at a specific daily dose: omeprazole** at a dose of 20 mg, lansoprazole at a dose of 30 mg, pantoprazole at a dose of 40 mg, rabeprazole at a dose of 20 mg, esomeprazole** at a dose of 20 mg. The duration of treatment is determined by the results of endoscopic monitoring, which is performed at intervals of 2-4 weeks. Basic antisecretory therapy with PPIs serves as the primary treatment method for idiopathic gastroduodenal ulcers.

When using PPIs metabolized by the cytochrome P450 system, issues of competitive drug interaction with drugs whose metabolism is also carried out via this system may arise acutely. Among all PPIs, pantoprazole and rabeprazole exhibit the lowest affinity for the cytochrome P450 system, their main metabolism being carried out without the involvement of this enzyme system.

• In case of PPI ineffectiveness or the presence of contraindications to their use in patients with peptic ulcer disease exacerbation, to achieve ulcer healing, it is recommended to prescribe H₂-receptor antagonists for 4-6 weeks [2].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. H2-receptor antagonists (ranitidine**, famotidine**) suppress hydrochloric acid secretion by displacing histamine from its binding to H₂ receptors of parietal cells. These drugs maintain intragastric pH > 3 throughout the day for 8-10 hours. Numerous studies have shown that the use of H₂ blockers for 4-6 weeks leads to scarring of the ulcer defect in 70-80% of patients with duodenal ulcers and in 55-60% of patients with gastric ulcers [2]. A recent meta-analysis demonstrated that H₂ blockers are significantly more effective than placebo in achieving ulcer defect scarring (OR = 3.80, 95% CI: 3.44-4.20; p < 0.0001) [36]. Nevertheless, after PPIs became widely used in clinical practice as basic antisecretory therapy, H₂ blockers lost their position and are currently used rarely, mainly when PPI use is impossible or in combination with them to enhance the antisecretory effect.

• In patients with peptic ulcer disease exacerbation, to accelerate ulcer healing times and improve the quality of the resulting scar, the use of rebamipide is recommended [39, 40].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comment. Rebamipide has both gastro- and enteroprotective effects. The mechanisms of action of the drug are based on the induction of the synthesis of prostaglandins E2 and I2 in the gastric and intestinal mucosa, which leads to the activation of its protective properties. As a result, blood flow in the gastric and intestinal wall improves, epithelial cell proliferation increases, mucosal permeability normalizes, oxygen radicals are scavenged, gastric mucus secretion increases, and an anti-inflammatory effect is implemented. Studies have demonstrated higher efficacy of rebamipide in healing gastric ulcers compared to placebo and similar efficacy of rebamipide and omeprazole** [39, 40].

• In all patients with peptic ulcer disease exacerbation and positive testing results for H. pylori infection, eradication therapy is recommended to achieve ulcer healing [41].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment. According to a meta-analysis, the efficacy of H. pylori eradication therapy in achieving ulcer healing exceeded that of antisecretory drugs (34 studies; relative risk (RR) of ulcer persistence 0.66 (95% confidence interval (CI) 0.58-0.76)) [41].

• In all patients with peptic ulcer disease and positive testing results for H. pylori infection, eradication therapy is recommended to prevent subsequent peptic ulcer recurrences [42, 43].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment. A meta-analysis summarizing the results of 5 randomized controlled trials in a population of patients with peptic ulcer disease complicated by perforation demonstrated that eradication therapy significantly reduces the risk of disease recurrence within one year after suture closure of the defect (OR = 1.49; 95% CI: 1.10–2.03) [42]. According to a Cochrane meta-analysis, H. pylori eradication therapy in patients with peptic ulcer disease significantly reduced the recurrence rate of duodenal ulcer (27 studies; OR = 0.20, 95% CI: 0.15–0.26) and gastric ulcer recurrence (12 studies; OR = 0.31, 95% CI: 0.22–0.45) compared with no such treatment [41].

• All patients with peptic ulcer disease who test positive for H. pylori infection are recommended to be prescribed, as first-line eradication therapy ensuring a high eradication rate, one of the following options:

- standard triple therapy including a PPI (at a standard dose twice daily), clarithromycin** (500 mg twice daily), and amoxicillin** (1000 mg twice daily), supplemented with bismuth potassium dicitrate** (120 mg 4 times daily or 240 mg twice daily) for 14 days [44, 45].

or

- classic quadruple therapy with bismuth potassium dicitrate** (120 mg 4 times daily) combined with a PPI (at a standard dose twice daily), #tetracycline (500 mg 4 times daily), and metronidazole** (500 mg 3 times daily) for 10 or 14 days [46, 47, 48, 49].

or

- non-bismuth quadruple therapy (A02BX Other drugs for peptic ulcer disease and gastroesophageal reflux disease (GERD)) which includes standard triple therapy (PPI at a standard dose twice daily), amoxicillin** (1000 mg twice daily), clarithromycin** (500 mg twice daily), supplemented with metronidazole** (500 mg 3 times daily) for 14 days [48].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment. The empirical choice of first-line eradication therapy regimens without determining the susceptibility of H. pylori to systemic antibacterial drugs is based on therapies with the highest proven efficacy. The addition of bismuth tripotassium dicitrate** to standard triple therapy convincingly increases the H. pylori eradication rate above 90% according to the European Registry on H. pylori Management [45]. According to a meta-analysis by S.W. Ko et al., supplementing standard triple therapy with a bismuth preparation increases its efficacy with an OR = 2.81 (95% CI 2.03–3.89), including in cases of proven H. pylori resistance to clarithromycin** [44]. Classical bismuth tripotassium dicitrate**-based quadruple therapy continues to demonstrate an eradication efficacy of over 90% according to both the European registry [46] and meta-analyses [47, 48]. Non-bismuth quadruple therapy (A02BX Other drugs for peptic ulcer disease and gastroesophageal reflux disease (GERD)) or concomitant therapy, including a PPI and a combination of amoxicillin**, clarithromycin**, and metronidazole**, according to meta-analysis, is not inferior in efficacy to classical quadruple therapy [48]. In essence, concomitant therapy is a standard triple regimen augmented with metronidazole**.

• Patients with peptic ulcer disease who test positive for H. pylori infection are recommended to be prescribed standard triple therapy for 14 days as first-line eradication therapy in regions where its efficacy is confirmed [46, 48, 50].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment. According to the European registry data, standard triple therapy administered for 7 days leads to successful eradication in 82.7% of cases; for 10 days, in 84.2%; for 14 days, in 86.2% [46]. A Cochrane meta-analysis of 45 parallel-group randomized controlled trials shows an increase in the H. pylori eradication rate with triple therapy when treatment duration is extended from 7 to 14 days (72.9% vs. 81.9%), with an OR for H. pylori persistence of 0.66 (95% CI: 0.60–0.74) and an NNT of 11 (95% CI: 9–14). A significant effect was observed when combining a PPI with clarithromycin** and amoxicillin** (34 studies [OR = 0.65, 95% CI: 0.57–0.75; NNT 12, 95% CI: 9–16]). A significant increase in H. pylori eradication efficacy occurs when the duration of triple therapy is increased from 7 to 10 days (24 studies, 75.7% vs. 79.9%; OR = 0.80, 95% CI: 0.72–0.89; NNT 21, 95% CI: 15–38) and from 10 to 14 days (12 studies, 78.5% vs. 84.4%; OR = 0.72, 95% CI: 0.58–0.90; NNT 17, 95% CI: 11–46); especially when combining a PPI with clarithromycin** and amoxicillin** when increasing duration from 7 to 10 days (17 studies, OR = 0.80, 95% CI: 0.70–0.91) and from 10 to 14 days (10 studies, OR = 0.69, 95% CI: 0.52–0.91) [50].

• Patients with peptic ulcer disease who test positive for H. pylori infection are recommended to be prescribed a doubled dose of a proton pump inhibitor to increase the efficacy of first-line eradication therapy [51, 52].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

Comment. A meta-analysis demonstrated an increase in the H. pylori eradication rate when high-dose PPIs were prescribed [51]. At the same time, attempts to show via meta-analysis an increase in treatment efficacy with higher drug doses for newer PPIs (rabeprazole and esomeprazole**) were not confirmed, possibly due to the inclusion of studies with low daily doses of rabeprazole (20 mg per day) adopted in some Asian countries, or the high baseline efficacy of these PPIs in H. pylori eradication (85.3% successful therapy with "high" doses and 84.2% with "standard" PPI doses, OR = 1.09 (95% CI: 0.86–1.37), p = 0.47) [52]. A meta-analysis of 16 randomized controlled trials (n = 3680) demonstrated a decrease in the efficacy of triple therapy with standard doses of omeprazole** and lansoprazole in rapid PPI metabolizers. Meanwhile, the efficacy of standard-dose triple therapy with rabeprazole and esomeprazole** did not depend on CYP2C19 genetic polymorphism and did not decrease in rapid PPI metabolizers [53].

• Patients with peptic ulcer disease who test positive for H. pylori infection are recommended to be prescribed a potassium-competitive acid blocker to increase the efficacy of eradication therapy [54, 55].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comment. A meta-analysis demonstrated an increase in the H. pylori eradication rate when triple therapy with vonoprazan was prescribed compared to classical PPIs [54]. A meta-analysis by S. Shinozaki et al. [55] comparing the efficacy of various second-line eradication therapy regimens also demonstrated the advantage of vonoprazan.

