BackgroundNecrotizing enterocolitis (NEC) is the most common
gastrointestinal (GI) medical/surgical emergency occurring in
neonates. An acute inflammatory disease with a multifactorial and
controversial etiology, the condition is characterized by variable
damage to the intestinal tract ranging from mucosal injury to
full-thickness necrosis and perforation (see the image below). (See
Etiology.)Normal (top) versus necrotic section of bowel. Photo
courtesy of the Department of Pathology, Cornell University Medical
College.Necrotizing enterocolitis represents a significant clinical
problem and affects close to 10% of infants who weigh less than
1500 g, with mortality rates of 50% or more depending on severity.
Although it is more common in premature infants, it can also be
observed in term and near-term babies. (See Epidemiology and
Prognosis.)NEC most commonly affects the terminal ileum and the
proximal ascending colon. However, varying degrees of NEC can
affect any segment of the small intestine or colon. The entire
bowel may be involved and may be irreversibly damaged.Numerous,
vague reports in 19th-century literature report described infants
who died fromperitonitisin the first few weeks of life. The first
half of the 20th century brought more reports of peritonitis with
ileal perforation due to what was called infectious enteritis. In
1953, Scmid and Quaiser called this condition newborn NEC.[1]The
first clear report of NEC did not appear until 1964, when Berdon
from the New York Babies Hospital described the clinical and
radiographic findings of 21 infants with the disease.[2]As neonatal
intensive care has progressed an d as premature newborns have come
to survive long enough for the disease to develop, the incidence of
NEC in neonatal intensive care units (NICUs) has increased. NEC
remains one of the most challenging diseases confronted by
pediatric surgeons. It likely represents a spectrum of diseases
with variable causes and manifestations, and surgical care must
therefore be individualized. (See Etiology, Epidemiology, and
Prognosis.)NEC typically occurs in the second to third week of life
in the infant who is premature and has been formula fed. Although
various clinical and radiographic signs and symptoms are used to
make the diagnosis, the classic clinical triad consists of
abdominal distension, bloody stools, and pneumatosis intestinalis.
Occasionally, signs and symptoms include temperature instability,
lethargy, or other nonspecific findings of sepsis. (See Clinical
and Workup.)Disease characteristicsNecrotizing enterocolitis
affects the GI tract and, in severe cases, can cause profound
impairment of multiple organ systems. Initial symptoms may be
subtle and can include 1 or more of the following (See Clinical.):
Feeding intolerance Delayed gastric emptying Abdominal distention,
abdominal tenderness, or both Ileus/decreased bowel sounds
Abdominal wall erythema (advanced stages) HematocheziaSystemic
signs are nonspecific and can include any combination of the
following: Apnea Lethargy Decreased peripheral perfusion Shock (in
advanced stages) Cardiovascular collapse Bleeding diathesis
(consumption coagulopathy)Nonspecific laboratory abnormalities can
include the following (See Workup.): Hyponatremia Metabolic
acidosis Thrombocytopenia Leukopenia or leukocytosis with left
shift Neutropenia Prolonged prothrombin time (PT) and activated
partial thromboplastin time (aPTT), decreasing fibrinogen, rising
fibrin split products (in cases of consumption
coagulopathy)ETIOLOGIAlthough the exact etiology of necrotizing
enterocolitis (NEC) remains unknown, research suggests that it is
multifactorial; ischemia and/or reperfusion injury, exacerbated by
activation of proinflammatory intracellular cascades, may play a
significant role. Cases that cluster in epidemics suggest an
infectious etiology. Gram-positive and gram-negative bacteria,
fungi, and viruses have all been isolated from affected infants;
however, many infants have negative culture findings.Furthermore,
the same organisms isolated in stool cultures from affected babies
have also been isolated from healthy babies. Extensive experimental
work in animal models suggests that translocation of intestinal
flora across an intestinal mucosal barrier rendered vulnerable by
the interplay of intestinal ischemia, immunologic immaturity, and
immunological dysfunction may play a role in the etiology of the
disease, spreading it and triggering systemic involvement. Such a
mechanism could account for the apparent protection breast-fed
infants have against fulminant NEC.Animal model research studies
have shed light on the pathogenesis of this disease. Regardless of
the triggering mechanisms, the resultant outcome is significant
inflammation of the intestinal tissues, the release of inflammatory
mediators (eg, leukotrienes, tumor necrosis factor [TNF],
platelet-activating factor [PAF]) and intraluminal bile acids, and
down-regulation of cellular growth factors, all of which lead to
variable degrees of intestinal damage.Abnormal intestinal floraIn
healthy individuals, the intestinal milieu is characterized by a
predominance of bifidobacteria. Such colonization is enhanced by
the presence of oligofructose, a component of human milk, in the
intestinal lumen. Infants who receive formula feedings without
oligofructose as a constituent have been noted to have a
predominance of clostridial organisms.Infectious organisms are
thought to play a key role in the development of NEC. Whether
bacterial infection has a primary inciting role in NEC or whether
an initial intestinal mucosal injury allows secondary bacterial
invasion is unclear. Positive blood cultures are found in 30% of
patients; the most commonly identified organisms areEscherichia
coliandKlebsiella pneumoniae. Proteus mirabilis, Staphylococcus
aureus, S epidermidis, Enterococcusspecies,Clostridium
perfringens,andPseudomonas aeruginosahave also been identified.E
coli, Klebsiellaspecies,Enterobacter cloacae, P aeruginosa,
Salmonellaspecies,S epidermidis, C perfringens, C difficile,andC
butyricumcommonly grow in stool cultures.Klebsiellaspecies,E coli,
S epidermidis,and yeast are most commonly identified on peritoneal
cultures. Fungal infection is believed to be an opportunistic
infection in the presence of an altered host intestinal defense
system.The observation of an epidemic or cluster of cases in a
short period in one nursery after sporadic cases supports the key
role of infectious organisms in NEC. Nursery personnel are known to
experience acute GI illnesses in association with these outbreaks,
and the institution of infection control measures has accordingly
reduced the rates of NEC.Rat pups colonized withStaphylococcus
aureusandEscherichia colidemonstrated increased incidence and
severity of necrotizing enterocolitis compared with those whose
intestines were populated with various bacterial
species.[3]Toll-like receptor signaling of intestinal mucosal
transmembrane proteins is accomplished by binding of specific
bacterial ligands that mediate the inflammatory response; the
character of the intestinal bacterial milieu is thought to play a
role in the up-regulation or down-regulation of intestinal
inflammation via toll-receptor signaling.Many preterm infants
receive frequent exposure to broad-spectrum antibacterial agents,
further altering the intra-intestinal bacterial
environment.Experimental and meta-analytical evidence suggests that
exogenous administration of the probiotics bifidobacteria and
lactobacilli (nondigestible substances that selectively promote the
growth of beneficial, probioticlike bacteria normally present in
the gut) may moderate the risk and severity of NEC in preterm
infants.[4, 5]Intestinal ischemiaEpidemiologically, some have noted
that infants exposed to intrauterine environments marked by
compromised placental blood flow (ie, maternal hypertension,
preeclampsia, cocaine exposure) have an increased incidence of NEC.
Similarly, infants with postnatally diminished systemic blood flow,
as is found in patients with patent ductus arteriosus or congenital
heart disease (both considered risk factors for NEC), also have an
increased incidence. Infants with patent ductus arteriosus are at
particularly high risk for developing NEC if pharmacologic closure
is attempted.A retrospective analysis compared outcomes of NEC in
patients with congenital heart disease with outcomes of NEC in
patients without congenital heart disease; the study demonstrated
improved outcomes in patients with heart disease. This somewhat
counterintuitive finding further emphasizes the multifactorial
pathophysiology underlying NEC.[6]Animal models of induced
intestinal ischemia have identified its significant role in the
development of NEC. Pathologically, ischemia induces a local
inflammatory response that results in activation of a
proinflammatory cascade with mediators such as PAF, TNF-a,
complement, prostaglandins, and leukotrienes such as C4 and
interleukin 18 (IL-18).Alterations in hepatobiliary cell junction
integrity result in leakage of these proinflammatory substances and
bile acids into the intestinal lumen, increasing intestinal injury.
