Associate Professor of Surgery
University of Pittsburgh School of Medicine
Co-Director, Fetal Diagnosis and Treatment Center, Children’s Hospital of Pittsburgh
- In mild to moderate cases of NEC, the outcome is very good; In severe cases, mortality rates are high, and long-term morbidity is common
1. The difficult problem that is necrotizing enterocolitis.
2. What is necrotizing enterocolitis?
3. Baby Jimmie – an infant with NEC.
4. Risk factors for the development of NEC.
Based on several large clinical series, several risk factors have been implicated in the development of NEC. The most common factors include prematurity and aggressive administration of enteral feeds. Other risk factors for the development of NEC include episodes of birth asphyxia, umbilical vessel catheterization (as is often required for monitoring and infusion of fluids in small infants), African American descent, and congenital heart disease. In addition, there are maternal factors that lead to the development of NEC, including maternal cocaine use and maternal pre-eclampsia. By contrast, the major protective factor in NEC that has been consistently revealed in a large series of studies is the administration of breast milk 5. These factors indicate that NEC typically develops in the setting of a stressed, formula-fed, preterm infant.
5. How is NEC diagnosed?
6. What are the pathological features of NEC?
In view of these observations made by ourselves and others 1, 3, 7-11, we propose that the mechanisms that regulate the integrity and repair of the intestinal barrier provide insights into the pathogenesis of NEC. To gain these insights, we have proposed a working model to understand the pathogenesis of NEC, as is shown in Figure 6 and described below 12-14. We hypothesize that an episode of systemic stress – which may include a global ischemic insult from congenital cardiac disease, remote infection, or effects related to a premature host – leads to translocation of bacteria across the intestinal barrier, and gives rise to two concomitant events. In the first, stress pathways become activated, resulting in a downstream signaling cascade that may progresses to the development of NEC. At the same time, we submit that pathways which normally suppress immune system activation - and therefore prevent luminal bacteria from causing intestinal injury constitutively - themselves become inhibited. The net effect therefore is activation of the host immune system and the release of circulating cytokines. These cause systemic effects, which are characterized by the global inflammatory response that is observed in patients with NEC, and local effects of the intestinal inflammation, characterized by impaired restitution and further intestinal damage. As the pro-inflammatory cascade builds, further tissue injury ensues, and the patient develops “full-blown” NEC. Under these circumstances, without urgent treatment death is inevitable.
b. Other theories to explain the development of NEC.
Other theories from a variety of investigators have also been proposed, and have provided valuable insights into the development of NEC. Ford et al have shown that cytokine activation can lead to persistent, local production of nitric oxide through activation of the inducible nitric oxide synthase (iNOS) gene, which leads to damage to the intestine 10, 15-19. Besner and colleagues have demonstrated that the cytoprotective agent heparin binding epidermal growth factor (HB-EGF) is decreased in infants with NEC, and that treatment of intestinal cells with HB-EGF leads to enhanced tissue healing 20. Walker and colleagues have demonstrated that the premature intestine responds in an exaggerated fashion to bacterial products, rendering the host susceptible to barrier dysfunction and the development of NEC21, 22. And while no definitive gene has been implicated in NEC development, several groups have sought to determine whether polymorphisms in genes related to the activation of the immune system may be increased in patients with NEC compared with control patients23-25. As was recently summarized by the 2006 National Institute of Child Health & Development (NICHD) workshop on NEC research, “NEC can be thought to arise from an uncontrolled exuberant inflammatory response to bacterial colonization that characterizes the intestine of premature infants.”