• Patients with peptic ulcer disease who test positive for H. pylori infection following failure of standard triple therapy, standard triple therapy supplemented with bismuth potassium dicitrate**, or concomitant therapy are recommended classic quadruple therapy with bismuth potassium dicitrate** as second-line therapy [56, 57].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment. A systematic review with network meta-analysis demonstrated high efficacy of quadruple therapy with bismuth potassium dicitrate** as second-line therapy [56]. According to a meta-analysis by Z. Han et al. [57], bismuth-containing regimens increase the eradication rate in the presence of clarithromycin** resistance by 40%, metronidazole** resistance by 26%, and dual resistance by 59%, making their choice as second-line therapy justified.

• Patients with peptic ulcer disease who test positive for H. pylori infection following failure of classic quadruple therapy with bismuth potassium dicitrate** are recommended a levofloxacin**-based triple regimen or levofloxacin**-based quadruple therapy (PPI at a standard dose twice daily, levofloxacin** 500 mg orally twice daily, and amoxicillin** 1000 mg orally twice daily) or levofloxacin**-based quadruple therapy (PPI at a standard dose twice daily, levofloxacin** 500 mg orally twice daily, amoxicillin** 1000 mg orally twice daily, and bismuth potassium dicitrate** 120 mg 4 times daily) for 14 days as second-line therapy [58, 59, 60, 61].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comment. The efficacy of levofloxacin**-based triple therapy (PPI, levofloxacin**, and amoxicillin**) or levofloxacin**-based quadruple therapy (PPI, levofloxacin**, amoxicillin**, bismuth potassium dicitrate** following the failure of previous eradication therapy courses has been noted in controlled studies and systematic reviews [58, 59].

• For patients with peptic ulcer disease infected with H. pylori, the addition of rebamipide to eradication regimens is recommended to increase the efficacy of eradication therapy [39, 40, 60, 62].

GOM ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment. Two meta-analyses involving 6 and 11 randomized controlled trials confirmed an increase in the eradication rate when rebamipide was included in the regimens [49, 60, 62].

• For patients with peptic ulcer disease who test positive for H. pylori infection, ensuring adherence to the prescribed treatment (compliance) is recommended when prescribing eradication therapy [63, 64].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comment. Compliance should be regarded as a key factor in the success of H. pylori eradication therapy. A controlled study showed that when more than 60% of the prescribed drugs were taken, the eradication rate was 96%, whereas when less than 60% (low compliance) were taken, it was 69% [63]. In a large-scale randomized controlled trial, the eradication rate decreased by 34% with low compliance (less than 80% of prescribed drugs taken), with H. pylori persistence observed in 59% of non-compliant patients [64]. The guidelines of the World Gastroenterology Organisation regarding H. pylori eradication outline measures to improve patient adherence to eradication therapy, ensuring a good treatment outcome. Patients must be informed that successful eradication depends on compliance with the treatment regimen. Time should be taken to counsel the patient, explain how to conduct the complex drug therapy, and evaluate potential side effects of antibiotic therapy. The necessity of completing the course of treatment should be specifically emphasized. It is emphasized that written or graphic information on how to conduct complex eradication therapy can promote high compliance. For the treatment of peptic ulcer disease, a combined drug is registered in the Russian Federation that contains a set of capsules and tablets for standard triple therapy: each strip, including 2 capsules of omeprazole** 20 mg, 2 tablets of clarithromycin** 500 mg, and 4 capsules of amoxicillin** 500 mg, is designed for 1 single day with clear instructions for morning and evening intake. The ready-to-use medication kit for eradication therapy ensures correct dosing and consistent dosing frequency, and improves patient compliance. As demonstrated by a domestic study, this allows achieving an H. pylori eradication rate of over 90% in peptic ulcer disease [65].

• For patients with peptic ulcer disease who test positive for H. pylori infection, the administration of strain-specific probiotics (A07FA: antidiarrheal microorganisms; A07FA02: Saccharomyces boulardii; as well as food supplements (dietary supplements) and functional foods containing them) that have proven efficacy in reducing the incidence of adverse events, including antibiotic-associated diarrhea, is recommended during eradication therapy [66, 67, 68, 69, 70, 71, 72, 73].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment. Specific single-strain or multi-strain probiotic strains (hereinafter — A07FA: antidiarrheal microorganisms; A07FA02: Saccharomyces boulardii; as well as dietary supplements and functional foods containing them) have proven efficacy in H. pylori eradication therapy [66, 67, 68, 69, 70, 71, 72, 73]. It is hypothesized that the administration of probiotics during anti-Helicobacter treatment reduces the incidence of adverse events, thereby increasing eradication efficacy [29].

A recent systematic review with meta-analysis summarizing the results of 42 RCTs demonstrated that the risk of antibiotic-associated diarrhea in patients taking probiotics was significantly lower compared to patients who did not take them (RR = 0.35; 95% CI: 0.27–0.47, p < 0.00001) or received placebo during antibacterial treatment (RR = 0.69; 95% CI: 0.60–0.80, p < 0.00001). The review also presents data from a meta-analysis of 7 RCTs on the use of probiotics combined with systemic antibacterial drugs exclusively during H. pylori eradication, noting a significant 45% reduction in the risk of antibiotic-associated diarrhea in such patients (RR = 0.55; 95% CI: 0.41–0.73, p < 0.0001) [74].

According to a Cochrane review with a meta-analysis of 31 RCTs, probiotic administration also reduces the risk of C. difficile-associated diarrhea by 60% (RR = 0.40; 95% CI: 0.30–0.52) compared to placebo or no probiotic support [75, 76].

A recent controlled study demonstrated that the inclusion of Saccharomyces boulardii (S. boulardii CNCM I-745) orally in a triple eradication regimen for the entire treatment period significantly reduced the number of adverse effects compared to the control group (5.3 ± 3.0 vs. 9.0 ± 3.1, P = 0.028) [74]. The efficacy of Saccharomyces boulardii (S. boulardii CNCM I-745) in both improving tolerability and increasing the H. pylori eradication rate was demonstrated in a recent controlled study. The H. pylori eradication rate in patients who took Saccharomyces boulardii (S. boulardii CNCM I-745) orally at a dose of 500 mg daily was significantly higher than that in the control subjects (86.0% and 74.7%, respectively; p = 0.02). Compared to the control group, patients in the experimental group experienced significantly fewer adverse side effects of eradication (17.0% vs. 55.7%; p < 0.001), including the development of antibiotic-associated diarrhea (2.0% vs. 46.4%; P = 0.02), and demonstrated higher treatment adherence (95.0% of experimental subjects completed the full course of therapy compared to 91.2% in the control group, p < 0.001) [77]. A meta-analysis of 18 studies (n = 3592) showed that adding Saccharomyces boulardii (S. boulardii CNCM I-745) to eradication therapy reduced the risk of total adverse events by 53% (RR = 0.47, 95% CI: 0.36–0.61), the incidence of diarrhea by 67% (RR = 0.37, 95% CI: 0.23–0.57), and increased successful eradication (RR = 1.09, 95% CI: 1.05–1.13) [67]. The meta-analysis also noted the efficacy of certain probiotics containing Lactobacillus acidophilus LA-5 and Bifidobacterium animalis subsp. lactis BB-12 as part of functional foods in reducing the total number of adverse events (RR 0.31, 95% CI 0.20–0.47), preventing antibiotic-associated diarrhea (RR 0.38, 95% CI 0.20–0.72), and improving H. pylori eradication outcomes (RR 1.16, 95% CI 1.05–1.28) [68].

• For patients with peptic ulcer disease and positive H. pylori test results undergoing eradication therapy, the administration of proven metabiotics (postbiotics) in the form of dietary supplements is recommended to increase treatment efficacy and tolerability [78, 79, 80].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Metabiotics (postbiotics) include non-viable bacteria or their components, as well as microbial metabolites that exhibit biological activity in the human body [78, 79]. The efficacy of metabiotics in H. pylori eradication was demonstrated in a multicenter randomized clinical trial involving 90 adult patients with gastritis and peptic ulcer disease. A significant improvement in the outcomes of standard triple eradication therapy was shown when a metabiotic containing inactivated Lactobacillus reuteri DSM 17648 at a dose of 1 × 10¹⁰ CFU twice daily was added to the treatment regimen (p = 0.024). According to the 13C-urea breath test for Helicobacter pylori, successful eradication was achieved in 86.7% of patients taking the metabiotic and in 66.7% of control patients treated with the components of the triple therapy regimen alone. Patients receiving the metabiotic experienced fewer treatment-related side effects such as nausea (60% vs. 86.7%, p = 0.033), diarrhea (36.6% vs. 50.0%, p = 0.35), constipation (20.0% vs. 33.3%, p = 0.026), and dysgeusia (43.3% vs. 60.0%, p = 0.047), although bloating was reported more frequently (40.0% vs. 13.3%, p < 0.001) [80].

• All patients with signs of upper gastrointestinal bleeding are recommended to immediately initiate intensive care at the pre-hospital stage and/or upon admission to the hospital [6, 20, 22, 27].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• All patients presenting with symptoms of ulcer-related gastroduodenal bleeding are recommended parenteral administration of proton pump inhibitors (A02BC) upon admission to the hospital [13, 19, 23, 81, 102].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. Administration of PPIs at the prehospital stage and prior to initial EGDS reduces the need for endoscopic hemostasis, but should not delay endoscopy.

