Necrotizing Enterocolitis Treatment & Management

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. ^{[36, 37]}

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. ^{[36, 37]}

Patients with mild (Bell stage II) NEC require gastrointestinal 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. ^[38]  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. ^{[4, 39, 40, 41]}

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. ^[42]

Two Cochrane Database of Systematic Reviews studies discussed very promising but also very preliminary treatments.

One evaluated 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 neurologic outcomes were not assessed, and the authors stress that dosing, duration, and type of lactoferrin prophylaxis need to be further studied. ^[43]

The other study found evidence that IV 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. ^[44]

Stem cell therapy is being investigated, both for its potential protective as well as curative effect. ^[45] Stem cells of various progenitors can be harvested from a number of sources, including amniotic fluid, bone marrow and enteric sources. McCulloh et al has shown promising results from more readily available amniotic fluid mesenchymal stem cells on gut barrier integrity and  permeability, decreasing both the incidence and severity of NEC in experimental models. ^{[46, 47]}

 

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 neonatal intensive care unit.

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 (nothing by mouth) 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.

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.

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.)

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. ^[48] 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. ^[49]  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. ^[50] 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. ^[51]

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.

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. ^[52] 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.

Feeding strategies

Breastfed babies have a lower incidence of necrotizing enterocolitis (NEC) than do formula-fed infants, ^{[53, 54]} particularly in very low birth weight (VLBW) (≤1500 g) neonates. ^[55] 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). ^[55] 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. ^{[56, 57]}

McKeown et al reported that rapid increase in feeding volume (>20 mL/kg/d) was associated with higher risk of NEC. ^[29] Later, 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. ^[58] Similarly, a systematic review published by the Cochrane Collaboration reported no effect on NEC from rapid feeding advancement for low birth weight infants. ^{[59, 60]}

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 gastrointestinal 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. ^[41]

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.