Cellular protective mechanisms such as epidermal growth factor
(EGF), transforming growth factor 1 (TGF-1), and erythropoietin are
down-regulated, further compromising the infant's ability to mount
a protective response. Subsequent norepinephrine release and
vasoconstriction result in splanchnic ischemia, followed by
reperfusion injury.Intestinal necrosis results in breach of the
mucosal barrier, allowing for bacterial translocation and migration
of bacterial endotoxin into the damaged tissue. The endotoxin then
interacts synergistically with PAF and a multitude of other
proinflammatory molecules to amplify the inflammatory
response.Activated leukocytes and intestinal epithelial xanthine
oxidase may then produce reactive oxygen species, leading to
further tissue injury and cell death. Experimental administration
of PAF inhibitors in animal models has not been shown to mitigate
intestinal mucosal injury. Many other modulators of the
inflammatory response are being studied both in vivo in animal
models and in vitro in an attempt to mitigate or prevent the
morbidity and mortality caused by fulminant necrotizing
enterocolitis.Intestinal mucosal immaturityNEC is principally a
disease of premature infants. Although approximately 5-25% of
infants with NEC are born full term, studies have found a markedly
decreased risk of NEC with increasing gestational age. This finding
suggests that maturation of the GI system plays an important role
in the development of NEC.The premature neonate has numerous
physical and immunologic impairments that compromise intestinal
integrity. Gastric acid and pepsin production are decreased during
the first month of life. Pancreatic exocrine insufficiency is
associated with low levels of enterokinase, the enzyme that
converts trypsinogen to trypsin, which allows hydrolysis of
intestinal toxins. Mucus secretion from immature goblet cells is
decreased. Gut motility is impaired, and peristaltic activity is
poorly coordinated. Finally, secretory immunoglobulin A (IgA) is
deficient in the intestinal tract of premature infants not fed
breast milk.In the preterm infant, mucosal cellular immaturity and
the absence of mature antioxidative mechanisms may render the
mucosal barrier more susceptible to injury. Intestinal regulatory
T-cell aggregates are a first-line defense against luminal
pathogens and may be induced by collections of small lymphoid
aggregates, which are absent or deficient in the premature
infant.Experimental and epidemiologic studies have noted that
feeding with human milk has a protective effect; however, donor
human milk that has been pasteurized is not as protective. Human
milk contains secretory immunoglobulin A (IgA), which binds to the
intestinal luminal cells and prohibits bacterial transmural
translocation. Other constituents of human milk, such as IL-10,
EGF, TGF-1, and erythropoietin, may also play a major role in
mediating the inflammatory response. Oligofructose encourages
replication of bifidobacteria and inhibits colonization with
lactose-fermenting organisms.Human milk has been found to contain
PAF acetylhydrolase, which metabolizes PAF; preterm human milk has
higher PAF acetylhydrolase activity (as much as 5 times greater in
one study[7]) than milk collected from women who delivered at
term.The initiation of early enteral feedings is associated with
NEC. Some series have reported decreased rates of NEC when feeding
volumes are reduced. In a prospective randomized trial, Book et al
found a significant increase in the development of NEC among
preterm infants fed a hyperosmolar elemental formula compared with
those fed a milk formula.[8]Innate genetic predispositionTwin
studies have suggested susceptibility to NEC may be affected by a
genetic component.[9]Given the frequent subtle and nonspecific
nature of presenting symptoms, identification of a biomarker for
infants at higher risk of developing necrotizing enterocolitis
could have significant impact on morbidity and mortality
rates.Animal models have focused on single-nucleotide polymorphisms
(SNPs) that negatively affect innate immune responses to bacterial
antigens. One such SNP, discovered in the gene that encodes
carbamoyl-phosphate synthetase I (the rate-limiting enzyme for the
production of arginine), has been reportedly associated with an
increased risk of NEC.[10]Infants with distinct genotypes of
various cytokines have also been associated with higher frequencies
of NEC. Given the interplay of inherent, infectious, ischemic,
inflammatory, iatrogenic, and environmental factors, alterations in
expression of proinflammatory and/or anti-inflammatory mediators
may play a role in neonatal susceptibility to the disease.[11,
12]MedicationsNumerous medications have been implicated as a risk
factor in NEC. Xanthine derivatives, such as theophylline and
aminophylline, slow gut motility and produce oxygen free radicals
during their metabolism to uric acid. Indomethacin, used to treat
patent ductus arteriosus, may cause splanchnic vasoconstriction
leading to impaired intestinal integrity. Vitamin E, used to treat
retinopathy of prematurity, is known to impair leukocyte function
and has been associated with NEC.The results from a multicenter,
prospective, observational study suggest that ranitidine treatment
in very low birth weight infants is associated with an increased
risk of infections, a 6.6-fold higher risk of NEC, and a
significantly higher mortality rate.[13]
EPIDEMIOLOGIAlthough some studies indicate a higher frequency of
NEC in black babies than in white babies, other studies show no
difference based on race. Most studies indicate that male and
female babies are equally affected.Occurrence in the United
StatesThe frequency of necrotizing enterocolitis (NEC) varies among
nurseries, without correlation with season or geographic location.
Outbreaks of NEC seem to follow an epidemic pattern within
nurseries, suggesting an infectious etiology, although a specific
causative organism has not been isolated.Population studies
conducted in the United States over the past 25 years indicate a
relatively stable incidence, ranging from 0.3-2.4 cases per 1000
live births. The disease classically presents among the smallest
preterm infants. Although it is reported among term infants with
perinatal asphyxia or congenital heart disease, differences in
severity and outcome suggest presentation in this population may
represent a distinct pathophysiologic entity.[6]International
occurrencePopulation-based studies from other countries suggest a
frequency similar to the United States. However, nations with a
lower rate of premature births than that in the United States
generally have a lower rate of NEC as well. For example, a large
study of NICUs in Japan identified a 0.3% incidence of NEC, which
is significantly lower than that in similar patient populations in
the United States.[14]An epidemiologic review of the disease in
infants born at less than 32 weeks' gestation who survived past 5
days of life in Canada reported an incidence of
6.4%.[15]Age-related demographicsNEC is more prevalent in premature
infants, with incidence inversely related to birth weight and
gestational age. Although specific numbers range from 4% to more
than 50%, infants who weigh less than 1000 g at birth have the
highest attack rates. This rate dramatically drops to 3.8 per 1000
live births for infants who weigh 1501-2500 g at birth. Similarly,
rates profoundly decrease for infants born after 35-36 weeks'
postconceptional age.The average age of onset in premature infants
seems to be related to postconceptional age, with babies born
earlier developing NEC at a later chronologic age. The average age
of onset has been reported to be 20.2 days for babies born at less
than 30 weeks' estimated gestational age (EGA), 13.8 days for
babies born at 31-33 weeks' EGA, and 5.4 days for babies born after
34 weeks' gestation.Term infants develop necrotizing enterocolitis
much earlier, with the average age of onset within the first week
of life or, sometimes, within the first 1-2 days of life.
Observational studies have suggested the etiology of the disease in
term and near-term infants may be different than that postulated in
the premature infant and could include entities such as cow's milk
proteininduced enterocolitis and glucose-6-phosphate dehydrogenase
deficiency.PreviousPROGNOSISWith improved supportive intensive
care, including ventilatory management, anesthetic techniques, and
total parenteral nutrition, the survival of infants with
necrotizing enterocolitis (NEC) has steadily improved since the
late 20thcentury. The improved prognosis is most notable in
critically ill neonates younger than 28 weeks' gestational age who
weigh less than 1000 g. However, these neonates are still at
significantly increased risk for pan involvement and are more
likely than other premature infants to require surgery.The
mortality rate in NEC ranges from 10% to more than 50% in infants
who weigh less than 1500 g, depending on the severity of disease,
compared with a mortality rate of 0-20% in babies who weigh more
than 2500 g. Extremely premature infants (1000 g) are still
particularly vulnerable, with reported mortality rates of 40-100%.
One study comparing mortality rates for term versus preterm infants
reported rates of 4.7% for term infants and 11.9% for premature
babies.[16]The improvement in treatment efficacy in infants with
NEC is underscored by the fact that if patients with pan
involvement are excluded, the survival in surgically treated
infants with NEC is 95%. However, comparison between reported
series is difficult because of wide variations in patient
populations, extent of disease, coexisting conditions, and severity
categorization between centers.Of those patients who survive, 50%
develop a long-term complication. The 2 most common complications
are intestinal stricture and short-gut syndrome.Intestinal
strictureThis complication, the incidence of which is 25-33%, can
develop in infants with or without a preceding perforation.
