The role of the gastrointestinal tract in systemic sepsis was proposed as early as the 1950s, and in the last two or three decades, the role of the gastrointestinal tract in the systemic inflammatory response and multi-organ dysfunction has received increasing attention, being considered the “center of the stress response” and the “engine of multiple organ dysfunction (MODS). Multiple organ dysfunction syndrome (MODS) engine”. Studies have shown that approximately 62% of ICU patients present with at least one symptom of gastrointestinal dysfunction, and there is growing evidence that the occurrence of gastrointestinal dysfunction is strongly associated with patient prognosis. However, the incidence and impact of GIF on patients has been reported with great variability due to different definitions of “Gastrointestinal failure (GIF)”.
In 2012, the European Society of Intensive Care Medicine (ESICM) introduced the concept of “acute gastrointestinal dysfunction”, which provides a more systematic description of gastrointestinal dysfunction in critically ill patients. The guideline defines “gastrointestinal function” as digestive, absorptive, barrier, immune and endocrine functions, and considers blood perfusion, secretion and peristalsis of the gastrointestinal tract, and coordinated intestinal-microbial interactions as important factors to ensure gastrointestinal function. The term “acute gastrointestinal dysfunction” is defined as “impairment of gastrointestinal function in critically ill patients caused by acute diseases”. The definition, classification and diagnosis of gastrointestinal dysfunction are relatively general, with symptoms such as vomiting, abdominal distension and gastrointestinal bleeding as the main descriptions, which lack specificity and are difficult to distinguish from other gastrointestinal diseases such as constipation, inflammatory bowel disease and mechanical intestinal obstruction. We believe that the ideal definition should be distinguished from the gastric dysfunction caused by these chronic diseases and defined based on their common pathophysiological features and clinical manifestations. Although more studies have been conducted on the mechanisms of acute gastrointestinal dysfunction, there is a lack of understanding of their common pathogenesis and pathophysiological features. This may be the fundamental reason that currently restricts further research and treatment of acute gastrointestinal function.
1, Pathogenesis of acute gastrointestinal dysfunction.
In the past, people’s understanding of gastrointestinal function was limited to digestion and absorption, and after the 1980s, the importance of the intestinal mucosal barrier was gradually recognized. As a place for food digestion and absorption, the intestine has a huge absorption area and needs to face a large number of “foreign bodies”, a large number of bacteria and toxins and various antigens, so in addition to the function of driving digestion and absorption, preventing the invasion of “foreign bodies” is also its Therefore, in addition to the function of digestion and absorption, it is also a major duty to prevent the invasion of foreign substances. In 1999, academician Li Jieshou proposed the important role of intestinal mucosal barrier in bacterial translocation, which aroused people’s attention to the intestinal mucosal barrier. The intestinal mucosal barrier includes mechanical barrier (intestinal epithelial cells and tight junctions between cells, etc.), biological barrier (normal flora), chemical barrier (gastric acid, bile, various digestive enzymes, lysozyme, mucopolysaccharide, glycoprotein and glycolipid secreted by gastrointestinal tract, etc.) and immune barrier (intestine-associated lymphoid group and diffuse immune cells). The barrier dysfunction leading to bacterial or toxin translocation has been mostly studied in isolation, and we believe that bacterial translocation is associated with dysbiosis (overproliferation of Gram-negative bacilli), impaired intestinal mucosal barrier, gastrointestinal dysmotility, and co-impairment of host immune defenses.
