NECROTIZING ENTEROCOLITIS (NEC)

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NECROTIZING ENTEROCOLITIS(NEC)

• Presented by Dr.Mohammad Mizyed
• Moderator Dr.Yousef Abu-osba

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• Definition
• Acute intestinal necrosis syndrome of unknown
  etiology.
• is the most common gastrointestinal emergency in
  the newborn infant .

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Epidemiology

• INCIDENCE
• NEC occurs in 1 to 3 per 1000 live births.
• 1.0 to 7.7 percent of admissions to NICU.
• The incidence is greatest in infants with birth
  weight less than 1500g occurring in 2 to 10
  percent of such infants, and decreases with
  increasing gestational age.
• Males and females are affected equally .
• NEC affects black and white infants more than
  Hispanic infants .
• NEC sometimes occurs in clusters or epidemics.
• mortality rate 9 - 29.
• 50 of survivors experience long-term sequelae.

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Risk factors

• Prematurity -The most important single risk
  factor
• however 10 of
  infants are full term.
  -Decreasing gestational age associated with
• increased risk for
  NEC.
• -Mean gestational age
  30 32 Weeks.
• -Mean age at onset 12
  days
• -90 of them have
  been fed before onset of NEC.
• Others a) cocain exposure.
  b) congenital heart disease.
  c) sepsis.
  d) seizures.
  e) hypoglycemia.
  f) hypercoagulable state.
  g) birth anoxia.
  h) polycythemia.

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Pathology

•  The pathology of NEC consists of intestinal
  infarction .
• The terminal ileum and colon are involved in the
  majority of cases, although the entire
  gastrointestinal tract is affected in severe
  cases.
• The bowel appears distended and hemorrhagic on
  gross examination.
• Subserosal collections of gas occasionally are
  present along the mesenteric border
• As the gut heals, thickening of the bowel wall,
  fibrinous adhesions, and areas of stenosis
  appear.
• The major histologic findings in NEC are mucosal
  edema, hemorrhage, and transmural necrosis.
• Other findings include acute inflammation,
  secondary bacterial infiltration, and collections
  of gas.

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Colon Necrotizing Enterocolitis Gross, natural
color, thickened constricted colon with linear
ulcerations and mucosal hyperemia
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Pathogenesis

•  The etiology of NEC is unknown, but it is
  probably caused by multiple factors in a
  susceptible host.
• Factors implicated in the pathogenesis of NEC
  include
• Prematurity.
• milk feeding.
• medications.
• circulatory instability.
• Infection.
• impaired mucosal defense.
• Others as inflammatory mediators and vasoactive
  agents.
• However, prematurity and milk feeding are the
  only consistent risk factors identified by
  epidemiologic studies for NEC.

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Prematurity 

•  Most cases of NEC occur in premature infants
  born before 34 weeks gestation who have been fed
  enterally.
• Immaturity of the gastrointestinal tract,
  including luminal function, motility, and barrier
  function, may predispose the preterm infant to
  NEC .
• Exposure to glucocorticoids matures intestinal
  barrier function, and antenatal treatment has
  been proposed to reduce the incidence of NEC.
• Poor motility can disturb feeding tolerance and
  result in stasis, bacterial overgrowth, and bowel
  distention that may lead to the development of
  NEC.
• Immature systemic and mucosal immune defense
  systems also may contribute.

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Milk feeding 

• More than 90 percent of infants who develop NEC
  have received milk feeding, although NEC also
  occurs in infants who have never been fed.
• Enteral feeding may contribute to the
  pathogenesis of NEC because human milk and
  commercial formulas serve as substrates for
  bacterial proliferation in the gut.
• Newborns partially malabsorb the carbohydrate and
  fat constituents in milk. As a result, reducing
  substances, organic acids, carbon dioxide, and
  hydrogen gas are produced by bacterial
  fermentation of these nutrients.