Comment. To stratify patients with peptic ulcer bleeding by severity of blood loss and probability of death, the Glasgow-Blatchford scores [16,20] (Appendix G4); AIMC65 score (Appendix G3), Shock Index (>0.8) [20] (Appendix G7), and ACS score (Appendix G2) may be used.

Management of patients with massive blood loss

The main objectives of intensive care are to ensure adequate cellular oxygen delivery and consumption, and to correct hemostasis.

• In patients with peptic ulcer bleeding and hemodynamic instability, volume resuscitation is recommended to begin with the administration of balanced salt solutions (B05CB) [28].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. Volume expanders and blood plasma products (ATC code: B05AA) may also be considered, but taking into account their negative impact on hemostasis and renal function.

• In patients with peptic ulcer bleeding and verified massive blood loss, it is recommended to immediately activate the massive transfusion protocol [28].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In patients with peptic ulcer bleeding and non-massive blood loss, it is recommended to administer restrictive infusion-transfusion therapy [27].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. In patients with peptic ulcer bleeding, target parameters of perfusion adequacy must be achieved after performing "surgical" hemostasis. Liberal infusion-transfusion therapy and early achievement of hemodynamic target levels (prior to surgical hemostasis) can lead to hemodilution and increased perfusion pressure, which entails increased blood loss [83, 84].

• In patients with peptic ulcer bleeding, it is recommended to perform blood transfusion when hemoglobin levels are less than 70 g/L; in patients with cardiovascular diseases, the transfusion threshold may be higher at 90 g/L [13, 27, 28].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. In patients with peptic ulcer bleeding, fresh frozen plasma transfusion is advisable in the presence of hypocoagulation and ongoing bleeding or a high risk of rebleeding.

• In patients with peptic ulcer bleeding and massive blood loss, it is recommended to maintain a platelet count above 50 x 10⁹/L [27].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. In some patients with peptic ulcer bleeding, it is advisable to use norepinephrine** (ATC code: C01CA03) and epinephrine** (ATC code: C01CA24) to maintain the required perfusion pressure.

The use of norepinephrine** (ATC code: C01CA03) and epinephrine** (ATC code: C01CA24) may also be considered in case of decreased cardiac contractility [27, 28].

Criteria for the restoration of adequate perfusion include: skin condition (mottling, capillary refill time, temperature); level of consciousness; urine output; normalization of acid-base balance and lactate; achievement of target hemodynamics [13, 16].

Criteria for the adequacy of transfusion therapy include: absence of pathological bleeding (provided "surgical" hemostasis has been performed); normalization of hemostasis based on global coagulological tests and/or viscoelastic hemostatic assays [16, 27, 28].

3.3. Endoscopic treatment

• In patients with peptic ulcer bleeding and ongoing ulcer hemorrhage (FIa, FIb), it is recommended to perform hemostasis via a flexible medical endoscope [13, 19, 23, 31].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

• In patients with peptic ulcer bleeding with F2A and F2B hemorrhage, it is recommended to perform endoscopic prevention of recurrent bleeding [13, 19, 23, 31, 201].

Level of Recommendations CLevel of Evidence 5Level of recommendations C (level of evidence – 5).

Comment. If a blood clot is detected in the ulcer base, it should be removed using targeted washing. If the patient has a non-washable, fixed clot-thrombus (FIIb), it can be removed by cutting at the base with a polypectomy snare [13, 19, 23, 31].

• In patients with bleeding gastroduodenal ulcers with stopped bleeding FIIC and FIII, endoscopic prevention of recurrent bleeding is not recommended [13, 19, 23, 31].

Level of Recommendations CLevel of Evidence 5Level of recommendations C (level of evidence – 5).

Comment. In such cases, ensuring adequate drug prophylaxis for recurrent bleeding is essential.

• In patients with bleeding gastroduodenal ulcers, endoscopic arrest (F1A-B) or prevention of bleeding recurrence (F2A-B) is recommended [13, 14, 19, 23, 31].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Endoscopic arrest (prophylaxis of recurrence) of bleeding must be performed within 2 hours of the patient's admission. In patients with bleeding gastroduodenal ulcers, for endoscopic arrest of ulcer bleeding and prevention of its recurrence, it is advisable to use injection hemostasis in combination with thermal methods (diatermocoagulation or argon plasma coagulation of a bleeding vessel (A22.30.033.001)) or clipping [13, 14, 19, 23, 31]. Injection hemostasis as monotherapy does not provide proper efficacy and should be used only in combination with other methods of endoscopic hemostasis. Other local methods of endoscopic hemostasis may be used as an adjunct to combined endoscopic hemostasis [13, 14, 19, 23, 31].

• In patients with bleeding gastroduodenal ulcers, a repeat follow-up endoscopic examination/intervention is recommended in case of inadequate initial examination/hemostasis and at high risk of recurrent bleeding [85, 86].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1).

Comment. Routine follow-up endoscopic examination in all patients with bleeding gastroduodenal ulcers is impractical. In case of inadequate initial examination/hemostasis, a repeat endoscopic examination should be performed within the first few hours after the initial EGD. At high risk of bleeding recurrence, it is advisable to perform a repeat EGD within 12 hours of the initial endoscopy [85, 86].

• In patients with bleeding gastroduodenal ulcers experiencing the first episode of bleeding recurrence in the hospital, it is recommended to perform repeat endoscopic hemostasis [12, 14, 19].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

• In patients with gastric ulcer after successful non-surgical arrest of bleeding, it is recommended to perform a follow-up endoscopic examination with gastric biopsy using endoscopy (A11.16.002) at the end of the course of conservative treatment [87, 88, 161].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment. This recommendation primarily concerns patients who continue to experience ulcer symptoms despite an appropriate course of drug therapy, or whose ulcer etiology remains unclear. Continued treatment of anemia in patients who have suffered ulcer bleeding is carried out on an outpatient basis until hemoglobin levels completely normalize. It is advisable to prescribe oral iron preparations to compensate for iron deficiency in the body, which complies with the Russian Ministry of Health Clinical Guidelines on Iron Deficiency Anemia (ID: 669) [99].

Diet and pharmacotherapy in patients with ulcer-related gastroduodenal bleeding

• In patients with a high risk of bleeding recurrence after its endoscopic arrest/prophylaxis, it is recommended to administer proton pump inhibitors immediately after endoscopic hemostasis [13, 19, 23, 81].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Intravenous administration of proton pump inhibitors is required, for example, omeprazole** or esomeprazole**, at a dosage of 80 mg as a bolus followed by a continuous infusion of 8 mg per hour for 72 hours, which reduces the rate of bleeding recurrence and mortality [19]. Switching to oral forms is advisable 72 hours after the start of therapy [13, 19, 23]. In addition to esomeprazole**, lansoprazole can also be used to stop ulcer bleeding, as it has shown high efficacy and good tolerability when administered intravenously in the treatment of bleeding caused by gastroduodenal ulcers [82].

• In patients with bleeding gastroduodenal ulcers with a low risk of bleeding recurrence, parenteral administration of proton pump inhibitors is recommended after endoscopy for 72 hours, followed by a transition to oral forms until discharge from the hospital and further until complete healing of the ulcer defect—the source of the previous bleeding [13, 19, 23].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment. In patients with a low risk of bleeding recurrence, switching to enteral nutrition is possible within the first few hours after the completion of the endoscopic intervention [13, 19, 23]. Patients with a high risk of bleeding recurrence are allowed to drink and consume liquid food within the first 24 hours after bleeding arrest [87].

• In patients with recurrent bleeding gastroduodenal ulcers and a high risk of bleeding recurrence, it is recommended to use somatostatin and its analogues (ATC code: H01CB) in treatment [13, 21, 83, 217].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment. It is also advisable to use somatostatin and its analogues in case of penetration of a bleeding ulcer into the pancreas, as well as in patients with a combination of bleeding ulcer and portal hypertension [83].

• In patients with bleeding gastroduodenal ulcers, the use of H2-receptor antagonists (A02BA) in treatment is not recommended [13, 19, 23, 83, 221].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

• All patients with peptic ulcer bleeding and confirmed H. pylori infection are recommended to undergo eradication therapy followed by confirmation of successful eradication [1, 2, 3].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Eradication therapy is initiated after switching patients to oral proton pump inhibitors (PPIs) [161]. Successful eradication significantly reduces the risk of peptic ulcer bleeding recurrence [162, 166].

3.4. Endovascular treatment

• In patients with recurrent peptic ulcer bleeding refractory to endoscopic and medical hemostasis, endovascular embolization of the gastric and duodenal arteries (A16.12.051) is recommended as an alternative to surgical treatment [13, 19, 89, 90, 91, 92].

GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2).

Comment. In patients at high risk of rebleeding, prophylactic endovascular embolization of the gastric and duodenal arteries performed after achieving endoscopic and medical hemostasis helps reduce the rate of recurrent bleeding and mortality [93, 94, 95].

3.5. Surgical treatment

• Patients with complicated forms of gastric and duodenal ulcers (bleeding, perforation, etc.) are recommended to be hospitalized in a surgical department for surgical treatment [200, 205, 206, 207, 208].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. Patients with complicated peptic ulcer disease generally require emergency hospital admission. Treatment of ulcer bleeding is advisable to start in the intensive care unit. The main objective of treatment in the intensive care unit is to stabilize the patient's condition—replenishing circulating blood volume, combating manifestations of hypovolemic shock, providing adequate analgesia, treating decompensated comorbidities and systemic inflammatory response syndrome, after which endoscopic, endovascular, and surgical treatments can be applied as indicated [199, 203, 206, 209, 210]. It is important to note that in ulcer bleeding, the risk of death in a comorbid patient directly correlates with the number of comorbidities [211]. This, in turn, requires the physician to be extremely careful when managing comorbid patients and to analyze all risk factors for ulcer complications before they manifest [112].

