Necrotizing enterocolitis:An update

Dr. S. Ismat Bukhari

• Necrotizing enterocolitis (NEC) is an inflammatory disease of the intestine affecting 5% to 10% of premature infants born weighing less than 1,500 g, with an associated mortality rate of 10% to 50%.

• Necrotizing enterocolitis (NEC) is the most common intestinal emergency in the preterm infant, occurring in 1% to 5% of patients admitted to the neonatal intensive care unit (NICU) and in 1 to 3 per 1,000 live births.

Pathophysiology

• In simple terms, the condition can be considered an aberrant response of the immature gut and immune system in the setting of enteral nutrition and the presence of bacteria.

FEEDING

• The introduction of enteral nutrition is a key component in the pathogenesis of NEC.

• Unfed infants rarely develop the disease; indeed, 90% to 95% of infants who develop NEC have been exposed to recent enteral volume advancement. Enteral nutrition may predispose to NEC by disrupting mucosal integrity, reducing gut motility, or altering gastrointestinal blood flow.

• Appropriate feeding advancements have not been elucidated for preterm infants, but it appears that aggressively increasing feedings increases the risk of NEC.

• The type of feeding also is critical. Human milk appears to decrease the risk of NEC compared with formula. The osmolality of formulas is important, with those that have high osmotic loads being associated with NEC.

BACTERIA/INFECTION

• Considerable attention has been directed to the relationship of intestinal microbes and the pathogenesis of NEC.

• Bacteremia occurs in up to 35% of cases of NEC. It is unclear whether bacteria play a primary role in the pathogenesis of NEC or bacterial translocation occurs due to an already compromised intestinal barrier.

• No pathogen is found consistently in NEC.

• On the other hand, bacteria also play a primary role in normal intestinal homeostasis.

• In the newborn period, the gut becomes colonized with E coli and streptococci from the maternal vaginal flora.

• Bacteria reported to be associated with NEC include Escherichia coli, Klebsiella, Enterobacter, Pseudomonas, Salmonella, Clostridium, coagulase-negative Staphylococcus, and Enterococcus sp.

• Gram-positive organisms are more common in stages I and II disease, and enteric organisms predominate in more severe cases.

• Viral pathogens, namely, rotavirus, coronavirus, and enteroviruses also have been described in association with NEC.

• The type of nutrition that a baby receives appears to have an impact on subsequent colonization patterns, with formula-fed infants showing an early increase in Enterobacteriaceae colonization and the guts of breast-fed infants colonized early with Enterobacteriaceae and Bifidobacterium.

IMMATURE GUT

• An immature gastrointestinal tract and immune response predispose preterm infants to NEC.

• The preterm intestine demonstrates increased permeability to high molecular weight molecules, decreased motility, and decreased mucus production compared with the gastrointestinal tract of more mature infants.

• Preterm infants show an inappropriate cellular and humoral response to intestinal pathogens.

• The immature gastrointestinal tract shows impaired circulatory dynamics in response to an enteral volume load.

Role of Hypoxia-Ischemia• The relationship between hypoxicischemic events and NEC is controversial.

• Hypoxia-ischemia was long believed to play a prominent role in the pathogenesis of NEC, but much of the supporting evidence was anecdotal.

• Unfortunately, this has been one of the major reasons for neonatologists withholding enteral feeding from babies who have experienced low or even borderline low Apgar scores.

• The late occurrence of NEC in preterm infants who do not have preceding evidence of ischemia argues against hypoxiaischemia as a primary causative agent in the development of NEC.

• However, histologic examination does reveal coagulation necrosis, suggesting the occurrence of ischemia, perhaps as a secondary event in the pathogenesis of NEC.

• Several clinical situations in the preterm infant that increase the risk of NEC are associated with compromised intestinal blood flow.

• For example, patients who have an active patent ductus arteriosus (PDA) associated with a large left-to-right shunt have decreased gut perfusion and appear to have an increased risk for NEC.

• Furthermore, patients treated with indomethacin to close the PDA have an increased risk for NEC, presumably due to the effect of the drug on the intestinal circulation.

