Necrotizing Enterocolitis

Background

  • Necrotizing enterocolitis (NEC) is an acute inflammatory disease occurring in neonates and characterized by variable damage to the intestinal tract ranging from mucosal injury to full-thickness necrosis and perforation.
  • NEC is a medical/surgical emergency that affects approximately 10% of newborns who weight less than 1500g
    • It has a mortality rate approaching 50%.
    • Full term infants that develop NEC, 13% of cases of all NEC cases, typically have preexisting illness.

Epidemiology

  • 1-3 per 1000 live births
    • 5-10 per 100 of infants admitted to the NICU
  • More common in African American infants

Pathology

  • NEC most commonly affects the terminal ileum and the proximal ascending colon, although the entire gastrointestinal tract is affected in severe cases.
  • On gross examination, the bowel appears distend and hemorrhagic.
  • Subserosal collections of gas occasionally are present along the mesenteric border.
  • Gangrenous necrosis occurs on the antimesenteric border and perforation may be present.
  • The isolation of strains of E.coli and Clostridia as well as reduction of disease incident with prophylatic antibiotics validate the role of infection in the pathogenesis of NEC.
  • In a study conducted by Holy CM et al., of 12 neonates with weekly stool examination by gel electrophoresis 3 neonates who developed NEC had abnormal bands for Clostridum perfringens as compared to control infants.

Risk Factors

  • Prematurity
  • SGA
  • Introduction of feeding (withholding feeds delays NEC onset but cannot prevent NEC—thus no need to delay feeds)
  • Intrauterine hypoxia (maternal HTN, placental abruption)
  • Other congenital disorders (i.e. congenital heart disease, respiratory distress, polycythemia sepsis, seizures, hypoglycemia, hypercoagulable state, gastroschisis)

Ways to reduce risk:

  • Breast feeding
  • Slow enteral feeds
  • Enteral supplementation of probiotics (optimal dosage and specific species remains under investigation)

Clinical Signs and Symptoms

  • Typically symptoms of NEC begin 8 to 10 days after birth, with a later onset among more premature infants.
  • A change in feeding tolerance with gastric retention is a frequent early sign of disease.
  • Other clinical signs that characterize the disease include:
    • Feeding intolerance
    • Delayed gastric emptying (residual milk in the stomach before a feeding)
    • Abdominal distension, abdominal tenderness
    • Ileus/decreased bowel sounds
    • Abdominal wall erythema
    • Hematochezia

Systemic signs are nonspecific and include:

  • Apnea
  • Lethargy
  • Decreased peripheral perfusion
  • Temperature instability
  • Hypotension from septic shock

Differential Diagnosis:

  • Sepsis
  • Spontaneous intestinal perforation of the newborn
  • Intestinal obstruction
  • Anal fissures
  • Neonatal appendicitis
  • Cow’s milk protein allergy

 

Bell Staging Criteria

This staging criteria allows for a uniform definition of NEC based upon the severity of systemic, intestinal and radiographic findings.

  • Stage I (suspected NEC): nonspecific systemic signs (e.g. temperature instability, apnea, lethargy). Abdominal signs such as increased gastric residuals, abdominal distention and emesis. Radiographs may be normal or show dilation of the bowel.
        
  • Stage II (proven NEC): Signs of stage I in addition to absent bowel sounds with or without abdominal tenderness.  Abdominal radiography findings include intestinal dilation, ileus, penumatosis, intestinalis, and ascites.
        
  • Stage III (advanced NEC): In this stage the bowel may be perforated and show signs of pneumoperitoneum on abdominal radiograph. In addition to presenting with signs typical of the above two stages, infants also commonly have hypotension, bradycardia, severe apnea and signs of peritonitis.

