Laboratory findings however are mostly non-specific (Yeo, 2006, p. 47). Although “abnormalities on laboratory evaluation may include metabolic acidosis, thrombocytopenia, leukopenia, leukocytosis with an increase in the proportion of immature white blood cells, glucose instability, hyponatremia, coagulation abnormalities (including disseminated intravascular coagulation) and increased C-reactive protein level” (Thompson & Bizarro, 2008, p. 1230-1231). “Gasless abdomen, bowel loop dilatation, or pneumotosis can be identified from the x-ray films.
Pneumotosis occurs because of the intramural hydrogen gas produced during bacterial fermentation of enteral feedings” (Yeo, 2006, p. 47). The diagnosis of NEC is usually made upon findings the presence of bloody gastric fluid or stool, abdominal distention, abnormal abdominal X-ray findings such as pneumatosis intestinalis or fixed dilated intestinal loops, and proven NEC by Bell’s staging (Kawase, Ishii, Arai and Huga, 2006, p. 600). See Table 1 for a list of signs and symptoms and Table 2 for the Bell’s staging and diagnosis (tables from Thompson and Bizzarro, 2008).
However, it must be noted that recently, spontaneous isolated gastrointestinal perforation (SIP) in VLBW infants has been reported as a distinct pathologic entity from NEC – which apparently share common risk factors such as prematurity, intestinal necrosis, and asphyxia. It was also found that indomethacin has been reported to be associated with both NEC and SIP and that antenatal indomethacin has been reported to increase the incidence of NEC. Postnatal indomethacin has been given significantly more in SIP cases, however (Kawase, Ishii, Arai and Uga, 2006, p. 599).
There are three commonly proposed mechanisms of pathogenesis by which NEC follows. These are a) hypoxic-ischemic injury, b) physiological immaturity of the gastrointestinal (GI) tract and c) alterations in normal GI microbiological flora and the role of enteral feedings (Thompson & Bizarro, 2008, p. 1230-1231). Although the exact etiology of NEC is not completely understood, it is known that a severe inflammatory process, possibly resulting from ischemia and acidosis, makes the intestinal tissue vulnerable to infection and leads to necrosis of the bowel (Carter, 2007, p. 377).
This aspect is usually the first of the three proposed mechanism and is viewed as a major contributing and potentially inciting factor. Apparently, any process that results in the hypoperfusion and subsequent hypoxic injury to the GI tract, including, but not limited to, the presence of a patent ductus, arteriosus, sepsis, polycythaemia, in utero cocaine exposure, peri- or postnatal asphyxia, respiratory distress syndrome, congenital heart disease, the presence of umbilical catheters and exchange transfusion, may predispose the neonate to develop NEC.
To further explain, in the event of hypoperfusion, the Herring-Breur or ‘diving reflex’ is initiated and blood is shunted away from ‘less important’ organs i. e. intestines, towards critical organs, such as the brain and heart. After the emergency period has elapsed, an event called reperfusion usually follows. This reperfusion can then possibly trigger a pro-inflammatory cascade that results in the damage of the mucosal barrier creating the potential for bacterial invasion and translocation and eventually NEC. (Thompson & Bizarro, 2008, p. 1229).
See Figure 1 for a conceptual framework proposed by K. E. Gregory (2008) pertaining to this particular pathogenesis theory. The second mechanism, on the other hand involves the physiological immaturity of the gastrointestinal (GI) tract. According to this proposed mechanism of pathogenesis: three major altered components of the intestinal barrier of preterm neonates contribute to the onset of NEC: (i) disruption of the integrity of epithelial tight junctions; (ii) impaired peristalsis; and (iii) deficiencies in components of the mucus coat.
(Thompson & Bizarro, 2008, p. 1229) Additionally, these three components when altered lead to increased presence of platelet activating factor (PAF), a potent inflammatory and vasoconstrictive mediator, and a decreased ability to neutralize PAF via its acetylhydrolase degrading enzyme, which become additional factors that predispose preterm neonates to NEC. Furthermore, nitric oxide, a vasodilator and free radical molecule, has also been implicated in NEC.