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• The rate of advancement of feedings has not been
  associated with the risk of NEC .
• The timing of the initiation of feedings (before
  or after four days) was not related to NEC .
• Providing minimal enteral or trophic feeding does
  not increase the incidence of NEC

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Human milk 

• Human milk, compared to formula, is more
  protective against NEC in premature infants.
• Factors present in human milk may play a role in
  this protection by reducing inflammation or the
  invasion of antigens in the gastrointestinal
  tract.
• These factors include platelet activating factor
  , secretory Immunoglobulin A, cytokines (IL-10,
  IL-11), epidermal growth factor , glutamine, and
  antioxidants such as vitamin E, carotene, and
  glutathione.

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Medications 

• Administration of hyperosmolar medications and/or
  formulas can cause mucosal injury and result in
  NEC.
• Oral medications such as theophylline,
  multivitamins, or phenobarbital contain
  hypertonic additives that might irritate the
  intestinal mucosa.
• Instillation of hyperosmolar contrast agents into
  the bowel for diagnostic radiographic studies
  also can cause mucosal injury, so Isotonic
  contrast agents should be used to avoid this
  complication.
• Histamine type 2 receptor (H2) antagonists, such
  as cimetidine, ranitidine, and famotidine, are
  associated with higher rates of NEC.
• A possible explanation for this finding is that
  gastric acidity, which may reduce the risk of NEC
  by inhibiting bacterial growth , was lowered by
  the use of H2-antagonists.

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Circulatory instability 

•  The pathogenesis of NEC has been attributed to
  an ischemic insult to the gastrointestinal tract,
  although most infants with NEC have not had an
  obvious perinatal hypoxic-ischemic event .
• Circulatory events implicated in the development
  of NEC include
• Perinatal asphyxia.
• Recurrent apnea.
• Hypoxia from severe RDS.
• Hypotension.
• Congenital heart disease.
• Patent ductus arteriosus.
• Heart failure.
• Umbilical arterial
  catheterization.
• Anemia.
• Polycythemia .
• Exchange transfusion.

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Infection

•  The role of gastrointestinal microorganisms in
  the pathophysiology of NEC is uncertain.
• Invasion of intestinal tissue by intestinal
  microflora can occur after ischemic damage to the
  mucosal barrier.
• In addition, primary invasion of the gut by
  enteric bacteria is an alternative mechanism that
  may be important in clusters or outbreaks of NEC.
  
• Specific organisms have characteristics that can
  result in NEC. For example, Clostridial species,
  are associated with pseudomembrane formation, and
  produce submucosal and subserosal gas blebs and
  intestinal gangrene that may lead to more severe
  NEC.

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• Approximately 20 to 30 percent of infants with
  NEC have associated bacteremia, although it
  probably represents bacterial translocation
  through the damaged intestinal mucosa.
• Bacterial organisms usually found in the distal
  gastrointestinal tract have been recovered from
  the blood and peritoneal cavities. These
  organisms include Escherichia coli, Klebsiella
  pneumoniae, Pseudomonas, and Clostridium
  difficile .
• In addition to these bacteria, viral and fungal
  pathogens have been isolated in some sporadic
  cases of NEC and in epidemic outbreaks.

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Impaired mucosal defense 

•  Premature infants are susceptible to the
  development of NEC because immunologic and
  gastrointestinal immaturity result in altered
  host resistance.
• Mucosal defense in the gut is mediated by
  several interrelated components .
• Factors that contribute to innate resistance
  include
• Luminal pH.
  
• Enzymes.
• Mucins.
  
• Epithelial barriers.
• Gut motility.
• Nonspecific antimicrobial factors as
  lactoferrin and
• lysozymes.

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• Premature infants have lower concentrations or
  more immature function of components that
  contribute to mucosal defense than do term
  infants.
• Growth factors, such as epidermal growth factor
  (EGF), are important in intestinal development
  and preservation of gut barrier function. In a
  study of neonates, infants who developed NEC had
  lower salivary epidermal growth factor (sEGF)
  levels compared to infants without NEC

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Inflammatory mediators

•  Inflammatory mediators, including
• -Tumor necrosis factor (TNF).
• - Interleukin- 6 (IL-6).
• -Platelet activating factor
  (PAF).
• These mediators Can aggravate the injury induced
  by ischemia,infectious agents,or mucosal
  irritants .
• Levels of cytokines are increased in premature
  infants with NEC and correlate with the severity
  of the disease.