Intestinal stricture occurs when an area of intestinal ischemia
heals with resultant fibrosis and scar formation that impinges on
the diameter of the lumen. The most common site of stricture is the
left colon, followed by the terminal ileum.Intestinal stricture is
most common in infants treated nonoperatively, because infants
treated operatively commonly undergo contrast enema before closure
of the ostomy, and any area of stricture is resected when the
ostomy is closed.Intestinal stricture should be suspected in any
infant who receives nonoperative treatment for NEC and who fails to
thrive and/or has bloody stools or bowel obstruction. Symptoms of
feeding intolerance and bowel obstruction typically occur 2-3 weeks
after recovery from the initial event.Short-gut syndromeShort-gut
syndrome is the most serious postoperative complication in NEC,
occurring in as many as 23% of patients after intestinal resection.
This is a malabsorption syndrome resulting from the removal of
excessive or critical portions of small bowel necessary for
absorption of essential nutrients from the intestinal
lumen.Symptoms are most profound in babies who either have lost
most of their small bowel or have lost a smaller portion that
includes the ileocecal valve. Loss of small bowel can result in
malabsorption of nutrients, as well as of fluids and
electrolytes.The neonatal gut grows and adapts over time, but
long-term studies suggest that this growth may take as long as 2
years to occur. During that time, maintenance of an anabolic and
complete nutritional state is essential for the growth and
development of the baby. This is achieved by parenteral provision
of adequate vitamins, minerals, and calories; appropriate
management of gastric acid hypersecretion; and monitoring for
bacterial overgrowth. The addition of appropriate enteral feedings
during this time is important for gut nourishment and
remodeling.Babies who can never successfully feed enterally and/or
who develop life-threatening hyperalimentation liver disease may be
candidates for organ transplantation. Centers specializing in
neonatal and infant small bowel and liver transplantation may
consider referrals on a case-by-case basis.Cholestatic liver
diseaseCholestatic liver disease is a multifactorial condition
caused by prolonged fasting and total parenteral nutrition. It is
characterized by hepatomegaly and elevated aminotransferase and
direct bilirubin levels. The treatment is initiation of enteral
feedings as early as possible to stimulate bile flow.Recurrent
NECRecurrent NEC is an uncommon complication that can occur after
either operative or nonoperative management of NEC. It is seen in
only 4-6% of patients with NEC. Recurrent NEC has not been
associated with the method of managing the initial episode, the
timing of enteral feedings, or the site of initial
disease.Neurodevelopmental disordersInfants who survive NEC are at
increased risk for neurodevelopmental disorders. As many as 50% of
infants who survive NEC have some abnormality in intelligence and
motor skills. However, the incidence of non-GI sequelae in matched
cohorts with and without NEC are similar, implying that
neurodevelopmental problems may be a function of underlying
prematurity rather than of NEC itself.Additional complicationsA
multicenter, retrospective study in Switzerland reported a 29% rate
of catheter-related sepsis in patients with Bell stage II kept on a
diet of nothing by mouth (NPO) for longer than 5 days.[17]Prolonged
hyperalimentation and the absence of enteral nutrition can cause
cholestasis, direct hyperbilirubinemia, and other metabolic
complications.
HISTORYThe clinical presentation of necrotizing enterocolitis
(NEC) includes nonspecific aspects of the history, such as
vomiting, diarrhea, feeding intolerance and high gastric residuals
following feedings. More specific GI tract symptoms include
abdominal distention and frank or occult blood in the stools.With
disease progression, abdominal tenderness, abdominal wall edema,
erythema, crepitans, or palpable bowel loops indicating a fixed and
dilated loop of bowel may develop. Systemic signs, such as apnea,
bradycardia, lethargy, labile body temperature, hypoglycemia, and
shock, are indicators of physiologic instability.Epidemiologic
studies demonstrate that demographics, risk factors, patient
characteristics, and clinical course differ significantly between
term and preterm infants with NEC.Term babyCompared with a preterm
infant, a term baby with NEC presents at a younger age, with a
reported median age of onset that ranges from 1-3 days of life in
the immediate postnatal period but that may appear as late as age 1
month.The term neonate who is immediately affected postnatally is
usually systemically ill with other predisposing conditions, such
as birth asphyxia, respiratory distress, congenital heart disease,
or metabolic abnormalities, or has a history of abnormal fetal
growth pattern.Maternal risk factors that reduce fetal gut blood
flow, such as placental insufficiency from acute disease (eg,
pregnancy-induced hypertension), chronic disease (eg, diabetes), or
maternal cocaine abuse, can increase the baby's risk for developing
NEC.Specific signs and symptoms that may be part of the history
include bilious vomiting or gastric aspirates, abdominal
distention, passage of blood per rectum, abdominal radiographs that
reveal dilated loops of bowel, pneumatosis intestinalis, free
abdominal air, and other signs of systemic infection, including
shock and acidosis.Premature babyPremature babies are at risk for
developing necrotizing enterocolitis for several weeks after birth,
with the age of onset inversely related to gestational age at
birth.Premature infants with patent ductus arteriosus are at higher
risk for developing NEC earlier in life, particularly if they are
treated with indomethacin for pharmacologic closure. However,
patients with persistent patent ductus arteriosus who ultimately
required surgical ligation were found to have a higher
NEC-associated mortality rate than did patients whose patent ductus
arteriosus was successfully closed without surgery.Patients are
typically advancing on enteral feedings or may have achieved
full-volume feeds when symptoms develop.Increased incidence in the
posttransfusion period has been reported in otherwise healthy
premature babies who are feeding enterally and undergo blood
transfusion for asymptomatic anemia of prematurity.Presenting
symptoms may include subtle signs of feeding intolerance that
progress over several hours to a day, subtle systemic signs that
may be reported enigmatically by the nursing staff as "acting
different," and, in advanced disease, a fulminant systemic collapse
and consumption coagulopathy.Symptoms of feeding intolerance can
include abdominal distention/tenderness, delayed gastric emptying
as evidenced by increasing gastric residuals, and, occasionally,
vomiting.Systemic symptoms can insidiously progress to include
nonspecific signs and symptoms, such as increased apnea and
bradycardia, lethargy, and temperature instability, among the
primary manifestation(s).Patients with fulminant NEC present with
profound apnea, rapid cardiovascular and hemodynamic collapse, and
shock.The baby's feeding history can help increase the index of
suspicion for early NEC. Babies who are breastfed have a lower
incidence of NEC than do formula-fed babies.Rapid advancement of
formula feeding has been associated with an increased risk of
NEC.[18]However, multiple subsequent studies have failed to
substantiate this finding.Physical ExaminationThe pertinent
physical findings in patients who develop necrotizing enterocolitis
(NEC) can be primarily GI, primarily systemic, indolent, fulminant,
or any combination of these. A high index of clinical suspicion is
essential to minimize potentially significant morbidity or
mortality.GI signs can include any or all of the following:
Increased abdominal girth Visible intestinal loops Obvious
abdominal distention and decreased bowel sounds Change in stool
pattern Hematochezia Palpable abdominal mass Erythema of the
abdominal wallSystemic signs can include any of the following:
Respiratory failure Decreased peripheral perfusion Circulatory
collapseWith insidious onset, the clinical signs may be mild,
whereas patients with fulminant disease can present with severe
clinical abnormalities.If abdominal signs are present, surgical
consultation may be advisable. Disease progression ranges from
indolent to fulminant, and early and expeditious involvement of
surgical colleagues can be helpful, especially if appropriate
surgical care requires transfer to another facility.DDNecrotizing
enterocolitis (NEC) is a clinical diagnosis that can be subtle at
its onset. Early symptoms frequently mimic more common clinical
conditions, such as poor gastric motility and benign feeding
intolerance. Retrospective review of the earliest clinical signs
once the diagnosis is apparent can seem misleadingly clear, even
though the prospective assessment was much less straightforward.
