AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Necrotizing enterocolitis (NEC) is the most common gastrointestinal medical/surgical emergency occurring in neonates. NEC 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. Despite intensive study over the past 30 years, its etiology remains elusive.

Pathophysiology

NEC affects the gastrointestinal tract and, in severe cases, can cause profound impairment of multiple organ systems.

Initial symptoms may be subtle and can include any of the following:

• 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:

• 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 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 pathogenesis of the disease, spreading it and triggering systemic involvement. Such a mechanism could account for the apparent protection breast-fed infants have against fulminant NEC.

Animal model research studies have shed light on the pathogenesis of this disease. Regardless of the triggering mechanisms, the resultant outcome is significant inflammation of the intestinal tissues, the release of inflammatory mediators (eg, leukotrienes, tumor necrosis factor [TNF], platelet-activating factor [PAF]) and intraluminal bile acids, and down-regulation of cellular growth factors, all of which lead to variable degrees of intestinal damage.

Although the pathogenesis of NEC remains uncertain, a large body of evidence suggests a multifactorial etiology, including the presence of abnormal bacterial flora, intestinal ischemia, reperfusion injury with activation of proinflammatory cellular cascades, and intestinal mucosal immaturity/dysfunction.

• 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.
  • Rat pups colonized with Staphylococcus aureus and Escherichia coli demonstrated increased incidence and severity of NEC compared with those whose intestines were populated with various bacterial species.¹ 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- or down-regulation of intestinal inflammation via toll receptor signaling. 
  • Many preterm infants receive frequent exposure to broad-spectrum antibacterial agents, further altering the intra-intestinal bacterial environment.
  • Experimental evidence suggests that exogenous administration of the probiotics bifidobacteria and lactobacilli or prebiotics (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.²
• 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, such as is found in patients with patent ductus arteriosus or congenital heart disease, also have an increased incidence.
  • Animal models of induced intestinal ischemia have identified its significant role in the development of clinical 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 IL-18. Alterations in hepatobiliary cell junction integrity results 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 results 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 NEC.
• Intestinal mucosal immaturity
• • 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 to 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 interleukin (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 (up to 5 times greater in one study³) than milk collected from women who delivered at term.

Frequency

United States

Frequency 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 is more prevalent among the smallest preterm infants. However, it is reported among term infants with perinatal asphyxia or congenital heart disease.

International

Population-based studies from other countries suggest a frequency similar to the United States. 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%.⁴

Mortality/Morbidity

• The mortality rate 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 particularly vulnerable, with reported mortality rates of 40-100%. One study compared mortality rates for term versus preterm infants and reported rates of 4.7% for term infants and 11.9% for premature babies.⁵
• Survivors can have significant short-term and long-term morbidities. Patients with mild disease (see Bell stage II under Medical Care) require gastrointestinal rest to facilitate resolution of the intestinal inflammatory process. These babies are 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. Prolonged hyperalimentation and the absence of enteral nutrition can cause cholestasis, direct hyperbilirubinemia, and other metabolic complications.
• Patients who are severely affected may require intestinal resection during the acute phase of their disease. Any patient can develop strictures, as part of the healing process, which require surgical intervention. In rare and severe NEC cases, the entire intestine can be involved, precluding surgical intervention. Depending on the location and extent of the bowel removed, long-term morbidities can include the need for ileostomy and/or colostomy, repeated surgical procedures, prolonged parenteral nutrition, short gut and malabsorption syndromes, failure to thrive due to suboptimal nutrition, and multiple hospitalizations. Intestinal transplantation for babies with severe short-gut syndrome is becoming more common. Combination liver and small bowel transplantation may be necessary for severely affected infants who have also acquired life-threatening hyperalimentation hepatitis.

Race

Although some studies indicate a higher frequency in black babies than in white babies, other studies show no difference based on race.

Sex

Most studies indicate that male and female babies are equally affected.

Age

• 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.
• Average age at 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.
• Infants with patent ductus arteriosus are at higher risk for developing the disease, particularly if pharmacologic closure is attempted. These infants may develop the disease sooner than infants without patent ductus arteriosus.
• Term infants develop NEC 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 pathophysiology 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.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
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• Medication
• Follow-up
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• References

History

Epidemiologic studies demonstrate that demographics, risk factors, patient characteristics, and clinical course differ significantly between term and preterm infants.