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Vasoactive agents

•  Mucosal injury and inflammation may alter the
  balance of endogenous vasoactive agents such as
  nitric oxide and
• endothelin-1 ( a potent vasoconstrictor)
  that may contribute to the development of NEC.

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CLINICAL PRESENTATION

• The majority of premature infants who develop NEC
  are healthy, feeding well, and growing.
• A change in feeding tolerance with gastric
  retention is a frequent early sign.
• The timing of the onset of symptoms varies and
  appears to be inversely related to gestational
  age.
• The clinical presentation of NEC consists of
  systemic and abdominal signs.

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• Systemic signs are nonspecific and include
• Apnea.
• Respiratory failure.
• Lethargy.
• Poor feeding.
• Temperature instability.
• Hypotension resulting from septic shock in the
  most severe cases.
• Acidosis and bleeding diathesis.
• Abdominal signs include
• Distention.
• Gastric retention (residual milk in the stomach
  before a feeding) , abdiminal tenderness or abd.
  Wall erythema and induration.
• Vomiting.
• Hematochezia.
• Ascites.

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Bell staging criteria 

•  The Bell staging criteria provide a uniform
  definition of NEC based upon the severity of
  systemic, intestinal, and radiographic signs .
• These definitions are useful in comparing cases,
  although treatment is directed at the clinical
  signs rather than the particular stage.
• Each stage includes the characteristics of the
  previous stage plus signs associated with added
  severity.

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Stage IA or suspected NEC

• Is characterized by nonspecific systemic signs
  such as temperature instability, apnea, and
  lethargy.
• Abdominal signs include increased gastric
  residuals, abdominal distention, emesis, and
  heme-positive stool cases with grossly bloody
  stool are called stage IB NEC.
• Abdominal radiographs may be normal or show
  dilation of the bowel consistent with mild ileus.
  

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Stage IIA or proven NEC

• Include the signs of stage 1 plus absent bowel
  sounds with or without abdominal tenderness. The
  abdominal radiograph shows intestinal dilation,
  ileus, and pneumatosis intestinalis.
• Infants with stage IIA are mildly ill, whereas
  those with stage IIB NEC are moderately ill and
  also have mild metabolic acidosis and
  thrombocytopenia.
• Abdominal tenderness is present, and some infants
  have cellulitis of the abdominal wall or a mass
  in the right lower quadrant. Ascites is apparent
  on the abdominal radiograph.

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Stages IIIA and IIIB or advanced NEC

• Are the most severe forms. In stage IIIA, the
  bowel is intact, whereas stage IIIB is
  characterized by bowel perforation visualized as
  a pneumoperitoneum on the abdominal radiograph.
• Infants with advanced NEC are critically ill. In
  addition to the signs of less severe stages, they
  typically have hypotension, bradycardia, severe
  apnea, and signs of peritonitis, including
  abdominal distention and marked tenderness.
• Laboratory signs include a combined respiratory
  and metabolic acidosis, neutropenia, and
  disseminated intravascular coagulation (DIC).

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• In approximately 25 percent of cases, NEC is
  suspected but not confirmed (stage I). The
  symptoms resolve gradually in these infants.
• In 25 to 40 percent of cases, the progression of
  NEC is fulminant, with signs of peritonitis and
  sepsis, and the rapid development of DIC and
  shock (stage III).

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Stage Classification of NEC Systemic signs Abdominal signs Radiographic signs
IA Suspected Temperature instability, apnea, bradycardia, lethargy Gastric retention, abdominal distention, emesis, heme-positive stool Normal or intestinal dilation, mild ileus
IB Suspected Same as above Grossly bloody stool Same as above
IIA Definite, mildly ill Same as above Same as above, plus absent bowel sounds with or without abdominal tenderness Intestinal dilation, ileus, pneumatosis intestinalis
IIB Definite, moderately ill Same as above, plus mild metabolic acidosis and thrombocytopenia Same as above, plus absent bowel sounds, definite tenderness, with or without abdominal cellulitis or right lower quadrant mass Same as IIA, plus ascites
IIIA Advanced, severely ill, intact bowel Same as IIB, plus hypotension, bradycardia, severe apnea, combined respiratory and metabolic acidosis, DIC, and neutropenia Same as above, plus signs of peritonitis, marked tenderness, and abdominal distention Same as IIA, plus ascites
IIIB Advanced, severely ill, perforated bowel Same as IIIA Same as IIIA Same as above, plus pneumoperitoneum
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DIAGNOSIS 

• The laboratory evaluation of infants with NEC
  includes blood studies, stool analysis, sepsis
  evaluation, and radiographic studies.
• The results of these studies often are
  nonspecific, although the radiograph may be
  diagnostic.
• However, the presence of abdominal distention,
  hematochezia, and pneumatosis intestinalis
  confirm the clinical diagnosis of NEC.

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Blood tests

•  Although blood tests are not used in the
  diagnostic and staging criteria for NEC, certain
  laboratory findings support the diagnosis and aid
  in the management of infants with NEC.
• In particular, low platelet count, metabolic
  acidosis, and an increasing blood glucose are
  associated with NEC .

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• Blood tests include
• Complete blood count
• A complete blood count and differential are
  performed when NEC is suspected. Alterations in
  the white blood count are nonspecific, although
  an absolute neutrophil count of less than
  1500/microL is associated with a poor prognosis.
• Thrombocytopenia is a frequent finding and
  can result in significant bleeding.
• In the early stages of NEC, declining
  platelet counts correlate with necrotic bowel and
  worsening disease, whereas rising platelet counts
  often signal improvement.

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• Coagulation studies
• Coagulation studies are not ordered routinely
  but should be obtained if the infant has
  thrombocytopenia or bleeding.
• In addition to a decreased platelet count,
  prolonged PT and PTT, and increased D-dimer
  indicate disseminated intravascular coagulation
  (DIC), which is a frequent finding in infants
  with severe NEC.

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• Serum chemistries
• Serum electrolytes, blood urea nitrogen,
  creatinine, and pH are routinely measured.
• An ABGs is performed in infants with signs of
  respiratory compromise.
• Electrolyte abnormalities often are nonspecific.
  However, persistence of hyponatremia , increasing
  glucose levels, and metabolic acidosis are signs
  of necrotic bowel or sepsis.
• Other nonspecific findings in infants with NEC
  include increased levels of C-reactive protein
  (used for assessment of response to therapy)

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•  Stool examination
• May be positive for occult blood.
• A positive finding may increase the diagnostic
  suspicion, but it is not specific for the
  disease.
• Carbohydrate malabsorption may indicate an early
  sign of development of NEC.
• Sepsis evaluation 
• A sepsis evaluation is performed when NEC is
  suspected.
• Cultures are obtained of blood and, if indicated,
  cerebrospinal fluid.
• Cultures of the stool typically reveal enteric
  flora.
• If Clostridium difficile is suspected, specific
  cultures and assays for its toxins are
  performed.

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• Adiagnostic abdominal paracentesis
• occasionally is performed to obtain fluid for
  culture and Gram stain in infants with severe
  ascites or when peritonitis is suspected because
  of progressive clinical deterioration and an
  unchanging radiographic bowel gas pattern.

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Radiographic studies

• Abdominal radiography 
•  Abdominal radiographs are essential to confirm
  the diagnosis of NEC and to follow the
  progression of the disease.
• Abdominal radiographs are obtained in the supine
  position . In infants with more advanced illness
  in whom pneumoperitoneum is suspected, films also
  are taken in the supine cross-table lateral view.
• After the initial evaluation, we obtain serial
  radiographs, usually every 8 to 12 hours during
  the first few days or until the infant improves.

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• Radiographic findings include
• An abnormal gas pattern with dilated loops of
  bowel that is consistent with ileus typically is
  seen in the early stages of NEC.
• Pneumatosis intestinalis , the hallmark of NEC,
  appears as bubbles of gas in the bowel wall.
• Pneumoperitoneum typically appears when bowel
  perforation occurs.
• A substantial amount of intraperitoneal air may
  result in the "football" sign on the supine
  radiograph. This sign consists of a large
  hypolucent area in the central abdomen with
  markings from the falciform ligament.
• Portal venous gas had been thought to be a
  predictor of poor outcome and an indication for
  surgical intervention.