Its upregulation causes damage to the intestinal epithelium by direct membrane peroxidation and induction of intestinal cell apoptosis (Thompson & Bizarro, 2008, p. 1229). The third mechanism, alterations in normal GI microbiological flora and the role of enteral feedings, is a well documented and literature-supported pathogenesis mechanism. Basically, the idea is that “approximately 90% of newborns who develop NEC do so after initiation of enteral feedings” (Yeo, 2006, p. 47).
Apparently, the initiation of enteral feedings allow for bacterial proliferation, consequently allowing the damaged mucosa to be invaded by gas-producing bacteria. The process may eventually lead to tissue necrosis, which can cause perforation of the bowel or sepsis (Carter and Holditch-Davis, 2008, p. 286). As, K. E. Gregory (2008) explains: Although NEC has been diagnosed in infants who have never been fed, 90%-95% of cases occur in infants with a history of recent feeding volume advancement or re-initiation of enteral feedings.
The introduction of enteral substrate presumably causes a disruption of mucosal integrity, blood flow, and motility, playing a key role in the pathogenesis of NEC. (p. 261). As a result, eventually enteric bacteria may ferment in the ‘provided’ substrate, producing intraluminal gas which characterizes pneumatosis intestinalis, a key diagnostic radiological feature of NEC. These gases cause distension and increased intraluminal pressure, which play a role in the decrease of mucosal blood flow (p. 261). Furthermore, abnormal colonization of the intestinal tract contribute to the onset of NEC.
Preterm neonates, given their high risk of infection, are frequently exposed to broad-spectrum antibacterials, which may alter the normal flora of their GI tract (Thompson & Bizarro, 2008, p. 1229). In fact, species of Staphylococcus, Enterobacter, Enterococcus and Clostridia are the predominant fecal bacterial species in premature neonates undergoing intensive care. Species of Escherichia and other bacterial, viral and fungal pathogens, including rotavirus and species of Candida, have been implicated in the etiology of NEC.
Bacteria, both commensal and pathogenic, use carbohydrates from enteral feedings as a substrate to grow and proliferate. Large volumes of substrate in a premature GI tract with decreased motility and digestive capabilities, and increased pathogenic bacteria, may result in stasis and proliferation of pathogenic bacteria. Proliferation may then result in invasion and bacterial translocation into the bowel wall, with subsequent production of inflammatory cytokines and endotoxins, which may result in mucosal and/or transmural necrosis (Thompson & Bizarro, 2008, p. 1230).
Adverse outcomes associated with NEC involve long-term health consequences that include significant growth and development delays, bowel stricture, fistula, abscess, recurrent NEC, short-gut syndrome, malabsorption, total parenteral nutrition-related complications, and neurodevelopmental delays that may be associated with complications from circulatory collapse pre- or postoperatively (Carter, 2007, p. 377; Gregory, 2008, p. 260).
Not to mention, NEC is a leading cause of death in preterms with a predilection towards higher prematurity and disease stage. Prognosis usually include that 25-33% of NEC infants will die. It is also the second most common cause of significant morbidity primarily involving short- and long-term GI problems. Furthermore, NEC also causes problems related to long-term us of TPN such as catheter-related blood stream infections, cholestasis and liver failure. Stricture formation from damaged intestinal mucosa may occur in up to 20% of all patients.
Additionally, NEC is associated with neurological morbity such as “neurodevelopmental impairment [that is] seen in 45% of neonates with NEC compared with 35% (odds ratio [OR] 1. 60; 95% CI 1. 30, 2. 00) of those with similar gestational age and birthweight without NEC. 20% developed cerebral palsy, 3% visual/hearing impairment, 36% cognitive impairment, 35% developed psychomotor impairment. Impairment were higher in neonates with more advanced stages of disease” (Thompson & Bizarro, 2008, p. 1231-1232).