Laboratory and radiographic evidence can bolster a clinical
impression of benign conditions.Not infrequently, free air is noted
on an abdominal radiograph of a premature infant, either as an
incidental finding on imaging performed for other reasons or during
an initial evaluation for abdominal pathology. Spontaneous
intestinal perforation (SIP) can be distinguished from NEC by its
lack of systemic involvement, absence of other clinical signs
common to bowel perforation, and higher rate of survival.[19]SIP is
further distinguished by its earlier onset in babies of smaller
birth weight and more extreme prematurity.[20]Associations have
been identified between SIP and
indomethacin,[19]dexamethasone,[21]and systemic
candidiasis.[20]Conditions to consider in the differential
diagnosis of NEC include the following: Hypoplastic left heart
syndrome Intestinal malrotation Intestinal volvulus Bacterial
meningitis Neonatal sepsis Omphalitis Prematurity Urinary tract
infection VolvulusDifferential Diagnoses Acidosis, Metabolic
Acidosis, Respiratory Apnea of Prematurity Bacteremia Candidiasis
Coarctation of the Aorta Enteroviral Infections Gastroesophageal
Reflux Hirschsprung Disease Hospital-Acquired Infections
APPROACH CONSIDERATIONInitial presentation of necrotizing
enterocolitis (NEC) usually includes subtle signs of feeding
intolerance, such as gastric residuals, abdominal distention,
and/or grossly bloody stools. Abdominal imaging studies are crucial
at this stage. In fact, radiographic studies should be obtained if
any concern about NEC is present.Laboratory studies are pursued,
especially if the abdominal study findings are worrisome or the
baby is manifesting any systemic signs. Laboratory values can give
insight into the severity of the disease and can aid in the
provision of appropriate therapy.However, although all of the
initial laboratory studies taken together may aid in the diagnosis
of NEC, they do not substitute for an appropriate appreciation of
the clinical presentation and appearance of the infant.Complete
blood countA complete blood count (CBC), with manual differential
to evaluate the white blood cell (WBC), hematocrit, and platelet
count, is usually repeated at least every 6 hours if the patient's
clinical status continues to deteriorate.White blood cell
countMarked elevation may be worrisome, but leukopenia is even more
concerning. Although elevated mature and/or immature neutrophil
counts may not be good indicators of neonatal sepsis after the
first 3 days of life, moderate to profound neutropenia (absolute
neutrophil count [ANC] < 1500/L) strongly suggests established
sepsis.Red blood cell countPremature infants are prone to anemia
due to iatrogenic blood draws, as well as anemia of prematurity;
however, blood loss from hematochezia and/or a developing
consumptive coagulopathy can manifest as an acute decrease in
hematocrit.An elevated hemoglobin level and hematocrit may mark
hemoconcentration due to notable accumulation of extravascular
fluid.Platelet countPlatelets are an acute phase reactant, and
thrombocytosis can represent physiologic stress to an infant, but
acute NEC is more commonly associated with thrombocytopenia (<
100,000/L). Thrombocytopenia may become more profound in severe
cases that become complicated with consumption coagulopathy.
Consumption coagulopathy is characterized by prolonged prothrombin
time (PT), prolonged activated partial thromboplastin time (aPTT),
and decreasing fibrinogen and increasing fibrin degradation
products concentrationsThrombocytopenia appears to be a reaction to
gram-negative organisms and endotoxins. Platelet counts of less
than 50,000 warrant platelet transfusion.Blood cultureObtaining a
blood culture is recommended before beginning antibiotics in any
patient presenting with any signs or symptoms of sepsis or NEC.
Although blood cultures do not grow any organisms in most cases of
NEC, sepsis is one of the major conditions that mimics the disease
and should be considered in the differential diagnosis. Therefore,
identification of a specific organism can aid and guide further
therapy.Serum electrolytesSerum electrolytes can show some
characteristic abnormalities. Obtain basic electrolytes (Na+, K+,
and Cl-) during the initial evaluation, followed serially at least
every 6 hours depending on the acuity of the patient's
condition.Serum sodiumHyponatremia is a worrisome sign that is
consistent with capillary leak and "third spacing" of fluid within
the bowel and peritoneal space. Depending on the baby's age and
feeding regimen, baseline sodium levels may be low normal or
subnormal, but an acute decrease (< 130 mEq/dL) is alarming, and
heightened vigilance is warranted.Metabolic acidosisLow serum
bicarbonate (< 20) in a baby with a previously normal acid-base
status is also concerning. It is seen in conjunction with poor
tissue perfusion, sepsis, and bowel necrosis.Other testsReducing
substances may be identified in the stool of formula-fed infants
because poorly digested carbohydrates are fermented in the colon
and excreted in stool. Similarly, results from a breath hydrogen
test may be positive with increased carbohydrate
fermentation.Imaging techniquesReports from outside of the United
States suggest that imaging techniques such as contrast
radiography, magnetic resonance imaging (MRI), and radionuclide
scanning may play a role in diagnosis the diagnosis of NEC. These
techniques are not currently in common use.GI tonometry is an
infrequently used technique that may be helpful in distinguishing
benign feeding intolerance from early NEC. The use of radiography
and ultrasonography in the diagnosis of NEC is discussed in detail
below.Arterial Blood GasesDepending on presentation acuity,
hypoventilation and frank apnea are seen in necrotizing
enterocolitis (NEC).Arterial blood gas (ABG)can aid in the
determination of the infant's need for respiratory support. The ABG
can also provide information of the acid-base status.Acute acidosis
is worrisome. Lactic acidosis results from decreased cardiac output
(as in cardiovascular collapse and shock), leading to poor
perfusion of peripheral tissues. Tissue necrosis may also add to
the observed metabolic acidosis.An arterial blood sample is a
convenient way to simultaneously obtain a blood culture, CBC, serum
electrolytes, and ABG for the initial evaluation (note that
arterial blood has a lower yield for demonstrating bacteremia than
does venous blood). Depending on presentation acuity, inserting a
peripheral arterial line while peripheral perfusion and
intravascular volume are still within the reference range may be
prudent. This peripheral arterial line facilitates serial blood
sampling and invasive blood pressure monitoring that is essential
if the baby's condition deteriorates.Abdominal RadiographyThe
mainstay of diagnostic imaging is abdominal radiography. An
anteroposterior (AP) abdominal radiograph and a left lateral
decubitus radiograph (left-side down) are essential for initially
evaluating any baby with abdominal signs. Perform abdominal
radiography serially at 6-hour or greater intervals, depending on
presentation acuity and clinical course.Characteristic findings on
an AP abdominal radiograph include an abnormal gas pattern, dilated
loops, and thickened bowel walls (suggesting edema/inflammation).
Serial radiographs help to assess disease progression. A fixed and
dilated loop that persists over several examinations is especially
worrisome.Radiographs can sometimes reveal scarce or absent
intestinal gas, which is more worrisome than diffuse distention
that changes over time.Pneumatosis intestinalisPneumatosis
intestinalis is a radiologic sign pathognomonic of necrotizing
enterocolitis (NEC). It appears as a characteristic train-track
lucency configuration within the bowel wall. Intramural air bubbles
represent gas produced by bacteria within the wall of the bowel.