• Finally, maternal cocaine abuse has been associated with an increased incidence of NEC in several retrospective cohort studies, and animal data suggest that intestinal blood flow is reduced with cocaine exposure.

• Several mucosal enzymes and gastrointestinal hormones are suppressed or deficient in preterm babies

• Many aspects of the intestinal host defense system are deficient or dysfunctional in the preterm infant, including the secretory immunoglobulin A (IgA) response, neutrophil function, macrophage activation, cytokine production and function, and activity of intestinal defensins.

• Furthermore, evidence suggests that autoregulation of the microcirculation differs in preterm babies and the physiologic mechanism in the prevention of bacterial overgrowth, is dysfunctional as well.

DIAGNOSIS

Clinical findingsSPECIFIC GASTROINTESTINAL SIGNS:• Early presenting signs:

– abdominal distention (70% to 98%)– feeding intolerance with increased gastric residuals (70%)– emesis (70%)– gross blood per rectum (25% to 63%)– occult gastrointestinal bleeding (22% to 59%)– diarrhea (4% to 26%).

• As the disease progresses, abdominal findings become more severe. Patients may develop marked abdominal distention due to increased intestinal dilation and ascites. Abdominal wall erythema may be caused by necrotic bowel loops abutting the thin abdominal wall.

• When the intestine is perforated, the abdomen may develop a bluish cast as intraperitoneal meconium is seen through the abdominal wall.

LABORATORY FINDINGS

• A patient who has NEC can present with an abnormal white blood cell count.

• It may be elevated, but more commonly it is depressed.

• A severely low white blood cell count (,1.5 3 109/L [,1,500 cells/cu mm]) has been reported in 37% of cases.

• It results from both decreased production and increased utilization of leukocytes.

• Thrombocytopenia is also common, seen in up to 87% of patients. • In addition, patients may develop other coagulation abnormalities, including prolongation of

prothrombin time and hypofibrinogenemia.

• Glucose instability (hypoglycemia or hyperglycemia), metabolic acidosis, and electrolyte imbalance may occur.

• Some patients have elevated C-reactive protein levels.

• Because no unique infectious agents have been incriminated in NEC, bacteriologic and fungal cultures may prove helpful but not conclusive.

A plain antero-posterior radiograph demonstrating pneumatosis.

Initial radiographic evaluation may reveal a fixed, dilated loop of bowel.

The characteristic radiologic finding is pneumatosis intestinalis, which is believed to be intraluminal gas produced by bacterial fermentation.

Pneumatosis intestinalis is found in 70% to 80% of confirmed cases of NEC.

Portal venous gas or pneumo-peritoneum may be seen with severe cases.

A left lateral decubitus radiograph demonstratingfree air (arrow) between the body wall and the liver.

A dependent radiographic view is required to visualize this smallamount of free air.

• Some authors have used other modes of imaging to diagnose NEC and assist in the decision for surgical intervention.

• The use of ultrasonography, contrast radiography, and even magnetic resonance imaging has been reported anecdotally, but their utility has not been established.

• These studies never should delay otherwise indicated medical or surgical management.

Photomicrograph of intestine with NEC. The cystic areas below the severely disrupted mucosal layer are pockets

of hydrogen gas that present radiographically as pneumatosis.

HISTOLOGY/GROSS PATHOLOGY

Histologically, NEC is characterized by mucosal edema, inflammation, hemorrhage, coagulation necrosis, andmucosal ulceration.

The terminal ileum and proximalcolon are the sections of bowel affected most commonly, although more extensive disease is possible from the stomach to the rectum.

• Staging of NEC is according to a modification of the system first proposed by Bell and colleagues in 1978.

• The staging system is based on clinical, laboratory, and radiologic findings.

• Stage I signs are nonspecific and can be due to a number of problems, including sepsis and simple feeding intolerance.

• Stage II and III criteria are more specific for NEC: pneumatosis intestinalis, pneumoperitoneum, grossly bloody stools, DIC, and metabolic acidosis.

