Necrotizing Enterocolitis

Necrotizing 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 from peritonitis in 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 and 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 Presentation and Workup.)

Disease characteristics

Necrotizing enterocolitis affects the gastrointestinal 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 Presentation.):

• Feeding intolerance

• Delayed gastric emptying

• Abdominal distention, abdominal tenderness, or both

• Ileus/decreased bowel sounds

• Abdominal wall erythema (advanced stages)

• Hematochezia

Systemic 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)

Although 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 downregulation of cellular growth factors, all of which lead to variable degrees of intestinal damage.

Abnormal intestinal flora

In 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.

Although infectious organisms have long been thought to play a key role in the development of NEC, specifics regarding this role continue to be elusive. Whether bacterial infection has a primary inciting role in NEC or whether an initial intestinal mucosal injury allows secondary bacterial invasion is unclear. Is it a straight-forward "infection" with a pathogenic organism that starts the disease cascade, or is it more complex? Positive blood cultures are found in 30% of patients; the most commonly identified organisms are Escherichia coli and Klebsiella pneumoniae. Proteus mirabilis, Staphylococcus aureus, S epidermidis, Enterococcus species, Clostridium perfringens, and Pseudomonas aeruginosa have also been identified.

However, more recent research is focusing not on individual species but rather the role of the premature gut microbiome as a risk factor. Unlike term infants, the premature gut becomes colonized with a limited number of bacterial species, the majority of which are gram-negative organisms in the Gammaproteobacteria class.[3, 4]  Termed "inappropriate colonization," or "dysbiosis," this class of bacteria has been shown in animal models to produce short-chain fatty acids and other bioactive substances, affecting epithelial cell health and integrity. How these mediators impact the immature gut continues to be explored.[5] This line of inquiry has been further supported by observational studies that have shown breastfed infants (not breast-milk fed) and those advanced more quickly to full enteral feeds were less likely to develop NEC than their counterparts.[5, 6]

E coli, Klebsiella species, Enterobacter cloacae, P aeruginosa, Salmonella species, S epidermidis, C perfringens, C difficile, and C butyricum commonly grow in stool cultures. Klebsiella species, 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.

New opportunistic and pathologic bacteria are being identified and speciated, especially as the protective role of probiotics continues to be elucidated.[4] Infant formulas contaminated with organisms such as Cronobacter species (previously called Enterobacter sakazakii)[7] further complicate the picture as to whether the formula or the bacteria are implicated in the disease or, conversely, whether the breast milk or the bacteria are protective.

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 gastrointestinal (GI) illnesses in association with these outbreaks, and the institution of infection control measures has accordingly reduced the rates of NEC.

Rat pups colonized with Staphylococcus aureus and Escherichia coli demonstrated increased incidence and severity of necrotizing enterocolitis compared with those whose intestines were populated with various bacterial species.[8] 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. Advances in genome sequencing of the gut microbiome of healthy as well as affected premature infants, along with the roles of host molecular and immune factors, continue to raise more questions than answers about the multifactorial etiology of this devastating condition.[3, 5]

That NEC is related to gut colonization of pathogenic flora is supported by findings showing administration of physiologic flora decreases the incidence of NEC. The protective effect of breast milk is thought, in part, to be related to delivery of Lactobacillus species that somehow repair the intestinal milieu. Work by Blackwood, et al suggests that the mechanism is more elegant: Both in vitro and in vivo models showed improved intestinal integrity in rat pups fed L rhamnosus and L plantarum probiotics.[9] By increasing capillary tight junctions, tested animals experienced less intestinal injury compared to control animals when challenged with a known cellular toxin.[9]

Intestinal ischemia

Epidemiologically, 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.[10]

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). This potential role of perhaps even antenatal inflammation in the eventual clinical occurrence of NEC is further supported by a recent systematic review of the evidence showing a strong correlation between antenatal clinical and/or histologic chorioamnionitis and subsequent NEC.[11]

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 β1 (TGF-β1), 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 immaturity

NEC 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-β1, 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[12] ) than milk collected from women who delivered at term.

