Necrotizing Enterocolitis

Presentation of necrotising enterocolitis has a broad spectrum of severity, from fulminant to insidious or asymptomatic forms at first. However, milder forms are more frequent in growing premature infants [8]. A decrease of gastric retention and feeding tolerance is a common early symptom of the disease. It is known that the level of glutamine and arginine have decreased for at least 10 days before clinical verification of NEC [6]. These amino acids are essential components for gastrointestinal muscle cells but it is still unclear if they can be considered as markers of the disease or part of pathogenesis.

Initial signs can involve one or more of the next:

• Meteorism: The increase of feeding intolerance and abdominal distension are initial clinical symptoms of NEC [8]. Meteorism caused by the accumulating of gas, that builds up in the intestine. Consequently, continued abdominal distension may compromise the bowel's wall perfusion. 
• Visible to naked eye intestinal loops
• Bilious vomiting
• Stool change (bloody mucoid)
• Decrease of peristaltic sounds
• Erythema of the abdomen wall
• Ascites

Nonspecific systemic signs can include:

• Apnea
• The decrease of peripheral perfusion
• Shock (in advanced stages) or cardiovascular collapse. It's important that term newborns may have systemic signs due to an underlying disease (metabolic abnormalities, congenital heart disease, birth asphyxia, respiratory distress,) or have an abnormal fetal growth in mother's obstetric anamnesis.

The clinical presentation and recognize of NEC are based on well-defined staging criteria [9] [10] [11]. It consists of the severity of systemic, intestinal symptoms and radiographic findings.

Bell Stage I - suspected necrotising enterocolitis (NEC)

• Systemic: general signs such as fiber, inactivity, apnoea, bradycardia.
• Gastrointestinal tract (GIT): gastric residuals, positive fecal occult blood test.
• Abdominal X-ray (AXR): without pathological finding or nonspecific changes.

Stage IB diagnosis is equivalent to IA, with the addition of the bloody stool.

Bell stage II - definite disease

Stage IIA - definite and mild NEC:

• Systemic: Nonspecific signs.
• GIT: Abdominal wall tenderness or abdominal distension, absent peristaltic sounds, blood in the stool.
• AXR: Ileus, focal pneumatosis of intestine.

Stage IIB - definite and moderate NEC:

• Systemic: Moderate acidosis, thrombocytopenia.
• GIT: Abdominal wall edema, tenderness, intestinal mass as a palpation symptoms.
• AXR: Extensive pneumatosis of the intestine, early ascites. Radiographs note a portal venous gas.

Bell stage III - advanced disease

Stage IIIA - advanced NEC:

• Systemic: Severe acidosis, apnea, hypotension, oliguria, leukopenia, disseminated intravascular coagulation (DIC).
• GIT: Spreading severe edema, erythema and an induration of the abdominal wall.
• AXR: Prominent ascites, sentinel loop sign, however, absent of perforation.

Stage IIIB - advanced NEC:

• Systemic: Drop of vital signs, shock, electrolyte imbalance.
• GIT and AXR: Signs of perforation.
• Stage IIIB use for the severely ill newborn with perforated bowel observed on X-rays in addition to the IIIA findings.

Laboratory workup

Despite the blood lab tests have low specificity, blood cultures, blood gas, full blood count (FBC) and biochemical tests should be taken for the support to the diagnosis. Moreover, thrombocytopenia, neutropenia, coagulopathy, acidosis may indicate the severity of NEC.

• Complete blood count: A complete blood count (CBC), with standard differential to estimate the white blood cell (WBC), hematocrit, and platelet volume, is regularly repeated every 6 hours if the patient's dynamic status is declining. Leukopenia is more common than a leukocytosis. This fact caused by massive sequestration of neutrophils in the peritoneal liquid [5].
• Serum chemistries: Electrolyte disorders are nonspecific finding, however, it may be suggestive of NEC. The hyponatremia, hypoglycemia, and metabolic acidosis are commonly seen in babies with NEC.
• Coagulation studies: These tests are necessary, especially in cases with thrombocytopenia or gastrointestinal bleeding. Moreover, disseminated intravascular coagulation is a common finding in babies with severe NEC.
• Bacteriological tests of the stool, blood, urine, or spinal fluid. Despite the fact that a direct relationship between a specific microbe and NEC is still unclear, the presence of bacteria can be critical for the NEC development [12] [13] [7].

