**6. Clinical presentation**

NEC presents acutely with feeding intolerance, heme-positive stools, abdominal distension, gastric residuals, and vomiting in a previously stable and feeding preterm infant. Commonly associated nonspecific symptoms are temperature instability, apnea, bradycardia, oxygen desaturation, and lethargy. There may be abdominal wall erythema, abdominal tenderness, and decreased or absent bowel sounds (**Figure 3**). As the disease process advances, cardiorespiratory

**31**

**Figure 4.**

*Necrotizing Enterocolitis*

**Figure 3.**

*DOI: http://dx.doi.org/10.5772/intechopen.85784*

decompensation, septic shock, and multi-organ failure may supervene. The diagnosis is confirmed by the presence of pneumatosis intestinalis in abdominal X-ray which is pathognomonic of NEC (**Figure 4**). The course may be mild to moderate with recovery with antibiotics, GI rest, and correction of biochemical and hematological anomalies, or fulminant with early signs of severe systemic

*Sharma, MD, Professor of Pediatrics, University of Florida at Jacksonville, USA].*

*Abdominal distension, erythema and skin ulceration in a case of necrotizing enterocolitis. [Courtesy of Renu* 

*Extensive pneumatosis with branching linear lucencies in the liver, consistent with portal venous gas. [Courtesy* 

*of Dr. Renu Aggarwal, Attending Neonatologist, NYU Winthrop Hospital, Mineola, NY, USA].*

#### **Figure 3.**

*Pediatric Surgery, Flowcharts and Clinical Algorithms*

mation, and gut necrosis (**Figure 2**).

**5.2 Feeding and immature GI function**

**5.3 Role of cytokines and chemokines**

replicate them in animal models [32].

**6. Clinical presentation**

mucosa is highly immunoreactive, and fetal human enterocytes have been shown to evoke excessive immunological and inflammatory response compared to adults. An imbalance between epithelial cell injury and repair leads to a gut barrier failure and a consequent cycle of bacterial invasion, immune activation, uncontrolled inflam-

Premature GIT is relatively deficient in digestive functions and peristaltic motility in addition to immune responses [28]. Dysfunctional gastric emptying and increased gastric pH add to gut barrier disruption and epithelial permeability [4, 29–31]. Aggressive feeding with peristaltic dysmotility leads to stasis of intraluminal contents and intestinal dilatation, which may further impair epithelial barrier (EB). These, in concurrence with microbial dysbiosis, result in abnormal signal transduction across the EB with consequent inflammation, apoptosis, and necrosis. The balance between the pro-inflammatory and anti-inflammatory signaling is affected with an inappropriate response to pathogenic microorganisms.

NEC is associated with increased expression of inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1β, IL-6, IL-8/CXC-motif ligand 8 (CXCL8), IL 10 monocyte chemoattractant protein-1/CC-motif ligand (CCL)-2, macrophage inflammatory protein-1β/CCL3, and C-reactive protein in plasma and affected tissues [32]. These cytokines can disrupt the epithelial barrier and augment intestinal injury. Serum levels of cytokines/chemokines are elevated in NEC, and increased TLR4 and abnormal IkB/NFkB suggest excessive abnormal immunological response [33–35]. Lower blood TGF-β and interleukin (IL)-2 and higher IL-8 levels are found in ELBW infants with NEC. A developmental immaturity is noted in IkB expression, the molecule that inhibits cytokines activation via NFkB in NEC. Recently the role of toll-like receptor 4 (TLR4) signaling in the pathogenesis of NEC has been highlighted. Hypoxia, infection, and prematurity accentuate the expression of TLR4 in the intestinal mucosa. TLR4 is subsequently activated by enteric bacteria, triggering an inflammatory cascade which results in increased gut mucosal injury and reduced epithelial repair. Activation of cytoplasmic innate immune receptors, NOD2 and TLR9 leads to inhibition of TLR4, with restoration of the intestinal epithelial barrier and reduction in severity of NEC in experimental models. Other factors implicated in pathogenesis of NEC are platelet-activating factor, nitric oxide, reactive oxygen species, and transforming growth factors. However, despite success in animal model systems, no significant improvement in treatment and outcomes of NEC has been achieved due to an incomplete understanding of the developing immune system in premature infants and inability to

NEC presents acutely with feeding intolerance, heme-positive stools, abdominal distension, gastric residuals, and vomiting in a previously stable and feeding preterm infant. Commonly associated nonspecific symptoms are temperature instability, apnea, bradycardia, oxygen desaturation, and lethargy. There may be abdominal wall erythema, abdominal tenderness, and decreased or absent bowel sounds (**Figure 3**). As the disease process advances, cardiorespiratory

**30**

*Abdominal distension, erythema and skin ulceration in a case of necrotizing enterocolitis. [Courtesy of Renu Sharma, MD, Professor of Pediatrics, University of Florida at Jacksonville, USA].*

decompensation, septic shock, and multi-organ failure may supervene. The diagnosis is confirmed by the presence of pneumatosis intestinalis in abdominal X-ray which is pathognomonic of NEC (**Figure 4**). The course may be mild to moderate with recovery with antibiotics, GI rest, and correction of biochemical and hematological anomalies, or fulminant with early signs of severe systemic

