Necrotizing enterocolitis of newborn

　　First, Etiology

　　The causes of necrotizing enterocolitis have not been fully elucidated, but it is generally believed to be caused by multiple factors, with premature birth and infection being the most important.

　　1. Premature birth Premature birth is an important risk factor for NEC due to poor immune function, poor peristalsis, and the increased risk of asphyxia at birth, which causes oxygen deficiency and damage to the intestinal wall, allowing bacteria to侵入.

　　2. Infection Infection is one of the main causes of NEC, mostly caused by intestinal bacteria such as Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa.

　　3. Hypoxia and ischemia During hypoxic and ischemic conditions such as neonatal asphyxia, respiratory diseases, and shock, the intestinal wall vessels constrict, leading to ischemic and hypoxic mucosal damage and necrosis. With the restoration of oxygen supply, the vessels dilate and become congested, and the reperfusion during dilation can increase tissue damage.

　　4. Feeding and blood exchange can both increase the reperfusion of the intestinal wall, becoming a cause of the disease, leading to bacterial invasion of the intestines. Once feeding begins, it provides an abundant substrate for bacterial proliferation. Intestinal feeding has always been considered a risk factor for NEC, and premature infants with infections or asphyxia who are fed cow's milk too early and in excessive amounts can induce NEC. However, the view that feeding can lead to NEC is still controversial, as there are reports that the incidence of NEC in premature infants who started feeding at 2 weeks was higher than that in those who started feeding early.

　　5. NEC incidence is higher in situations such as umbilical artery or vein catheterization, exchange transfusion, polycythemia, patent ductus arteriosus, and hypothermia.

　　Second, Pathogenesis

　　In children with necrotizing enterocolitis, there are usually three factors in the small intestine: persistent intestinal ischemic damage, bacterial colonization, and intraluminal substrates (such as enteral feeding).

　　1. The lack of oxygen and inflammatory damage in the intestinal wall of premature infants leads to poor immune function and poor peristalsis, causing food to stay longer and facilitating bacterial growth; high osmotic pressure of cow's milk can exacerbate mucosal damage in premature infants with infections or asphyxia, and induce NEC. Asphyxia at birth causes oxygen deficiency and damage to the intestinal wall, allowing bacteria to侵入, and excessive bacterial growth and their toxins can cause inflammation in the oxygen-deficient intestinal wall. Inflammation releases cytokines such as platelet-activating factor, α-tumor necrosis factor, prostaglandins, etc., which intensify the inflammatory response and promote the occurrence of NEC. Klebsiella bacteria have a strong fermentation effect on lactose in food, producing hydrogen gas that causes the intestinal wall to produce cystic gas accumulation.

　　2. Hypoxia and reperfusion injury Ischemic damage can be caused by hypoxic damage, such as neonatal asphyxia, respiratory system diseases, triggered by the primary diving reflex, causing mesenteric artery spasm and significantly reducing intestinal blood flow. During the exchange transfusion process, during the sepsis period, or when feeding with high-tension formula milk, intestinal blood flow decreases, leading to ischemic damage to the intestines. Similarly, in situations of shock, congenital heart disease, and other ischemic conditions, systemic blood flow can be reduced, or arterial oxygen saturation can decrease, leading to ischemic hypoxia of the intestinal mucosa and necrosis; reperfusion during the recovery of oxygen supply, feeding, and blood exchange increases tissue damage.

　　3. Pathological changes NEC can affect the entire small and large intestines, but the most common sites are the distal ileum and the proximal ascending colon. In mild cases, the necrotic intestinal segment is only a few centimeters long, while in severe cases, it can extend to the jejunum and colon. Generally, it does not affect the duodenum. Bacteria can penetrate through the intestinal wall, produce hydrogen and accumulate, resulting in characteristic intestinal wall gas accumulation visible on X-rays. The gas can enter the portal vein and be visible on abdominal X-ray films or liver B-ultrasound as gas accumulation in the portal vein above the liver. With the progression of the lesion, it can lead to complete necrosis, perforation, peritonitis, sepsis, and death of the entire intestinal wall. Early lesions are mainly congestion, edema, hemorrhage, and necrosis of the intestinal mucosa and submucosa. Progressive lesions involve the muscular layer, and in severe cases, the entire intestinal wall may necrotize, leading to intestinal perforation and peritonitis.