Other gastrointestinal disorders, such as inflammatory bowel disease mainly associated with intestinal autoimmunity, constipation mainly associated with anatomical abnormalities or dysmotility, and intestinal obstruction usually caused by luminal stenosis or intestinal paralysis, are usually caused only by dysfunction of one of the intestinal tract, whereas in acute gastrointestinal dysfunction, these functions of the intestine are jointly impaired. Under severe stress such as trauma, shock and severe infection, we can find that ischemia-reperfusion injury after intestinal stress is its common pathophysiological process. When intestinal ischemia-reperfusion injury occurs, intracellular calcium overload and release of oxygen radicals cause increased permeability of endothelial cells of blood vessels and lymphatic vessels, extravasation of plasma and lymphatic fluid and impaired reflux, resulting in inflammatory edema of tissue cells, while increasing the entry of bacteria and toxins into The inflammatory edema of tissue cells and the opportunity for bacteria and toxins to enter the circulation are increased. Inflammatory edema of intestinal mucosal epithelial cells, resulting in collapse of villi, impaired secretion of sIgA, impaired tight junctions between cells, etc.-impaired mechanical and immune barriers; swelling of gastrointestinal glands, resulting in impaired secretion of digestive juices and disturbance of the intestinal internal environment-impaired chemical barriers The disturbance of the intestinal environment causes the imbalance of intestinal-bacterial interaction, the decrease of the colonization of normal flora, and the excessive proliferation of pathogenic bacteria – the impairment of the biological barrier; at the same time, due to factors such as intestinal mucosal edema, ganglion cell dysfunction and imbalance of the vegetative nervous system, the intestinal dynamics is impaired, resulting in the retention of bacteria and toxins. The above factors together promote the translocation of bacteria and toxins, causing the development of a systemic inflammatory response. Therefore, we hypothesize that impaired microcirculation is the main cause of systemic inflammatory response and MODS.
Early animal experiments and some clinical studies found bacterial and toxin translocation through the damaged intestinal mucosal barrier into the portal vein, and suggested that bacteria and toxins activate inflammatory cells such as hepatic kupffer cells, causing systemic inflammatory response. However, this idea was challenged by Moore et al. who failed to find bacteria and endotoxins in portal venous blood from patients with severe trauma, including those who had developed MODS. And an animal study showed no effect of portal vein rerouting on intestinal ischemia-reperfusion-induced lung injury. A reasonable explanation for this finding is that the causative agent leaves the intestine through the intestinal lymphatics rather than the portal vein. Animal studies of hemorrhagic shock or burns have shown that shunting lymph before shock prevents shock-induced increases in pulmonary permeability, whereas isolation of lymphatic fluid after shock has no effect. It has also been observed in clinical work that acute lung injury is often the first to occur in patients with severe trauma or shock in the absence of aspiration lung injury or contusion lung. This led to the idea of blocking the lymphatic pathway by ligating the thoracic duct or mesenteric lymphatics, so that inflammatory substances of intestinal origin could not directly enter the body circulation and cause an inflammatory response, and it was shown that ligating the mesenteric lymphatics could have a protective effect on the lungs. Numerous studies have shown that blocking mesenteric lymphatic fluid from entering the systemic circulation can prevent lung injury caused by trauma or hypovolemic shock and the resulting activation of lung neutrophils, damage to endothelial cells, and expression of adhesion molecules. Subsequently, the “mesenteric lymph” hypothesis was proposed: intestinal-derived factors in intestinal lymph are the key to acute lung injury caused by trauma or hypovolemic shock. This hypothesis reveals an intrinsic link between the intestinal tract and the lung after severe trauma or shock and MODS.
In addition, the intestine, as the largest immune organ in the body, possesses a large amount of lymphoid tissue (intestine-associated lymphoid tissue, including SIgA, submucosal and lamina propria lymphocytes, Peyer’s Patch, mesenteric lymph nodes, etc.). Under stress conditions such as severe infection and trauma, severe edema and exudation of the intestinal canal and damage to the intestinal mucosa make the immune system of the intestine activate, causing systemic inflammatory reactions and MODS.
2, clinical manifestations of acute gastrointestinal dysfunction.
The most important role of the intestine is to digest and absorb water and nutrients, the intestine is also the largest lymphatic organ in the body, but also has a barrier to prevent the body from abnormal absorption of bacteria and their products in the intestinal lumen. A multicenter study in France showed that almost all critically ill patients had varying degrees of abdominal distension, diminished bowel sounds or difficulty in defecation, 40% of ICU patients presented with diarrhea or intolerance to enteral nutrition, 16% presented with constipation, and about 2/3 of ICU patients developed gastrointestinal motility disorders.