It has long been suspected that the initiation of early enteral feedings is associated with NEC, sparked in part by the observation that unfed infants rarely develop NEC. Some series have reported decreased rates of NEC when feeding volumes are reduced, however, a more recent multicenter, matched case-control study (EPIFLORE: Epidemiologic Study of Flora) comprising data from 64 neonatal intensive care units, reported the opposite.[5]  Earlier, 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.[13] The complex relationship between feeding and NEC is further confounded by the recognition that NEC is much more likely to occur in infants who receive packed red blood cell (RBC) transfusion, especially in infants who are enterally feeding.[14]  Up to one third of all NEC cases in very low birth weight infants may occur within 24-48 hours after RBC transfusion, with the highest risk potentially in infants transfused with the most severe anemia.[15]

Innate genetic predisposition

Twin studies have suggested susceptibility to NEC may be affected by a genetic component.[16] 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.[17]

A more recent study of 184 neonates reported an association between the functional SNP IL-6 (rs1800795) and the development of NEC (6-fold increase) as well as an increased severity of NEC (7-fold increase in stage III disease) in white neonates.[18] There was also an association between TRIM21 (rs660) (increased incidence) and TGFβ-1 (rs2241712) (decreased incidence) with NEC- related perforation.[18]

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.[19, 20]

Medications

Numerous 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. Inhibitors of gastric acid secretion alter the pH of the intestinal milieu, which subsequently affects the intestinal flora. Several recent studies, including meta-analysis, have identified a higher incidence of NEC in infants exposed to gastric antacids.[21]

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.[22]

Many of the most premature infants are exposed in utero to magnesium sulfate (MgSO4) administered to the mother for a variety of obstetric indications. Data exist suggesting a neuroprotective effect of MgSO4 on the extremely premature infant has further increased its use, fueling concerns of an increased risk of NEC in these infants. However, in a retrospective (2011-2014) cohort of over 4,000 extremely premature infants, no difference in odds ratios were seen for the risk of NEC in MgSO4-treated infants (n = 2,055) compared to those without such exposure (n = 2,300).[23]

Although 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 States

The 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.[10]

International occurrence

Population-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.[24]

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%.[25]

Age-related demographics

NEC 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 protein–induced enterocolitis and glucose-6-phosphate dehydrogenase deficiency.

With 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 20th century. 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.[26]

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 stricture

This 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 syndrome

Short-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 disease

Cholestatic 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 NEC

Recurrent 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 disorders

Infants who survive NEC are at increased risk for neurodevelopmental disorders.[27] As many as 50% of infants who survive NEC have some abnormality in intelligence and motor skills. However, the incidence of non-gastrointestinal 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 complications

A 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.[28] Prolonged hyperalimentation and the absence of enteral nutrition can cause cholestasis, direct hyperbilirubinemia, and other metabolic complications.

The 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 gastrointestinal 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 baby

Compared 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 baby

Premature 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.[29] However, multiple subsequent studies have failed to substantiate this finding.

The pertinent physical findings in patients who develop necrotizing enterocolitis (NEC) can be primarily gastrointestinal (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 wall

Systemic signs can include any of the following:

• Respiratory failure

• Decreased peripheral perfusion

• Circulatory collapse

With 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.

Initial 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 count

A complete blood cell (CBC) count, with manual differential to evaluate the white blood cell (WBC) count, hematocrit, and platelet count, is usually repeated at least every 6 hours if the patient's clinical status continues to deteriorate.

White blood cell count

Marked 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/μL) strongly suggests established sepsis.

Red blood cell count

Premature 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 count

Platelets 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/μL). 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 concentrations

Thrombocytopenia appears to be a reaction to gram-negative organisms and endotoxins. Platelet counts of less than 50,000 warrant platelet transfusion.

Blood culture

Obtaining 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 electrolytes

Serum 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 sodium

Hyponatremia 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/L) is alarming, and heightened vigilance is warranted.