　　If the condition progresses, intestinal necrosis begins from the mucosal layer and gradually involves the entire intestinal wall, leading to intestinal perforation, peritonitis, and ascites. One-third of neonates may develop sepsis, accompanied by multiple organ dysfunction and DIC. Sepsis refers to the acute systemic infection caused by the invasion and growth of pathogenic bacteria or opportunistic pathogens in the blood circulation, producing toxins. Sepsis accompanied by multiple abscesses and a long course is called septicemia.

　　More male infants than female infants are affected, mainly in sporadic cases, with no obvious seasonal variation. The disease usually occurs within 2-3 weeks after birth, with a peak between 2-10 days. NEC can also present as a small outbreak during an epidemic of neonatal diarrhea. There are no differences in gender, age, or season during the outbreak.

　　1. Abdominal distension and decreased bowel sounds:The patient initially exhibits delayed gastric emptying, gastric retention, followed by abdominal distension. In mild cases, there is only abdominal distension. In severe cases, symptoms rapidly worsen, with abdominal distension resembling a drum, decreased bowel sounds, and even disappearance. Neonates with NEC may not show typical abdominal distension, and decreased bowel sounds are early symptoms of NEC. It is necessary to observe the changes in the frequency of abdominal distension and bowel sounds in high-risk infants at any time.

　　2. Vomiting:The child often vomits, and the vomit may be coffee-colored or contain bile. Some children do not vomit, but coffee or bile-like stomach contents can be aspirated from the stomach.

　　3. Diarrhea and bloody stool:Initially, it is watery stool, 5 to 6 times a day up to more than 10 times, and 1 to 2 days later, it becomes bloody stool, which may be fresh blood, jam-like, or black stool. Some cases may have no diarrhea and visible blood in stool, only positive occult blood in stool.

　　4. General symptoms:NEC patients often have poor response, apathy, refusal to eat. In severe cases, the complexion may become pale or bluish, the extremities cold, shock, acidosis, jaundice, and the body temperature may be normal or slightly low. Premature infants are prone to repeated apnea, bradycardia, normal or slightly low body temperature.

　　NEC can occur in outbreaks with infectivity. Therefore, if several cases of necrotizing enterocolitis occur within a short period, the patients should be isolated, and the other exposed infants should be evaluated. Directly or indirectly exposed newborns and premature infants need to be checked daily for the appearance of abdominal distension and changes in stool nature. Once abdominal distension occurs, be vigilant of the occurrence of NEC. For very small or sick premature infants, delayed feeding for several days or weeks by using total parenteral nutrition can reduce the occurrence of necrotizing enterocolitis (NEC).

　　Stool occult blood test (OBT), stool bacterial culture, vitamin K, arterial blood gas analysis, blood routine, stool routine, abdominal puncture, abdominal flat film, retroperitoneal pneumography, smear.

　　1. Peripheral blood count:White blood cell count increases, with left shift of the nuclear division, and thrombocytopenia.

　　2. Blood gas analysis and electrolyte measurement:It can understand the degree of electrolyte imbalance and acidosis, and guide the treatment of fluid and intravenous nutrition.

　　3. Stool examination:The appearance is dark, with positive occult blood, and under the microscope, there are an unequal number of white blood cells and red blood cells. The stool bacterial culture is often dominated by Escherichia coli, Klebsiella, and Pseudomonas aeruginosa.

　　4. Blood culture:If the bacteria cultured is consistent with the stool culture, it is significant for the diagnosis of the etiology of NEC.

　　5. Abdominal X-ray flat film examination:It is of great value for the diagnosis of NEC, and multiple follow-up examinations should be conducted to observe the dynamic changes.

　　(1) Early manifestations:

　　① The small intestine is slightly to moderately distended, while the colon may be underdistended or distended.

　　② There may be small liquid levels in the intestinal cavity.

　　③ The mucosa of the intestinal wall and the intestinal spaces become thickened.

　　④ The intestinal tubes are arranged in disorder, with a rigid shape, irregular or narrowed tubes.

　　(2) Progressive changes:

　　The intestinal cavity becomes more distended, with increased liquid levels, showing a stepped pattern, indicating that the lesion involves the muscular layer.