Analysis of gas aspirated from these air bubbles reveals that it
consists primarily of hydrogen, suggesting that the bubbles are
caused by bacterial fermentation. Carbohydrate (often lactose)
fermentation by intestinal flora yields hydrogen and carbon dioxide
and a series of short-chain organic acids, which can promote
inflammation.Pneumatosis is present in 70%-80% of patients with
NEC, although it may be fleeting or intermittent and is often an
early finding. The extent of gas is not correlated with the
severity of disease, nor is it specific to NEC. Pneumatosis is also
seen in Hirschsprung disease, severe diarrhea, carbohydrate
intolerance, and inspissated milk syndrome. (See the images
below.)Pneumatosis intestinalis. Photo courtesy of Loren G
Yamamoto, MD, MPH, Kapiolani Medical Center for Women &
Children, University of Hawaii, with permission.Pneumatosis
intestinalis. Photo courtesy of Loren G Yamamoto, MD, MPH,
Kapiolani Medical Center for Women & Children, University of
Hawaii, with permission.Pneumatosis intestinalis. Photo courtesy of
Loren G Yamamoto, MD, MPH, Kapiolani Medical Center for Women &
Children, University of Hawaii, with permission.Pneumatosis
intestinalis. Photo courtesy of Loren G Yamamoto, MD, MPH,
Kapiolani Medical Center for Women & Children, University of
Hawaii, with permission.Extensive pneumatosis
intestinalis.Necrotizing enterocolitis totalis. Pneumatosis
intestinalis and multiple areas of perforation were
seen.Pneumatosis intestinalis.Free airAbdominal free air is ominous
and usually requires emergency surgical intervention. The presence
of abdominal free air can be difficult to discern on a flat
radiograph, which is why decubitus radiographs are recommended at
every evaluation. A subtle, oblong lucency over the liver and
abdominal contents is characteristic of intraperitoneal air on a
flat plate. It represents the air bubble that has risen to the most
anterior aspect of the abdomen in a baby lying in a supine
position. The free air can be difficult to differentiate from
intraluminal air.For this reason, left-side down (left lateral)
decubitus radiography is essential and allows the detection of
intraperitoneal air, which rises above the liver shadow (right-side
up) and can be visualized more easily than it can be on other
views. Obtain this view with every AP examination until progressive
disease is no longer a concern.Although free air typically
indicates intestinal perforation, other causes include dissecting
mediastinal air from barotrauma in a ventilated neonate, gastric
perforation (most commonly due to a nasogastric tube), and
Hirschsprung disease. Free air is seen in only 50-63% of infants
who have intestinal perforation identified at surgery.Portal
gasPortal gas appears as linear, branching areas of decreased
density over the liver shadow and represents air present in the
portal venous system. Its presence is considered to be a poor
prognostic sign. Portal gas is much more dramatically observed on
ultrasonography.Although once heralded as an ominous sign in NEC,
portal gas is now believed to be less so. It is caused by gas
produced by bacteria in the portal veins or by the transmigration
of gas from the bowel wall to mesenteric veins and into the portal
vein. It is frequently a transient finding; the pattern is
demonstrated in only 9-20% of infants with NEC.Loop
distentionDistended loops of small bowel are one of the most
common, although nonspecific, radiographic findings in NEC.
Air-fluid levels and bowel wall edema may also develop. Serial
radiographic studies are important to monitor the degree of
distention and to observe for any fixed or dilated loops of bowel
persistent in nature and location for 24 hours. Some series have
shown that intestinal necrosis requiring operative management
develops in approximately 50% of infants with bowel
loops.Intraperitoneal fluidIntraperitoneal free fluid is indicated
by a generalized opacification of the abdomen and often by a
gasless abdomen or medial displacement of bowel loops with
opacification peripherally and increased distance between bowel
loops. The finding of ascites may indicate intestinal fluid leakage
from perforation and is an indication for paracentesis.Ascites is a
late finding that usually develops when peritonitis is present or
after bowel perforation. Ascites is observed on an AP radiograph as
centralized bowel loops that appear to be floating on a background
of density. It is better appreciated on ultrasonography.Abdominal
UltrasonographyAbdominal ultrasonography can be helpful when
suspected necrotizing enterocolitis (NEC) in neonates is evaluated.
Advantages include the following: Available at bedside Noninvasive
imagery of intra-abdominal structuresDisadvantages of
ultrasonography include the following: Limited availability at some
medical centers Requires extensive training to discern subtle
ultrasonographic appearance of some pathologies Abdominal air
(easily observed on ultrasonography and in grossly distended
patients) can interfere with assessing intra-abdominal
structures.With abdominal ultrasonography, a skilled clinician can
identify a larger amount of diagnostic information faster and with
less risk to the baby than with the current standard evaluation
methods.Ultrasonography can be used to identify areas of loculation
and/or abscess consistent with a walled-off perforation when
patients with indolent NEC have scarce gas or a fixed area of
radiographic density. Ultrasonography is also excellent for
identifying and quantifying ascites. Serial examinations can be
used to monitor the progression of ascites as a marker for the
disease course.In addition, ultrasonography can be used to
visualize portal air, which can easily be seen as bubbles present
in the venous system. Moreover, abdominal ultrasonography has been
reported to be more sensitive than plain radiography in the
detection of pneumatosis intestinalis.Ultrasonographic assessment
of major splanchnic vasculature can help in the differential
diagnosis of NEC from other disorders that are either more benign
or emergent.The orientation of the superior mesenteric artery in
relationship to the superior mesenteric vein can provide
information regarding the possibility of a malrotation with a
subsequent volvulus. If a volvulus is present, the artery and vein
are twisted and, at some point in their courses, their orientation
switches. This abnormality can be detected, even if the rotation is
360, if the full path of the vessels can be observed.Doppler study
of the splanchnic arteries early in the course of NEC can help to
distinguish developing NEC from benign feeding intolerance in a
mildly symptomatic baby.A clinical study from Europe and a small
series in the United States demonstrated markedly increased peak
flow velocity (>1) of arterial blood flow in the celiac and
superior mesenteric arteries in early NEC.[22]Such a finding at the
presentation of symptoms can further aid in diagnosis and therapy,
potentially sparing those individuals at low risk for NEC from
unnecessary interventions.Upper GI SeriesUpper GI with or without
small bowel follow-through is performed acutely only when a
diagnosis other than necrotizing enterocolitis (NEC), such as bowel
obstruction, is being considered because of bilious vomiting,
abdominal distention, or other symptoms. This procedure is commonly
performed in infants with resolved NEC who develop a picture of GI
obstruction, usually due to a stricture or fibrous band. Perform
this before contrast enema because the presence of contrast in the
colon can obscure pertinent findings.ParacentesisAscites can
develop during fulminant necrotizing enterocolitis and can
compromise respiratory function. Paracentesis may be considered.
This is most safely performed using ultrasonographic guidance.
However, paracentesis is not without risks and should not be
performed until a pediatric surgical consultation has been
performed.A positive finding on paracentesis with the free flow of
at least 0.5 mL of brownish fluid that contains bacteria on Gram
staining is highly specific for intestinal necrosis. A negative
finding on paracentesis is uncommon with intestinal necrosis but
may occur in the setting of a localized and walled-off
perforation.If no peritoneal fluid is aspirated, peritoneal lavage
is performed with 30 mL/kg of isotonic sodium chloride solution,
and the fluid is then suctioned.Place an intra-abdominal drain as
an alternative to laparotomy if the baby is not a surgical
candidate (eg, in cases of extreme prematurity or cardiovascular
collapse and shock).Histologic FindingsWith NEC, the areas most
commonly affected are the terminal ileum and the proximal ascending
colon. The pattern of disease may involve a single isolated area or
multiple discontinuous lesions. The most common histologic findings
are associated with mucosal injury. These include coagulation
necrosis of the mucosa with active and chronic inflammation,
mucosal ulceration, edema, hemorrhage, and pneumatosis of the
submucosa.Advanced disease may result in full-thickness necrosis of
the intestinal wall. Regenerative changes with epithelial
regeneration, granulation tissue formation, and fibrosis are seen
in as many as two thirds of patients. This indicates an
inflammatory process lasting several days, with concurrent areas of
continuing injury and healing. (See the images below.)Micrograph of
mucosal section showing transmural necrosis. Photo courtesy of the
Department of Pathology, Cornell University Medical
College.Histologic section of mucosal wall demonstrating
pneumatosis. Photo courtesy of the Department of Pathology, Cornell
University Medical College.Histologic section of bowel mucosa
showing regeneration of normal cellular architecture. Photo
courtesy of the Department of Pathology, Cornell University Medical
College.Staging of NECThe Bell system is the staging system most
commonly used to describe necrotizing enterocolitis (NEC).Bell
stage I suspected diseaseStage IA characteristics are as follows:
Mild, nonspecific systemic signs such as apnea, bradycardia, and
temperature instability are present Mild intestinal signs such as
increased gastric residuals and mild abdominal distention are
present Radiographic findings can be normal or can show some mild
nonspecific distention.Stage IB diagnosis is the same as stage IA,
with the addition of grossly bloody stool.Bell stage II definite
diseaseStage IIA characteristics are as follows: Patient is mildly
ill. Diagnostic signs include the mild systemic signs present in
stage IA Intestinal signs include all of the signs present in stage
I, with the addition of absent bowel sounds and abdominal
tenderness Radiographic findings show ileus and/or pneumatosis
intestinalisThis diagnosis is sometimes referred to as "medical"
necrotizing enterocolitis as surgical intervention is not needed to
successfully treat the patient.Stage IIB characteristics are as
follows: Patient is moderately ill Diagnosis requires all of stage
I signs plus the systemic signs of moderate illness, such as mild
metabolic acidosis and mild thrombocytopenia Abdominal examination
reveals definite tenderness, perhaps some erythema or other
discoloration, and/or right lower quadrant mass Radiographs show
portal venous gas with or without ascitesBell stage III advanced
diseaseThis stage represents advanced, severe NEC that has a high
likelihood of progressing to surgical intervention.Stage IIIA
characteristics are as follows: Patient has severe NEC with an
intact bowel Diagnosis requires all of the above conditions, with
the addition of hypotension, bradycardia, respiratory failure,
severe metabolic acidosis, coagulopathy, and/or neutropenia
Abdominal examination shows marked distention with signs of
generalized peritonitis Radiographic examination reveals definitive
evidence of ascitesStage IIIB designation is reserved for the
severely ill infant with perforated bowel observed on radiograph in
addition to the findings for IIIA.