Imaging 

• Diagnosis of NEC must be verified by abdominal radiograph (supine and erect) and should be done as soon as the NEC can be suspected. 
• Early X-rays may be nonspecific and show only signs of ileus. Nevertheless, the dilated and fixed intestinal loop that give not change on repeated radiographs may recognize NEC. Other X-ray signs of NEC are intestinal pneumatosis and portal vein gas. Consequently, pneumoperitoneum indicates a perforation of bowel's wall and requires an urgent surgical intervention.
• Ultrasonography (USG) is frequently used in the diagnosis of NEC. Typical findings on ultrasonography include the appearance of an intestinal wall with central echogenic locus and hypoechoic rim or pseudo-kidney sign. It may mean necrotic bowel and following perforation. Ultrasound can also be used for the detection of gas in the liver parenchyma or the portal venous system.

Over than half of all premature infants reveal feeding intolerance during their hospital course, but at the same time less than 25% of those newborns have necrotizing enterocolitis (NEC). As with all neonatal clinical cases, the risks and benefits of different clinical approaches to NEC must be considered thoroughly.

In over 75% of cases, conservative treatment without surgical intervention is sufficient. If NEC is suspected, feedings must be terminated immediately. Furthermore, the intestine should be decompressed. Decompression is necessary at the first indication of abdominal pathology. It may involve:

• Large-bore catheter with multiple side perforations and a lumen to block vacuum attachment to the mucosa.
• Install the catheter for low, continuous or intermittent suction.
• If profuse amounts of intestinal or gastric secretions are eliminated, IV replacement with a physiological solution must be considered.

Monitoring should involve complete blood count, platelet count, serum electrolyte every 12 hours. The serial abdominal X-rays should repeat at 6-hour intervals.

The initial treatment consists of the next:

• Stop enteral feedings
• Make abdominal decompression
• Broad-spectrum antibiotics. Systemic antibiotics should be begun immediately with a β-lactam antibiotic (eg, ampicillin, ticarcillin) and an aminoglycoside (amikacin). Antibiotic therapy should coverage anaerobic bacteria (clindamycin, metronidazole) and should continue at least 10 days.

Bell stages IA and IB

The infant is directed on an NPO diet with antibiotics for 3 days. IV fluids must be given and include total parenteral nutrition (TPN).

Bell stages IIA and IIB

Treatment must involve respiratory and cardiovascular support with fluid resuscitation, NPO, and a course of antibiotics for 14 days. Surgical consultation should be immediately considered. After stabilization, TPN should be given during all period of NPO diet.

Bell stage IIIA

Treatment must involve NPO for at least 14 days, fluid resuscitation, inotropic and ventilator support. Surgical consultation is necessary. TPN should be prolonged during the period of NPO diet.

Bell stage IIIB

Surgical intervention includes primary peritoneal drainage (PPD at the bedside in the NICU), the laparoscopic resection of the affected intestinal segment with proximal enterostomy, distal mucous fistula. Surgical intervention is needed in approximately 25% of babies. With the resolution of peritonitis and sepsis, intestinal continuity may be renewed some weeks or months later.

Necrotizing enterocolitis is a dangerous condition. Nearly one every 4 affected infant dies. Therefore, only early and aggressive treatment can improve the outcome. Moreover, in surgically treated cases of NEC, the postoperative survival approaches to 95%, even if it must be considered that this improvement in treatment efficacy could be explained by the exclusion of the patients with pan-involvement forms of NEC. Necrotic process rises in the mucosa and may involve and affect the full width of the intestinal wall. It can lead to the dangerous complications such as pneumoperitoneum, perforation with following peritonitis, septic shock, and multiple organ dysfunction.

Consequently, the most significant NEC complications include:

• Perforation.
• Malabsorption syndrome following surgery (Acquired short bowel syndrome).
• Stoma-related complications [7].
• Disseminated intravascular coagulation.
• Sepsis and shock.
• Intestinal strictures. This complication usually happen within 2-3 months of presentation, however, it may befall later. Intestinal strictures occur in over 20% of cases and aren't associated with the severity of the disease.
• Entero-colic fistulae.
• Abscess formation.

In spite of the development of medical sciences, necrotising enterocolitis is still an idiopathic disease. The exact etiology is unknown. However, researchers suggest that an ischemic damage of the intestinal lining lead to increasing of bowels wall permeability and make the intestine more sensitive to microbial invasion. Often gram-positive and gram-negative bacteria, as well as fungi have been isolated from affected newborns, however, patients with NEC can have negative culture findings. This condition commonly develops in compromised and premature infants. Additionally, NEC is probable to occur while the newborn is still in the hospital.