#### **Figure 4.**

*Extensive pneumatosis with branching linear lucencies in the liver, consistent with portal venous gas. [Courtesy of Dr. Renu Aggarwal, Attending Neonatologist, NYU Winthrop Hospital, Mineola, NY, USA].*

#### *Pediatric Surgery, Flowcharts and Clinical Algorithms*


**Table 3.**

*Modified Bell's staging criteria for necrotizing enterocolitis in neonates [33].*

inflammatory response and poor response to correction of metabolic and hematological derangements, such as severe metabolic acidosis, hyponatremia, hyperglycemia, thrombocytopenia, DIC, anemia, and neutropenia, eventually progressing to death.

Age of onset varies in an inverse relationship with GA at birth, and the average post menstrual gestational age of NEC is estimated to be 31–32 weeks. In a cohort of preterm infants under 33 weeks gestational age, NEC presented at a mean of 7 days in more mature infants, while it was delayed to 32 days in lower birth weight and gestational age neonates [1]. The average age of onset has been reported to be 20.2 days for babies born at less than 30 weeks' estimated gestational age, 13.8 days for babies born at 31–33 weeks, and 5.4 days for babies born after 34 weeks of gestation. Term infants develop necrotizing enterocolitis much earlier, with the average age of onset within the first week or within the first 1–2 days of life [36].

To classify the severity of NEC based on clinical findings, a staging criterion was proposed by Bell in 1978 which was later modified (**Table 3**) [37]. In about one third of cases, NEC is suspected but not confirmed (stage I), and symptoms resolve gradually with treatment. In 25–40% of cases, the progression of NEC is fulminant with signs of peritonitis and sepsis and the rapid development of DIC and shock (stage III). About 30% of the cases may develop intestinal perforation, peritonitis, and other complications necessitating surgical intervention. Mean LOS is 62 days in surgical and 36 days in medical NEC cases [15]. Surgical NEC cases incur higher hospital costs.

## **7. Laboratory and radiological investigations**

In all cases of NEC, CBC with diff, blood culture, C-reactive protein, serum electrolytes, pH, lactate, acid-base indicators, arterial blood gases,

**33**

**Figure 5.**

*Necrotizing Enterocolitis*

*DOI: http://dx.doi.org/10.5772/intechopen.85784*

is excluded with a negative predictive value of 0.96 [38].

*Neonatologist, NYU Winthrop Hospital, Mineola, NY, USA].*

*On left: massive pneumoperitoneum with visualization of falciform ligament, massive lucency involving the entire abdomen, visualization of the liver margin. On right: left lateral decubitus radiograph demonstrating massive lucency with visualization of the liver margin and bowel. [Courtesy of Dr. Renu Aggarwal, Attending* 

and pertinent radiography should be done. The characteristic anomalies are metabolic or mixed acidosis, high C-reactive protein (CRP), hyponatremia, hyperglycemia, thrombocytopenia, neutropenia, or leukocytosis with high I/T ratio. CSF studies are suggested, and peritoneal fluid analysis for bacteria and fecal material should be done if paracentesis abdominis is performed for therapeutic or diagnostic purposes. Presentation of NEC is similar to, or may be associated with sepsis, and the differentiation is confirmed by the presence of pneumatosis intestinalis (PI) on radiography (**Figure 5**). Apart from PI other radiological features of NEC are ileus, bowel wall thickness, and bowel perforation with peritoneal air. Bowel wall thickening, with or without echogenicity, indicates increasing inflammation, swelling, and perfusion of the area. Bowel loops may be separated by the presence of peritoneal fluid and give an impression of thickening. Thin bowel wall with a central echogenic focus and a hypoechoic rim, called pseudo-kidney sign, if present, may indicate necrotic bowel and imminent perforation. Ultrasound detection of small air bubbles in the bowel wall as in pneumatosis intestinalis can be spatially differentiated from air bubbles in stool that can sometimes be misdiagnosed as pneumatosis on radiographs. Ultrasonography also can detect intermittent gas bubbles in the liver parenchyma and portal venous system that are not detected on radiography. Ultrasound is more sensitive in detecting peritoneal fluid collections. Doppler ultrasound is dynamic and permits real-time visualization of bowel wall thickness, peristalsis, and perfusion. It is more sensitive than abdominal radiography in detecting bowel necrosis [15]. Evidence of free peritoneal air and ascites indicate intestinal perforation. Contrast enemas are not recommended if NEC is suspected, as it may result in bowel perforation with extravasation of contrast material into the peritoneum. Near-infrared spectroscopy (NIRS) is a new, noninvasive method of estimating local tissue hemoglobin oxygen saturation by measuring the difference between oxyhemoglobin and deoxyhemoglobin and may have utility in diagnosing intestinal ischemia in NEC. Fortune et al. demonstrated cerebro-splanchnic oxygenation ratio < 0.75 to have a positive predictive value of 0.75 for intestinal ischemia, whereas, if above 0.75, intestinal ischemia