The concept of acute gastrointestinal injury (AGI) was introduced by the European Society of Intensive Care Medicine Working Group on Abdominal Diseases in 2012, which mentioned that in acute gastrointestinal dysfunction, the main gastrointestinal symptoms are the following: (1), vomiting and reflux: any visible reflux of gastric contents, regardless of the amount of vomit; (2), gastric retention: a single gastric fluid retraction of more than 200 ml is defined as massive gastric retention. WGAP still considers a total residual amount of more than 1000 ml in 24 hours as an indication of abnormal gastric emptying; (3), diarrhea: resolution of more than three times daily dilute watery stools and an amount greater than 200-250 g/day (or more than 250 ml/day), which is recommended in the ICU and classified as 90 disease-related, drug-related, and food/feeding-related diarrhea; (4), gastrointestinal bleeding. Any bleeding into the lumen of the gastrointestinal tract, confirmed by occult blood testing of specimens such as vomit fluid, gastric contents or stool; (5), lower gastrointestinal paralysis (paralytic intestinal obstruction): in the absence of mechanical obstruction, at least three days of anal cessation of defecation and presence or absence of bowel sounds; (6), abnormal bowel sounds: diminished, absent or hyperactive; (7), dilated intestine: abdominal plain film or CT showing colon diameter Feeding intolerance syndrome (FI): continuous enteral nutrition for 72 hours without reaching the nutritional requirement target of 20kcal/kg BW/d, or if enteral nutrition needs to be discontinued for any clinical reason.
In addition to the above local manifestations of the gastrointestinal tract, patients who develop acute gastrointestinal dysfunction usually have significant systemic symptoms (which may also be an important distinction from chronic gastrointestinal dysfunction), such as fever, malaise, poor appetite, and sleep disturbances. In patients with MODS due to acute gastrointestinal dysfunction, the lungs are usually the most frequently involved organ, which we speculate may be related to the lymphatic circulation mechanism of acute gastrointestinal dysfunction. In acute gastrointestinal dysfunction, impaired intestinal microcirculatory (blood and lymphatic microcirculation) pathways lead to bacterial translocation and the development of a systemic inflammatory response. There is evidence that in a mouse model of hemorrhagic shock, ligation of the thoracic duct reduces the involvement of vital organs such as the lungs and the severity of the systemic inflammatory response.
Although clinical signs of acute gastrointestinal dysfunction are very well described, there is a lack of uniform and systematic criteria. We hypothesize that proposing a clinical syndrome based on common pathophysiological alterations is the key to solving the above problems. Current clinical descriptions of acute gastrointestinal dysfunction include digestion and absorption, secretory dysfunction, dysmotility, impaired intestinal barrier, dysbiosis, and dysregulated immune response We believe that unlike chronic diseases such as constipation, pseudo-intestinal obstruction, and inflammatory bowel disease, whether acute gastrointestinal dysfunction is caused by infectious, non-infectious, or medical factors, gastrointestinal mucosal ischemia and hypoxia and ischemia-reperfusion injury may are the common pathophysiological changes. Therefore, its clinical manifestations such as abdominal distension, diarrhea and abdominal pain, intestinal flatulence, intestinal contents accumulation, intestinal nutrition intolerance and intestinal paralysis are different from chronic gastrointestinal dysfunction caused by other specific factors, and the clinical manifestations of acute gastrointestinal dysfunction all occur and develop on this common basis. Therefore, in the future related research, it should be one of the possible directions to sort out the clinical characteristics according to this idea.
3. Grading and diagnosis of acute gastrointestinal dysfunction.
In 2008, Reintam et al. reported a new criterion for assessing gastrointestinal dysfunction, the GIF score, including food intolerance syndrome (FI) and intra-abdominal hypertension (IAH). the details of the GIF score are as follows: 0 – normal gastrointestinal function; 1 point – enteral nutrition provision <50% of the expected need or no food 3 days after abdominal surgery; 2 points-FI or IAH; 3 points-FI and IAH; 4 points-ACS (abdominal compartment syndrome). This scale is associated with mortality and provides prognostic value for the SOFA score, but fails to provide a specific criterion that can be used as a measure of gastrointestinal dysfunction in critically ill patients. Its limitations are: first, enteral nutrition tolerance is a subjective indicator that reflects more on the inherent characteristics of the patient than the clinical decision that it reflects - retention of feeding. Second, abdominal hypertension is not strictly an indicator of gastrointestinal function; it is a combination of both elevated intra-abdominal pressure and decreased abdominal wall compliance, and the risk factor for abdominal hypertension is the need for massive fluid replacement in the presence of elevated capillary permeability.