Differential diagnosis

• Sepsis with ileus, in both term and preterm patients, can mimic NEC.

• Both present with systemic signs of infection and abdominal distention.

• Fortunately, the treatment for both conditions is similar: bowel rest, antibiotic administration, and supportive care.

• Isolated gastric perforation can result in pneumo-peritoneum. • Gastric perforation may be associated with administration of

indomethacin or corticosteroids. • Iatrogenic gastric perforation from feeding tubes occurs rarely.

• Patients who have Hirschsprung enterocolitis or severe gastroenteritis may present with pneumatosis.

MANAGEMENT

Medical management• Most patients who have NEC are treated non-operatively.

• The maxim of ABCs (airway, breathing, and circulation) holds in these infants. Most require some mechanical ventilatory support.

• Peripheral arterial access should be established for accurate measurement of systemic blood pressure and arterial blood gases.

• Many patients will be hypovolemic and require fluid resuscitation and correction of acid base imbalance. The acidemia in NEC is often mixed, with a respiratory component from hypoventilation as well as a metabolic contribution from hypoperfusion.

• If there is evidence of coagulopathy, administration of platelets, fresh-frozen plasma, or cryoprecipitate may be indicated.

• Sodium bicarbonate should be given in severe metabolic acidosis.

• Dopamine and epinephrine infusions may be necessary when hypoperfusion does not respond to fluid administration.

• After obtaining blood cultures, broad-spectrum antimicrobial therapy appropriate to cover bowel flora should be initiated.

• Ampicillin and gentamicin are possible choices, but the common use of these antibiotics in the NICU typically results in the development of resistant organisms.

• Antibiotic therapy may be guided by patterns of resistance in the individual unit.

• In addition, VLBW infants are at risk for bacteremia from coagulase-negative Staphylococcus.

• Accordingly, empiric treatment with vancomycin and a third-generation cephalosporin is appropriate.

• Because anaerobic flora can be acquired as early as 1 week of age, a third agent to cover these organisms may be warranted.

• The severity of the disease and the need for long-term coverage with broad-spectrum antibiotics places patients who have NEC at risk for fungal sepsis.

• Amphotericin, administered either empirically or following proven culture, may be necessary later in the course of treatment.

• Discontinuation of enteral feeding and gastric decompression with a large-bore (10 or 12 French) orogastric tube should be facilitated.

• Although fraught with imprecision, serial measurements of the abdominal girth are warranted.

• More important is serial examination by the same examiner.

• Antimicrobial therapy and bowel rest should be continued for 7 to 14 days, depending on the severity of the episode.

• At the end of this period, it is important to increase feedings gradually over many days.

• Some patients who appear to respond successfully to medical treatment will manifest increased gastric residuals, abdominal distention, and bilious emesis as enteral feeds are advanced.

• This scenario suggests the development of intestinal strictures. Strictures occur in areas of the intestine that suffered ischemia without full-thickness necrosis.

• These areas heal by scarring, and contraction of the scar leads to stricture. Strictures may occur anywhere in the intestine, but the most common site is at the junction of the descending and sigmoid colon. Radiographic studies reveal evidence of a partial bowel obstruction, with intestinal dilatation on the anteroposterior view and air-fluid levels on the dependent view.

• High suspicion of stricture warrants bowel rest until 6 weeks after the initial diagnosis of NEC to allow complete fibrous healing.

• A contrast enema should be performed at the completion of this period.

• If results of a lower gastrointestinal study are normal, an upper gastrointestinal contrast study is indicated. If a stricture is identified, it should be resected surgically.

Surgical management• Even with aggressive and appropriate medical management, 34% to 50% of

patients who have NEC require surgical intervention.

• The operation of choice in patients weighing greater than 1,500 g is laparotomy with resection of frankly necrotic bowel. In some cases, there is a well-defined segment of dead bowel, with the remainder of the intestine appearing normal.

• In others, disease may be patchy, involving multiple segments of the intestine, or large areas of intestine may be of questionable viability.

