Wednesday, January 11, 2012

Necrotizing enterocolitis

Author :
David J. Hackam, MD, PhD
Attending Pediatric Surgeon, Children’s Hospital of Pittsburgh
Associate Professor of Surgery
University of Pittsburgh School of Medicine
Co-Director, Fetal Diagnosis and Treatment Center, Children’s Hospital of Pittsburgh

  • Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in neonates (newborn babies)
  • The pathological manifestations of NEC include patchy inflammation leading to full thickness necrosis and perforation of the intestine
  • Treatment of NEC involves cardiorespiratory support, broad spectrum antibiotics, and surgical resection of necrotic intestine
  • 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.

   Ask any practicing neonatologist or pediatric surgeon to describe the most vexing and frustrating problem that they face as they take care of newborn patients, and they are likely to give you the same answer – “necrotizing enterocolitis.” This is a disease that in many ways is a product of our success as caregivers to those born too soon, a disease that attacks predominantly (although by no means exclusively) preterm infants, a disease that strikes seemingly without warning, always without regard for the fragility of the tiny host. Necrotizing enterocolitis – or NEC as it is usually abbreviated – is a disease that attacks the intestines from within, and transforms them into a necrotic (dead tissue), septic stew that if untreated progresses to multi-system organ failure and death in over a third of patients. In certain cases, surgery may be indicated, in which the abdomen may be drained and/or the necrotic bowel may be removed, potentially leaving the tiny patient with inadequate intestine to support his or her nutritional needs. As for the families of children with NEC, they are hurt in two ways: first, through the pain and suffering of having a tiny child face such a devastating disease, and second, through the almost universal lack of even the remotest awareness as to what NEC actually is.
2. What is necrotizing enterocolitis?
   Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in preterm neonates, and will likely soon overtake respiratory disease as the leading case of death overall in these patients. NEC is diagnosed in between 0.9 to 2.4 per 1000 live births, and the increase in survival rates of premature infants have led to an overall increase in the incidence of this disease 1-4. NEC is both an acute and chronic disorder that is characterized initially by intestinal inflammation, yet may progress to intestinal necrosis, with perforation in more advanced cases. In the most severe form, NEC may lead to overwhelming multi-system organ failure and death from systemic sepsis. NEC may indeed be considered as a spectrum of diseases. At one end of the spectrum, patients with NEC may have relatively mild symptoms that are readily responsive to medical treatment. At the other end of the spectrum, patients may develop a fulminant course, which is characterized by near total destruction of the entire intestine. The recognition of the fact that patients with NEC exist along a wide spectrum of presentations facilitates a greater understanding of the mechanisms that lead to its development, as well as strategies that may be most appropriate to treat it.
3. Baby Jimmie – an infant with NEC.
NEC is a disease that initially affects the gastrointestinal system, then progresses to lead to the development of multi-system organ failure in certain cases. A baby with NEC is shown in Figure 1 – note his small size in comparison with the nurse’s hands, the numerous monitors and tubes to which he is attached, and the swollen distended abdomen. In order to more clearly illustrate the clinical presentation of NEC, consider the following description of baby Jimmie (NB: for those of you that don’t like unhappy endings, you may want to skip ahead. But that’s NEC.)
   After five years of trying, and having almost given up entirely on their chances, Rhonda and James were finally pregnant. Both in their early forties, they were wondering if being first time parents was such a good idea after all anyway. But they so desperately wanted a child that they didn’t dwell on anything but their immense desire to raise a family. The first trimester couldn’t go away fast enough, but Rhonda settled into the idea of being pregnant so that by the time the second trimester arrived, she started to plan for the future. And when she first felt tiny Jimmie (they had decided on that name before even knowing that they were having a boy) move, it was as if her whole life had been transformed. On her ultrasound at 24 weeks they actually came face to face (or face to ultrasound probe) with their tiny child, and started to bond with him in a way that only expectant parents can ever understand. And then, a month after her ultrasound, when Rhonda was just seven months pregnant, a bad thing happened. Rhonda went into labor. At first she didn’t believe it – she thought the fluid trickling down her inner leg must just be normal discharge; she hoped that the pain in her lower abdomen was indigestion.  But when the pain worsened and the fluid gushed, she knew that she was going to meet Jimmie face to face much sooner than anyone had predicted.