TREATMENTApproach ConsiderationsAs many as 50% of all premature
infants manifest feeding intolerance during their hospital course,
but less than one fourth of those infants develop necrotizing
enterocolitis (NEC). As with all neonatal care, the risks and
benefits of various clinical approaches to NEC must be considered
carefully.Patients with mild (Bell stage II) NEC require GI rest to
facilitate resolution of the intestinal inflammatory process. These
babies are traditionally kept on a diet of nothing by mouth (NPO)
for 7-10 days, making parenteral hyperalimentation necessary. Many
of these babies have difficult intravenous (IV) access. Therefore,
the need for prolonged parenteral nutrition frequently requires
placing central venous catheters, which have attendant risks and
complications that include thromboembolic events and nosocomial
infections.Cessation of feeding and initiation of broad-spectrum
antibiotics in every baby with feeding intolerance impedes proper
nutrition and exposes the baby to unnecessary antibacterials that
may predispose to fungemia. On the other hand, failure to intervene
appropriately for the baby with early NEC may exacerbate the
disease and worsen the outcome. Clearly, managing this population
requires a high degree of clinical suspicion for possible untoward
events, tempered by cautious watching and waiting.Placement of a
peripheral arterial line may be helpful at the beginning of the
patient's treatment to facilitate serial arterial blood sampling
and invasive monitoring.Placement of a central venous catheter for
administration of pressors, fluids, antibiotics, and blood products
is prudent because severely affected patients often have
complications that include sepsis, shock, and disseminated
intravascular coagulation (DIC).If the baby is rapidly
deteriorating, with apnea and/or signs of impending circulatory and
respiratory collapse, airway control and initiation of mechanical
ventilation is indicated.Abdominal decompressionDecompression is
essential at the first sign of abdominal pathology. Abdominal
decompression in infants with necrotizing enterocolitis is as
follows: Use a large-bore catheter with multiple side holes and a
second lumen to prevent vacuum attachment to the stomach mucosa
(eg, Replogle tube) Set the catheter for low, continuous or
intermittent suction and monitor output; the tube should be
irrigated with several milliliters of normal saline to maintain
patency If copious amounts of gastric/intestinal secretions are
removed, consider IV replacement with a physiologically similar
solution; maintaining electrolyte balance and intravascular volume
is essentialConsultationsConsult with a pediatric surgeon at the
earliest suspicion of developing necrotizing enterocolitis. This
may require transferring the patient to another facility where such
services are available.TransferIn the acute phase, patients with
progressive NEC require pediatric surgical consultation. During
refeeding, patients with or without previous surgical history may
demonstrate signs of obstruction requiring surgical evaluation
and/or intervention. Transfer the patient to a facility offering
pediatric surgical expertise, if it is not available at the current
location.Future possibilitiesTwoCochrane Database of Systematic
Reviewsstudies discuss very promising but also very preliminary
treatments.One discusses lactoferrin supplementation in the milk of
infants and suggests it shows promising preliminary results in
reducing the incidence of late-onset sepsis in infants weighing
less than 1500 g. When given alone, it did not reduce the incidence
of NEC in preterm neonates. Long-term neurological outcomes were
not assessed, and the authors stress that dosing, duration, and
type of lactoferrin prophylaxis need to be further studied.[23]The
other study found evidence that intravenous pentoxifylline as an
adjunct to antibiotic therapy may reduce mortality and duration of
hospitalization in neonates with sepsis; no completed studies were
found confirming outcomes of treatment for patients with NEC.
Although these results also are promising, more research is needed
to validate the findings.[24]Treatment by StageThe mainstay of
treatment for patients with stage I or II necrotizing enterocolitis
(NEC) is nonoperative management. The initial course of treatment
consists of stopping enteral feedings, performing nasogastric
decompression, and initiating broad-spectrum antibiotics.
Historically, antibiotic coverage has consisted of ampicillin,
gentamicin, and either clindamycin or metronidazole, although the
specific regimen used should be tailored to the most common
nosocomial organisms found in the particular NICU.Authors in some
series have proposed the use of enteral aminoglycosides for the
treatment of NEC, but several prospective trials have shown no
efficacy for this treatment. In addition, a strong index of
suspicion for fungal septicemia must be maintained, especially in
the infant with a deteriorating condition and negative bacterial
cultures.Bell stages IA and IBThe patient is kept on an NPO diet
with antibiotics for 3 days. IV fluids are provided, including
total parenteral nutrition (TPN).Bell stages IIA and IIBTreatment
includes support for respiratory and cardiovascular failure,
including fluid resuscitation, NPO, and antibiotics for 14 days.
Surgical consultation should be considered. After stabilization,
TPN should be provided during the period that the infant is
NPO.Bell stage IIIATreatment involves NPO for 14 days, fluid
resuscitation, inotropic support, and ventilator support. Surgical
consultation should be obtained. TPN should be provided during the
period of NPO.Bell stage IIIBSurgical intervention, as outlined in
the next section, is provided.Surgical TreatmentIndicationsThe
principle indication for operative intervention in necrotizing
enterocolitis (NEC) is perforated or necrotic intestine. Infants
with necrotic intestine are identified based on various clinical,
laboratory, and radiologic findings. The most compelling predictor
of intestinal necrosis indicating a need for operative intervention
is pneumoperitoneum (see the image below). Other relative
indications for operative intervention are erythema in the
abdominal wall, gas in the portal vein, and positive
paracentesis.Pneumoperitoneum. Photo courtesy of the Department of
Pathology, Cornell University Medical College.Surgery is generally
indicated in the medically treated patient whose clinical condition
deteriorates. The signs of deterioration include worsening
abdominal examination findings, signs of peritonitis, worsening and
intractable acidosis, persistent thrombocytopenia, rising
leukocytosis or worsening leukopenia, and hemodynamic
instability.Note that evaluation by a pediatric surgeon early in
the course of NEC is important to avoid any delay in operative
intervention. Many infants may have isolated perforations or
necrotic tissue that wall off the abdominal cavity and do not show
free intraperitoneal air. Knowing whether these infants may benefit
from early operative intervention is
difficult.ContraindicationsContraindications to surgical
intervention include patients with stage I or stage II disease, for
whom nonoperative medical therapy is the treatment of choice. In
addition, surgical intervention should be deferred in patients with
more severe disease whose condition responds to initial medical
management.Patients who are extremely small and ill may not have
the stability to tolerate laparotomy. If free air develops in such
a patient, one may consider inserting a peritoneal drain under
local anesthesia in the nursery.Preoperative careAfter the decision
to proceed with surgery is made, the patient's general physiologic
condition should be optimized. Provide vigorous fluid replacement,
correct any clinically significant anemia or coagulopathy, and
ensure adequate urine output of at least 1 mL/kg/h. To minimize
heat loss, place the infant on a heated air pad; in addition, a
warmed operating room and warmed IV and irrigation fluids should be
used. The use of heated and humidified oxygen and anesthetic gases
may further minimize heat loss. Blood products should be available
during surgery.Intraoperative detailsThe abdomen can be entered via
a right transverse incision just below the umbilicus by using
electrocautery to ensure hemostasis. This incision provides
adequate exposure away from a frequently large liver and decreases
the risk of retractor injury to the liver. Care must be taken at
the time of entry into the peritoneal cavity to avoid injury to
dilated loops of intestine. If any free intraperitoneal fluid is
identified, samples may be taken for aerobic, anaerobic, and fungal
culture. Bloody peritoneal fluid is seen in necrosis and brown
turbid fluid is found in perforation.The abdominal cavity is then
systematically inspected for evidence of necrosis and perforation.