The main objectives of surgical intervention for peptic ulcer bleeding are: ensuring reliable hemostasis, eliminating the source of hemorrhage when possible, and preventing ulcer recurrence [13, 15, 19, 23].

• Patients with ongoing bleeding when endoscopic hemostasis is ineffective ( અથવા impossible), as well as those with a combination of bleeding and ulcer perforation, are recommended to undergo emergency surgery [13, 15, 19, 23].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment. In cases of recurrent bleeding refractory to endoscopic, medical, and endovascular hemostasis, surgical treatment is indicated. The extent of surgery is determined by the localization and size of the ulcer, the presence of other complications of peptic ulcer disease, and the severity of the patient's condition. In critically ill patients, gastrotomy (or duodenotomy) with suture ligation of the bleeding vessel in the ulcer may be performed [11, 15].

Treatment of patients with recurrent ulcer-related gastroduodenal bleeding

Recurrent bleeding is diagnosed based on established clinical, laboratory, and endoscopic findings.

• For the first episode of recurrent ulcer bleeding, repeat endoscopic hemostasis is recommended [11, 13, 15, 19, 21, 23].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment. In such cases, endovascular embolization of the gastric and duodenal arteries is also advisable for additional prevention of recurrent bleeding.

In patients at high risk of recurrent ulcer bleeding where endoscopic, medical, and endovascular hemostasis cannot be fully performed, urgent surgery may be carried out to prevent further hemorrhages [11, 13, 15, 19, 23].

Treatment of patients with NSAID-associated bleeding

• All patients requiring long-term NSAID therapy are recommended to undergo risk stratification for hemorrhagic complications [96, 97].

GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2).

• In patients at high risk of bleeding, it is recommended to switch to coxibs (ATX code: M01AH) combined with continuous PPI therapy [96, 97, 219].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

If bleeding develops, NSAID therapy must be discontinued (replaced with drugs from other groups).

Management of patients receiving long-term antithrombotic therapy

• If ulcer bleeding occurs in patients on long-term antithrombotic therapy (ATX code: B01A), discontinuation of these drugs is recommended; however, the balance between the risk of cardiovascular complications and the risk of recurrent bleeding must be considered in each individual case [85, 93, 98].

GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)

• Resumption of antithrombotic therapy in patients with peptic ulcer bleeding is recommended as soon as stable hemostasis is achieved [85, 93, 98].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

• Patients with perforation of a gastric and/or duodenal ulcer are recommended to undergo emergency surgery to close the perforation site [108, 110, 112].

GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2).

• Treatment of patients with perforated ulcers should involve the earliest possible closure of the perforation or excision of the ulcer with the perforation, prevention of ulcer recurrence, and prevention of potential surgical complications. The choice of surgical method depends on the individual clinical features of the specific patient [104, 105, 108, 114, 115, 116, 128, 191].

GR BLEL 3Grade of Recommendation B (Level of Evidence – 3).

Comments: Ulcer perforation is a common complication that inevitably leads to peritonitis and carries high mortality among patients, reaching 30%. The highest mortality is observed among elderly patients and in the group with delayed hospital admission (more than 24 hours from the onset of the complication). Open laparotomy has no advantages over laparoscopy. Laparoscopic management—closure of the perforation with peritoneal lavage and drainage—is preferred. However, the clinical presentation of such a severe complication can be very diverse, and experts acknowledge that the scope of surgery primarily depends on the patient's condition. Russian clinical guidelines for the treatment of perforated ulcers discuss surgical options in greater detail [103].

• Conservative management of patients with perforated ulcers is not recommended due to the high risk of complications and mortality [114, 115, 132, 133, 134].

GRL CLEL 4Recommendation Grade C (Level of Evidence – 4).

Comment. Conservative treatment of perforated ulcers, known in medical literature as Taylor's method (1946), has not gained widespread acceptance among Russian surgeons. Meanwhile, Taylor's method is included in treatment protocols abroad and is used in exceptional cases of covered perforation confirmed by oral contrast-enhanced CT. In Russia, the conservative approach for perforated ulcers is used only when the patient and relatives categorically refuse surgery or when surgery is impossible due to the patient's extreme condition and absolute contraindications to surgery.

Taylor's method involves active nasogastric aspiration of gastric contents, antibiotic therapy, antisecretory therapy, detoxification therapy, and analgesia. It has been established that every hour of delay from admission to surgery reduces the probability of survival by 2.4% compared to the previous hour [134].

Preoperative Preparation

• Patients with perforated ulcers are recommended to undergo preoperative preparation, including empirical systemic antibiotics, correction of organ dysfunction caused comorbidities, nasogastric tube placement for gastric decompression, and hygienic preparation of the surgical site. The first dose of systemic antibiotics must be administered before surgery begins [108, 110, 112, 135, 136, 137, 138, 139, 140].

GR BLEL 3Grade of Recommendation B (Level of Evidence – 3).

• To assess the severity of patients with perforated ulcers, it is recommended to use scoring systems (qSOFA, SOFA) [115, 183].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• Patients with perforated ulcers presenting with clinical and laboratory signs of sepsis and decompensation of comorbid conditions are recommended to undergo preoperative preparation in the intensive care unit to reduce mortality. Target physiological parameters are: SBP >65 mmHg, urine output >0.5 mL/kg/h, and normalization of lactate levels [135, 136, 137, 138, 139, 140].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Patients with signs of sepsis, in a state of decompensation, and with unstable vital signs require emergency therapeutic measures in the intensive care unit in parallel with preparation for surgery. The treatment of this group of patients corresponds to the general principles of managing patients with sepsis and vital function decompensation [135, 136, 137, 138, 139, 140].

• In patients with perforated ulcer, it is recommended to initiate broad-spectrum empirical antibiotic therapy (targeting Gram-positive, Gram-negative, and anaerobic bacteria) as soon as possible, followed by de-escalation once the results of microbiological testing of the peritoneal fluid with antimicrobial susceptibility testing are obtained, in order to reduce the risk of postoperative purulent-septic complications [115].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. In the absence of septic complications, antibiotic therapy should be initiated as part of preoperative preparation (30–60 minutes before skin incision); in the presence of septic complications, it should be started as early as possible.

• Postoperatively, patients with a perforated ulcer are recommended a short course of antibiotic therapy (within 3–5 days or until inflammatory markers normalize) to prevent the development of bacterial antibiotic resistance [212].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• Patients with a perforated ulcer are not recommended routine empirical antifungal therapy [220].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. The efficacy of routine empirical antifungal therapy has been disproven. Empirical systemic antifungal therapy is administered to patients at high risk of fungal infection (immunocompromised, elderly, with severe comorbidities, or with a prolonged ICU stay) [141].

• During the surgical treatment of patients with a perforated ulcer, the surgeon is recommended to choose one of three types of surgical interventions: closure of the perforation, excision of the perforated ulcer, or gastric resection. At the same time, the scope of intervention should be kept to a minimum [110, 115, 117, 142, 143, 144, 145, 146, 147, 148, 149, 150].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In patients with a perforated ulcer less than 2 cm in size, recommended management is closure of the ulcer defect using interrupted or horizontal mattress sutures. Application of a greater omentum flap is not a mandatory procedure in this case [115, 147, 148, 150].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. When closing a perforated ulcer, the necessity of applying an omental patch to the ulcer defect remains at the surgeon's discretion. Published retrospective studies fail to prove the superiority of omental patching in ulcer closure. This technique showed no advantage regarding complication rates, operative time, or hospital stay duration [115, 147, 148, 150].

• In the treatment of patients with a perforated ulcer greater than 2 cm in diameter, an individualized approach based on the ulcer location is recommended [115, 149, 150, 151, 152, 153, 154, 155, 156].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In cases of large gastric ulcers with suspected malignancy, resection with urgent intraoperative pathomorphological examination of the surgical specimen (if feasible) is recommended [115, 149, 150, 151, 152, 153, 154, 155, 156].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In cases of large duodenal ulcers, it is recommended to perform resection or closure with or without pyloroplasty and external biliary drainage [115, 149, 150, 151, 152, 153, 154, 155, 156].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• Gastrostomy and duodenostomy are recommended only in exceptional cases when the surgeon cannot eliminate the perforation using any of the methods listed above [115, 149, 150, 151, 152, 153, 154, 155, 156].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Perforation closure can be performed in the majority of cases. Exceptions include the following situations:

1. Cut-through of sutures in the tissues being repaired, doubts regarding the hermetic seal of the closed perforation due to tissue infiltration around the ulcer defect;

2. Pyloroduodenal stenosis;

3. Perforation of a giant or penetrating ulcer;

4. Suspected ulcer malignancy.

Methods for closing the perforation:

1. Closure with interrupted or horizontal mattress sutures;

2. Closure with interrupted single-layer sutures with an omental flap sutured like a cloak over the suture line;

3. Closure with interrupted single-layer sutures with plugging of the perforation by a pedicled omental flap (Oppel–Polikarpov operation).