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Intramural gas is seen as rounded bubbles in the
submucosa (arrows).
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Left panel There is marked abdominal distention
due in part to dilated bowel loops, and bubbles
of gas in the bowel wall due to extensive
pneumatosis intestinalis (arrow). An orogastric
tube is in place. Right panel There is marked
abdominal distention, pneumatosis intestinalis,
and a suspicion of portal venous (arrow) and/or
free intraperitoneal air.
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Pneumatosis Intestinalis
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Pneumoperitoneum
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Abdominal ultrasonography

•  Although we currently rely on radiographs, the
  use of abdominal ultrasonography is increasing .
• The sonographic appearance of bowel wall with a
  central echogenic focus and a hypoechoic rim (the
  pseudo-kidney sign) may indicate necrotic bowel
  and imminent perforation.
• Ultrasonography also can detect intermittent gas
  bubbles in liver parenchyma and the portal venous
  system that are not detected by radiographs.
• Color Doppler ultrasonography has also been used
  to diagnose NEC.
• In a small study, color Doppler ultrasonography
  was more sensitive than abdominal radiography in
  detecting bowel necrosis and alterations in bowel
  wall perfusion as confirmed at laparotomy.

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DIFFERENTIAL DIAGNOSIS 

•  The differential diagnosis of NEC includes other
  conditions that cause rectal bleeding, abdominal
  distension, gastric retention, or other
  gastrointestinal abnormalities. In addition,
  infants with sepsis can have an ileus that is
  difficult to distinguish from early signs of NEC.
• Pneumatosis coli is a rare and benign form of NEC
  that affects premature infants .Affected infants
  typically have gastric retention and vomiting,
  apnea and lethargy, mild abdominal distention,
  and bloody stools. In contrast to typical NEC,
  intramural bowel gas occurs in the colon rather
  than in the small bowel. Infants recover within
  three days without sequelae.
• Pathogenic organisms, including Campylobacter, C
  difficile, Salmonella, and Shigella, sometimes
  cause infectious enterocolitis. These organisms
  are identified by stool cultures, although their
  causative role is often uncertain.

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• Anatomic or functional conditions that cause
  intestinal obstruction can result in
  enterocolitis. These disorders include
  Hirschsprung disease, ileal atresia, volvulus,
  meconium ileus, and intussusception.
• Anal fissures can result in rectal bleeding. This
  condition usually is benign, although the
  diagnosis of NEC must be strongly considered in
  any premature infant who has occult or gross
  blood in the stools.
• Severe allergic colitis may present with abd.
  Distension and bloody stool but they are well
  appearing and have normal radiographs.
• Pneumonia and Sepsis may present with ileus but
  they lack radiographic findings seen in NEC.
• Feeding intolerance.

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Medical Management

• The medical management consists of supportive
  care and close monitoring and should be initiated
  promptly when NEC is suspected.
• Supportive care includes bowel rest (NPO) ,
  parenteral nutrition, antibiotic therapy, and
  correction of metabolic and hematologic
  abnormalities.
• Critically ill infants frequently require
  cardiovascular or respiratory support.

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• Specific interventions include the following
• Discontinuation of enteral feedings .
• Gastrointestinal decompression with intermittent
  nasogastric suction
• Fluid replacement to correct third space losses
• Total parenteral nutrition.
• Broad-spectrum antibiotics.
• Nasogastric suction is continued until the
  infant's clinical condition improves, the ileus
  resolves, and pneumatosis is no longer seen on
  the abdominal radiograph. Enteral feedings are
  resumed gradually after 10 to 14 days if the
  infant's clinical condition allows.

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Antibiotic therapy 

• Infants are treated for 10 to 14 days with
  parenteral antibiotics that cover a broad range
  of aerobic and anaerobic organisms.
• We use a combination of ampicillin, gentamicin,
  and piperacillin-taxobactam, although the pattern
  of resistance at individual institutions will
  influence the choice of specific antibiotics.

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Laboratory monitoring

• Laboratory monitoring depends upon the results of
  the initial evaluation and the clinical condition
  of the infant.
• In the early stages of illness, we obtain a
  complete blood count and differential, platelet
  count, serum electrolyte measurements, blood urea
  nitrogen, creatinine, and acid-base studies
  approximately every 12 hours.
• Specific abnormalities, such as thrombocytopenia,
  may require more frequent testing to evaluate the
  need for and response to treatment. Stools that
  are not grossly bloody can be checked for occult
  blood if indicated.
• Platelets ,FFP and PRBCs transfusions my be
  needed to correct hematological abnormalities.
• Frequent ass. Of renal functions is indicated .

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Radiographic monitoring 

•  Radiographic monitoring is an important guide to
  the progression of the disease .
• We obtain an abdominal radiograph in the supine
  position is obtained every six to eight hours
  during the initial phase of illness.
• Films in the lateral decubitus view with the
  infant's left side down also are obtained in
  order to visualize the presence of free air over
  the liver. If the infant does not tolerate being
  moved and pneumoperitoneum is suspected, a supine
  cross-table lateral view is substituted.
• As the infant improves, usually within two to
  three days, radiographs are obtained less
  frequently. Radiographic monitoring is
  discontinued when the pneumatosis resolves.

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Surgical management

•  When the diagnosis of NEC is confirmed, a
  pediatric surgical consultation for evaluation
  and management of the infant and to decide if
  surgery is needed.
• Infants with NEC require surgical intervention
  when necrosis extends through the bowel wall and
  results in perforation.
• The decision to perform surgery is clear when
  pneumoperitoneum is recognized on the abdominal
  radiograph.
• However, extensive necrosis or perforation can
  occur without evidence of free air on the
  radiograph.

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• Signs of advanced NEC that may require surgery
  include
• Unremitting clinical deterioration.
• The presence of an abdominal mass.
• Ascites .
• Intestinal obstruction.
• Surgery also may be needed in infants who have
  severe peritonitis.

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Procedures 

• Surgical procedures performed in infants with NEC
  include either exploratory laparotomy with
  resection of the affected section or sections of
  bowel as indicated or peritoneal drainage
  placement.
• Laparotomy usually involves resection of the
  affected bowel segment and placement of a
  proximal enterostomy (usually an ileostomy) and
  distal mucous fistula.
• Reanastomosis, if required, usually is performed
  8 to 12 weeks after the initial procedure,
  depending upon the infant's clinical condition. A
  contrast enema usually is performed before the
  reanastomosis to detect intestinal strictures.
• If NEC affects only a short segment of bowel and
  the resection is limited, some surgeons perform a
  primary anastomosis.

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Complications 

• NEC is associated with significant complications
  during the acute stage of the disease and after
  recovery.
• The acute complications are primarily infectious
  and hematologic. They include
• Sepsis .
• Meningitis.
• Peritonitis.
• Abscess formation.
• DIC.
• Hypotension.
• Shock.
• Respiratory failure.
• Hypoglycemia.
• Metabolic acidosis.

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• The most common late complications of NEC
• Intestinal narrowing or stricture formation
• -Strictures occur in 9 to 36 percent of
  infants treated medically or surgically and are
  unrelated to the severity of NEC, the presence of
  pneumatosis intestinalis, or gestational age.
• -The majority of strictures occur in the
  colon.
• -Strictures typically develop within two to
  three months of the acute episode but are
  sometimes detected as late as 20 months.
• Short bowel syndrome.
• As a result, infants can develop bacterial
  overgrowth in the small bowel, repeated
  infections, bloody stools, failure to thrive, and
  symptoms of bowel obstruction.
• occurs in approximately nine percent of
  infants who undergo surgery.

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• Rare complications of NEC include enterocele,
  enterocolic fistula, and intraabdominal abscess.
• Infants also are at risk for cholestasis
  complications related to the use of central
  venous catheters and total parentral nutrition.

