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Necrotizing enterocolitis: Current concepts in practice

Agnoni, Alysia MS, PA-C; Lazaros Amendola, Christine MS, PA-C

Journal of the American Academy of PAs: August 2017 - Volume 30 - Issue 8 - p 16–21
doi: 10.1097/01.JAA.0000521131.85173.f9
CME: Pediatrics
Free
CME

ABSTRACT Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in preterm infants and continues to be a major cause of morbidity and mortality. The incidence of NEC as well as mortality from the disease has persisted at unacceptably high levels for decades as current understanding of the cause remains incomplete. Identifying infants at risk and preventing NEC are mainstays of care. This article briefly examines disease presentation and treatment, identifies gaps in current understanding of disease pathology, and highlights new research that may lead to a decrease in the incidence of NEC in the future.

Alysia Agnoni practices in the neonatal intensive care unit at Geisinger Medical Center in Danville, Pa., and has worked in pediatric general and trauma surgery. Christine Lazaros Amendola is an assistant clinical professor and clinical education coordinator in the PA program at Pace University in New York City and Westchester, N.Y. She also practices emergency medicine at Jacobi Hospital in the Bronx, N.Y. The authors have disclosed no potential conflicts of interest, financial or otherwise.

Earn Category I CME Credit by reading both CME articles in this issue, reviewing the post-test, then taking the online test at http://cme.aapa.org. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of August 2017.

Box 1

Box 1

Necrotizing enterocolitis (NEC), with its high morbidity and mortality, remains the most common gastrointestinal (GI) emergency affecting preterm infants in neonatal ICUs (NICUs) worldwide. Although reports of the disease span back at least 5 decades, its pathogenesis remains elusive. The incidence has remained constant and may have even increased in some NICUs.1-5 Advances in preventive care, such as human milk feeding and probiotic supplementation, may help to decrease the overall incidence of NEC. The disease is associated with a high mortality, with nearly half of patients requiring surgery. Survivors may suffer long-term morbidities such as short-bowel syndrome and neurodevelopmental impairment.3,4 Because outcomes are variable, the mainstay of care rests in recognizing infants at risk for NEC and preventing the disease.5

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EPIDEMIOLOGY AND PATHOGENESIS

NEC affects 7% to 13% of preterm infants (those born before 37 weeks gestation) and carries a mortality as high as 35%.1-6 Although the increase in incidence of NEC correlates with low birth weight, very low birth weight, and extremely low birth weight infants (Table 1), NEC also affects up to 10% of babies born at term, (37 to 42 weeks gestation).7 One explanation for the increased incidence of NEC may be advances in neonatology with subsequent improved survival rates in extremely low birth weight infants.2-6 Other risk factors for NEC include hypoxia (such as in infants with congenital heart and lung diseases), chorioamnionitis, and perinatal hypoxic ischemic injury.2-4,6 Although controversy exists over whether red blood cell transfusion may be a risk factor for developing NEC, a meta-analysis conducted by Mohamed and Shah concluded that neonates with a recent history of transfusion are at increased risk for developing severe NEC.2,8 Onset of disease typically occurs in infants of 28 to 32 weeks gestational age.3,8 Some centers have reported outbreaks of NEC in clusters and noted seasonal variation, indicating a potential nosocomial cause.3,5

TABLE 1

TABLE 1

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Box 2

The reason NEC remains an enigma is because it does not appear to have a single cause. In fact, the development of NEC is most likely attributed to a combination of factors: inappropriate bacterial gut colonization, immaturity and fragility of the intestine, and an exaggerated inflammatory response in the neonate.2-5,9-11 This evolving picture has become a hot topic in medical research. Identifying how each factor contributes to the development of NEC could elucidate further measures for prevention and treatment.

Although no single bacterial strain has been identified as the causative organism in NEC, the concept of dysbiosis has emerged as a common theme among researchers investigating the pathogenesis of NEC.3,4 Dysbiosis refers to the imbalance between protective commensal bacteria and harmful opportunistic bacteria.3 Preterm neonates lack protective bacterial colonization. Because these neonates are restricted to the NICU environment, more virulent strains of nosocomial bacteria may colonize the gut. Other factors resulting in decreased exposure to commensal bacteria include cesarean delivery, formula feeding, early empiric antibacterial therapy, and histamine2-blocker therapy.2,4,10