Closure of a perforated duodenal ulcer may be supplemented by vagotomy at the surgeon's discretion [154, 155, 156, 157, 158, 159]. It should be noted that the eradication of Helicobacter pylori combined with injectable proton pump inhibitors on the 1st postoperative day yields effects comparable to vagotomy and can replace it [160, 161, 162, 163, 164, 165, 166, 167].

When choosing the optimal strategy, one must be guided by the location and size of the ulcer defect and infiltrate, the presence of duodenal stenosis, and the surgeon's proficiency in performing the intervention.

For a perforated callosal gastric ulcer greater than 2 cm in diameter, it is necessary to excise the perforated gastric ulcer along with the infiltration zone, and close the defect in the gastric wall with interrupted sutures without narrowing the gastric lumen [153, 157].

For perforated callosal ulcers of the anterior and posterior walls of the duodenum, the possibility of performing gastric resection should be considered. If gastric resection is not feasible, the ulcer is sparingly excised, the posterior wall wound is closed without tension, and pyloroplasty in any modification is performed on the anterior wall.

Excision of a gastric ulcer on the lesser or greater curvature most often requires mobilization of the stomach, similar to gastric resection. A duodenal ulcer should be excised along with the infiltration zone.

If giant perforated ulcers (greater than 2 cm) complicated by an extensive dense infiltrate cannot be eliminated in a single operation, the procedure should be divided into 2 stages:

Stage 1 — emergency: closure of the perforation is performed regardless of location;

Stage 2 — elective: gastric resection or gastrectomy is performed, potentially with resection of organs involved in the inflammatory process [112, 115, 168, 169, 170].

From the perspective of suppressing gastric acid production, radical operations include distal resection of at least 2/3 of the stomach and antrectomy with various types of vagotomy. An analysis of long-term surgical results using the Visick scale established that the best treatment outcomes were achieved after primary resection of 2/3 of the stomach according to Billroth I (95.2% of patients) and antrectomy with anterior selective and posterior truncal vagotomy (95%); after Billroth II gastric resection, positive results were obtained in 78.1% of patients [170]. Conditions for gastric resection: the patient's compensated state and the surgeon's proficiency in the technique of gastric resection [115, 170].

In the presence of a perforated duodenal ulcer complicated by stenosis, one of the following approaches must be used: close the perforation while creating a long-loop gastroenteroanastomosis with an enteroenterostomy; excise the ulcer with Heineke–Mikulicz pyloroplasty; or perform gastric resection [113, 115, 168, 169, 170]. Isolated closure of a duodenal ulcer in the presence of stenosis leads to the development of gastrostasis and breakdown of the closed perforation.

When two complications of peptic ulcer disease coexist — hemorrhage and perforation of the anterior duodenal wall — closure is required; if closure is not feasible, excision and pyloroplasty are performed [115, 145, 156, 157, 158, 159].

In cases of perforation of the anterior duodenal wall and hemorrhage from a posterior wall ulcer, minimally invasive treatment methods should be prioritized first (endoscopic hemostasis, oversewing of the posterior gastric ulcer with intraoperative endoscopic control), along with closure or excision of the anterior wall ulcer. If minimally invasive methods are ineffective or impossible, gastric resection is indicated [113, 115, 155, 156, 157, 158, 159]. The bleeding vessel in the base of the posterior wall ulcer is identified, oversewn, and ligated. The edges of the posterior wall ulcer are excised circumferentially by 1–2 mm to the depth of the mucosal and submucosal layers. Typically, this restores their mobility and differentiation, allowing the wall defect to be closed over the ulcer base and oversewn vessels without tension or risk of damaging underlying structures of the pancreas, the major duodenal papilla, the common bile duct, and other structures of the hepatoduodenal ligament.

If it is impossible to suture or excise a perforated ulcer, or to perform a gastric resection, a drainage tube or a large-headed self-retaining latex catheter of the Pezzzer type (Charrière scale size 18-20) should be inserted into the perforation, the drainage channel should be sealed with the omental patch, the outer end of the tube should be brought out through a counter-incision onto the anterior abdominal wall, the exudate should be evacuated, and the anterior abdominal wall wound should be closed or a laparostomy should be formed [115, 168, 170]. In the immediate postoperative period, the patient should be consulted at a regional surgery center.

Minimally invasive treatment for PU

• In patients with a perforated peptic ulcer and stable vital signs, laparoscopic surgery is recommended [115, 128, 129, 142, 144, 171-177].

GCR BLEL 1Grade of Recommendation B (Level of Evidence – 1).

• Open surgery is recommended in the absence of laparoscopic equipment or appropriate skills of the surgeon [115, 128, 129, 142, 144, 171-177].

GCR BLEL 1Grade of Recommendation B (Level of Evidence – 1).

Comment. In foreign publications, the frequency of laparoscopic closure of perforated peptic ulcers reaches 23% [171, 174]. The advantages of the laparoscopic approach include reduced pain intensity, lower incidence of postoperative complications, and shorter hospital stay.

Indications for laparoscopic closure of a perforated ulcer:

1. Stable patient condition;

2. Localization of the perforation on the anterior wall of the stomach or duodenum;

3. Small size of the perforation (less than 10 mm for gastric ulcers and less than 6 mm for duodenal ulcers).

Contraindications:

1. Late hospitalization (more than 24 hours after disease onset) [178, 179, 180, 181, 182, 183];

2. Unstable patient condition;

3. Hard-to-reach ulcer localization;

4. Suspicion of ulcer malignancy;

5. Callosal ulcer;

6. Perifocal inflammation of the organ wall up to 10 mm;

7. Secondary diffuse purulent peritonitis, severe sepsis;

8. Presence of concomitant diseases and conditions preventing the creation of capnoperitoneum.

Along with the closure of the perforation, the following procedures can be performed laparoscopically: excision of the perforation, pyloroplasty, bilateral truncal, selective and selective proximal vagotomies, and gastric resection.

An alternative to laparoscopic closure of a perforated ulcer is laparoscopically assisted closure of a perforated ulcer, which includes: diagnostic laparoscopy, removal of effusion, and peritoneal lavage; a minilaparotomy stage and closure of the perforation, closure of the mini-access; and a stage of laparoscopic lavage [111, 113].

• In patients with a perforated peptic ulcer and unstable vital signs, surgery via a laparotomy approach is recommended [115, 128, 129, 142, 144, 171, 172, 173, 174, 175, 176, 177].

GCR BLoE 1Grade of Recommendation B (Level of Evidence – 1).

• In patients with a perforated peptic ulcer, prognostic systems including the J. Boey, PULP, and ASA scores are recommended for risk stratification and outcome prediction [178, 182, 183].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4).

Comment. The J. Boey score is the most widely used among foreign surgeons due to its high prognostic accuracy (93.8%). It consists of 3 risk factors, each scored at 1 point: hemodynamic instability upon admission (systolic blood pressure less than 100 mm Hg), late hospitalization (over 24 hours), and concomitant diseases (ASA >3). If 2–3 factors are present (2–3 points on the J. Boey scale), the European Association for Endoscopic Surgery (EAES) advises against using laparoscopic surgery in these patients and suggests proceeding directly with an open approach. In addition to the aforementioned scales, Thorsen A.L. et al. noted a number of indicators that are predictors of an adverse outcome in perforated peptic ulcers. These include advanced age, concomitant oncological disease, hypoalbuminemia, hyperbilirubinemia, elevated creatinine, and a disease duration of more than 24 hours [183].

• In patients with a perforated peptic ulcer, endoscopic treatment in the form of clipping, fibrin glue sealing, or stenting is not recommended [115, 192].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Closure of acute iatrogenic perforations with endoscopic clips has been described [189, 190], but clips may be ineffective in perforated ulcers with fibrous tissue. Combined laparoscopic and endoscopic approaches are used to close perforated ulcers [193].

In patients with severe comorbidities, gastroscopy and stent placement followed by fluoroscopically guided drainage may be an alternative to standard treatment [193].

Endoscopic omental fixation and its invagination into the perforation is also described as an effective adjunct alongside duodenal plication. However, all of the aforementioned treatment methods are not recognized as standard approaches in the management of perforated peptic ulcers and require further improvement [116].

Postoperative management of patients with PU

• In the postoperative period, patients with a perforated peptic ulcer are recommended to receive medical treatment including systemic antibacterial drugs, analgesics, proton pump inhibitors, and intravenous infusions [18, 110, 115, 166, 167, 186, 188].

GCR BLEL 1Grade of Recommendation B (Level of Evidence – 1).

Comment. Antibiotic therapy implies the continuation of empirical antibiotic therapy according to one of the standard regimens prescribed during preoperative preparation. Upon receiving the results of microbiological examination of the peritoneal fluid with the determination of microorganism susceptibility to systemic antibacterial drugs, the antibiotic therapy is adjusted.

Antisecretory therapy consists of administering proton pump inhibitors (e.g., pantoprazole 40 mg IV twice daily for no more than 7 days, followed by a transition to oral forms for the entire hospital stay).

Postoperative management of patients with impaired vital functions complies with the basic principles of sepsis management [135, 136, 137, 138, 139, 140, 184, 185].

In the postoperative treatment of patients with perforated peptic ulcers abroad, the FTS (Fast track surgery) or ERAS (Enhanced recovery after surgery) program is implemented, the main points of which are: short-acting anesthetics in the early postoperative period, early patient rehabilitation, early initiation of postoperative oral fluid and food intake, early removal of the urinary catheter, and avoidance of a nasogastric tube [186, 187, 188]. This program is most often prescribed to patients with local peritonitis [167]. The implementation of the program is monitored dynamically, with the primary criterion for its application being the early recovery of intestinal motility. At the early signs of a complicated postoperative course or in the absence of intestinal motility, the program is stopped.