Metabolic acidosis

Low serum bicarbonate (< 20 mEq/L) 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 tests

Reducing 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. Although early diagnosis is one of the most important ways to minimize morbidity and mortality, the lack of early biomarkers has hampered the clinician's ability to reliably distinguish early NEC from benign feeding intolerance. Results from a cohort of 119 premature infants, 85 of whom had NEC, published in the Journal of Pediatrics is encouraging for the possible identification of 7 urine protein biomarkers.[33]

Imaging techniques

Reports 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.

Gastrointestinal 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.

Depending 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.

The 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 intestinalis

Pneumatosis 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 air

Abdominal 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 gas

Portal 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 distention

Distended 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 fluid

Intraperitoneal 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 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 structures

Disadvantages 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. This modality offers the ability to confirm findings of traditional radiographs (ie, pneumatosis intestinalis, portal venous air) with the added ability to better assess the integrity of the intestinal walls, decreased peristalsis, and bowel wall perfusion. Despite its benefits, however, integration of the additional information provided by this modality into clinical decision-making has been slow.[34]

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 360⁰, 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.[35] 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 gastrointestinal (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.

Ascites 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).

With 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.

The Bell system is the staging system most commonly used to describe necrotizing enterocolitis (NEC).

Bell stage I ̶ suspected disease

Stage 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 disease

Stage 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 intestinalis

This 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 ascites

Bell stage III ̶ advanced disease

This 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 ascites

Stage IIIB designation is reserved for the severely ill infant with perforated bowel observed on radiograph in addition to the findings for IIIA.

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.

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.[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.

Pharmacologic therapy for necrotizing enterocolitis (NEC) includes agents to treat the developing disease and those to provide supportive and symptomatic relief.

As previously mentioned, 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).

The initial course of treatment in stage I or II NEC 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. Probiotics are emerging as a possible preventive therapy.[4, 41]

Class Summary

Although no single infectious etiology is known to cause necrotizing enterocolitis (NEC), clinical consensus finds that antibiotic treatment is appropriate. Broad-spectrum parenteral therapy is initiated at the onset of symptoms after obtaining blood, spinal fluid, and urine for culture. Antibiotic coverage for staphylococcus should be considered in NICUs that have a high colonization rate. Antifungal therapy should be considered for premature infants with a history of recent or prolonged antibacterial therapy or for babies who continue to deteriorate clinically or hematologically despite adequate antibacterial coverage.

Various antibiotic regimens can be employed; one frequently used regimen includes ampicillin, aminoglycoside (eg, gentamicin) or third-generation cephalosporin (cefotaxime), and clindamycin or metronidazole. Vancomycin should be included if staphylococcus coverage is deemed appropriate. This combination provides broad gram-positive coverage (including staphylococcal species), excellent gram-negative coverage (with the exception of pseudomonads), and anaerobic coverage.

Doses are adapted from Neofax.[61] Postmenstrual age (PMA) is equivalent to gestational age plus postnatal age. Postnatal age is used as a secondary qualifier to determine dose.

Cefotaxime (Claforan)

Cefotaxime is a broad-spectrum, third-generation cephalosporin with excellent nonpseudomonal, gram-negative coverage at the expense of gram-positive effects. Its safety profile is more favorable than that for aminoglycosides. Cefotaxime penetrates cerebrospinal fluid to treat meningitis.

Ampicillin

Ampicillin is a broad-spectrum penicillin. It interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. Ampicillin is an alternative to amoxicillin when medication cannot be taken orally. Previously, the HACEK bacteria were uniformly susceptible to ampicillin. However, beta-lactamase–producing strains of HACEK have been identified.

Gentamicin

Gentamicin is an aminoglycoside antibiotic for gram-negative coverage of bacteria, including Pseudomonas species. It is synergistic with beta lactamase against enterococci. Gentamicin interferes with bacterial protein synthesis by binding to 30S and 50S ribosomal subunits. Dosing regimens are numerous and are adjusted based on CrCl and changes in volume of distribution, as well as the body space into which the agent needs to distribute. Monitor gentamicin by serum levels obtained before the third or fourth dose (0.5 h before dosing); the peak level may be drawn 0.5 hour after a 30-minute infusion.

Vancomycin (Vancocin)

Vancomycin provides excellent gram-positive coverage, including of methicillin-resistant Staphylococcus species and Streptococcus species. The drug blocks bacterial cell wall synthesis. The parenteral formulation is widely bioavailable throughout all body tissues and fluids, including cerebrospinal fluid. Vancomycin is recommended for empiric use in patients with central lines and ventriculoperitoneal (VP) shunts, and for those with probable staphylococcal or streptococcal infection. Enteral administration is used for Clostridium difficile intoxication.

Clindamycin (Cleocin)

Clindamycin inhibits bacterial protein synthesis; it is bacteriostatic or bacteriocidal, depending on the drug concentration and organism. Coverage includes anaerobes commonly found in the intestinal tract and many staphylococcal and streptococcal species.

Metronidazole (Flagyl)

Metronidazole is used to treat susceptible anaerobic bacterial and protozoal intraabdominal, systemic, or central nervous system (CNS) infections.

Class Summary

Babies with serious illness may progress to shock and require pharmacologic blood pressure support.

Dopamine

Dopamine is an adrenergic agonist that increases blood pressure by stimulating alpha-adrenergic vascular receptors, resulting in vasoconstriction. It has some inotropic effects via beta1 cardiac receptors and, at low doses, increases glomerular filtration via renal dopaminergic receptors. Dopamine is useful for babies with hypotension who are not responsive to volume repletion. It may be mixed in dextrose so that glucose delivery is not compromised.

Dobutamine

Dobutamine is an adrenergic agonist with specific effects on beta1-receptors in the heart, resulting in increased contractility. It has minimal alpha-adrenergic activity. Dobutamine can be used for babies in shock, usually adjunctively with dopamine, to increase cardiac output. It may be mixed in dextrose so that glucose delivery is not compromised.

Epinephrine (Adrenalin)

Epinephrine is a nonspecific adrenergic agonist that stimulates alpha receptors, beta1 receptors, and beta2 receptors. It can be used to support blood pressure in severe hypotension that is refractory to other treatment modalities.

Naloxone

Naloxone is an opioid receptor blocker. Experimental evidence suggests that it may increase blood pressure for babies in shock, perhaps by blocking the binding of endogenously produced endorphins released in sepsis, particularly from gram-negative organisms.

Class Summary

Patients with severe illness may experience fluid shifts to the extracellular space, resulting in intravascular depletion that requires expansion.

Albumin (5% and 25%)

Albumin is used to increase intravascular oncotic pressure in hypovolemia and helps to mobilize fluids from the interstitial to the intravascular space. The concentration can be either 5% (5 g/100 mL) or 25% (25 g/100 mL), depending on the desired effect.

Sodium chloride hypertonic, ophthalmic (Normal saline, NS, Isotonic saline)

Sodium chloride can be used as a volume expander and can be as effective as albumin in acute hypovolemia.

Fresh frozen plasma

Fresh frozen plaza is especially helpful as a volume expander in patients with concomitant coagulopathy.

Class Summary

These agents correct the inappropriate adrenal response that is often present in very ill neonates. Once hydrocortisone therapy is initiated, hypotension typically resolves.

Hydrocortisone (Solu-Cortef)

Hydrocortisone elicits mineralocorticoid activity and glucocorticoid effects.

Class Summary

Although difficult to assess, premature infants presumably experience pain with severe illness and invasive procedures. Narcotic analgesics are safe and effective in premature infants and have a long history of clinical experience.

Morphine sulfate (Duramorph, Astramorph, Oramorph SR, MS Contin)

Morphine 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.

Fentanyl (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.

Class Summary

The 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.

Fluconazole (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.

Class Summary

A 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.[62, 63, 64, 65, 66, 67, 68, 69, 70] 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 acid–producing 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.