• The surgeon must resect all of the necrotic intestine yet avoid removing intestine that ultimately could prove viable. A portion of viable intestine is used to create an

• enterostomy and mucous fistula. Once evidence of bowel function returns, enteral feeds are introduced slowly.

• The period of time to bowel reanastomosis varies; 6 weeks is the minimal waiting period.

• Primary resection and anastomosis of an isolated perforation has been reported anecdotally, but this procedure is not widely accepted.

• When multiple segments of bowel are affected, the surgeon traditionally is forced to create multiple stomas.

• An alternative technique is the so-called “patch, drain, and wait” approach. Each perforation is sutured closed, Penrose drains are placed in the lower abdominal quadrant, and parenteral nutrition is continued.

• For patients who have pan-necrosis with extensive involvement, the appropriate surgical management is unclear.

• Resection of affected bowel results in severe short bowel syndrome. Because of the poor outcomes seen in these patients, some surgeons support the practice of foregoing any treatment.

• For patients weighing fewer than 1,500 g, the best operative management is not known.

• Historically, the surgical management of VLBW neonates who had perforated NEC was the same as that for larger babies: laparotomy, resection, and stoma creation.

• However, applying classic surgical techniques in these very small babies may increase mortality and morbidity.

Long term outcome• In addition to post-NEC intestinal strictures, patients who undergo surgical

intervention for NEC have a high probability of long-term adverse outcomes.

• The most common intestinal complication is short bowel syndrome (25%). • In this condition, the amount of remaining intestine is not sufficient to

provide adequate absorption of enteral nutrients and fluid. Because the bowel is not functional, the patient is dependent on parenteral nutrition.

• As many as 50% of patients who survive NEC develop neurodevelopmental delay.

• Although NEC is not believed to be directly causative, any condition that results in prolonged hospitalization has been shown to place neonates at risk.

Predictive markers• Individual markers that are elevated at presentation of clinical symptoms of NEC that

may be useful for supporting the diagnosis include serum amyloid A (SAA), anaphylatoxin (C5a), urinary intestinal fatty acid–binding protein (I-FABP), claudin-3, stool platelet-activating factor (PAF), and calprotectin.

• A decreased plasma level of inter-a-inhibitory protein (IaIp) appears to be a reliable marker for the diagnosis of NEC.

• Serial measurement of C-reactive protein (CRP), SAA, and fecal calprotectin (FC) all appear to be helpful in monitoring the response to therapy.

• Last, CRP, C5a, and I-FABP may be variably helpful in predicting severity of disease and overall prognosis for poor outcomes (eg, death or perforation) related to NEC.

• Interestingly, plasma citrulline may predict dependence on total parenteral nutrition (TPN) as a sign of morbidity related to NEC

Serum Amyloid A• SAA is a rapidly acting acute-phase protein produced by hepatocytes in

response to activated monocytes/ macrophages.

• SAA has also been found to be elevated in infants who have NEC and levels decrease rapidly after the initial peak with the resolution of disease.

• However, SAA levels remained elevated on days 3 and 7 of diagnosis in patients who died, suggesting that persistent elevations in SAA may predict higher mortality.

Anaphylatoxin

• The complement activation product, C5a is a strong chemo-attractant peptide that helps to recruit inflammatory cells and activates phagocytic cells.

• It has been reported as a contributing factor leading to mesenteric ischemia/ reperfusion injury.

• C5a levels in the serum at the time of diagnosis were more accurate than SAA, CRP, and interleukin-6 in predicting severity of disease, for example, death.

Intestinal Fatty Acid–Binding Protein

• I-FABP is a cytosolic water-soluble protein released from mature enterocytes in the small and large intestine when cell membrane integrity is compromised.

• Because of its small size, I-FABP passes the glomerular filter and can be detected in the urine quickly.

• Urinary I-FABP levels were higher in infants who had NEC versus those infants without NEC, with specificity of 90% and a sensitivity of 93% with a cutoff value of 2.20 pg/nmol creatinine.

• I-FABP may be useful as a predictor of disease severity in NEC.

Claudin-3

• Another marker specific to intestinal integrity loss is claudin- 3, which is an important tight junction protein.