• In the postoperative period, a daily severity assessment is recommended for patients who have undergone surgery for a perforated peptic ulcer [18, 114].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In the postoperative period, serial determination of key laboratory parameters is recommended for patients who have undergone surgery for a perforated peptic ulcer [18, 114, 115, 212, 214].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In the postoperative period, monitoring and care of abdominal drains, a nasogastric or nasointestinal tube, as well as their timely removal, are recommended for patients who have undergone surgery for a perforated peptic ulcer [18, 114, 212, 214].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment. Drain monitoring implies determining its functional capacity, the nature and volume of the discharge, and removal in the absence of exudate. If the discharge volume exceeds 50.0 ml, drain removal is inadvisable to avoid the formation of an intra-abdominal abscess.

• Following surgery for a perforated peptic ulcer in the presence of severe forms of diffuse peritonitis and sepsis, patients are recommended to be treated in an intensive care unit [161, 165, 166].

GCR BLOCE 2Level of recommendation validity B (Level of evidence – 2).

• In the postoperative period, patients with suspected complications are recommended to undergo a comprehensive ultrasound examination of the abdominal organs or abdominal CT [195, 196, 197].

GRL CLEL 4Recommendation Grade C (Level of Evidence – 4).

Diet therapy for PU

• Patients with a perforated peptic ulcer are recommended to be kept fasting in the preoperative period and on the day of surgery [110, 186, 188, 189].

GCR BLOCE 2Level of recommendation validity B (Level of evidence – 2).

• In the postoperative period, early enteral nutrition with a gradual increase in the frequency and volume of ingested fluid and food is recommended [110, 186, 188, 189].

GCR BLOCE 2Level of recommendation validity B (Level of evidence – 2).

Comment. Fluid intake in limited amounts (up to 500 ml) is generally permitted the day after surgery; from days 2–3, the drinking regimen is unrestricted. The start of food intake generally falls on the 2nd–3rd postoperative day, allowing meals every 2–3 hours in limited portions from the products of diet tables 0a and 0b, gradually expanding by days 6–7 to 6 meals a day based on diet No. 1a with the exclusion of whole milk dishes [110, 186, 188, 189]

• Patients with peptic ulcer disease after surgical treatment are recommended diagnostic tests aimed at detecting H. pylori (see the diagnostics section) and eradication and maintenance therapy to prevent peptic ulcer recurrence and its complications [199, 213, 214].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment. The completed surgical treatment stage does not reduce the risk of a new round of surgical complications of peptic ulcer disease, primarily bleeding; therefore, it is important to continue the course of conservative treatment until the patient is completely cured.

• For patients with pyloroduodenal stenosis and an ulcer without signs of perforation/penetration, endoscopic balloon dilation is recommended to eliminate it [206].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• If endoscopic balloon dilation is ineffective, pyloroplasty and drainage procedures are recommended [206].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments. Indications for surgical treatment in patients with pyloroduodenal stenosis are determined by the degree of its compensation and the patient's condition. Endoscopic balloon dilation is only possible in patients with subcompensated stenosis and a scar localized on the anterior wall of the duodenum. This endoscopic procedure often brings temporary success and is associated with a high rate of stenosis recurrence.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• For patients with gastric and duodenal ulcers in remission, spa-and-resort treatment in sanatoriums located within the patient's climatic zone is recommended to maintain remission [5].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. For patients with peptic ulcer disease, 2–3 months after the subsiding of an acute exacerbation, spa-and-resort treatment lasting 14–21 days is advisable. Spa-and-resort treatment is carried out in sanatoriums such as Dorokhovo, Essentuki, Zheleznovodsk, etc., and includes mud and peat therapy, pine-sea baths, and drinking alkaline mineral waters [5].

5. Prevention and Dispensary Observation

• All individuals with H. pylori infection in the absence of contraindications are recommended to undergo eradication therapy to prevent peptic ulcer disease and its recurrences [52].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment. Confirmation of the leading role of H. pylori infection in the development of peptic ulcer disease has made eradication therapy the primary method of preventing this disease

• Dispanserization (clinical observation) of patients with gastric and duodenal ulcers is recommended annually for 5 years from the moment of the last exacerbation [5].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

6. Organization of Medical Care

Indications for planned hospitalization of patients with gastric and duodenal peptic ulcer disease include a pronounced clinical picture with persistent (more than 7 days) pain syndrome, the presence of ulcers in the stomach requiring differential diagnosis between benign ulcers and gastric cancer, exacerbation of peptic ulcer disease with a history of complications, and peptic ulcer disease with comorbid conditions [99].

The duration of inpatient treatment for patients with an exacerbation of peptic ulcer disease should be 21 days.

An indication for emergency hospitalization is the presence of signs of gastrointestinal bleeding, perforation, and penetration of the ulcer.

Patients with an uncomplicated course of peptic ulcer disease exacerbation of the stomach and duodenum are eligible for outpatient treatment.

Patients with an exacerbation of peptic ulcer disease are provided with specialized medical care both in outpatient and inpatient settings, in accordance with the standard of specialized medical care for gastric and duodenal peptic ulcer disease.

All patients with signs of acute gastrointestinal bleeding or with a justified suspicion thereof must be immediately referred to hospitals that are fully prepared organizationally, personnel-wise, and materially and technically to receive and treat patients of this profile. In large cities, it is advisable to refer patients with GI bleeding to multidisciplinary hospitals or specialized GI bleeding treatment centers.

Every clinic providing care to patients with acute bleeding peptic gastroduodenal ulcers (BPGDU) must have a protocol for the multidisciplinary management of such patients. The protocol for patient diagnostics and treatment must be based on national clinical guidelines and take into account the specifics of the emergency care delivery structure and the equipment of the specific medical and preventive facility.

A clinic providing care to patients with acute BPGDU must have modern endoscopic video equipment, instrumentation, and personnel proficient in basic diagnostic and therapeutic endoscopy methods, as well as highly qualified surgical, intensive care-anesthesiological, and, if possible, interventional radiological services available 24/7.

All patients with acute gastrointestinal bleeding must be hospitalized in a surgical hospital or ICU.

Patients with moderate-to-severe BPGDU, a high risk of rebleeding, and comorbid pathology should remain hospitalized until the threat of BPGDU recurrence has been eliminated, acute posthemorrhagic disorders are fully corrected, and comorbid conditions are compensated, but for no less than 4 days.

In compliant patients with mild BPGDU, low risk of rebleeding, and no comorbid pathology, early discharge from the hospital (on days 1^–2 following admission) is possible.

7. Additional Information

7.1. Features of PUD course in specific patient groups

7.1.1. Features of PUD course during pregnancy

The course of peptic ulcer disease during pregnancy generally differs little from that in non-pregnant women. The diagnosis is established based on clinical manifestations, medical history, upper GI endoscopy (EGD), and abdominal ultrasound [100]. X-ray examination of the stomach and duodenum is contraindicated in pregnant women.

In diagnostically unclear cases, when complications are suspected (bleeding, pyloric stenosis, cancer), EGD can be performed at any stage of pregnancy due to its safety for the fetus [101]. To rule out occult bleeding, a fecal occult blood test and a complete blood count are performed.

Differential diagnosis of peptic ulcer disease exacerbation must be carried out with erosive gastroduodenitis, pancreatitis, biliary tract diseases, acute appendicitis, and early pregnancy toxemia (hyperemesis gravidarum). Stenosing ulcer of the gastric antrum can simulate hyperemesis gravidarum. Early toxemia is characterized by agonizing, almost constant nausea intensified by various odors, and sialorrhea. In this case, vomiting occurs regardless of food intake, especially in the mornings, and abdominal pain is generally absent. Bleeding caused by peptic ulcer disease must be differentiated from bleeding in erosive gastritis, Mallory-Weiss syndrome, gastric cancer, and respiratory tract bleeding.

Pregnancy has a favorable effect on the course of peptic ulcer disease: 75–80% of women experience disease remission, and it does not have a noticeable effect on the pregnancy outcome. However, some patients may experience an exacerbation. This is most often observed in the 1st trimester of pregnancy (14.8%), the 3rd trimester (10.2%), 2–4 weeks before the expected delivery date, or in the early postpartum period. Uncomplicated peptic ulcer disease does not have a negative impact on fetal development.

Treatment includes adherence to generally accepted "regimen" measures and diet; intake of standard therapeutic doses of non-absorbable antacids (e.g., colloidal aluminum phosphate and adsorbents in the form of dioctahedral smectite). If ineffective, H_2-blockers are prescribed.

For severe pain caused by motor disorders, the prescription of antispasmodics (drotaverine** 40 mg 3–4 times a day, if the benefit to the mother outweighs the potential risk to the fetus) and prokinetics (metoclopramide** may be used in the 2nd and 3rd trimesters of pregnancy at 5–10 mg 2–3 times a day) is possible. Bismuth preparations (A02BX Other drugs for peptic ulcer disease and GERD) are contraindicated in pregnant women. Eradication therapy for H. pylori infection is not performed in pregnant women.

7.1.2 Features of PUD course in elderly and senile patients

In the development of gastroduodenal ulcers in elderly patients—in addition to H. pylori infection and the acid-peptic factor—atherosclerotic changes in gastric blood vessels and certain background diseases (e.g., chronic non-specific lung diseases) that reduce the protective properties of the gastric mucosa, as well as the use of medications (primarily NSAIDs) with ulcerogenic action, may also play a role.