8. Management of the patient with NEC
The management of infants with NEC represents one of the most challenging tasks faced by neonatologists and pediatric surgeons. Issues that make this disease particularly difficult to manage, as compared with other septic processes, include the small size of the premature infant, difficulties obtaining vascular access in these often hypotensive patients, the presence of coexisting cardiac anomalies, the difficulty in providing optimal ventilatory support to the premature lung, and the narrow therapeutic window for many antibiotics and other drugs in this population. The timing of surgery and the choice of an individual surgical procedure must be carefully balanced against the overall risks associated with operating on these very small and sick individuals. To this end, patients with NEC are perhaps best managed using a multidisciplinary approach, in which pediatric surgeons, neonatologists, pharmacologists, and ethicists are involved.
a. First line therapy for infants with NEC
The first line of therapy for infants with NEC involves resuscitation with isotonic solutions. This step must be carefully regulated to avoid fluid overload, which can easily occur. Broad spectrum antibiotics are then administered, and although various treatment options are available, a typical approach is vancomycin and cefotetan which provide coverage of Gram-positive, Gram-negative, and anaerobic bacteria 26. Care is taken to optimize ventilation, and in certain circumstances infants may be treated with high frequency oscillation ventilation along with permissive hypercapnia to minimize barotrauma.
b. Second line therapy for infants with NEC
The second line of treatment for patients with NEC is then determined by the specific stage of the infant’s disease (see Figure 1). In patients with stage I NEC, intravenous antibiotics, nasogastric decompression, and intravenous fluids are administered for 7-10 days and serial abdominal x-rays are performed to evaluate those that demonstrate radiographic progression. Although radiographs may not specifically guide therapy, the findings on abdominal imaging can be tremendously informative, as findings of pneumatosis intestinalis or pneumoperitoneum can precede clinical manifestations. In patients with stage II NEC, consideration is given to operative intervention in those patients that demonstrate marked abdominal distention, the rapid progression to multisystem organ failure, or the presence of significant erythema or portal air, both of which may indicate that diffuse intestinal necrosis is present. In patients with stage III NEC, in which pneumoperitoneum is detected, an operative intervention is generally recommended unless other conditions preclude further intervention (such as massive intracranial bleeding or parental refusal of further treatment).
c. Surgical intervention for infants with NEC
As described above, NEC typically presents in a preterm infant who develops feeding intolerance, leading to abdominal distention, evidence of sepsis, and ultimately to intestinal perforation and a decrease in tissue and organ perfusion. Although this pattern of presentation may represent the diagnosis of NEC there are several other diagnostic considerations that should be entertained and excluded before actually committing to the diagnosis of NEC. In particular, it is important to exclude the diagnosis of spontaneous ileal (intestinal) perforation, an acute process that shares many features with NEC, but is thought to be a discrete entity. Other sources of sepsis, as descried in the Google Knol “Neonatal Sepsis,” can develop an ileus as one of their manifestations. It is important to exclude the diagnosis of intestinal malrotation with volvulus, an acute condition that develops in susceptible neonates that is characterized by a twisting of the small intestine around a narrow pedicle, and can cause abdominal distention and feeding intolerance similar to that of the infant with NEC. The diagnosis of malrotation with volvulus typically occurs in older i.e., term infants. Treatment of intestinal volvulus requires urgent surgery to untwist the intestine and/or to remove necrotic bowel. In the term infant, it is important to consider infectious etiologies, such as invasive viruses, salmonella, yersinia species, C. difficile enteritis, or invasive E. coli infections.
10. Does NEC ever occur in older infants?
As described above, NEC is typically a disease that affects preterm infants, leading to intestinal necrosis. However, in the mid- and late 1980s, several independent groups of surgeons recognized a tendency for early onset of NEC in term and near-term infants. In these patients, the pattern of disease was found to be different. Specifically, NEC in older infants typically is localized to the end of the small intestine and beginning of the colon, suggestive of an ischemic pathophysiology. There are four pertinent associations that are observed in term infants that develop NEC: congenital heart disease, in utero growth restriction, polycythemia, and perinatal hypoxic-ischemic events. As with NEC in preterm infants, NEC in older patients is also associated with formula consumption and is very rare in exclusively breast-fed infants. Patients with NEC at full term typically present with bloody stools, and may have a fairly rapid onset of symptoms, progressing quite quickly to the same septic picture observed in NEC in preterm infants. Thus, although it is true that NEC is typically a disease of premature babies, in the appropriate setting, NEC can develop at any age. This disease should always be considered in the differential diagnosis of the sick neonate, particularly when intestinal symptoms are present.
11. Spontaneous intestinal perforation versus NEC: A tale of two entities.
In addition to NEC, preterm infants with intestinal pathology may have a condition termed “spontaneous intestinal performed,” which is abbreviated as “SIP.”SIP is a distinct clinical entity from NEC, and is essentially a perforation in the terminal ileum. The histopathology of SIP is different from NEC. Specifically, the mucosa is intact and not necrotic, there is no sign of ischemia, and the submucosa is thinned at the site of perforation. As well, air in the wall of the intestine (pneumatosis intestinalis) that is characteristic of NEC is absent in SIP. Moreover, the demographics of NEC and SIP are slightly different, in that patients with SIP tend to be slightly more premature, smaller, and more likely to have been on inotropic support; however, both NEC and SIP occur with similar prevalence in low birth weight infants. The outcome of patients in the two groups is slightly different: because patients with SIP have isolated disease without necrosis, they tend to have a better outcome. In short, the diagnosis of SIP versus NEC has important prognostic significance. The treatment strategies, however, are essentially the same.
12. What is the prognosis for patients with NEC?
Unfortunately, the overall prognosis for patients with NEC has changed very little over the past 15 to 20 years. This may reflect the fact that we are seeing increasing numbers of vulnerable preterm patients, many of whom have concomitant premature lung disease. The overall mortality of NEC, which varies depending on the series examined and the nature and extent of disease, ranges between 10-40% 12, 27. As well, there are several long term problems that can develop in infants that survive NEC. In the first few months after the initial surgical procedure, infants are at risk of anastomotic stricture formation, leading to symptoms of partial or complete intestinal obstruction. In patients that underwent medical treatment for Stages I and II NEC (i.e., without undergoing a surgical resection), there is a significant incidence of stricture formation requiring surgery that presents several weeks after the initial presentation. There is also a significant incidence of long term developmental delay and growth delay in patients with NEC, which is greater than that predicted by the effects of prematurity alone28. A major problem that affects infants that have been treated surgically for NEC is short bowel syndrome (SBS) – a condition in which there is insufficient intestinal length to support the absorption of nutrients that are required for normal growth and development. Patients with SBS require long-term total parenteral nutrition – an intravenous feeding strategy that caries tremendous risks, including liver toxicity and multiple infectious episodes. Patients that develop SBS after treatment for NEC often require intestinal and liver transplantation for survival, due to the high frequency of liver failure in these patients. As can be seen, patients with a diagnosis of NEC may be faced with longer term problems beyond the initial newborn period. For this reason, it is important that patients with NEC are part of a multidisciplinary team focused on all aspects of the growth and development of these fragile patients.
13. Novel approaches to the prevention of NEC – the role of probiotics.
Recently, there has been significant increase in the protective role of antibiotic preparations in the prevention of NEC. Specifically, two randomized trials have shown a beneficial effect of probiotics in the prevention of NEC. Bin-Nun et al, in a study from Israel, showed that the provision of Bifidobacteria infantis, Streptococcus thermophilus, and Bifidobacteria bifidus led to an incidence of NEC of 4% versus 16% in untreated patients29. Similarly, Lin and colleagues showed that oral administration of Lactobacillus acidophilus and Bifidobacterium infantis twice daily until discharge led to a reduction in the incidence of NEC from 5% to 1% in very low birth weight infants 30. A recent large meta-analysis suggested that there may be some benefit to the role of probiotics in the prevention of NEC, although additional study is required31.
14. Summary and conclusions:
NEC is a common and devastating intestinal inflammatory disorder that affects preterm (and occasionally term) infants, leading to intestinal destruction and systemic sepsis. Although relatively responsive to treatment in early stages, many patients progress to severe NEC, in which the rates of mortality and long term morbidity are high. Treatment of NEC requires multidisciplinary care, involving a combination of antibiotics and surgical interventions, which may include abdominal drainage and/or surgical resection of involved intestine. The future of research in NEC holds great promise, as we seek to gain important insights into the nature of the newborn intestinal barrier, and the interaction between the premature immune system and the organisms that colonize the preterm intestinal tract14. It is our hope that by focusing time, energy, and effort on understanding the mechanisms that lead to the development of NEC, novel therapeutic approaches will be developed, leading to improved outcomes for the children – and the families – that are facing this most devastating of diseases.
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