• Urinary claudin-3 with a specificity of 81% and a sensitivity of 71%.

• However, this marker was not helpful as a predictor of severity of NEC.

Platelet-Activating Factor• PAF is an endogenous phospholipid mediator synthesized from plasma membrane

precursors, and is involved in many physiologic processes largely through local paracrine effect.

• Levels of PAF are higher in infants with stage II and III NEC versus those without, and levels steadily increased with progression of disease and returned to baseline after recovery.

• In addition, fecal PAF has been shown to be elevated days before the clinical appearance of NEC in human neonates.

• However, like other nonspecific markers of inflammation, PAF can be elevated in conditions other than NEC, such as perinatal asphyxia, bronchopulmonary dysplasia, persistent pulmonary hypertension of the newborn, and neonatal sepsis, all common co-diagnoses in the population at risk for NEC.

• Nonetheless, because of the difficulty in measuring this nonprotein mediator, it is unlikely that clinical laboratories will consider this suitable for routine use.

Calprotectin• Calprotectin is a heterodimeric peptide that binds calcium and zinc and constitutes up to

60% of the cytosolic content of neutrophils.

• In intestinal inflammation, neutrophils are sequestered into the gut wall.

• Calprotectin is extremely resistant to degradation by fecal bacteria, which allows calprotectin to be reliably measured in fecal matter as a marker for gut wall inflammation.

• FC levels have been useful for monitoring exacerbations of inflammatory bowel disease in children.

• Levels did differ between well and sick infants based on their clinical condition, with values greater than 350 mg/g stool noted in infants with signs of gastrointestinal injury, that is, bloody stool or bowel perforation.

• FC levels appeared to decrease after the initiation of treatment, which may allow it to be helpful in monitoring response to therapy.

• FC levels were not related to disease severity. In addition, fecal samples are not always easily obtainable in infants who have NEC.

Inter a Inhibitor Proteins• IaIps are serine protease inhibitors that play an important regulatory role in

systemic inflammation and are also an acute-phase reactant.

• IaIp downregulates endogenous serine proteases that can contribute to epithelial cell necrosis and possibly to NEC.

• Normally, these proteins are found in high concentrations in human plasma.

• In newborns and adults who have sepsis, a significant decrease in IaIp has been demonstrated, and levels correlate with disease severity and frequency of mortality.

• IaIp levels are also decreased in disease states such as neonatal sepsis, so this marker may not be helpful in distinguishing infants who have gastrointestinal ileus secondary to sepsis from infants who have NEC.

C-Reactive Protein• CRP is perhaps one of the best studied and most widely used serological biomarkers used in

various diseases.

• CRP is an acute-phase reactant that increases in the serum in the face of inflammation from infection or tissue injury.

• CRP may be helpful at the time of diagnosis for differentiating benign gastrointestinal processes such as ileus from more severe NEC.

• However, an elevated CRP level may not be seen until 12 to 24 hours after clinical symptoms because of a variable lag period, which makes it less helpful for making early diagnoses.

• However, CRP levels do decrease as the disease process is improved, so it may be helpful as a marker of response to therapy.

• CRP is not helpful in distinguishing NEC alone from other inflammatory processes, or ileus due to other infectious processes. Mean peak CRP value did not differ between infants with stage II and stage III NEC, although time to reach peak CRP was shorter in NEC stage III versus stage II.

• Persistently elevated levels may suggest the need to evaluate for complications or ongoing disease that may indicate the need for surgical intervention.

Citrulline• Citrulline is a nonprotein amino acid produced in the small intestine and serves as a precursor

of arginine, which is important in protein synthesis and nitric oxide production, among other things.

• Historically, serum citrulline levels in various intestinal diseases have been shown to correlate with functional intestinal mass. Specifically, in children who have short-bowel syndrome, citrulline levels have been a fair marker of residual bowel length and TPN dependence.

• In infants who develop NEC, mean citrulline levels were lower than in controls at a comparable day after birth and were reduced within 48 hours of symptoms, with an optimal cutoff value of 17.75 mmol/L providing a sensitivity of 76% and a specificity of 87%.

• Although citrulline levels may not be helpful for early diagnosis based on a variable lag time, further studies are needed to examine whether an acute decrease in serially measured levels in healthy preterm infants may be used as an early indicator of compromised intestinal function before the development of symptoms of NEC.

• Citrulline level at presentation of NEC correlated inversely with the duration of parenteral nutrition needed.

PREVENTIVE STRATEGIES

Probiotics• The interest in the use of probiotics for the prevention of NEC arose after several

observations: (1) that genera such as Bifidobacterium and Lactobacillus are lower in hospitalized infants than healthy term infants(2) that probiotic bacteria are useful in other settings of gastrointestinal disease(3) that bifidobacteria supplementation could reduce the risk of disease and decrease the gut proliferation of Gram-negative enteric pathogens in a neonatal rat model of NEC(4) that probiotic bacteria downregulate the intestinal inflammatory response in a variety of animal and cell culture models.

• More recent studies have demonstrated that probiotic bacterial products alone, such as TLR ligands or CpG segments (areas of the genome with high concentrations of cytosine linked to guanine by phosphodiester bonds, which often are near gene promoter regions) of bacterial DNA, can activate anti-inflammatory pathways via TLR9 binding, and may lessen the inflammatory response seen in NEC.

• In addition, prebiotics, or nutrients that enhance the growth of beneficial intestinal microbes, such as galactose, fructose, and lactulose, are being studied.

Human Milk• Infants fed human milk, as opposed to formula-fed infants, have a lower

incidence of and less severe NEC.

• Infants fed more human milk than formula (>50%) versus infants fed more formula than human milk (<50% human milk) had a threefold decreased risk of NEC.

• However, mothers of premature infants often have difficulty in producing enough milk to meet their infants’ needs.

Epidermal Growth Factor• Epidermal growth factor (EGF) has been shown to have a role in gut

maturation and function, so it has been considered for its preventive potential in NEC.

• Infants who have NEC, as well as premature infants, have lower levels of salivary EGF.

PREVENTION

Infection control

• Good hygiene practice (eg, handwashing) has been demonstrated to be effective in controlling outbreaks of NEC.

Trophic Feedings• Minimal enteral nutrition, also referred to as trophic, trickle, or hypocaloric

feedings, is the term applied to topical nutrition of the small intestine administered in the first week or two after birth.

• During this time, enteral feedings are limited for several days, with most nutrition provided parenterally. After this initial period, enteral feedings are advanced judiciously.

• Infants exposed to minimal enteral feedings have not shown an increased risk of NEC compared with infants kept NPO. This “gut priming” has been shown to increase gut motility, reduce the incidence of cholestasis, and improve tolerance of subsequent feedings.

• There is increasing evidence that not introducing at least small amounts of food to the gastrointestinal tract results in atrophy and predisposes the intestine to inflammation and likely translocation of bacteria.

Human Milk• Enteral feeding with human milk has been shown to decrease the severity

of NEC compared with formula feeding.

• Fresh human milk contains many immunoprotective factors, such as immunoglobulins (Igs), lactoferrin, neutrophils, lymphocytes, lysozyme, and PAF acetylhydrolase (which inhibits PAF).

• Human milk also is believed to promote intestinal colonization with Lactobacillus.

Antenatal Steroids• Antenatal steroids are not administered to expectant mothers as

prophylaxis against NEC, but when administered to prevent respiratory distress syndrome, antenatal steroids decrease the risk for NEC.

• The mechanism by which steroids protect against NEC is unclear but probably involves a decrease in inflammatory mediators, increased activity of enzymes involved in digestion and absorption, and potentially maturation of the microvillus membrane.

• A protective effect of postnatal glucocorticoids has not been demonstrated clearly, although their long-term use to treat chronic lung disease has been associated with adverse neuro-developmental effects.

Oral Antibiotics

• Oral antibiotics, primarily aminoglycosides, clearly reduce the incidence of NEC and death due to NEC.

• However, concerns regarding the emergence of bacterial resistance have rendered oral antibiotic prophylaxis an inappropriate intervention.

Probiotics• The human gut is normally colonized with commensal organisms such as

Bifidobacterium and Lactobacillus sp. • The widespread use of broadspectrum antibiotics in the NICU disrupts

development of normal microflora and allows for growth of pathogenic organisms.

• Promising recent studies have shown that probiotic supplementation has a positive impact on the incidence of NEC in preterm infants.

• Further study is necessary to determine which probiotic formulation provides the maximal protection.

• Recent evidence suggests that probiotic bacteria may not need to be alive to impart a positive effect; even bacterial products, such as TLR ligands or CpG segments of DNA, may be effective in ameliorating inflammation in the intestine.

Immunoglobulins

• Another possible preventive measure is oral supplementation with Igs.

• A recent Cochrane review, which examined five studies on Ig supplementation, found no significant difference in NEC or death from NEC with IgG or IgA preparations.

Acidification

• Preterm infants have been shown to have decreased gastric acid production in response to enteral feeding.

• An acid environment is an important barrier to many pathogenic microorganisms.

• A lower incidence of NEC is demonstrated in infants whose enteral feedings were supplemented with acid to keep the pH between 3 and 4.

Glutamine

• Glutamine has been shown to be important in immunity and intestinal function.

• A couple of single-center studies in human neonates have shown decreased sepsis and improved intestinal function with glutamine supplementation.

• Other studies did not show a decrease in sepsis, but the trial of enteral supplementation suggested a lower prevalence of intraventricular hemorrhage and periventricular leukomalacia.

Arginine

• Arginine is a substrate for nitric oxide, which demonstrates vasodilatory and anti-inflammatory properties.

• Arginine also is a precursor for other amino acids that are important in intestinal homeostasis, including glutamine and glutamate.

• Although initial results suggest that arginine supplementation may play a role in protecting against NEC.

COMPLICATIONS/OUTCOMES

Strictures

• Infants who survive episodes of NEC are at risk for serious complications, the most common of which is stricture formation.

• Up to 39% of affected patients develop stricture(s).

• Strictures may form as soon as 2 weeks following acute disease. Most strictures are colonic.

• Occasionally, partial strictures may present with recurring episodes of sepsis and feeding intolerance, which should be ruled out with appropriate radiologic contrast studies.

Malabsorption/Short Gut• Although short gut syndrome and malabsorption are expected when

significant amounts of bowel need to be resected, malabsorption also occurs in cases of NEC that do not require resection.

• This may be due to persistent mucosal injury from an ongoing inflammatory process.

Complications Associated with Total Parenteral Nutrition

• Most infants who have confirmed NEC require central catheterization for prolonged parenteral nutrition.

• The catheters employed for total parenteral nutrition are associated with significant risks of infection, vessel perforation, and iatrogenic pleural and pericardial effusions.

• The use of parenteral nutrition and NPO status also place the patient at risk for cholestasis and delay in intestinal maturation.

Recurrence

• As many as 6% of infants who develop NEC experience disease recurrence.

Extraintestinal Complications• Infants who recover from an episode of NEC have been shown to be at

increased risk of developing extraintestinal complications, such as sepsis, bronchopulmonary dysplasia, and neurodevelopmental delay.

• A recent retrospective study found that infants who had experienced an episode of NEC are at increased risk for microcephaly, short stature, and serious developmental delay.

• An increased incidence of spastic diplegia and hemiplegia suggests periventricular damage.

References • The Pathophysiology of Necrotizing Enterocolitis

Michael S. Caplan, MD, and Tamas Jilling, MD NeoReviews Vol.2 No.5 May 2001 e103

• Necrotizing Enterocolitis: Predictive Markers and Preventive StrategiesAlison Chu, MD, Joseph R. Hageman, MD, Michael S. Caplan, MDNeoReviews Vol.14 No.3 March 2013 e113

• Clinical Management of Necrotizing EnterocolitisReed A. Dimmitt and R. Lawrence MossNeoReviews 2001;2;e110