Particular attention is paid to the right lower quadrant because
the terminal ileum and proximal ascending colon are most commonly
involved. The guiding principle of surgery for NEC is to resect
only perforated and unquestionably necrotic intestine and to make
every effort to preserve the ileocecal valve. (See the images
below.)Normal (top) versus necrotic section of bowel. Photo
courtesy of the Department of Pathology, Cornell University Medical
College.Resected portion of necrotic bowel. Photo courtesy of the
Department of Pathology, Cornell University Medical College.White
or gray bowel indicates ischemic necrosis. Hemorrhagic or edematous
areas of bowel may represent areas of mucosal ischemia and injury
but do not necessarily indicate nonviable bowel. Saccular
protrusions of bowel wall have undergone mucosal, submucosal, and
muscularis necrosis and are covered only by a layer of serosa.
These are areas of impending intestinal perforation.Palpation may
also be helpful, because resilient pliable bowel is typically
viable, and lax and boggy bowel that indents on palpation is often
necrotic. If the viability of remaining bowel is significantly
questionable, a second-look operation can be performed in 24-48
hours to assess the viability of the remaining intestine.If a
single area of bowel is resected, a proximal ostomy and distal
mucus fistula are created. The viability of the bowel at the cut
margins can be ascertained by whether the cut edges bleed. The
enterostomy and mucus fistula are brought out at opposite ends of
the incision, with the serosa sutured to the abdominal wall fascia
with interrupted sutures. About 2 cm of bowel is left to protrude
above the abdominal wall, and the end of the ostomy is not matured.
If ostomy viability is in question postoperatively, the ends of the
intestine may be excised and observed for adequate bleeding.Primary
anastomosis is not generally advocated, because of the risk of
ischemia at the anastomosis, leading to increased incidence of
leakage, stricture, fistula, or breakdown. However, intestinal
resection with primary anastomosis may be safely performed in
select cases. Patients must demonstrate a clearly demarcated small
segment of injured bowel with normal-appearing residual intestine
and be in good general condition with no evidence of sepsis,
coagulopathy, or physiologic compromise.If multiple segments of
intestine are involved because of necrosis or perforation, a
decision must be made regarding the course of action. Historically,
the individual segments of affected intestine are resected, and
multiple ostomies are created. However, a number of other surgical
options have been proposed. A single proximal stoma may be created
and the distal bowel segments anastomosed in continuity, thus
avoiding multiple stomas.Moore proposes a technique of patch,
drain, and wait, which involves transverse, single-layer repair of
bowel perforations (patch); placement of 2 Penrose drains in the
lower quadrants (drain), and initiation of long-term parenteral
nutrition (wait); however, this technique is not widely advocated.
The thin, distended bowel wall holds suture poorly, and the
abdominal cavity does not drain freely with open gravity drainage.
In addition, this technique does not address the source of
intra-abdominal sepsis, because necrotic bowel is not resected.In a
small series, Vaughn describes a different technique of clip and
drop-back.[25]The unquestionably necrotic segments of intestine are
resected and the transected ends are stapled closed. A second-look
operation is performed in 48-72 hours when the clips are removed,
and reanastomosis is performed without any ostomies.NEC totalis
occurs when less than 25% of the intestinal length is found to be
viable at the time of operation; this finding results in a number
of grim treatment options. Simple closure of the abdomen is
supported by findings that show a 42-100% mortality rate in
patients with pan involvement. Massive resection with excision of
the ileocecal valve requires at least 20 cm of residual bowel for
any hope of adequate enteral nutrition. Patients with a decreased
bowel length require permanent parenteral nutrition.Martin and
Neblett describe a technique of enterostomy diversion proximal to
the involved bowel without bowel resection.[26]This technique may
facilitate bowel healing by allowing bowel decompression, reducing
intestinal bacterial load, and decreasing metabolic demand.After
intestinal resection, the length of remaining viable bowel should
be sequentially measured along the antimesenteric border of the
intestine and recorded.Enterostomy closureTiming of enterostomy
closure to restore intestinal continuity is the principal follow-up
issue for infants who are surgically treated for NEC. This
procedure is generally performed 1-2 months after the original
operation, depending on weight gain and ostomy output, among other
factors. The argument against early ostomy closure is the
difficulty of operating in a peritoneal cavity replete with
adhesions and resolving inflammation; the ideal time is
approximately 8 weeks.If goal enteral feeds can be accomplished,
there is some benefit in discharging the patient home and
performing a reanastamosis after several months. This gives the
infant a chance to grow and better tolerate an additional
laparotomy.Abnormally high ostomy output may indicate a need for
early ostomy closure. A patient with a high jejunostomy may have
substantial loss of fluid and electrolytes, with consequences such
as failure to thrive and peristomal skin injury. These patients may
benefit from early ostomy closure with attendant colonic water
absorption.However, infants with a high ostomy and extensive ileal
resection who undergo ostomy closure may have considerable
secretory diarrhea after the colon comes in contact with unabsorbed
bile salts. They may require treatment with a bile saltbinding
agent, such as cholestyramine. Sodium chloride supplementation (1-3
mcg/kg/day) has been recommended to optimize growth in infants with
small-bowel stomas.All patients who have any remaining large
intestine after an initial operation for NEC must be examined with
contrast-enhanced enema of the colon to identify any areas of
stricture before the ostomy is closed. If any such areas are
present, they are resected when the enterostomy is closed. In
addition, some advocate a screening contrast enema study
approximately 30 days after recovery in infants who have been
nonoperatively treated for NEC. Symptomatic colonic strictures
require treatment, whereas asymptomatic strictures may be
observed.Peritoneal drainageNeonates who are extremely ill and
unable to tolerate surgery may be treated by means of peritoneal
drainage in a technique described by Ein et al.[27]A right lower
quadrant incision is made at the bedside under local anesthesia,
and a Penrose drain is inserted. The procedure was initially
intended as a means of temporizing with regard to surgical
treatment, and indeed, some infants survived with this procedure
alone and did not require subsequent laparotomy.A multicenter,
randomized clinical trial failed to show a significant difference
in survival at 90 days between primary peritoneal drainage and
laparotomy with resection for premature infants with very low birth
weight (< 1500 g) and perforated NEC.[28]Critically ill newborns
with a relative contraindication to formal operative exploration
may be treated with the placement of a peritoneal drain. Although
this is typically a temporizing measure, these extremely ill
infants may recover with drain placement alone and do not require
exploratory laparotomy.Peritoneal drain placement may be the
treatment of choice for extremely small (< 600 g) premature
newborns. Such premature, critically ill infants cannot tolerate
formal exploration, and drain placement may be preferred and
definitive. Nevertheless, many infants whose condition is too
unstable for formal exploration do not survive, regardless of
intervention.Postoperative detailsAfter undergoing an operation for
NEC, infants should continue to receive intravenous antibiotics and
total parenteral nutrition for at least 2 weeks. Supportive care,
including ventilatory support, fluid and electrolyte monitoring and
replacement, and correction of anemia and coagulopathy, should
continue.During surgery infants with NEC often develop a
coagulopathy that continues after surgery and can be difficult to
manage. Blood can fill the abdominal cavity rapidly and create a
compartment syndrome that requires drainage. Any infants with
continued clinical deterioration must be evaluated for residual
intestinal gangrene and possibly repeat surgical exploration.