In 2012, the European Society of Intensive Care Medicine Working Group on Abdominal Diseases proposed the following grading criteria for acute gastrointestinal injury (AGI): acute gastrointestinal injury grade I: presence of risk factors for gastrointestinal dysfunction and failure; acute gastrointestinal injury grade II: gastrointestinal dysfunction; acute gastrointestinal injury grade III: gastrointestinal failure: acute gastrointestinal injury grade IV: gastrointestinal failure with distant compartment organ dysfunction [2]. However, this grading criterion still has some limitations, such as the lack of objective measurements of gastrointestinal function, and is not based on certain digital variables that cannot be quantified.
The use of serum citrulline concentration and intestinal fatty acid binding protein (I-FABP) has been proposed as an indicator of acute intestinal failure. Citrulline is an amino acid produced by the epithelial cells of the small intestine. Normal serum citrulline concentration is 20-40 μmol/L. Serum citrulline concentration is mainly determined by the balance between intestinal epithelial cell production and renal degradation. Citrulline is not utilized by the liver, but can be converted to arginine by the kidneys and is therefore usually considered a processed form of arginine. Various acute and chronic intestinal epithelial cell reductions are associated with low serum citrulline concentrations, and critically ill patients in shock usually have an acute reduction in intestinal epithelial count as well as a reduction in intestinal production of citrulline, resulting in low serum citrulline concentrations. There is also a correlation between serum citrulline concentration and prognosis. low serum citrulline concentration within 24 h is an independent risk factor for poor prognosis, and in addition, patients with low serum citrulline concentration have higher serum CRP concentration and nosocomial infection rate and lower serum arginine concentration.
In addition, diamine oxidase (DAO) as an indicator of intestinal mucosal damage and D-lactate as an indicator of increased intestinal mucosal permeability can assist in the diagnosis as indicators of gastrointestinal barrier damage.
A reasonably valid indicator should have several characteristics.
1.Response to the number of functional cells.
2.It can be interpreted by a pathophysiological model.
3. Easy for clinicians to perform, less invasive to patients, low cost, and able to obtain results quickly and accurately enough. At present, how to effectively diagnose acute gastrointestinal dysfunction is an urgent clinical problem to be solved.
4.Treatment of acute gastrointestinal dysfunction.
The treatment of acute gastrointestinal dysfunction includes systemic and local treatment, involving a wide range of individualized needs, and is now a brief introduction to its treatment measures for gastrointestinal conditioning.
4.1.Actively treat the primary disease.
The primary disease should be diagnosed as early as possible and treated actively and effectively, and the early treatment of shock, trauma and infection should be strengthened to eliminate the basis for the generation of SIRS.
4.2.Gastrointestinal decompression
(1), gastrointestinal decompression
Gastrointestinal decompression can be achieved by placing a nasogastric tube or nasogastric tube. In the treatment of acute gastrointestinal dysfunction and postoperative intestinal obstruction, placement of a gastrointestinal drainage tube has long been widely accepted. For patients with significant bowel dilatation, the recommendation of the 2012 ESICM Working Group on Abdominal Issues is to use gastrointestinal decompression (1D) based on maintenance of water-electrolyte balance, and nasogastric tube decompression (1A) is not routinely recommended for patients after elective surgery. Non-surgical decompression using colonoscopy (1C) is recommended for those whose cecum diameter exceeds 250 px and does not improve after 24-48 hours of conservative treatment.
(2), Early enteral nutrition
Early enteral nutrition refers to the start of enteral nutrition within 24-48 hours, provided that the hemodynamic is relatively stable and there is no contraindication to enteral nutrition, such as the presence of shock or the use of high-dose antihypertensive drugs and other early stages of acute resuscitation should be suspended enteral nutrition.
It has been proved that enteral nutrition (EN) support can improve the circulation of portal venous system, help restore intestinal peristalsis, maintain intestinal barrier function, improve hepatobiliary function, promote protein synthesis, rehabilitation of intestinal loop tissues, and regulation of immune function, especially maintaining intestinal barrier function, which makes up for the deficiency of PN support. reduce the occurrence of enteric-derived infections significantly. Some observational studies have shown that patients receiving early enteral nutrition in the ICU have a better prognosis than those without early enteral nutrition. A meta-analysis that included six RCTs showed that early enteral nutrition given to ICU patients within 24 hours reduced mortality and the incidence of pneumonia in ICU patients compared to starting enteral nutrition after 24 hours.