   Rhonda and James rushed to the hospital, where a fetal assessment indicated that their baby was sick, that his heart rate had become irregular, that he needed to be delivered. And so, barely an hour after the onset of labor, little Jimmie was born – a tiny child, precious and fragile and beautiful. Unable to breathe on his own, Jimmie was intubated and placed on a ventilator. For the first week of his life, Jimmie seemed to do pretty well, and the doctors stated that he would just need to feed and grow and would likely be fine. And so they started to feed him – dripping infant formula into a little tube that was passed into Jimmie’s nose. And while Jimmie seemed to like the formula, his body clearly did not. Two days after the feedings had started, Rhonda and James came to Jimmie’s bedside to see that his abdomen had become swollen, his previously warm skin was now cold and clammy, and he looked like he was dying. An x-ray revealed that his intestines were sick – a disease the doctors called necrotizing enterocolitis – a disease that Rhonda and James had never heard of.  Jimmie needed urgent surgery, where a portion of his intestines were removed, leaving him with two tiny pieces of separate intestine extruding through his skin – temporary stomas, as the doctors called them. Little Jimmie began to improve, and a few weeks later underwent another operation to reattach his intestine. He was now starting to tolerate feeds, and was starting to grow, to interact, to babble to laugh. But the effects of NEC never went away. Jimmie had insufficient bowel length to absorb his formula – a condition that the doctors called “short bowel syndrome.” Dependent upon being fed through a vein, little Jimmie began to get worse. He suffered infection after infection, then a slow, steady, downward spiral. At the age of six months of age, his little body unable to keep up with ever increasing infections, he died with his parents at his side.
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?
   NEC is typically diagnosed on the basis of a combination of clinical, radiographic, and laboratory features, and is observed along a spectrum of disease severity. In order to understand the modes of presentation of NEC, and for the purposes of the current discussion , several scoring systems for the diagnosis have been devised that grade disease severity based upon the presenting symptoms and evaluations. The most commonly used classification system for NEC was described by Bell and colleagues in 1978 and remains commonly used today. Specifically, Bell and colleagues characterized the severity of NEC as Stage I (mild), Stage II (moderate) and Stage III (severe, see Figure 2 and reference 6). In all cases, the diagnosis of NEC and the particular grade of NEC is established using a combination of clinical and radiographic findings. 
   In mild cases (Bell Stage I), infants demonstrate difficulty breathing (apnea, nasal flaring, retractions). There may be episodes of heart rate irregularities (bradycardia, tachycardia), as well as temperature instability and abdominal distention. Radiographic findings include intestinal ileus, which bear similarities to other infectious processes in preterm infants. In moderate cases (Bell Stage II), infants develop bloody stools, marked abdominal distention, bilious emesis, and poor systemic perfusion. Radiographic findings include gas in the wall of the intestine (called “pneumatosis intestinalis,” see Figure 3), and occasionally air in the biliary tree. These findings point to an evolving intra-abdominal septic process along with signs of systemic illness. In the most severe form of NEC (Bell Stage III), infants develop peritonitis with abdominal wall edema and crepitus, as well as systemic effects of hypotension, renal failure, and thrombocytopenia. Radiographic findings reveal pneumoperitoneum as shown in Figure 4, reflective of intestinal perforation. Patients with Bell Stage III typically progress to multi-system organ failure. Whereas survival in early stages is over 75%, half of patients with early NEC progress to the most severe form, in which survival with current treatment options is 10-25%.   
   Blood tests can be helpful in assessing the severity of NEC. A common finding is that of thrombocytopenia, which is reflective either of platelet consumption in small peripheral clots, or under-production by the bone marrow. It is not uncommon to observe a metabolic acidosis in advanced cases of NEC, reflective of tissue hypoperfusion and the generation of acidic byproducts from the necrotic intestine. Anemia and bandemia may be observed, as well as a leucopenia or leukocytosis. As a general rule, the diagnosis of NEC is established on the basis of clinical findings and x-ray findings. However the severity of NEC may be determined in part by the severity of the abnormalities on the blood work.