Infants who improve postoperatively should not resume enteral
feedings for at least 10-14 days.Parenteral NutritionIn patients
with necrotizing enterocolitis (NEC), prolonged parenteral
nutrition is essential to optimize the baby's nutrition while the
GI tract is allowed enough time to recover and return to normal
function. Central venous access is essential to facilitate
parenteral delivery of adequate calories and nutrients to the
recovering premature baby to minimize catabolism and promote
growth.Prolonged central venous access may be associated with an
increased incidence of nosocomial infection, predominately with
skin flora such as coagulase-negativeStaphylococcusspecies, as well
as methicillin-resistantS aureus(MRSA). A high degree of clinical
suspicion must be maintained to detect the subtle signs of such
infection as early as possible.Parenteral administration of lipid
formulations via central venous catheters is also associated with
an increased incidence of catheter-related sepsis.Lipids coat the
catheter's interior, allowing ingress of skin flora through the
catheter lumen. A high degree of clinical suspicion is required for
early detection of such an infection.If line infection is
suspected, obtain a blood culture through the central line and from
a peripheral vein or artery. Antibiotics effective against skin
flora, such as vancomycin, should be administered (although
prolonged broad-spectrum antibacterial therapy increases the
premature infant's risk for fungal sepsis). Persistently positive
cultures require removal of the central line. Remove the central
line once sepsis and bacteremia are confirmed, because eradication
is almost impossible when the central line is kept in
place.Prolonged parenteral nutrition may be associated with
cholestasis and direct hyperbilirubinemia. This condition resolves
gradually following initiation of enteral feeds.Restarting enteral
feedingsEnteral feedings are traditionally restarted 10-14 days
after findings on abdominal radiographs normalize in the case of
nonsurgical NEC. However, balancing the risks and benefits of NPO
versus enteral feeds may alter this timeline. Reinitiating enteral
feeds in postsurgical babies may take longer and may also depend on
issues such as the extent of surgical resection, return of bowel
motility, timing of reanastomosis, and preference of the consulting
surgical team.Because of the high incidence of postsurgical
strictures, some clinicians prefer to evaluate intestinal patency
via contrast studies prior to initiating enteral feeds. When feeds
are restarted, if human milk is not available, formulas containing
casein hydrolysates, medium-chain triglycerides, and
safflower/sunflower oils (eg, Alimentum, Pregestimil, Nutramigen)
may be better tolerated and absorbed than standard infant
formulas.Deterrence and PreventionFeeding strategiesBreastfed
babies have a lower incidence of necrotizing enterocolitis (NEC)
than do formula-fed infants.[29, 30]Much anecdotal evidence details
the role of feeding regimens in the etiology of NEC, but clinical
research does not demonstrate definitive evidence for either
causation or prevention. Although conventional wisdom recommends
slow initiation and advancement of enteral feeds for premature
infants, random trials do not show an increased incidence of NEC in
babies in whom feeds have been started early in life versus after 2
weeks' chronologic age.[31, 32]In 1992, McKeown et al reported that
rapid increase in feeding volume (>20 mL/kg/d) was associated
with higher risk of NEC.[18]In 1999, however, Rayyis et al showed
no difference in the occurrence of NEC Bell stage II or greater in
patients advanced at 15 mL/kg/day compared with those advanced at
35 mL/kg/day.[33]A systematic review published by the Cochrane
Collaboration in 1999 reported no effect on NEC from rapid feeding
advancement for low birth weight infants.[34, 35]Antenatal and
postnatal conditions that diminish intestinal blood flow may
increase an infant's risk of developing NEC. Antenatal conditions
causing placental insufficiency, such as hypertension,
preeclampsia, or cocaine use, may justify a more cautious and
vigilant approach to enteral feeding in these infants. Similarly,
postnatal conditions that diminish splanchnic blood flow, such as
patent ductus arteriosus (particularly when associated with
reversed aortic diastolic flow demonstrated on echocardiography),
other cardiac disease, or general hypotension/cardiovascular
compromise, may increase the risk.Because early presentation of NEC
can be subtle, high clinical suspicion is important when evaluating
any infant with signs of feeding intolerance or other abdominal
pathology. In general, continuing to feed a baby with developing
NEC worsens the disease.Pharmacologic strategiesEfforts to reduce
the incidence of NEC may target infection control in the newborn
nursery, augmentation of premature host defenses, stimulation of GI
tract maturation, inhibition of inflammatory mediators, and
reduction of enteric bacterial load.Enteral immunoglobulin A (IgA)
is deficient in the premature GI system, and oral IgA
supplementation reduces the incidence of NEC in rat models. In
addition, a series in human infants found that patients who
received an oral IgG-IgA preparation were significantly less likely
to develop NEC than were control subjects.The administration of
prenatal glucocorticoids to mothers for fetal pulmonary maturation
significantly reduces the incidence of NEC. In addition, postnatal
treatment decreases the incidence of NEC, although not as
effectively as prenatal treatment.In laboratory models PAF
antagonists reduced bowel injury. However, their role in the
prevention and treatment of NEC in humans has not been well
established.Nonabsorbable oral antibiotics have been used in
attempts to reduce the intestinal bacterial load and presumably
inhibit the progression of NEC. However, several investigators
found no significant difference in outcome between infants
receiving oral antibiotics and control subjects.Long-Term
MonitoringFollowing hospital discharge, caring for premature
infants has shifted away from neonatologists at regionalized
centers to general pediatricians and other health care providers in
the community. Adequate interaction between subspecialists and
community providers and formulation of well-communicated health
care plans for these vulnerable babies are crucial to serving their
best interest and to optimizing their health outcome.If a baby goes
home with a colostomy, parents need thorough instruction regarding
the baby's care. Having the parent(s) room with the baby at the
hospital for several days prior to discharge is advisable so that
they can learn and demonstrate adequate caregiving skills.Babies
who have undergone intestinal resection may experience short-gut
syndrome. These babies require vigilant nutritional regimens to
maintain adequate calories and vitamins for optimum growth and
healingMorphine sulfate is an opioid analgesic with a long history
of safe and effective use in neonates. It inhibits ascending pain
pathways by binding to the opiate receptors in the CNS, causing
generalized CNS depression. Morphine sulfate is used for sedation
and analgesia.View full drug informationFentanyl (Onsolis, Fentora,
Actiq, Duragesic)Fentanyl is an opioid analgesic that is 50-100
times more potent than morphine. Its mechanism of action and
indications for use are similar to those of morphine; however,
fentanyl has less hypotensive effect than morphine does, because of
minimal to no associated histamine release. Fentanyl is
administered as an IV bolus or as a continuous infusion. Because of
the small volumes used in neonates for bolus administration, it is
not usually cost-effective to administer as a bolus.Antifungal
AgentsClass SummaryThe mechanism of action in these agents may
involve an alteration of ribonucleic acid (RNA) and
deoxyribonucleic acid (DNA) metabolism or an intracellular
accumulation of peroxide, which is toxic to the fungal cell.If
antifungal therapy is warranted, fluconazole can be initiated.
Fluconazole is less toxic than amphotericin B, which is substituted
if no clinical response to fluconazole occurs or if evidence of
microbiologic resistance is present.View full drug
informationFluconazole (Diflucan)Fluconazole is an antifungal agent
with good activity against Candida albicans. It is associated with
less toxicity and is easier to administer than amphotericin B;
however, fluconazole-resistant candidal species are being isolated
with increasing frequency. This agent can be administered enterally
or parenterally.ProbioticsClass SummaryA meta-analysis of published
studies showed that oral administration of nonpathogenic bacterial
species may result in beneficial alteration of intestinal bacterial
flora, reducing the risk and severity of disease.[37, 38, 39, 40,
41, 42, 43, 44, 45]However, data are insufficient regarding the
optimal time of initiation, type and dose of bacteria to be used,
duration of administration, and potential adverse effects.Some
probiotic formulations used in these studies are not available in
the United States, and no regimen or available preparation can be
issued based on the meta-analysis. Because of these unknown
factors, this therapy is experimental and is not accepted as a
standard of care.Lactobacillus acidophilus/Bifidobacterium infantis
(Floranex, Bacid, Dofus, Culturelle)These lactic acidproducing
organisms are thought to acidify the intestinal contents and to
prevent selective bacterial growth. Probiotic live cultures are
intended to restore or maintain healthy microbial flora. Data are
currently emerging regarding their use in NEC. Various products are
available and doses may vary between products. Infloran has
specifically been studied in very low birth weight (VLBW) infants
with NEC. It has completed phase II clinical
trials.http://emedicine.medscape.com/article/977956-medication#showall