Groups with higher risk of NEC include:

• Preterm infants
• Babies with medical formula feeding
• Infants who contact with outbreak of diseases 
• Infants with blood exchange transfusions in anamnesis

The incidence of necrotising enterocolitis rangse from 1% to 7% of all neonatal intensive care unit (NICU). In other words, from one to three per thousand live births, and it befalls in males and females approximately equally [2]. Despite the varied mortality ranges from 4% to over 50%, newborns with mass fewer than 1000 g have the significant highest risk. [3] It decreases to 3.8 per 1000 newborns who weigh 1501-2500 g [4] [5].

Different sources with epidemiologic studies report that risk factors, infants characteristics, and severe of disease differ between term and preterm babies with NEC. Although full-term infants may have a non-severe clinical course, these patients frequently have a compromised intestinal perfusion due to the polycythemia, birth asphyxia, transfusion, complications during pregnancy, or cardiovascular defects.

One of the hypotheses indicates that the damage in NEC starts with a disturbance of the bowels mucosal barrier. This process causes bacterial migration across the epithelial layer. It begins the cascade of pathological excessive inflammatory reaction and the development of the clinical picture of necrotizing enterocolitis.

According to animal model studies, irregardless the type of trigger, the consequent outcome is a massive inflammation of the intestinal wall tissues. The inflammatory mediators such as tumor necrosis factor (TNF), leukotrienes, platelet-activating factor (PAF), and others cytokines cause a severe alteration of tissues which can lead to intestinal damage including perforation [6].

An effective intervention in the prevention of necrotising enterocolitis (NEC) is still natural feeding with human milk [6]. However, other interventions have an insufficient evidence base, and they are directed to reduce the various contributing factors in a sensitive organism. Probiotics (Bifidus infantis, Lactobacillus acidophilus) may help to prevent NEC, even if further studies to define optimal dosing and suitable strains are needed. Attempts to reduce the incidence of NEC may target infection prevention in the newborn nursery, increase of premature resistance, inhibition of inflammatory mediators, stimulation of GI tract maturation.

Necrotising enterocolitis (NEC) was described above one century ago, however, the term had been introduced by Rossier and Schmid in 1959. Now, it is the most frequent and serious gastrointestinal disorder among hospitalized neonates [1]. Necrotizing enterocolitis befalls commonly in the second and third week of preterm infant's life. This disorder can be characterized by different damage to the intestine, varying from mucosal inflammation to severe necrosis of all bowel's layers and perforation.

Presentation of NEC includes feeding intolerance, apathy, fever, in some cases obstruction of the intestine signs, tympanism, emesis, hematochezia, more frequent stools, apnea, and signs of intoxication. Diagnosis of the disease is based on clinical findings and needs to be confirmed by imaging studies. Therapy of NEC is essentially supportive and may include parenteral nutrition, antibiotics, isolation in cases of severe infection, and surgery if the indications are present.

Definition

Necrotizing enterocolitis is a nonspecific inflammation of the bowels. It is most frequent in babies who are born early (preterm infants). Many newborns who have it alive and live normal lives. But if the condition becomes in severe form, it can cause critical damage to the intestine, which can be fatal.

Causes

The exact cause of NEC is unknown. There are hypotheses, however, that a decline in blood flow to the bowel blocks the bowel from producing mucus. The mucus protects the bowel's wall. Moreover, bacteria in the compromised intestine can be a cause. It may happen when a baby is born early or when there are difficulties during pregnancy or birth.

Symptoms

Symptoms depend on how critical the problem is. They may involve:

• Abdominal bloating
• Diarrhea or blood in the stool
• Feeding obstacles
• Loss of energy
• Fiber
• Vomiting

Diagnosis

The doctor will examine your baby's symptoms and may perform some tests, such as:

• A radiograph of your newborn's abdomen. 
• An analysis to check for blood in your baby's stool (fecal occult blood test).
• Tests to verify bacteria in the stool, blood, urine, or spinal fluid.

Treatment

Treatment for a baby with necrotizing enterocolitis includes:

• Halting normal feedings
• Removing gas in the bowel by embedding a tube in the stomach
• Intravenous solutions and antibiotic medicines
• Monitoring the baby's condition with serial abdominal x-rays and blood tests.

If your baby does not respond to a treatment or gets a hole in the bowels, he or she require surgical intervention. The surgeon will:

• Remove dead bowel segment
• Perform an ileostomy or colostomy

Your baby will be able to leave the hospital when he or she is eating well and is not missing body mass.

Prevention

All infants should be fed only natural breast milk, and feedings should start with small volumes that are gradually increased agreeing to standards and protocols.

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