　　The submucosal layer of the intestinal wall shows air accumulation, manifested as dense small bubble-like transparent areas, known as pneumatosis cystoides intestinalis. Subserosal air accumulation appears as thin strips, semi-arc or annular shadow.

　　③ The time of intestinal wall gas accumulation is longer, and the gas can rise from the intestinal wall to the portal vein, causing gas in the portal vein, presenting as a tree-like upward lucency at the portal of the liver, which can be absorbed and disappear within 4 hours.

　　④ The intestine is fixed.

　　⑤ There is gas in the abdominal cavity during acute intestinal perforation, and if the perforation is covered and sealed by the mesentery, the escaped gas is absorbed, and it may not be easily visible on the X-ray film.

　　6. Bacterial culture:The abdominal puncture fluid smear and culture are mostly bacilli, and the abdominal fluid obtained during surgery should be cultured, with a high positive rate.

　　7. Abdominal ultrasound: Intermittent small bubbles appear in the liver parenchyma and portal vein.

　　The diet for neonatal necrotizing enterocolitis patients should be light, easy to digest, with an emphasis on eating more vegetables and fruits, and a reasonable diet should be maintained. In addition, patients should also avoid spicy, greasy, and cold foods.

　　First, treatment

　　1. For children who may develop NEC or are suspected of having necrotizing enterocolitis, fasting should be initiated immediately, and the specific duration should be determined based on the condition. Initially, fasting for 1 to 2 days can be considered to observe the progression of the disease and plan the next treatment.

　　For confirmed cases, children with mild symptoms should be fasting for 3 to 5 days, and those with severe symptoms should be fasting for 7 to 10 days, with most children also needing gastrointestinal decompression. During the fasting period, nutrition and fluids are mainly supplemented through parenteral nutrition, which can be administered through peripheral veins. Feeding can only be started when bloating and vomiting disappear, bowel sounds return, appetite recovers, and the occult blood test in the stool becomes negative.

　　When starting to eat, first try feeding 5% glucose water 3 to 5ml, 2 to 3 times, and if there is no vomiting or bloating, you can start feeding milk. Fresh breast milk is the best, and it is advisable to start with small amounts; for artificial feeding, it is advisable to start with a small amount of diluted milk, 3 to 5ml per time, and gradually increase the amount if tolerated, increasing by 1 to 2ml each time, and avoid using hypertonic milk. If there is milk retention in the stomach, do not increase the amount or reduce it to the previous dose. If symptoms recur after adding milk, you need to start fasting again. In cases with severe and extensive primary lesions, temporary lactase deficiency may occur, and breastfeeding should be temporarily avoided to prevent symptoms such as bloating and diarrhea.

　　2. Gastrointestinal decompression is a routine measure, using a double-lumen nasogastric tube connected to a suction apparatus to relieve intestinal gas.

　　3. Antimicrobial therapy should be administered systemically immediately, selecting antibiotics based on the results of bacteriological examination. Before reports are available, third-generation cephalosporins such as ceftriaxone or cefoperazone can be used initially, with a dose of 50 to 80mg/(kg·d), administered intravenously; or beta-lactamase antibiotics (ampicillin, ticarcillin) and aminoglycoside drugs. In addition, the use of anti-anaerobic drugs (such as clindamycin, metronidazole) should also be considered, as polymyxin E has a neutralizing toxin effect (10 to 15mg/kg daily orally). For suspected gastrointestinal infections or positive blood cultures, the selection of antibiotics should be based on the bacteria causing the infection. Treatment should be continued for 10 days.

　　4. Parenteral fluid supplementation and nutritional maintenance for NEC infants due to extensive intestinal inflammation and peritonitis can lead to a significant loss of fluid in the third space. Water and electrolyte imbalances often occur, and it is very important to maintain water and electrolyte balance. Immediate fluid replenishment, correction of acidosis, and electrolyte disorder correction are needed. Children have a longer period of fasting, and parenteral fluid replenishment is necessary during the fasting period, and attention should be paid to nutritional supplementation. Appropriate parenteral colloids and crystalloids are infused to maintain circulation. At the same time as the intestinal repair, total parenteral nutrition is required for 14-21 days.

　　(1) Fluid volume: The total fluid volume per day is 100-150ml/kg based on the age.