• Term baby
• • Compared with a preterm infant, the term baby with necrotizing enterocolitis (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 may appear as late as one month of age.
  • 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, 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 NEC 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 of developing NEC earlier in life, particularly if treated with indomethacin for pharmacologic closure. However, patients with persistent patent ductus arteriosus that ultimately required surgical ligation had a higher NEC mortality rate than those whose patent ductus arteriosus were 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 progresses 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 representing 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 formula-fed babies.
  • Rapid advancement of formula feeding has been associated with an increased risk of NEC.⁶ However, multiple subsequent studies have failed to substantiate this finding.

Physical

• The pertinent physical findings in patients who develop NEC can be primarily gastrointestinal, primarily systemic, indolent, fulminant, or any combination of these. A high index of clinical suspicion is essential to minimize potentially significant morbidity or mortality.
• Gastrointestinal 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
  • A 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.

Causes

See Pathophysiology.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Not infrequently, free air is noted on an abdominal radiograph of a premature infant, either as an incidental finding on imaging performed for other reasons or during an initial evaluation for abdominal pathology. Spontaneous intestinal perforation (SIP) can be distinguished from necrotizing enterocolitis (NEC) by its lack of systemic involvement, absence of other clinical signs common to bowel perforation, and higher rate of survival.⁷ SIP is further distinguished by its earlier onset in babies of smaller birthweight and more extreme prematurity.⁸ Associations have been identified between SIP and indomethacin,⁷ dexamethasone,⁹ and systemic candidiasis.⁸

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Initial presentation 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 necrotizing enterocolitis (NEC) is present. Laboratory studies are pursued, especially if the abdominal study findings are worrisome or the baby is manifesting any systemic signs.
• CBC count, with manual differential to evaluate the WBC, hematocrit, and platelet count, is usually repeated at least every 6 hours if the patient's clinical status continues to deteriorate.
• • WBC 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.
  • RBC 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.
  • 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 PT, prolonged aPTT, and decreasing fibrinogen and increasing fibrin degradation products concentrations
  • 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 NEC and should be considered in the differential diagnosis. Therefore, identification of a specific organism can aid and guide further therapy.
• 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/dL) is alarming and heightened vigilance is warranted.
  • Metabolic acidosis: Low serum bicarbonate (<20) in a baby with a previously normal acid-base status is also concerning. It is seen in conjunction with poor tissue perfusion, sepsis, and bowel necrosis.
• Arterial blood gasses
• • Depending on presentation acuity, hypoventilation and frank apnea are seen in NEC. 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 count, serum electrolytes, and ABG for the initial evaluation (note that arterial blood has a lower yield for demonstrating bacteremia than venous blood). Depending on presentation acuity, inserting a peripheral arterial line while peripheral perfusion and intravascular volume is 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.
• Although all of these initial laboratory studies taken together may aid in the diagnosis of NEC, they do not substitute for an appropriate appreciation of clinical presentation and appearance of the infant. The laboratory values can give insight into the severity of the disease and can aid in the provision of appropriate therapy.

Imaging Studies

• 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 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 is a radiologic sign pathognomonic of 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 these 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.
  • Abdominal free air is ominous and usually requires emergency surgical intervention (see Other Problems to be Considered). 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 easier than on other views. Obtain this view with every AP examination until progressive disease is no longer a concern.
  • Portal gas is thought to be ominous when detected. Portal gas appears as linear branching areas of decreased density over the liver shadow and represents air present in the portal venous system. Portal gas is much more dramatically observed on ultrasonography.
  • Ascites is a late finding that usually develops some time after perforation when peritonitis is present. 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 NEC in neonates is evaluated.
• • Advantages include the following:
  • • Available at bedside
    • Noninvasive imagery of intra-abdominal structures
  • Disadvantages include the following:
  • • Limited availability at some medical centers
    • Requires extensive training to discern subtle ultrasonographic appearance of some pathologies
  • With abdominal ultrasonography, a skilled physician can identify a larger amount of diagnostic information faster and with less risk to the baby than with the current standard evaluation methods.
  • Abdominal air (easily observed on ultrasonography and in grossly distended patients) can interfere with assessing intra-abdominal structures.
  • 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 excellent identifying and quantifying ascites. Serial examinations can be used to monitor the progression of ascites as a marker for the disease course.
  • Portal air can be easily observed as bubbles present in the venous system. This finding has been informally termed the "champagne sign" because of its similar appearance to a champagne flute.
  • Ultrasonographic assessment of major splanchnic vasculature can help in the differential diagnosis of NEC from other more benign and emergent disorders.
• 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 360º, if the full path of the vessels can be observed.
• Doppler study of the splanchnic arteries early in the course of NEC can help 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.¹⁰ 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.

Other Tests

• Reports from outside of the United States suggest that more contemporary imaging techniques, such as contrast radiography, portal vein ultrasonography, MRI, and radionuclide scanning, may play a role in diagnosis. 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.

Procedures

Nonsurgical procedures for NEC are as follows:

• Upper GI (with or without) small bowel follow-through is only performed acutely when diagnosis other than NEC are being considered (eg, bowel obstruction) because of bilious vomiting, abdominal distention, or other symptoms. This procedure is commonly performed in infants with resolved NEC who develop a picture of gastrointestinal 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. 
• 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 as severely affected patients often have complication 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 in infants with NEC is as follows:
• • Decompression is essential at the first sign of abdominal pathology.
  • 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 suction and monitor output. The tube should be irrigated with several mililiters 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.
• Ascites can develop during fulminant NEC and can compromise respiratory function. Paracentesis may be considered.
• Place an intra-abdominal drain as an alternative to laparotomy if the baby is not a surgical candidate (eg, extreme prematurity or cardiovascular collapse and shock).

Histologic Findings

Inspecting the affected bowel reveals mucosal ischemia progressing to cell death and sloughing. Necrosis can be limited to the mucosal layer, can be observed radiographically as pneumatosis, or can affect the full wall, resulting in perforation with subsequent peritonitis. Necrotic or perforated intestine must be resected.

Staging

See Medical Care.

TREATMENT

Section 6 of 11  

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Medical Care

Diagnosis of necrotizing enterocolitis (NEC) is based on clinical suspicion supported by findings on radiologic and laboratory studies. Treatment of NEC depends on the degree of bowel involvement and severity of its presentation. Objective staging criteria developed by Bell have been widely adopted or modified to help tailor therapy according to disease severity.

• Bell stage I - Suspected disease
• • Stage IA
  • • 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.
    • Treatment is NPO with antibiotics for 3 days.
  • Stage IB
  • • Diagnosis is the same as IA, with the addition of grossly bloody stool.
    • Treatment is NPO with antibiotics for 3 days.
• Bell stage II - Definite disease
• • Stage IIA
  • • 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" NEC as surgical intervention is not needed to successfully treat the patient.
    • Treatment includes support for respiratory and cardiovascular failure, NPO, and antibiotics for 14 days. Surgical consultation should be considered.
  • Stage IIB
  • • 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.
    • Treatment includes support for respiratory and cardiovascular failure, NPO, and antibiotics for 7-10 days.
• Bell stage III - Represents advanced NEC with severe illness that has a high likelihood of progressing to surgical intervention
• • Stage IIIA
  • • 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.
    • Treatment involves NPO for 14 days, fluid resuscitation, inotropic support, and ventilator support. Surgical consultation should be obtained.
  • Stage IIIB
  • • This stage is reserved for the severely ill infant with perforated bowel observed on radiograph in addition to the findings and treatment recommendations for IIIA.
    • Surgical intervention as outlined below.

Surgical Care

• Free air visible on abdominal radiograph is an indication for surgery. Surgical treatment includes resecting the affected portion of the bowel, which may be extensive. Initially, an ileostomy with a mucous fistula is typically performed, with reanastomosis performed later. Strictures may occur, with or without a history of surgical intervention, which may require surgical treatment.
• 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.
• The surgical community remains divergent on the risks and benefits of open laparotomy versus peritoneal drain placement. Two retrospective reviews of the use of peritoneal drains as initial therapy for perforated bowel concluded that, although most patients ultimately require open laparotomy, initial peritoneal drainage may allow systemic stabilization and recovery in the smallest, sickest infants until they become better surgical candidates.^{11, 12} More recent prospective randomized trials have failed to show a difference in outcomes between the 2 approaches, although local custom may continue to impact the decision for surgical intervention in patients who are surgical candidates.
• Any patient requiring surgical intervention and many of those patients not progressing to surgery require protracted courses of parenteral nutrition and intravenous antibiotics.
• • Secure central venous access is optimal for ensuring uninterrupted delivery of antibiotics and nutrition as well as maximizing nourishment with central venous formulations.
  • Some units successfully use percutaneously inserted central venous catheters (PCVCs), whereas other units prefer surgically placed central lines such as Broviac catheters. Both types carry an increased risk of infection, particularly if they are used to administer lipids.

Consultations

Consult with a pediatric surgeon at the earliest suspicion of developing NEC. This may require transferring the patient to another facility where such services are available.

Diet

• When NEC is suspected, enteral feedings are withheld and parenteral nutrition is initiated. Centrally delivered formulations with appropriate nutritional components are infused for optimal IV nutrition (see Surgical Care). Enteral feedings can be restarted 10-14 days after findings on abdominal radiographs normalize in the case of nonsurgical NEC. 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, 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.

MEDICATION

Section 7 of 11  

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• Medication
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• References

Pharmacologic therapy includes agents to treat the developing disease and those to provide supportive and symptomatic relief. Probiotics are emerging as a possible preventive therapy.

Drug Category: Antimicrobial agents

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. Antibacterial coverage for gram-positive and gram-negative organisms is essential, with the addition of anaerobic coverage for infants older than 1 week who show radiologic or clinical disease progression. 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 used; one frequently used regimen includes vancomycin, cefotaxime, and clindamycin or metronidazole. This combination provides broad gram-positive coverage (including staphylococcal species), excellent gram-negative coverage (with the exception of pseudomonads), and anaerobic coverage.

Drug Name	Cefotaxime (Claforan)
Description	Broad-spectrum third-generation cephalosporin with excellent nonpseudomonal gram-negative coverage at the expense of gram-positive effects. Safety profile is more favorable than aminoglycosides. Penetrates cerebrospinal fluid to treat meningitis.
Adult Dose	1-2 g IV/IM q6-8h
Pediatric Dose	Varies with weight and postnatal age <1 month, <1200 g: 50 mg/kg/dose IV/IM q12h >7 days, >2000 g: 50 mg/kg/dose IV/IM q6h
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase cefotaxime levels; coadministration with furosemide and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in severe renal impairment; has been associated with severe colitis

Drug Name	Clindamycin (Cleocin)
Description	Inhibits bacterial protein synthesis and is bacteriostatic or bacteriocidal depending on drug concentration and organism. Coverage includes anaerobes commonly found in the intestinal tract and many staphylococcal and streptococcal species.
Adult Dose	600-1200 mg IV/IM q6-8h
Pediatric Dose	Dependent on weight and postnatal age Parenteral recommendation range: <7 days, <2000 g: 10 mg/kg/d IV divided q12h; not to exceed 4.8 g/d >7 days, >2000 g: 20 mg/kg/d IV divided q6h; not to exceed 4.8 g/d
Contraindications	Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Dosage may require adjustment if patient has hepatic impairment; overgrowth of Clostridium difficile and associated development of pseudomembranous colitis can occur; C difficile infection has been associated with the development of postinflammatory adhesions and/or stricture (Freeman, 1999); metronidazole also has anaerobic coverage and may be an acceptable substitute

Drug Name	Metronidazole (Flagyl)
Description	Used to treat susceptible anaerobic bacterial and protozoal intraabdominal, systemic, or CNS infections.
Adult Dose	Anaerobic infections: 30 mg/kg/d PO/IV divided q6h; not to exceed 4 g/d
Pediatric Dose	Dosing adjusted by postnatal age and weight Neonates 0-28 days, <1200 grams: 7.5 mg/kg IV q48h Postnatal age <8 days: 1200-2000 grams: 7.5 mg/kg IV q24h >2000 grams: 15 mg/kg/d IV divided q12h Postnatal age >8 days: 1200-2000 grams: 15 mg/kg/d IV divided q12h >2000 grams: 30 mg/kg/d IV divided q12h
Contraindications	Documented hypersensitivity; first trimester of pregnancy
Interactions	May increase toxicity of anticoagulants, cyclosporine, lithium, phenytoin, tacrolimus, and carbamazepine; cimetidine may increase toxicity of metronidazole; disulfiram reaction may occur with orally ingested ethanol; coadministration increases amiodarone toxicity (QT prolongation); increases disulfiram toxicity (psychotic symptoms) with concurrent use; phenobarbital and rifampin may increase metabolism of metronidazole
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in liver impairment, blood dyscrasias, or CNS disease; reduce dosage in severe liver impairment; monitor for seizures and development of peripheral neuropathy

Drug Category: Vasopressors

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

Drug Name	Dobutamine (Dobutrex)
Description	Adrenergic agonist with specific effects on beta1-receptors in the heart, resulting in increased contractility. Has minimal alpha-adrenergic activity. Can be used for babies in shock, usually adjunctively with dopamine, to increase cardiac output. May be mixed in dextrose so that glucose delivery is not compromised.
Adult Dose	1-20 mcg/kg/min IV
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; idiopathic hypertrophic subaortic stenosis; atrial fibrillation or flutter
Interactions	Beta-adrenergic blocking agents antagonize effects; general anesthetics may increase toxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Hypovolemic state should be corrected before using this drug

Drug Name	Epinephrine (Adrenaline)
Description	Nonspecific adrenergic agonist that stimulates alpha-, beta1-, and beta2-receptors. Can be used to support blood pressure in severe hypotension refractory to other treatment modalities.
Pediatric Dose	0.1-1 mcg/kg/min IV
Contraindications	Documented hypersensitivity; cardiac arrhythmias or angle-closure glaucoma; local anesthesia in areas such as fingers or toes because vasoconstriction may produce sloughing of tissue; do not use during labor (may delay second stage of labor)
Interactions	Increases toxicity of beta- and alpha-blocking agents and that of halogenated inhalational anesthetics
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in hypertension, hyperthyroidism, and cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias

Drug Name	Naloxone (Narcan)
Description	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.
Pediatric Dose	Bolus dose: 0.1 mg/kg IV For continuous IV infusion, administer a test dose as above, observe for magnitude and duration of effect, and calculate continuous dose appropriately Reported dosage range 2.5-160 mcg/kg/h IV
Contraindications	Documented hypersensitivity; opioid addiction in baby or mother if baby is <7 d
Interactions	Blocks the effects of narcotic analgesics and those of endogenous endorphins that may be involved in intrinsic pain relief pathways
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in cardiovascular disease; naloxone may precipitate withdrawal symptoms in patients addicted to opiates

Drug Category: Volume expanders

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

Drug Name	Sodium chloride 0.9% (Normal saline, NS, Isotonic saline)
Description	Can be used as a volume expander and be as effective as albumin in acute hypovolemia.
Pediatric Dose	10-20 mL/kg IV infused over 30 min
Contraindications	Fluid retention; hypernatremia; cardiac failure
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in congestive heart failure, hypertension, edema, liver cirrhosis, renal insufficiency, and sodium toxicity

Drug Name	Fresh frozen plasma
Description	Used as a volume expander, especially helpful for patients with concomitant coagulopathy.
Pediatric Dose	10-15 mL/kg IV infused over 1 h
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Carries all of the risks and restrictions associated with administering blood products

Drug Category: Opioid analgesics

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.

Drug Name	Fentanyl (Sublimaze)
Description	Opioid analgesic 50-100 times more potent than morphine; mechanism of action and indications for use are similar; has less hypotensive effects than morphine because of minimal-to-no associated histamine release. Administered bolus IV or as a continuous infusion. Because of small volumes used in neonates for bolus administration, it is not usually cost-effective to administer bolus.
Pediatric Dose	Bolus dose: 1-4 mcg/kg/dose slow IV push Continuous infusion: 0.5-1 mcg/kg/h IV; titrate to desired effect If used during ECMO, higher doses can be anticipated, typically 1-5 mcg/kg/h initially Because of tachyphylaxis, dose may need to be increased during the ECMO run, with doses as high as 20 mcg/kg/h reported by day 7 of treatment
Contraindications	Documented hypersensitivity; hypotension; potentially compromised airway when establishing rapid airway control would be difficult
Interactions	Other CNS depressants (eg, drugs not typically used in neonates) and MAOIs may potentiate adverse effects; naloxone reverses fentanyl
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Rapid IV administration may result in chest wall rigidity, severely compromising ability to ventilate the baby; higher doses are associated with respiratory depression/apnea; should be administered by qualified health care professionals trained in the use of general anesthetic agents; patient should be closely monitored, dose should be titrated, and lowest effective dose should be used; prolonged use (>5 d continuous infusion) results in physiologic dependence and abrupt cessation precipitates neonatal abstinence syndrome

Drug Category: Antifungal agents

The mechanism of action in these agents may involve an alteration of RNA and 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 microbiological resistance is present.

Drug Category: Probiotics

Oral administration of nonpathogenic bacterial species may result in beneficial alteration of intestinal bacterial flora, reducing risk and severity of disease.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Prolonged parenteral nutrition is essential to optimize the baby's nutrition while the gastrointestinal tract is allowed enough time for recovery and return to normal functioning. 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 (eg, vancomycin) should be administered. Persistently positive cultures require removing the central line. Many clinicians remove the central line once sepsis and bacteremia are confirmed because eradication is almost impossible when the central line is kept in place.
• Prolonged parenteral nutrition may be associated with cholestasis and direct hyperbilirubinemia. This condition resolves gradually following initiation of enteral feeds.
• Prolonged broad-spectrum antibacterial therapy increases the premature infant's risk for fungal sepsis.
• See Fungal infection in Preterm Infants.

Further Outpatient Care

• 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 (see Short-gut syndrome under Complications). These babies require vigilant nutritional regimens to maintain adequate calories and vitamins for optimum growth and healing.

Transfer

• In the acute phase, patients with progressive necrotizing enterocolitis (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.

Deterrence/Prevention

• Breastfed babies have a lower incidence of NEC than formula-fed babies.^{13, 14}
• Much anecdotal evidence details the role of feeding regimens in the etiology of NEC. 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 for babies in whom feeds have been started early in life versus after 2 weeks' chronologic age.^{15, 16} In 1992, McKeown et al reported that rapid increase in feeding volume (>20 mL/kg/d) was associated with higher risk of NEC.⁶ However, in 1999, Rayyis et al showed no difference in NEC Bell stage greater than or equal to II in patients advanced at 15 mL/kg/d compared with those advanced at 35 mL/kg/d.¹⁷ Systematic review published by the Cochrane Collaboration in 1999 reported no effect on NEC of rapid feeding advancement for low–birth weight infants.¹⁸
• 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.

Complications

Approximately 75% of all patients survive, with those requiring surgical intervention during the acute phase of the disease demonstrating much lower survival rates. Of those patients who survive, 50% develop a long-term complication. The 2 most common complications are intestinal stricture and short-gut syndrome.

• Intestinal strictures
• • This complication can develop in infants with or without a preceding perforation.
  • Incidence is 25-33%.
  • Although the most likely location for acute disease is the terminal ileum, strictures most commonly involve the left side of the colon.
  • Symptoms of feeding intolerance and bowel obstruction typically occur 2-3 weeks after recovery from the initial event.
  • The presence and location of the obstruction is diagnosed using contrast enema; surgical resection of the affected area is required. Many surgeons routinely perform contrast enemas in their patients before bowel reanastomosis so that all necessary surgical intervention can be performed at one time.
• Short-gut syndrome
• • This is a malabsorption syndrome resulting from 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 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.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• 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 physicians and formulation of well-communicated health care plans for these vulnerable babies are crucial to serve their best interest, to optimize their health outcome, and to minimize the opportunities for malpractice law suits.
• Failure to recognize signs of necrotizing enterocolitis (NEC) early enough to effect appropriate care inclu