Gastroduodenal ulcers in elderly and senile patients are localized predominantly in the stomach (along the lesser curvature of the body or in the subcardiac region), are sometimes very large, often present with masked and indefinite clinical symptoms, and have a tendency to develop complications (primarily gastrointestinal bleeding). When ulcers are detected in the stomach in elderly patients, performing a differential diagnosis with the infiltrative-ulcerative form of gastric cancer is of critical importance.

Gastroduodenal ulcers in elderly and senile patients are characterized by slow healing and a high risk of perforation following hemostatic procedures. Pharmacotherapy should be administered with caution, given the higher risk of adverse events in elderly patients compared to young and middle-aged patients.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Al Sabunchi O.A., Doctor of Medical Sciences, Professor, member of the Russian Society of Surgeons. There is no conflict of interest.

2. Andreev D.N., Candidate of Medical Sciences, Associate Professor, member of the Russian Gastroenterological Association. There is no conflict of interest.

3. Anishchenko M.A., Candidate of Medical Sciences, member of the Russian Society of Surgeons. There is no conflict of interest.

4. Baranskaya E.K., Doctor of Medical Sciences, Professor, member of the Russian Gastroenterological Association. There is no conflict of interest.

5. Bordin D.S., Doctor of Medical Sciences, Professor, member of the Russian Gastroenterological Association. There is no conflict of interest.

6. Burkov S.G., Doctor of Medical Sciences, Professor, member of the Russian Gastroenterological Association. There is no conflict of interest.

7. Vakurova E.S., Candidate of Medical Sciences, member of the Russian Society of Surgeons; member of the ENDO-RUSSIA Endoscopic Society Association. There is no conflict of interest.

8. Gromov D.G., Doctor of Medical Sciences, member of the Russian Scientific Society of Interventional Cardioangiologists. There is no conflict of interest.

9. Derinov A.A., Candidate of Medical Sciences, Associate Professor, member of the Russian Society of Colorectal Surgeons. There is no conflict of interest.

10. Efetov S.K., Candidate of Medical Sciences, Associate Professor, member of the Russian Society of Colorectal Surgeons. There is no conflict of interest.

11. Zatevakhin I.I., Doctor of Medical Sciences, Professor, Academician of the RAS, member of the Russian Society of Surgeons. There is no conflict of interest.

12. Zakharchenko I.A., Candidate of Medical Sciences, member of the Federation of Anesthesiologists and Reanimatologists. There is no conflict of interest.

13. Ivakhov G.B., Candidate of Medical Sciences, member of the Russian Society of Surgeons. There is no conflict of interest.

14. Ivashkin V.T., Doctor of Medical Sciences, Professor, Academician of the RAS, President of the Russian Gastroenterological Association, President of the Scientific Community for the Promotion of Clinical Study of the Human Microbiome. Chief Freelance Gastroenterologist of the Ministry of Health of the Russian Federation. There is no conflict of interest.

15. Karsanov A.M., Candidate of Medical Sciences, member of the Russian Society of Surgeons. There is no conflict of interest.

16. Korovin A.Ya., Doctor of Medical Sciences, Professor, member of the Russian Society of Surgeons. There is no conflict of interest.

17. Korolev M.P., Doctor of Medical Sciences, Professor. There is no conflict of interest.

18. Korymasov E.A., Doctor of Medical Sciences, Professor, member of the Russian Society of Surgeons. There is no conflict of interest.

19. Lapina T.L., Candidate of Medical Sciences, Associate Professor, member of the Russian Gastroenterological Association. There is no conflict of interest.

20. Lutsevich O.E., Doctor of Medical Sciences, Professor, Corresponding Member of the RAS, member of the Board of the Russian Society of Surgeons. There is no conflict of interest.

21. Maev I.V., Doctor of Medical Sciences, Professor, Academician of the RAS, member of the Russian Gastroenterological Association. There is no conflict of interest.

22. Natalsky A.A., Doctor of Medical Sciences, Professor, member of the Russian Society of Surgeons. There is no conflict of interest.

23. Olovyanny V.E., Doctor of Medical Sciences, member of the Russian Society of Surgeons. There is no conflict of interest.

24. Pavlov P.V., Candidate of Medical Sciences, member of the ENDO-RUSSIA Endoscopic Society Association. There is no conflict of interest.

25. Pavlychev A.V., Candidate of Medical Sciences, member of the Russian Society of Surgeons. There is no conflict of interest.

26. Panin S.I., Doctor of Medical Sciences, Professor, member of the Russian Society of Surgeons. There is no conflict of interest.

27. Pasko V.G., Doctor of Medical Sciences, Professor, Federation of Anesthesiologists and Reanimatologists. There is no conflict of interest.

28. Pirogov S.S., Doctor of Medical Sciences, member of the ENDO-RUSSIA Endoscopic Society Association. There is no conflict of interest.

29. Poluektova E.A., Doctor of Medical Sciences, member of the Russian Gastroenterological Association, Vice-President of the Scientific Community for the Promotion of Clinical Study of the Human Microbiome. There is no conflict of interest.

30. Prudkov M.I., Doctor of Medical Sciences, Professor, member of the Board of the Russian Society of Surgeons. There is no conflict of interest.

31. Revishvili, A.Sh., MD, PhD, Professor, Academician of the Russian Academy of Sciences, Director of the A.V. Vishnevsky National Medical Research Center of Surgery of the Russian Ministry of Health, Chief Freelance Surgeon and Endoscopist of the Russian Ministry of Health. No conflict of interest.

32. Sazhin, V.P., MD, PhD, Professor, Board Member of the Russian Society of Surgeons. No conflict of interest.

33. Sazhin, I.V., PhD, Associate Professor, Member of the Russian Society of Surgeons. No conflict of interest.

34. Tarasenko, S.V., MD, PhD, Professor, Member of the Society of Surgeons. No conflict of interest.

35. Tkachev, A.V., MD, PhD, Professor, Member of the Russian Gastroenterological Association. No conflict of interest.

36. Trukhmanov, A.S., MD, PhD, Professor, Member of the Russian Gastroenterological Association. No conflict of interest.

37. Ulyanin, A.I., Gastroenterologist, Member of the Russian Gastroenterological Association, Member of the Scientific Society for the Promotion of Clinical Study of the Human Microbiome. No conflict of interest.

38. Fedorov, A.V., MD, PhD, Professor, Secretary General of the Russian Society of Surgeons. No conflict of interest.

39. Fedorov, E.D., MD, PhD, Professor, President of the ENDO-RENDO Endoscopic Society Association. No conflict of interest.

40. Khripun, A.I., MD, PhD, Professor, Board Member of the Russian Society of Surgeons. No conflict of interest.

41. Tsarkov, P.V., MD, PhD, Professor, President of the Russian Association of Colorectal Surgeons. No conflict of interest.

42. Shabunin, A.V., MD, PhD, Professor, Academician of the Russian Academy of Sciences, President of the Russian Society of Surgeons. No conflict of interest.

43. Sheptulin, A.A., MD, PhD, Professor, Member of the Russian Gastroenterological Association. No conflict of interest.

44. Shchegolev, A.A., MD, PhD, Professor, Member of the Russian Society of Surgeons. No conflict of interest.

45. Yudin, V.A., MD, PhD, Professor, Board Member of the Russian Society of Surgeons. No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines

1. Gastroenterologists

2. General practitioners (family physicians)

3. Internists

4. Surgeons

5. Endoscopists

6. Anesthesiologists-resuscitators

7. Endovascular surgeons (diagnostic and therapeutic)

8. Clinical residents

Methodology for evidence collection

Methods used for evidence collection/selection:

Search for publications in peer-reviewed journals with an impact factor >0.3;

Search in electronic databases

Databases used for evidence collection/selection:

The evidence base for the guidelines includes publications from the Cochrane Library, PubMed, and MEDLINE databases. The search depth was 30 years.

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• assessment of the significance of evidence in accordance with the evidence rating scheme (Tables A2.1–A2.3).

In accordance with this draft of recommendations, certain generally accepted diagnostic methods are assigned the level GPP (Good Practice Point) based on expert consensus.

The scale for grading levels of evidence for diagnostic, preventive, therapeutic, and rehabilitative methods (interventions) and the scale for grading recommendation grades for preventive, diagnostic, therapeutic, and rehabilitative methods (interventions) are presented below.

Table P1 – Scale for assessing levels of evidence certainty (LEC) for diagnostic methods (diagnostic interventions)

Table P2 – Scale for grading levels of evidence (LoE) for preventive, therapeutic, and rehabilitative methods (interventions)

Table P3. Scale for grading recommendation grades (RG) for preventive, diagnostic, therapeutic, and rehabilitative methods (interventions)

Procedure for updating clinical guidelines

Updates are carried out at least once every three years or earlier, taking into account newly emerged information on diagnosis and patient management tactics. The decision on updating is made by the Russian Ministry of Health based on proposals submitted by professional medical non-profit organizations. The formulated proposals must take into account the results of a comprehensive assessment of medicinal products and medical devices, as well as the results of clinical evaluation.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

• Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template for clinical guidelines, and the requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines" (with amendments and additions)

• Order of the Ministry of Health of the Russian Federation No. 104n dated February 28, 2019, "On approval of the procedure and timelines for the approval and endorsement of clinical guidelines, criteria for the Scientific and Practical Council's decision to approve, reject, or send for revision clinical guidelines, or a decision on their revision"

• Order of the Ministry of Health of the Russian Federation No. 922n dated November 15, 2012, "On approval of the Procedure for the provision of medical care to the adult population in the field of 'surgery'" (with amendments and additions dated February 21, 2020)

• Order of the Ministry of Health of the Russian Federation dated May 10, 2017 No. 203n "On approval of criteria for assessing the quality of medical care."

