As 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.

In a study of extremely low birth weight infants, standardized slow enteral feeding (SSEF) was
associated with a reduced risk of NEC compared with early enteral feeding. A total of 125
infants were treated with the SSEF protocol; these infants were compared with 294 historic
controls. Days to full feeds ranged from 16 to 22 among controls, from 44 to 52 days for babies
weighing under 750 grams in the SSEF group, and from 32 to 36 days for infants in the SSEF
group weighing 750 to 1,000 grams at birth.[28, 29]

NEC occurred in 5.6% of infants in the SSEF group and 11.2% of infants in the control group,
and 1.6% of SSEF infants and 4.8% of controls required surgery for NEC. Among infants
weighing less than 750 grams at birth, the risk of NEC was 2.1% in the smallest SSEF babies,
compared to 16.2% for the smallest infants in the control group. Risk of combined NEC and
death was 12.8% for infants in the SSEF group weighing less than 750 grams, and 29.5% for
small infants in the control group. Infants on the SSEF protocol who developed NEC got sick at
60 days of age, on average, compared to 30 days for controls. Among surviving infants, there
was no difference between SSEF and control infants in discharge weight or length.[28, 29]

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.

In a Cochrane review of 15 studies comprising 979 infants, investigators found similar safety and
efficacy between newer lipid emulsions (LE) from alternative lipid sources with
reduced polyunsaturated fatty acid (PUFA) content and that of conventional pure soybean oil–
based LEs that have high PUFA content for the parenteral nutrition of preterm infants.[30] There
were no statistically significant differences in clinically important outcomes including death,
growth, bronchopulmonary dysplasia, sepsis, retinopathy of prematurity of stage 3 or higher, and
parenteral nutrition–associated liver disease with the use of newer alternative LEs versus the
conventional pure soy oil–based LEs.

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. However, 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.

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.[31, 32, 33]

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 decompression

Decompression 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 essential

Consultations

Consult 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.

Transfer

In 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 possibilities

Lactoferrin appears to have potential for prevention of neonatal sepsis and NEC, but few safety
and efficacy studies are complete and available.[34]  

Two Cochrane Database of Systematic Reviews studies 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.[35]

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.[36]

Treatment by Stage
The 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 IB

The 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 IIB

Treatment 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 IIIA

Treatment 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 IIIB

Surgical intervention, as outlined in the next section, is provided.

Surgical Treatment
Indications

The principal 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.

Contraindications
Contraindications 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 care

After 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 details

The 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.[37] 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.[38] 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 closure

Timing 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 salt–binding 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 drainage

Neonates 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.[39] 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.[40]

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 details

After 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 Nutrition
In 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-negative Staphylococcus species, as
well as methicillin-resistant S 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
but may be less likely with use of a fish oil–based lipid formulation.[41] This condition resolves
gradually following initiation of enteral feeds.

Restarting enteral feedings

Enteral 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 Prevention
Feeding strategies

Breastfed babies have a lower incidence of necrotizing enterocolitis (NEC) than do formula-fed
infants,[42, 43]  particularly in very low birth weight (VLBW) (≤1500 g) neonates.[44]  In a
retrospective study of 550 VLBW neonates who received donor human milk, those who received
human milk on 50% or more of hospital days had equivalent growth outcomes but significantly
lower rates of NEC (3.4% NEC) compared to infants who received human milk on fewer than
50% of hospital days (13.5% NEC).[44] Mortality was also reduced, although this was not a
significant difference (1.0% vs 4.2%, respectively).

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.[45, 46]

In 1992, McKeown et al reported that rapid increase in feeding volume (>20 mL/kg/d) was
associated with higher risk of NEC.[21] 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.[47]

A systematic review published by the Cochrane Collaboration in 1999 reported no effect on NEC
from rapid feeding advancement for low birth weight infants.[48, 49]

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 strategies

Efforts 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.

A meta-analysis of 12 trials that included 10,800 premature neonates (5,144 receiving

prophylactic probiotics; 5,656 controls) revealed a significant reduction in the incidence of NEC
and mortality in the prophylactic probiotic group, although the incidence of sepsis did not differ
significantly between the groups.[33]

Long-Term Monitoring

Following 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 healing