The preterm infant's gut is highly susceptible to injury from harmful bacteria because of its inherent fragility and increased permeability.2,4,10 Opportunistic organisms penetrate the wall and propagate, triggering inflammation and tissue necrosis.9 The preterm infant's heightened inflammatory response produces increased intestinal damage with subsequent inability to recover from injury. Researchers have identified several factors that participate in the exaggerated inflammatory response in the preterm infant's gut: toll-like receptor 4 (TLR4), platelet-activating factor (PAF), interleukin-8 (IL-8), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2). Additionally, two factors that modulate the intestinal gut microcirculation, endothelin-1 and nitric oxide, contribute to NEC by causing ischemic mucosal injury and reperfusion free-radical damage during inflammatory states. Mucosal recovery is impaired because preterm infants have insufficient epidermal growth factor. Epidermal growth factor, necessary for mucosal development and repair, is provided to the preterm infant through maternal milk and subsequently produced by the infant's salivary glands.3,4,10 All of these immune and microvascular mediators potentiate intestinal injury initiated through colonization with virulent bacteria. This cascade can progress to infant death if clinical signs and symptoms are not quickly recognized.

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CLINICAL MANIFESTATIONS AND DIAGNOSIS

Early recognition of NEC can be difficult. Initial signs are often indistinguishable from other GI emergencies and neonatal sepsis. One explanation for the variability of NEC rates between NICUs relates to the difficulty in diagnosing the disease. Some neonates are diagnosed preemptively, such as those on NEC watch, and recover without incident. Others diagnosed with NEC actually have spontaneous intestinal perforation, a separate disease entity.12 Timely diagnosis is based on heightened clinical suspicion supported by radiographic evidence of intestinal disease. Abdominal distension and intolerance to feeding are often initial signs, but not all infants present in the same way. Other clinical findings include abdominal tenderness, vomiting, guaiac-positive stool, and lethargy. Late manifestations indicative of severe disease are abdominal ecchymosis or erythema, bilious emesis, bloody stools, bradycardia, apnea, and temperature instability. An ecchymotic abdomen indicates peritonitis and is highly suspicious for intestinal perforation.3,4,6,13

Although no diagnostic biomarkers are specific to the diagnosis of NEC, laboratory findings, when paired with physical examination and radiographic findings, can aid in substantiating the diagnosis.3 An infant with NEC may exhibit either increased or decreased WBC count with left shift. Other common laboratory findings include elevated C-reactive protein (CRP), thrombocytopenia, metabolic acidosis, high or low blood glucose, and electrolyte imbalances. Blood cultures may be positive for Gram-negative bacteria.2,3,6,14

Clinical suspicion for NEC is confirmed by radiologic evidence, often with a simple abdominal film. Radiographs may demonstrate distended loops of bowel filled with gas, consistent with ileus; although this can occur in other disorders and is not specific to NEC. Thickening of the bowel wall is another common but nonspecific sign. The presence of intramural intestinal gas (pneumatosis intestinalis) or portal venous gas is pathognomonic for NEC (Figure 1).3,6,15 Pneumoperitoneum indicates bowel perforation but can be difficult to detect on a neonatal film. When clinical suspicion is high for bowel perforation, a horizontal beam cross-table lateral film with the infant placed in the left lateral decubitus position is preferable to the typical anterior-posterior abdominal film.3,13 Some infants will have abdominal ascites, which can mask important radiographic findings.13,14 Although ultrasonography typically is not used in the initial diagnostic evaluation of NEC, it can be helpful if the diagnosis remains unclear after abdominal radiographs are obtained. Other imaging modalities such as CT, MRI, and contrast studies provide no diagnostic benefit and are not routinely ordered.3

FIGURE 1

FIGURE 1

The Modified Bell's Staging Criteria are used to grade the severity of the disease. Based on clinical examination, laboratory results, and radiographic findings, these criteria also outline medical and surgical treatment goals (Table 2).11,13 NEC stage IA or IB represents suspected NEC. Medical treatment should be initiated at this point despite lack of radiographic evidence of disease. Treatment guidelines are based on the severity of NEC. As severity of illness increases, treatment recommendations become more intensive.11,13

TABLE 2

TABLE 2

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TREATMENT

Every infant with NEC, whether suspected or confirmed, should receive the same medical management; nearly half will go on to require surgical treatment.16 Medical management focuses on preventing disease progression, treating intra-abdominal infection and septicemia, and maintaining hemodynamic stability. As soon as NEC is suspected (stage IA through IIB), discontinue enteral feeding and place a nasogastric tube for gut decompression. Consider parenteral nutrition, as the infant may not be able to resume feedings via the gut for some time. IV fluid resuscitation and IV antibacterials are indicated. Hemodynamically unstable infants may need inotropic support and intubation. Closely monitor electrolyte and glucose levels and correct as necessary; periodic CBCs can identify anemia and thrombocytopenia. Obtain serial abdominal examinations and radiographs to monitor disease progression and assess for intestinal perforation.3,13

Broad-spectrum antibacterial therapy is required for coverage of Gram-positive, Gram-negative, and anaerobic organisms. The Surgical Infection Society and the Infectious Diseases Society of America recommend regimens of ampicillin, gentamicin, and metronidazole; or ampicillin, cefotaxime, and metronidazole; or meropenem.17 If methicillin-resistant Staphylococcus aureus (MRSA) or ampicillin-resistant infections are suspected, vancomycin can be given instead of ampicillin.17,18 In NEC stage IIB and greater, antibacterial therapy and bowel rest should continue for 10 to 14 days.3,6,13,18 If Gram stain or cultures are positive for fungal infection, fluconazole or amphotericin B are the recommended antifungal agents.17

Nearly half of all infants diagnosed with NEC will require surgery.3 Risk factors for surgery are lower birth weight, younger gestational age, and lower APGAR scores at birth. Surgical intervention, independent of operative technique, is associated with a higher mortality (35%) than medical therapy alone (21%).16,19 Pneumoperitoneum is an absolute indication for surgical intervention. Clinical signs indicating intestinal gangrene or necrosis, such as a tender ecchymotic abdomen or rapidly deteriorating clinical status, require prompt operative exploration.3

Surgical interventions include primary peritoneal drainage and/or laparotomy. Primary peritoneal drainage typically is performed at the bedside under local anesthesia. A peritoneal drain is placed into the peritoneum via a left or right lower quadrant incision. Bilateral drains are sometimes required to decompress the abdomen and stabilize the infant until further intervention can be undertaken.5,6

Reports on mortality associated with primary peritoneal drainage versus laparotomy are conflicting. When performed as the only procedure, primary peritoneal drainage has been associated with a higher mortality than laparotomy, with a 5.7 odds ratio of death.16,20,21 Infants undergoing primary peritoneal drainage at the beside and subsequent laparotomy in the OR have a mortality similar to the laparotomy group.16 Laparotomy in the OR consists of resection of the affected segments of intestine with subsequent primary anastomosis or creation of an enterostomy. Surgical discretion may be used to differentiate infants stable and safe enough for primary anastomosis from those requiring enterostomy.20,22 Severely ill infants, such as those on inotropic support and high-flow oscillation ventilation, are not stable enough for transport to the OR. In these cases, bedside laparotomy in the NICU may be considered. This procedure is associated with a mortality as high as 80% and may only serve to confirm a devastating diagnosis, such as NEC totalis, in which less than 25% of the bowel remains viable.23

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COMPLICATIONS

Although infants requiring surgery have worse outcomes, all infants with NEC can suffer short- and long-term complications. Surgical complications include wound infections or dehiscence; intra-abdominal abscess and sepsis can occur in all infants with NEC.6,22,24 Intestinal strictures occur in 10% to 35% of those diagnosed with NEC, independent of medical or surgical management.5 Up to 25% of infants requiring surgery for NEC suffer long-term complications such as short-bowel syndrome and problems related to dependence on total parenteral nutrition.4,5 Infants with NEC also suffer from increased risk for neurodevelopmental impairment, such as cerebral palsy, deafness, and blindness. Those who require surgery have more significant long-term complications.5,6,25

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PREVENTION

Given the significant morbidity and mortality of NEC, prevention has been advocated as the mainstay of disease control. The most significant discovery in prevention of NEC has been the use of human breast milk in lieu of formula for feeding preterm infants.26-28 In a 1990 study of 926 infants, Lucas and Cole found that formula-fed infants were 6 to 10 times more likely to develop NEC when compared with exclusively breastfed infants.26 Researchers speculate that this is attributable to important elements that are lacking in formula compared with mother's breast milk. Breast milk contains vital immunomodulatory factors such as IgA, antimicrobial proteins, cytokines, epidermal growth factor, and fatty acids that are especially important for preterm infants.4,10 Protective strains of bacteria can be passed through mother's milk; breastfed infants also obtain these via skin-to-skin contact.14 When mother's milk is not available for preterm or very low birth weight infants, donor breast milk should be used.28,29

Standardized feeding protocols also have been shown to be successful in preventing NEC. Adopting these protocols in the NICU provides consistent guidelines for initiating and advancing feedings, as well as recommended interventions when neonates do not tolerate feedings.30,31 A meta-analysis measuring the effect on neonatal outcomes has indicated an 87% decrease in the rate of NEC after adoption of standardized feeding protocols.31 Essentially, any standardized feeding protocol is better than no protocol; and most NICUs are developing guidelines based on those already studied.30 Delaying enteral nutrition for 4 or more days after birth has not been associated with a decreased risk of NEC in preterm or very low birth weight infants.32 Delayed feeding can postpone the beneficial effects of breast milk and may expose the infant to other risks, such as longer hospital stay, central line infections, and GI complications from lack of trophic stimuli.14,20 Enteral feeding should be initiated without delay in preterm and very low birth weight infants.29,32 Additionally, slow advancement of feedings has not been proven to prevent NEC and is not recommend for these patients.20

The most recent advancement in NEC research has been in the use of probiotics for disease prevention. Chen and Walker suggest that probiotics protect the infant gut against virulent organisms by providing colonization with favorable bacterial strains and increasing intestinal barrier protection to prevent translocation of harmful bacteria across the GI mucosa.33 Probiotic supplementation given to very low birth weight infants in the first week of life and continued for at least 2 weeks significantly decreased the risk of severe NEC as well as overall NEC-related mortality in these infants. Infants who received probiotic supplementation also took less time to reach full feeding and had overall shorter hospital stays compared with other preterm or low birth weight infants. Although probiotic supplementation has been recommended for all preterm infants to prevent NEC, this recommendation remains controversial for several reasons.20,33,34 Extremely low birth weight infants—those at highest risk for NEC—have been disproportionately represented in US studies, and the recommendations do not include this patient population.3,34 Additionally, because probiotics are not regulated by the FDA, concern exists over which preparation, dose, and duration of therapy may be the most appropriate. Until additional randomized controlled trials are conducted to compare the safety and efficacy of different preparations, most NICUs will refrain from adopting probiotic supplementation as standard practice.34

Inappropriate antibacterial use has been associated with increased risk of NEC because it results in a loss of bacterial diversity in the preterm infant's gut. NICUs commonly begin empiric antibacterial therapy (with unrestricted duration) if infection is clinically suspected in an infant. This practice is discouraged in preterm infants because it may produce heightened susceptibility to colonization with virulent organisms. Empiric antibacterial therapy, when indicated, should be given for the shortest appropriate duration.2,14,35 Histamine2-receptor antagonists such as ranitidine and famotidine, commonly used to treat reflux in infants, have been associated with an increased risk of NEC.36,37 Opportunistic bacteria thrive in the nonacidic environments induced by these medications. Clinicians must weigh risks against benefits before initiating empiric antibacterials or histamine2-receptor antagonists in preterm or low birth weight infants.2,14,21,36,37

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CONCLUSION

Recent advances in neonatology have led to heightened survival rates for preterm and extremely low birth weight infants. Unfortunately, these infants are at risk for NEC. Though the pathogenesis of the disease still remains unclear, clinicians are better-equipped to implement preventive measures. Standardized feeding regimens have proven to significantly reduce the rate of NEC in some NICUs.30,31 Research identifying human milk and probiotics as tools to significantly lower the risk of NEC in preterm infants has led to a better understanding of the role of dysbiosis in the preterm infant's gut and how it may influence the development of NEC.2-5,26-28 Although probiotics have been shown to reduce disease and mortality associated with NEC, administration of probiotic supplements to preterm infants has not yet become standard practice. Randomized controlled trials are needed to compare probiotics with specific preparations, dosage, and length of administration recommendations.17,33,34 In the meantime, the focus remains on preventing NEC.

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REFERENCES

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33. Chen CC, Allan Walker W. Probiotics and the mechanism of necrotizing enterocolitis. Semin Pediatr Surg. 2013;22(2):94–100.
34. AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2014;(4):CD005496.
35. Greenwood C, Morrow AL, Lagomarcino AJ, et al Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of Enterobacter. J Pediatr. 2014;165(1):23–29.
36. Terrin G, Passariello A, De Curtis M, et al Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics. 2012;129(1):e40–e45.
37. Gupta RW, Tran L, Norori J, et al Histamine-2 receptor blockers alter the fecal microbiota in premature infants. J Pediatr Gastroenterol Nutr. 2013;56(4):397–400.
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    Keywords:

    necrotizing enterocolitis; neonatal; gastrointestinal; preterm; probiotics; low birth weight

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