　　(2) Caloric intake: Initially, ensure 209.2kJ/kg (50kcal/kg) per day, and gradually increase to 418.4-502.1kJ/kg (100-120kcal/kg) thereafter. Among them, 40%-50% is provided by carbohydrates, 45%-50% by fats, and 10%-15% by amino acids.

　　(3) Carbohydrates: Generally, glucose is used, 5-18g/kg per day, and if the blood glucose is >7.28mmol/L, the input of sugar should be reduced; if the blood glucose is measured multiple times >11.2-16.8mmol/L, insulin 0.25-0.5U/kg should be added.

　　(4) Proteins: Commonly used 6% pediatric amino acid injection, starting with 0.5g/kg per day, increasing by 0.25-0.5g/kg per day, and the maximum amount is 2.5g/kg per day. The main purpose of amino acid infusion is to promote protein synthesis while ensuring calorie intake, so the ratio of non-protein to protein calories should be about 10:1, and the calorie requirement per gram of amino acid nitrogen input should be 628-837kJ.

　　(5) Fats: Commonly used 10% fat emulsion (Intralipid), starting with 0.5g/kg per day, increasing by 0.25-0.5g/kg per day, and the maximum amount is 3g/kg per day. The infusion rate is not more than 3.0ml/kg per hour for those with a gestational age of 33 weeks.

　　(6) Electrolytes: Generally, provide 3-4 mmol/kg of sodium, 2-3 mmol/kg of potassium, and 2-3 mmol/kg of chloride every day, and mix them with the above nutrients to form 1/4 to 1/5 of the liquid input. However, blood electrolyte concentration should be monitored and adjusted at any time. The concentration of potassium should not exceed 3‰. If there is additional loss (vomiting, diarrhea, and gastrointestinal decompression), it is necessary to increase the supply of sodium chloride, generally mixed into 1/3 of the liquid input. If acidosis is present, 3-5 ml/kg of 5% sodium bicarbonate can be administered each time, and necessary adjustments can be made according to blood gas tests.

　　(7) Various trace elements and vitamins: Common trace element injections (Andamai) 1ml/kg per day, WaterSolvit (containing various water-soluble vitamins) 1ml/kg per day, and Vitalic (containing various fat-soluble vitamins) 5ml/day.

　　5. Improve circulatory function NEC infants often suffer from shock, the cause of shock is often due to infectious, hypovolemia, or multi-organ failure. Expansion of volume is required, and dopamine and dobutamine can be used.

　　6. Symptomatic treatment For patients with severe symptoms and shock, timely treatment is required, including expansion of volume, in addition to using 2:1 sodium-containing solution, plasma, human serum albumin, and 10% low-molecular-weight dextran. Vasoactive drugs such as dopamine and phentolamine can be selected, and hydrocortisone 10-20mg/kg can be administered every 6 hours. Oxygen should be inhaled through a mask when hypoxia occurs. Observe the development of the condition and perform surgery in a timely manner.

　　7. Surgical treatment is required for about 1/3 of cases, the indications for surgery are:

　　(1) Worsening of the condition: For infants with necrotizing enterocolitis, surgical treatment should also be considered when the clinical and laboratory conditions worsen after non-surgical treatment.

　　(2) Intestinal perforation, peritonitis: When intestinal perforation and severe intestinal necrosis have signs of pneumoperitoneum or peritonitis, or purulent material is aspirated through peritoneal puncture, surgical treatment is required, including the resection of necrotic and perforated intestinal segments, and if the remaining intestinal segments show no ischemia, reanastomosis of the intestinal segments can be performed. With the improvement of sepsis and peritonitis, enteral nutrition can be re-established after a few weeks or months.

　　(3) Intestinal stricture: A few infants develop intestinal stricture after a few weeks or months of non-surgical treatment, usually in the colon at the splenic flexure, and it is necessary to resect the stricture to restore the normal structure of the intestines.

　　II. Prognosis

　　This condition is an extremely serious disease of the neonatal digestive system, with a mortality rate of 20% to 40%. About 2/3 of newborns with necrotizing enterocolitis survive, and the prognosis can be improved through active supportive treatment and careful and timely surgical intervention. About 70% of cases require non-surgical treatment, and 5% to 30% of children may develop strictures at the ileocolonic anastomosis or short bowel syndrome after surgery, and follow-up is required after surgery.