• Clinical Guidelines of the Ministry of Health of the Russian Federation "Peptic Ulcer Disease" (ID 277)

Appendix B. Physician Action Algorithms

Physician action algorithm for peptic ulcer disease

Physician action algorithm for UGIB

Appendix C. Patient Information

Currently, a microorganism called Helicobacter pylori is recognized as the primary factor causing peptic ulcer disease. Therefore, every patient diagnosed with peptic ulcer disease must be tested for this infection. If confirmed, treatment aimed at eliminating these bacteria (eradication) is necessary, followed by a follow-up test after 4–6 weeks. If the first course of eradication fails, a repeat course of therapy with a different regimen of medications should be performed. It is important to adhere to treatment and strictly monitor medication intake. A patient with peptic ulcer disease must follow a diet (frequent, fractional meals; chemically, mechanically, and thermally sparing food) and be very cautious when taking drugs that have a damaging effect on the mucosa of the stomach and duodenum (acetylsalicylic acid, nonsteroidal anti-inflammatory drugs). If their administration is necessary, mandatory "coverage" with medications protecting the gastric and duodenal mucosa is required.

Bleeding peptic gastroduodenal ulcer is a severe complication of peptic ulcer disease. This complication can develop both in patients with a previously diagnosed ulcer and in cases where the patient is unaware of having a gastric or duodenal ulcer, such as in acute and so-called "silent" ulcers.

Bleeding typically occurs during the exacerbation stage of peptic ulcer disease and is characterized by the sudden subsiding of pain, the onset of weakness, dizziness, pallor of the skin, and other signs of acute blood loss. The condition is accompanied by vomiting of blood and/or foul-smelling black stools (melena). The patient must be laid down before the ambulance arrives, ensuring that aspiration of vomit does not occur. Intake of food and fluids is strictly prohibited.

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

Appendix G1.

Severity of blood loss

Source: Gorbashko A.I. Diagnostics and treatment of blood loss / A.I. Gorbashko – L., 1982. – 224.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: determination of the severity of blood loss

Content:

Key (interpretation): present in the table

Notes: not required

Appendix G2.

ACS Bleeding Severity Scale

Original title: American College Of Surgeons Bleeding Score

Source: American College of Surgeons Committee on Trauma / ATLS® Student Manual

10th Edition. Chicago: American College of Surgeons; 2018

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: determination of the severity of blood loss

Content:

Key (interpretation): present in the table

Notes: not required

Appendix G3.

AIMS65 Score

Original title: The AIMS65 Score

Source: Hyett B.H., Abougergi M.S., Charpentier J.P., Kumar N.L., Brozovic S, Claggett BL, Travis AC, Saltzman JR. The AIMS65 score compared with the Glasgow-Blatchford score in predicting outcomes in upper GI bleeding. Gastrointest Endosc. 2013 Apr;77(4):551-7. doi: 10.1016/j.gie.2012.11.022.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: prediction of in-hospital mortality, blood transfusion requirements, and transfer to the intensive care unit

Content:

Key (interpretation): in the absence of the above risks, in-hospital mortality is 0.3% compared to 31.8% in patients with 5 points.

An AIMS65 score >2 points in patients with bleeding peptic gastroduodenal ulcers indicates the need for blood transfusion, transfer to the intensive care unit, and a high risk of in-hospital mortality

Comments: not required

Appendix G4.

Glasgow-Blatchford Score

Original title: The Glasgow-Blatchford Bleeding Score

Source: Chandra S, Hess EP, Agarwal D, Nestler DM, Montori VM, Song LM, Wells GA, Stiell IG. External validation of the Glasgow-Blatchford Bleeding Score and the Rockall Score in the US setting. Am J Emerg Med. 2012 Jun;30(5):673-9. doi: 10.1016/j.ajem.2011.03.010.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: prediction of blood transfusion requirements, invasive intervention, transfer to the intensive care unit, and in-hospital mortality

Content:

Key (interpretation): Values > 6 points are associated with a more than doubled risk of the need for endoscopic, endovascular, or surgical intervention.

Comments: not required

Appendix G5.

Endoscopic classification of ulcer bleeding source, Forrest: The Forrest Classification

Source: Forrest, JA.; Finlayson, ND.; Shearman, DJ. (Aug 1974). ‘Endoscopy in gastrointestinal bleeding’. Lancet. 2 (7877): 394–7., 1974

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: Standardization of ulcer bleeding description to improve communication among endoscopists. Prediction of in-hospital mortality and rebleeding.

Content:

• F1 – active bleeding from the ulcer at the time of endoscopic examination:

  • F1a – active spurting arterial hemorrhage, often pulsatile.

  • F1b – active oozing hemorrhage, presenting as diffuse blood leakage (typically from small capillaries).

• F2 – bleeding from the ulcer has stopped at the time of endoscopic examination; stigmata (signs) of recent hemorrhage are visible in the ulcer base:

  • F2a – a visible, protruding vessel (distinctly seen large thrombosed vessel) in the ulcer base, typically appearing as a grayish-pink projection.

  • F2b – an adherent clot in the ulcer base that cannot be washed away or removed with a directed jet of fluid through the endoscope.

  • F2c – flat pigmented spots (red, maroon-brown, black) in the ulcer base, representing small thrombosed vessels.

• F3 – bleeding from the ulcer has stopped at the time of endoscopic examination; no stigmata (signs) of recent hemorrhage are found in the base of the ulcer defect that caused the bleeding (the ulcer crater is covered with "clean" fibrin).

Key (interpretation): included in the scale description.

Comments: not required

Appendix G6.

Rockall risk score

Original title: The Rockall Risk Scoring System

Source: Vreeburg EM, Terwee CB, Snel P, Rauws EA, Bartelsman JF, Meulen JH, Tytgat GN. Validation of the Rockall risk scoring system in upper gastrointestinal bleeding. Gut. 1999 Mar;44(3):331-5. doi: 10.1136/gut.44.3.331.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: prediction of in-hospital mortality and rebleeding

Content:

Key (interpretation): A scoring system for assessing the risk of rebleeding and mortality in patients with upper GI bleeding.

Total score calculation:

0-2: minimal risk of rebleeding <6%, mortality <2%.

3-7: high risk of rebleeding <40%, mortality <40%.

≥8: critically ill patients, risk of rebleeding ≥40%, mortality ≥40%.

Comments: not required

Appendix G7.

PULP prognostic score

Original title: the Peptic Ulcer Perforation (PULP) score

Russian title: PULP score

Source (official developer website, validation publication): Møller MH, Engebjerg MC, Adamsen S, Bendix J, Thomsen RW. The Peptic Ulcer Perforation (PULP) score: a predictor of mortality following peptic ulcer perforation. A cohort study. Acta Anaesthesiol Scand. 2012 May; 56(5):655-62. doi: 10.1111/j.1399-6576.2011.02609.x. Epub 2011 Dec 23. PMID: 22191386.

Type (underline):

- rating scale

- index

- questionnaire

Purpose: determination of mortality risk in perforated peptic ulcer

Key: PULP score >7 points – increases the risk of postoperative mortality.

Asa Meyer AC, Eklund H, Hedström M, Modig K. The ASA score predicts infections, cardiovascular complications, and hospital readmissions after hip fracture - A nationwide cohort study. Osteoporos Int. 2021;32(11):2185-2192. doi:10.1007/s00198-021-05956-w

Appendix G8.

J. Boey prognostic score

Original title: J. Boey score

Russian title: J. Boey prognostic score

Source (official developer website, validation publication): Boey J., Choi K.Y., Alagaratnam T.T., Poon A: Risk Stratification in Perforated Duodenal Ulcers. A Prospective Validation of Predictive Factors. Ann Surg 1986, 205:22-6.

Type (underline):

- rating scale

- index

- questionnaire

Purpose: determination of mortality risk in perforated peptic ulcer

Key: Consists of 3 factors:

• hemodynamic instability on admission (systolic BP less than 100 mm Hg) – 1 point

• delayed hospital admission (over 24 h) – 1 point

• presence of severe comorbid conditions (ASA ≥ 3) – 1 point

In the absence of all risk factors, postoperative mortality is 1.5% (OR = 2.4), with 1 factor – 14.4% (OR = 3.5), with 2 factors – 32.1% (OR = 7.7). When all three factors are present, mortality increases to 100% (P < 0.001, Pearson's χ² test).

Appendix G9.

American Society of Anesthesiologists (ASA) Physical Status Classification System

Original title: American Society of Anesthesiologists score

Source: Thorsen K, Søreide JA, Søreide K. Scoring systems for outcome prediction in patients with perforated peptic ulcer. Scand J Trauma Resusc Emerg Med. 2013 Apr 10; 21:25. doi: 10.1186/1757-7241-21-25. PMID: 23574922; PMCID: PMC3626602.

Type (underline):

- rating scale

- index

- questionnaire

Purpose: determination of intraoperative and postoperative risk of complications

Key: