Necrotizing enterocolitis
kibaru
introduction
Necrotizing enterocolitis (NEC) is one of the
most common gastrointestinal emergencies in
the newborn infant.
First described in 1965
the etiology of NEC remains uncertain
It is a disorder characterized by ischemic
necrosis of the intestinal mucosa
this is associated with inflammation, invasion of
enteric gas forming organisms, and dissection of
gas into the muscularis and portal venous system
early recognition and aggressive treatment of
this disorder has improved clinical outcomes
NEC accounts for substantial long-term
morbidity in survivors of neonatal intensive
care
More in premature very low birth weight infants
(birth weight below 1500 g)
EPIDEMIOLOGY
— Necrotizing enterocolitis (NEC) occurs in 1
to 3 per 1000 live births
1 to 7.7 percent of admissions to neonatal
intensive care units (NICUs)
Preterm infants — The incidence decreases
with increasing gestational age (GA) and birth
weight (BW), and is about 6 to 7 percent in
very low birth weight (VLBW) infants (BW less
than 1500 g)
approximately 13 percent of cases occur in
term infants.
Term infants — NEC in term infants is
generally associated with predisposing or
underlying conditions, such as
congenital heart disease
perinatal asphyxia
polycythemia
sepsis
respiratory disease
PATHOGENESIS
The pathogenesis of necrotizing enterocolitis
(NEC) remains unknown
it is probably a heterogeneous disease
resulting from multiple factors that result in
mucosal injury in a susceptible host.
The following factors have been implicated in the
pathogenesis of NEC
●Prematurity
●Microbial bowel overgrowth
●Milk feeding
●Impaired mucosal defense
●Circulatory instability of the intestinal tract
●Medications that cause intestinal mucosal injury or
enhance microbial overgrowth
Currently, epidemiologic studies have
identified prematurity and milk feeding as
consistent risk factors for NEC
a) Prematurity
About 90 percent of NEC cases occur in
premature infants born who have been fed
enterally.
Factors in premature babies
Immature mucosal barrier with increased
permeability and bacterial penetration into
the intestinal wall compared with term infants
Immature local host defenses
with diminished concentrations of secretory IgA
mucosal enzymes (eg, pepsin and proteases)
other protective agents (eg, lactoferrin)
increased gastric pH
which promotes bacterial overgrowth
Immature bowel motility and function.
Premature infants have decreased small bowel
motility, resulting in delayed transit time,
which increases bacterial proliferation and
overgrowth
Bacterial overgrowth and increased intestinal
permeability are factors that contribute to
greater bacterial translocation from the
intestinal lumen into the intestinal tissue
leading to an inflammatory response with
activation of cytokines
Exposure to glucocorticoids matures intestinal
barrier function, and antenatal treatment has
been proposed to reduce the incidence of NEC
Milk feeding
More than 90 percent of infants who develop
NEC have received milk feeding
Enteral feeding may contribute to the
pathogenesis of NEC because human milk and
commercial formulas serve as substrates for
bacterial proliferation in the gut
premature infants, have not developed the ability to
completely digest and absorb nutrients.
As a result, bacterial fermentation products of
incompletely digested carbohydrates and lipids (eg,
reducing substances, organic acids, short chain
fatty acids, carbon dioxide, and hydrogen gas) in
the intestine of premature infants may cause
mucosal injury.
Delayed transient time due to impaired motility in
the premature infant exacerbates this process.
Factors in enteral feeding
A) Rate of advancement
that slow advancement of feeds was not
associated with a reduced risk of NEC and was
associated with a delay in regaining birth
weight and establishing full enteral feeds
compared with faster rates of advancement
B) Timing of initial feeding
that a delay in the introduction of enteral
feeds (after four days of age) was not
associated with a reduced risk of NEC and that
the delay is associated with a longer time to
establish full enteral feeds
C)●Providing minimal enteral or trophic
feeding does not increase the incidence of
NEC
D) Type of the milk
Human milk — Human milk, compared with formula,
is more protective against NEC in premature infants.
Human milk feeding is associated with a lower
intestinal pH to facilitate the growth of
nonpathogenic bacteria, which counteract
pathogenic bacteria.
The mucus coat of the intestine is less affected by
human milk, and growth factors within human milk
(such as epidermal growth factors) repair
disruptions in this layer.
Human milk improves intestinal motility,
which avoids milk stasis and decreases
intestinal permeability.
Human milk also stimulates the mucosal
defense system so that local immune
activation is thwarted.
Protective factors within human milk include
platelet activating factor acetylhydrolase,
secretory Immunoglobulin A
cytokines (IL-10, IL-11)
epidermal growth factor nucleotides
glutamine
antioxidants such as vitamin E, carotene, and
glutathione.
Microbial colonization
Bacterial colonization is believed to play a
pivotal role in the development of NEC
because NEC does not occur in utero when the
gut is sterile.
After delivery, rapid colonization of the
intestinal tract by commensal bacteria from
the maternal rectovaginal flora occurs
intestinal noncommensal bacterial
overgrowth, especially with coagulase-
negative staphylococci, appears to be
associated with NEC
Overgrowth of noncommensal bacteria may
cause mucosal injury by affecting intestinal
maturation, increasing inflammation and
apoptosis, and releasing endotoxin
empiric antibiotic therapy greater than
five days duration is associated with an
increased risk of NEC or death
most likely due to a change in the bacterial
colonization of the gastrointestinal tract
Primary infection
NEC may be due to primary invasions of the
gut by pathogenic enteric bacteria.
Bacterial organisms usually found in the
distal gastrointestinal tract have been
recovered from the blood and peritoneal
cavities of patients with NEC.
[32-34].
These organisms include Escherichia coli, Klebsiella
pneumoniae, Pseudomonas, and Clostridium
difficile .
Clostridium species, toxin-producing bacteria that
are associated with pseudomembrane formation,
submucosal and subserosal gas blebs, and
intestinal gangrene, have been associated NEC,
particularly more severe cases
Circulatory instability
Ischemic insult to the gastrointestinal tract has been proposed as
a major contributor to NEC
Circulatory events include
perinatal asphyxia
recurrent apnea
hypoxia from severe respiratory distress syndrome
hypotension
congenital heart disease
heart failure
umbilical arterial catheterization
anemia
Polycythemia
red blood cell and exchange transfusions
A diminished blood supply to the gut may contribute to the
pathogenesis of NEC in infants exposed to cocaine
Medications
The administration of hyperosmolar medications and/or
formulas can cause mucosal injury and may 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
because of fluid shifts, bowel distention, and ischemia.
Isotonic contrast agents should be used to avoid this
Histamine type 2 receptor (H2)-antagonists,
such as cimetidine, ranitidine, and famotidine,
are associated with higher rates of NEC as that
gastric acidity, which may reduce the risk of NEC
by inhibiting bacterial growth was lowered by the
use of H2-antagonists
Pathological findings in NEC
The pathologic findings of NEC vary
depending upon the progression of the
disease.
In general, the bowel appears distended and
hemorrhagic on gross examination.
The major histologic findings include mucosal
edema, hemorrhage, and transmural bland
necrosis
CLINICAL PRESENTATION
The majority of premature infants who
develop necrotizing enterocolitis (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
25 percent of cases present later than 30 days
after birth.
The median age at onset in infants with a
gestational age of less than 26 weeks was 23 days
for those with a gestational age of greater than
31 weeks, the median age at onset was 11 days.
The clinical presentation of NEC consists of
systemic and abdominal signs.
●Systemic signs are nonspecific and include
apnea
respiratory failure
lethargy
poor feeding
temperature instability.
Hypotension resulting from septic shock may be
present in the most severe cases.
Twenty to 30 percent of infants with NEC have
associated bacteremia
Abdominal signs include
Distention
gastric retention (residual milk in the stomach before a
feeding)
tenderness
vomiting
diarrhea
rectal bleeding (hematochezia), and bilious drainage
from enteral feeding tubes
Bell staging criteria
The Bell staging criteria provide a uniform definition of
NEC based upon the severity of systemic, intestinal, and
radiographic findings, and are the most commonly used
criteria in practice
These definitions are useful in comparing cases and
studies; however, treatment is directed at the clinical
signs rather than the particular stage of NEC.
Each advancing stage includes the characteristics of the
previous stage plus additional findings due to increasing
severity of the disease.
Stage I, 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.
Abdominal radiographs may be normal or show
dilation of the bowel consistent with mild ileus.
●Stage II, or proven NEC
encompasses the signs of stage I plus absent
bowel sounds with or without abdominal
tenderness.
Abdominal tenderness is present, and some infants
have cellulitis of the abdominal wall or a mass in
the right lower quadrant.
Abdominal radiograph findings include intestinal
dilation, ileus, pneumatosis intestinalis, and ascites.
Stage III, or advanced NEC
is the most severe form.
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.
they typically have hypotension, bradycardia,
severe apnea, and signs of peritonitis (eg,
abdominal distention and marked tenderness).
Laboratory signs include a
combined respiratory and metabolic acidosis
neutropenia
and disseminated intravascular coagulation
(DIC).
In about one-third of cases, NEC is suspected
but not confirmed (stage I), and 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).
DIAGNOSIS
The diagnosis of necrotizing enterocolitis (NEC)
is based on
the presence of the characteristic clinical
features of abdominal distention and rectal
bleeding (heme-positive or grossly bloody
stools)
the abdominal radiographic finding of
pneumatosis intestinalis.
Assessment of infants with suspected NEC includes
abdominal imaging
blood studies
stool analysis
sepsis evaluation.
Although the results of this evaluation often are
nonspecific, certain findings are supportive of the
diagnosis of NEC, and in the case of abdominal
imaging (ie, pneumatosis intestinalis), may be
diagnostic.
Radiographic studies
Abdominal radiography
Abdominal radiographs confirm the diagnosis of
NEC and follow the progression of the disease.
Of note, although abdominal radiography is usually
useful in making the diagnosis of NEC, when there
are equivocal radiographic findings, treatment
decisions should be based upon clinical suspicion.
Abdominal radiographs are obtained in the supine
position or in the lateral decubitus position with the
left side down to detect free air in the abdomen.
After the initial evaluation, we obtain serial
radiographs to follow the course of the disease,
usually every 8 to 12 hours during the first few days
or until the infant improves.
The following characteristic radiographic features are
seen in the majority of infants with suspected NEC
●An abnormal gas pattern with dilated loops of
bowel that is consistent with ileus, and is typically
seen in the early stages of NEC.
●Pneumatosis intestinalis, the hallmark of NEC,
appears as bubbles of gas in the small bowel wall,
and is seen in most patients with stages II and III
NEC
Pneumoperitoneum typically appears when
bowel perforation occurs in patients with IIIB
NEC.
Portal venous gas (PVG) had been thought to
be a predictor of poor outcome and an
indication for surgical intervention
Abdominal ultrasonography
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.
Free gas, focal fluid collections, and increased
bowel wall thickness and echogenicity are
associated with more severe NEC
Color Doppler ultrasonography
Doppler ultrasonography was more sensitive
than abdominal radiography in detecting
bowel necrosis and alterations in bowel wall
perfusion as confirmed at laparotomy
Contrast enema — Contrast enemas are NOT
recommended if NEC is suspected, as it may
result in bowel perforation with extravasation
of contrast material into the peritoneum.
LABORATORY EVALUATION
Blood tests
blood tests are not used in the diagnostic and
staging criteria for necrotizing enterocolitis (NEC),
laboratory findings may support the diagnosis and
aid in the management of infants with NEC.
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 more commonly observed in patients
with NEC and is associated with a poor prognosis
Thrombocytopenia is a frequent finding and can result in
significant bleeding.
In the early course of NEC, declining platelet counts
correlate with necrotic bowel and worsening disease,
whereas a subsequent rise in platelet counts often
signals improvement
Coagulation studies –
Coagulation studies are not ordered routinely, but
should be obtained if the infant has
thrombocytopenia or bleeding, because
disseminated intravascular coagulation (DIC) is a
frequent finding in infants with severe NEC.
Serum chemistries – Serum electrolytes, blood urea
nitrogen, creatinine, and pH are routinely
measured.
An arterial blood gas analysis is performed in
infants with signs of respiratory compromise.
Electrolyte abnormalities often are nonspecific.
persistence of hyponatremia (serum sodium levels of
less than 130 mEq/L), increasing glucose levels, and
metabolic acidosis are suggestive of necrotic bowel or
sepsis
●Other nonspecific findings in infants with NEC
include increased levels of C-reactive protein
lysosomal acid hydrolase, and alpha-1-acid
glycoprotein (orosomucoid).
Sepsis evaluation — A sepsis evaluation (blood
culture, and if indicated, cerebral spinal fluid
culture) is performed when NEC is suspected
because sepsis is a common concomitant finding
Culture results may be used in guiding antibiotic
therapy
MEDICAL MANAGEMENT
Medical management should be initiated
promptly when necrotizing enterocolitis (NEC)
is suspected. It consists of the following:
●Supportive care
●Antibiotic therapy
●Close laboratory and radiologic monitoring
Supportive care and antibiotic therapy are focused
on limiting the progression of the disease
Laboratory and radiologic studies monitor the
course of the disease and are used to help
determine whether there is clinical improvement or
progressive deterioration, and if and when surgical
intervention is required.
Supportive care
●Bowel rest with discontinuation of enteral
feedings and gastrointestinal decompression with
intermittent nasogastric suction.
Nasogastric suction is continued until the infant's
clinical condition improves, the ileus resolves, and
pneumatosis is no longer seen on the abdominal
radiograph.
●Total parenteral nutrition, which may require a
central venous catheter.
Enteral feedings are resumed gradually as the infant's
clinical condition allows
●Fluid replacement to correct third space losses
Assessment and support of both the cardiovascular
(eg, inotropic support in addition to fluid resuscitation)
and respiratory systems (eg, supplemental oxygen and
mechanical ventilation as needed).
Critically ill infants frequently require both
cardiovascular and respiratory support.
●Correction of hematologic (eg, disseminated
intravascular coagulation) and metabolic
abnormalities (eg, metabolic acidosis).
Antibiotic therapy
after obtaining appropriate specimens for culture,
broad spectrum antibiotic treatment should be
initiated for suspected or proven NEC.
Since 20 to 30 percent of neonates with NEC have
concomitant bacteremia, empiric regimens should
provide coverage for pathogens that cause late-
onset bacteremia.
Anaerobic coverage should be considered,
especially if peritonitis or pneumoperitoneum,
suggesting intestinal perforation, are
suspected or confirmed
Empiric broad-spectrum antibiotics combinations
used to treat NEC include, but are not limited to,
the following choices
●Ampicillin, gentamicin (or amikacin), and
metronidazole
●Ampicillin, gentamicin (or amikacin), and
clindamycin
●Ampicillin, cefotaxime, and metronidazole
●Piperacillin-tazobactam and gentamicin (or
amikacin)
Vancomycin, piperacillin-tazobactam, and
gentamicin
●Meropenem
Empiric regimens can be modified based upon
the results of cultures of blood, peritoneal
fluid, or surgical specimens.
A 10- to 14-day course usually suffices unless
the course is complicated by abdominal
abscess formation
SURGICAL MANAGEMENT
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.
COMPLICATIONS
Acute complications — Necrotizing enterocolitis
(NEC) is associated with the following significant
complications during the acute stage of the disease
and immediate post-recovery stage.
●Infectious complications – Sepsis, meningitis,
peritonitis, and abscess formation
Disseminated intravascular coagulation, which
contributes to intestinal or extraintestinal bleeding
●Respiratory and cardiovascular complications –
Hypotension, shock, and respiratory failure
●Metabolic complications – Hypoglycemia and
metabolic acidosis
Late complications — The most common late
complications of NEC are intestinal narrowing (ie,
stricture formation) and short bowel syndrome.
Stricture formation — Although some areas of
intestinal narrowing resolve spontaneously, others
become more stenotic and form strictures, which
require surgical resection.
outcome
Prognosis of NEC has improved with earlier
recognition and treatment, with survival rates
of about 70 to 80 percent of affected
The mortality rate is higher in infants with more
severe disease requiring surgical intervention.