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Prognosis 

•  Advances in neonatal intensive care, earlier
  diagnosis, and aggressive treatment have improved
  the outcome of infants with NEC.
• As a result, approximately 70 to 80 percent of
  infants who have NEC survive, and approximately
  one-half of these are normal.
• The mortality rate is higher in infants who
  require surgery for NEC. (28 percent died within
  30 days after surgery ).
• Mortality is highest in infants with a
  gestational age less than 27 weeks and in those
  with extensive involvement of the small and large
  bowel.
• Approximately 10 percent of infants have late
  gastrointestinal morbidity.
• In comparison, the majority of infants who have
  not had extensive intestinal resection have
  normal gastrointestinal function at one to 10
  years.

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Prevention 

• Efforts to minimize the frequency or severity of
  NEC are directed at reducing exposure to risk
  factors and encouraging early feeding of human
  milk.
• The most important is to prevent premature
  births.
• Other preventive measures include
• Induction of GI maturation by prenatal steroids.
• Avoidance of hypertonic formula ,medications or
  contrast agents.
• Prompt treatment of polycythemia.
• Placement of umbilical artery catheters with the
  tip below the level of the inferior mesenteric
  artery.
• Other interventions, such as probiotic therapy,
  oral immunoglobulins, and nutritional
  supplements, are being investigated as potential
  preventive measures.

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Feeding 

• Human milk compared to formula is associated with
  a lower risk of NEC .
• This was best illustrated in a meta-analysis of
  five randomized controlled trials that
  demonstrated the risk of NEC was increased 2.5
  times in infants who were fed formula compared to
  those who were breast fed.
• Early institution of minimal enteral (trophic)
  feeding also may be beneficial.
• Furthermore, trophic feeding was not associated
  with an increased risk of NEC.

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Miscellaneous 

• Probiotics 
• Probiotics are defined as live nonpathogenic
  microbial preparations that colonize the
  intestine and provide benefit to the host .
• Probiotic microorganisms commonly used are
  strains of Lactobacillus, Bifidobacterium,
  Streptococcus salivarius, and Saccharmomyces
  boulardii.
• Proposed mechanisms for their effect include the
  following.
• Improvement of intestinal barrier function
• Modulation of the immune system
• Suppression of growth or epithelial
  binding/invasion by pathogenic bacteria

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• Randomized controlled trials and systematic
  review have demonstrated that probiotic therapy
  prevents NEC .Findings from studies are as
  follows
• Infants who received probiotics versus controls
  were less likely to develop NEC.
• Infants who received probiotics had a decreased
  mortality rate.

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Immunoglobulins

• Oral immunoglobulins may act in part by
  inhibiting the release of proinflammatory
  cytokines.
• In a randomized trial, oral administration of IgA
  and IgG in amounts similar to human milk reduced
  the incidence of NEC in formula-fed premature
  infants.
• In contrast, other data demonstrate that
  immunoglobins do not reduce the risk of NEC.
• In a meta-analysis of five trials (including 2 of
  the above studies), the oral administration of
  IgG or IgG/IgA combination did not reduce the
  incidence of definite NEC ,suspected NEC ,need
  for surgery ,or death from NEC.

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Avoidance of histamine 2 blockers

•  Innate gastrointestinal immunity provided by
  gastric acid may be important in preventing the
  cascade of infectious and inflammatory events
  leading to NEC.
• Histamine 2 blockers (H2 blockers) suppress
  gastic acidity and are associated with a increase
  risk of NEC. As a result, the use of H2 blockers
  should be avoided if at all possible.

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Recommendations 

1.  Recommendations include early institution of
   enteral feeding with human milk for all premature
   infants and feeding with minimal volumes of human
   milk for infants with less than 1500 g birth
   weight and, if possible avoidance of H2 blockers.
2. Although there is evidence of the potential
   benefits of probiotic therapy and nutritional
   supplements, large controlled trials are required
   to confirm the efficacy and safety of these
   interventions before they can be routinely
   recommended.
3. Immunoglobulin therapy should not be routinely
   used because there is a lack of data
   demonstrating any benefit from this therapy.

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