 

Clinical Decision Making

Laboratory Work Up

  • Blood tests are not used in the staging criteria for NEC but the findings can help in the diagnosis and have a role in the management of infants of NEC.
    • Complete blood count: Thrombocytopenia is frequently found in infants with NEC and can result in substantial bleeding. Declining platelet counts can be seen in the early of NEC and commonly correlates with necrotic bowel and worsening disease.
    • Coagulation studies: Should be obtained, especially if the child has thrombocytopenia or bleeding, given that disseminated intravascular coagulation is a frequent finding in infants with severe NEC.
    • Serum chemistries: Electrolyte abnormalities are nonspecific but can be suggestive of NEC. The persistence of hyponatremia, increasing glucose levels and metabolic acidosis are abnormalities commonly see in infants with NEC.
    • Must also evaluate for sepsis:  ABG, bacterial cultures of the blood, urine, stool, and CSF

Imaging

  • Abdominal radiographs confirm the diagnosis of NEC. 
    • Abdominal radiographs are obtained in the supine position.
    • If penumoperitoneum is suspected, films are also taken in the supine cross-table lateral view or in the lateral decubitus position with the left side down to detect free air. 
    • Abdominal radiographs should be performed serially at 6-hr or greater intervals to follow the progression of the disease.

Characteristic findings on anteroposterior view include:

  • Abnormal gas pattern with dilated loops of bowel that is consistent with ileus
  • Pneumatosis intestinalis is pathognomonic of NEC. It is bubbles of gas in the small bowel wall that appear as train-track lucency configuration within the bowel wall.
  • Penumoperitoneum is seen when bowel perforation had occurred
  • Sentinel loops, which is a loop of bowel that remains in fixed position. It suggest necrotic bowel and/or perforation.
  • Portal gas that appears as linear, branching areas of decreased density over the liver shadow and represents air in the portal venous system.

    NEC.png         Upper arrow points to portal air and lower arrow points to pneumatosis intestinalis. Adapted from Neu, 201

 

  • Abdominal ultrasonogram is increasingly used in the diagnosis of NEC.
    • Characteristic findings on ultrasongraphy include appearance of bowel wall with central echogenic focus and hypoechoic rim (pseudo-kidney sign), which may indicate necrotic bowel and imminent perforation.
    • Ultrasound can also be used to detect intermittent gas bubbles in liver parenchyma and the portal venous system.

Diagnosis:

  • Based on clinical Features + rectal bleeding + radiologic findings
  • Biomarkers that may be elevated: serum amyloid A, anaphylatoxin (C5a), urinary intestinal fatty acid-binding protein (I-FABP), claudin-3, stool platelet-activating factor (PAF), and calprotectin.
  • Biomarkers that may be decreased: Inter-alpha-inhibitory protein

Treatment

  • Medical Management
    • Medical management typically consists of supportive care, antibiotic therapy and close laboratory and radiologic monitoring.
  • Supportive care
    • Consists of bowel rest with discontinuation of enteral feedings and gastrointestinal decompression with intermittent nasogastric suction.
    • Total parenteral nutrition.
    • Fluid replacement to correct third space losses.
    • Correction of hematologic and metabolic abnormalities.
  • Antibiotic therapy
    • Should be initiated in infants with suspected or confirmed NEC once specimens for cultures have been collected and should consist of broad spectrum treatment, specifically providing coverage for pathogens that anaerobic and those that cause late-onset bacteremia.
    • Antibiotic administration for 7-10 days (optimal duration indeterminate)
      • Commonly used regimen: ampicillin, gentamicin, metronidazole
      • May also use cefotaxime, vancomycin, clindamycin
      • No particular antibiotic regimen demonstrated to be most superior
  • Monitoring should include both laboratory monitoring (complete blood count, platelet count, serum electrolyte) every 12 hours and serial abdominal radiographs at 6-hour intervals.
         