6. What are the pathological features of NEC?
   The cardinal pathological feature of NEC is patchy necrosis of the small intestine as well as the hepatic and splenic flexures of the colon (Figure 5A). At sites of maximal involvement, intestinal perforation is noted. Microscopic features include patchy ulceration of the mucosa and submucosa in association with full thickness necrosis, thrombosis of blood vessels, and the influx of inflammatory cells into the submucosa (Figure 5B). These dramatic pathological features provide insights into the mechanisms that lead to the development of NEC, and provide an explanation as to why infants with NEC can become so ill so quickly.
7. What causes NEC?

a. Disrupted intestinal-bacterial interactions in the pathogenesis of NEC.

   Although we have a pretty good handle on the risk factors that lead to the development of NEC, and we are fairly good at diagnosing NEC, we have a limited understanding regarding the specific mechanisms that cause this disease. Several theories have been proposed to explain the development of NEC, and each propose a central role for a stressed, premature intestine in association with bacteria. In order to more precisely understand the mechanisms that contribute to the pathogenesis of NEC, our laboratory has focused on understanding the potential clues that may be revealed by studying patients that have progressed from Bell stage I to Bell stage III disease. In general terms, the development of diffuse pneumatosis intestinalis – which is associated with the development of stage II NEC – is thought to be due to the presence of gas within the wall of the intestine from enteric bacteria 4, suggesting the causative role of bacteria in the pathogenesis of NEC. Furthermore, the presence of pneumoperitoneum – which demonstrates that the intestinal barrier has been markedly disrupted – often precedes the development of severe clinical manifestations of sepsis, indicating the importance of an intact barrier in the progression of disease. Finally, the progression of local intestinal injury to a diffuse multisystem process suggests the role for circulating proinflammatory cytokines in the pathogenesis 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

   There are two choices of operative interventions that are generally considered in patients with NEC. These procedures can be performed at the bedside in the NICU, therefore obviating the need to transfer a sick neonate to the operating room (Figure 7). Procedure choices include peritoneal drainage with irrigation of the peritoneal cavity, and laparotomy with removal of necrotic intestine and the creation of stomas (Figure 8). In patients with diffuse intestinal necrosis previous authors have recommended creating a proximal stoma to allow intestinal decompression, followed by relaparotomy as a means to limit the extent of intestinal resection that is performed. Patients treated with primary drainage may improve through the evacuation of enteric contents and occasionally the creation of a fistula. In certain cases however, patients may deteriorate after peritoneal drainage, necessitating laparotomy.
   The choice of whether to perform primary peritoneal drainage versus laparotomy as first line treatment has been a topic of much study and debate over the past twenty years 27. Ein and Morgan have demonstrated a clear benefit for peritoneal drainage in premature infants, where as Cheu et al have clearly shown a survival advantage for laparotomy. To resolve these apparently inconsistent results, a multi-center randomized control trial was performed in which 117 preterm infants (delivered before 34 weeks gestation) with birth weights less than 1500 g and perforated NEC at 15 pediatric centers were randomly assigned to undergo primary peritoneal drainage or laparotomy with bowel resection. Primary outcome was survival at 90 days, while secondary outcomes included dependence on parenteral nutrition 90 days postoperatively, and length of hospital stay. The authors concluded that the type of operation performed for perforated NEC does not influence survival, dependence on parenteral nutrition, or length of hospital stay in preterm infants 27. The particular choice of approach is based to some degree on the experience and preference at an individual center. In general, most pediatric surgeons will perform abdominal drainage in infants under 1000g, and will perform a laparotomy in patients larger than this.

9. If it’s not NEC, what else could it be?
   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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