**7.1 Differentiating medical and surgical NEC: use of biomarkers**

Pneumoperitoneum is not a very reliable clinical feature for surgical NEC and is observed in less than half of all infants with intestinal perforation or necrosis [15, 39]. Clinical deterioration despite maximal medical therapy is considered a relative indication for surgical intervention. Research has been done to identify a dependable predictor for intestinal necrosis. The most commonly used biochemical markers for bowel necrosis among pediatric surgeons are platelet count (99%), C-reactive protein (CRP) concentration (90%), white blood cell count (83%), lactate levels (43%), fecal calprotectin 10%, and interleukin (IL)-6 or interleukin-8 10% [40]. Fecal calprotectin is a marker of intestinal inflammation and can differentiate between local Bell stage II and systemic Bell III NEC with 76% sensitivity and 92% specificity [41]. Fecal levels of another protein, S100A12, are noted to be higher in infants with suspected NEC who subsequently develop bowel perforation. Unremitting and relentlessly high CRP levels despite treatment may indicate advanced stage of NEC and bowel necrosis. IL-8 levels have been shown to be significantly elevated in patients developing surgical NEC compared to medically managed NEC [42]. The levels can also discriminate NEC totalis from focal and multifocal diseases and predict 60-day mortality [43]. Maximum concentration of CRP and duration of CRP elevation are increased in infants who developed intestinal strictures following NEC, while the negative predictive value of CRP levels <10 mg/dL for stricture development is 100% [44]. Intestinal fatty acid-binding protein (I-FABP), a marker of intestinal injury and progression to severe NEC, is located in mature enterocytes of small intestinal villi and is released into the blood stream after cell disruption and subsequently excreted into the urine. At onset of symptoms, I-FABP concentrations have been shown to be significantly higher in infants who later developed surgical NEC [45]. Other biomarkers being investigated for surgical NEC are serum amyloid A protein, liver fatty acid-binding protein, urine peptides, and heart rate characteristic index.