  • Surgical  Management
           
    • Consultation with a pediatric surgeon is important to determine when and if surgery is needed.
    • Surgery is necessary when necrosis extends through the bowel wall, which is clearly indicated by pneumoperitoneum on abdominal radiograph but may also occur without radiographic evidence of free air.
    • Clinical signs must therefore also be considered, including:
      • Clinical deterioration
      • Abdominal mass
      • Ascites
      • Intenstinal obstruction
      • Progressive erythema of the abdominal wall
      • Peritoneal signs.  
    • Timing of surgery is an important consideration, as this will determine both how much bowel length may be preserved as well as the stability of the patient and his/her ability to tolerate the procedure.
    • Surgical options include primary peritoneal drainage (PPD at the bedside in the NICU or laparoscopic resection of the affected bowel segment with proximal enterostomy and distal mucous fistula. Many institutions begin with PPD and only proceed to laparotomy if a patient fails to respond to PPD.

Complications

NEC is associated with several significant complications that may arise both during and soon after acute presentation.

  • Infection: sepsis, meningitis, peritonitis, and abscess
  • Disseminated intravascular coagulation
  • Respiratory and cardiovascular complications: hypotension, shock, and respiratory failure
  • Metabolic complications: hypoglycemia and metabolic acidosis
  • Intestinal strictures
    • This common complication usually develop within 2-3 months of presentation, but may develop as late as 20 months. These occur in 20-36% of cases and are unrelated to severity of disease. Multiple strictures may develop, with most arising in the colon but some also occurring in the ileum or jejunum.
           
      They may lead to bacterial overgrowth in the small bowel, which can present as repeated infections, bloody stools, failure to thrive, and bowel obstruction. Because of the high incidence of strictures arising after acute cases of NEC, contrast enemas are performed before closure of enterostomy and reanastomosis of the bowel 4-6 weeks after acute presentation. Strictures require surgical resection.

Prognosis:

  • 15-30% mortality (increased GA and BW decreases mortality)
  • 10-22% develop abdominal stricture
  • NEC is the most common cause of short bowel syndrome
  • Higher risk of nosocomial infection, malnutrition, growth failure, bronchopulmonary dysplasia, and neurodevelopmental delay

References

  1. Bell EF and Acarregui, MJ. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Chochrane Database of Systemic Reviews 2014, Issue 12. Art. No.: CD000503. DOI:10.1002/14651858.CD000503.pub3.

  2. Chu, A et al. Necrotizing enterocolitis: Predictive markers and preventive strategies. NeoReviews. 2013; 14(3):e113.

  3. Downward, CD et al. Treatment of necrotizing enterocolits: An American pediatric surgical association outcomes and clinical trials committee systematic review. J Pediatr Surg. 2012; 47(11):p2111-22.

  4. Henry, MCW and Moss, RL. Necrotizing enterocolitis. Annu. Rev. Med. 2009;  60:111-24.

  5. Hunter, CJ et al. Understanding the susceptibility of the premature infant to necrotizing enterocolitis (NEC). Pediatric Research, 2008; 63:117-123.

  6. Neu, J and Walker, WA. Necrotizing enterocolitis. NEJM,  2011; 364:255-64.

  7. Patel, BK and Shah, JS. Necrotizing enterocolitis in very low birth weight infants: A systemic review. ISRN Gastroenterol. 2012;2012:562594.

  8. Shah, D and Sinn, JKH. Antibiotic regimens for the empirical treatment of newborn infants with necrotising enterocolitis. Chochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD007448. DOI: 10.1002/14651858.CD007448.pub2.

  9. Stey, A et al. Outcomes and costs of surgical treatments of necrotizing enterocolitis. Pediatrics, 2015; 135(5):e1190-7.

  10. Tickell D and Duke, T. Evidence behind the WHO guidelines: Hospital care for children: For young infants with suspected necrotizing enterocolitis (NEC), what is the effectiveness of different parenteral antibiotic regimens in preventing progression and sequelae? J of Trop Ped, 2010; 56(6): 373-78.

  11. Walsh, MC et al. Necrotizing enterocolits: A practitioner’s perspective. Pediatrics in review, 1988; 9(7):p219.

  12. Yee, WH et al. Incidence and timing of presentation of necrotizing enterocolitis in preterm infants. Pediatrics, 2012; 129(2):e298-304.

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