(3), Selection of specific nutritional substrates
Glutamine is a tissue-specific amino acid that is required for rapidly growing cells. The intestinal mucosal cells need glutamine as its main energy. Therefore, glutamine should be added to nutrients to promote the growth of intestinal mucosal cells. It has been proved that glutamine can promote the proliferation of intestinal mucosal cells and effectively maintain the permeability of intestinal mucosa, which is conducive to the maintenance of intestinal mucosal barrier function, thus improving the prognosis of critically ill patients and reducing the incidence of infection. The effects of glutamine given by intestinal instillation or glutamine bipeptide by parenteral route are still differently understood.
Dietary fiber is another substance that is beneficial for restoring gastrointestinal function. In the diet, both water-soluble and non-water-soluble fibers stimulate and promote mucosal growth and cell proliferation in the small intestine and colon. Insoluble fiber (cellulose) increases stool volume and promotes intestinal peristalsis, while specific soluble fiber (such as gum) delays gastric emptying and slows down intestinal food transport time, thus having anti-diarrheal effects. Fermentable water-soluble fiber (non-starch polysaccharides) can be catabolized by anaerobic bacteria to produce short-chain fatty acids (SCFA). SCFA (acetic acid, propionic acid, butyric acid) are easily absorbed by the colonic mucosa and utilized as energy, and have a nutritional stimulating effect on both small intestine and colonic mucosa, promoting intestinal mucosal cell proliferation, especially the absorption of water and sodium in the colon.
For overall digestive dysfunction, a pre-digested formula can be taken, which requires only a small amount of digestive function to be absorbed, with the following main ingredients.
(1), enriched with maltodextrin and glucose.
(2), Nitrogen is provided in the form of short peptides.
(3), low fat, only free fatty acids.
(4), Improve intestinal perfusion and microcirculation.
In acute gastrointestinal dysfunction, rapid restoration of blood flow, improvement of perfusion and microcirculation to increase oxygen supply, energy supplementation and reduction of tissue energy metabolism are active and effective measures to prevent further deterioration of gastrointestinal function. gao et al. found that continuous infusion of hyperoxic fluid from the intestinal lumen after 60 min of ischemia could ensure the structural and functional integrity of intestinal mucosa; intra-intestinal administration of glucose could increase intestinal mucosal blood flow and improve ischemia-reperfusion intestinal injury in rats with ischemia-reperfusion injury; glutamine can dose-dependently induce heat shock protein 70 (HSP70) mRNA expression in rats, thus reducing the injury of several organs. Clinically, the traditional treatment principles for intestinal ischemia-reperfusion injury are to restore normal blood supply before intestinal necrosis occurs, prevent the expansion of necrosis, and remove necrotic tissues in a timely manner; depending on the condition, intravenous fluids, intestinal rest and various supportive treatments can be administered first, and then surgical treatment can be performed if the condition cannot be improved. A recent study found that the interventional treatment program based on the infusion of poppies in the mesenteric artery has a positive effect on ischemic enteropathy and can reduce the death rate of patients.
(5), Use of gastrointestinal prokinetic drugs.
In the treatment of gastric emptying disorders, the use of prokinetic drugs such as gastrofacial and erythromycin is advocated. Erythromycin may be more effective than gastrofacial, but strong evidence of clinical benefit is still lacking. It can be used to stimulate the upper gastrointestinal tract (stomach and small intestine), while neostigmine can promote small intestine and colon motility. Despite the lack of well-controlled studies and sufficient evidence, prokinetic agents should be used as a standard treatment for intestinal motility disorders (1D). Drugs that inhibit bowel motility (e.g., catecholamines, sedatives, opioids) and correction of factors that impair bowel motility (e.g., hyperglycemia, hypokalemia) should also be discontinued whenever possible. Intravenous neostigmine (2B) is recommended after exclusion of mechanical intestinal obstruction in those with a cecum diameter greater than 250 px that does not improve within 24 hours.