Intestinal failure associated cholestasis in surgical necrotizing enterocolitis and spontaneous intestinal perforation.

BACKGROUND: Surgery for necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) is often complicated by intestinal failure (IF) and intestinal failure associated cholestasis (IFAC). OBJECTIVE: Assessment of incidence, predictors, and mortality associated with IFAC in surgically treated NEC and SIP. METHODS: A retrospective observational study based on hospital records during 1986-2014 in the two largest Finnish neonatal intensive care units was performed. IFAC was defined as conjugated bilirubin >34 µmol/l (2.0 mg/dl) for ≥ two postoperative weeks while receiving parenteral nutrition (PN). RESULTS: In total 225 patients underwent surgery for NEC (n = 142; 63%) or SIP (n = 83; 37%). Included were 57 survivors with ≥two weeks PN. Sixty-five (42%) patients developed IFAC. Two-year survival with IFAC was 80% and without IFAC 89% (p = 0.13). Of the 65 patients with IFAC, all eight with unresolved IFAC died in comparison to six of 57 (11%) whose IFAC resolved (p < 0.0001), while IFAC resolved in all survivors. Survival among patients with resolved IFAC was 89% and with unresolved IFAC (n = 8) 0%, (p < 0.0001). IFAC lasted for median 83 (IQR 45-120) days and correlated with the duration of PN (R2 = 0.16, p = 0.03), delay of starting enteral feeds (R2 = 0.12, p = 0.05) and PN lipid emulsion (RR = 1.0 (95% CI = 1.0-1.1) (p = 0.02). In multivariate logistic regression analysis, IFAC development associated with septicemias and reoperations. CONCLUSIONS: 42% of prematures who underwent surgery for NEC or SIP developed IFAC. Reoperations and septicemias increased the risk of IFAC. None of the patients with unresolved IFAC survived, but IFAC did not increase overall mortality. TYPE OF STUDY: Retrospective prognosis study. LEVEL OF EVIDENCE: Level II.

Outcomes of surgery for necrotizing enterocolitis and spontaneous intestinal perforation in Finland during 1986-2014.

BACKGROUND: Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are the most common abdominal surgical conditions in preemies. Associated mortality remains high and long periods of parenteral nutrition (PN) may be required. We assessed the developments in the outcomes of surgically treated NEC and SIP in the two largest Finnish neonatal intensive care units (NICU). METHODS: Retrospective observational study based on hospital records during 1986-2014. Main outcome measures were three-month survival during 1986-2000 compared with 2001-2014 and predictors of mortality. RESULTS: Included were 225 patients (NICU A 131 and NICU B 94) with NEC in 142 (63%) and SIP 83 (37%). The median birth weight (BW) (870 vs 900 g) and gestation age (GA) (27 vs 27 weeks, p = 0.96) were similar in NEC and SIP. Small intestine was affected in 85% of NEC and 76% of SIP patients (p = 0.12). In 5% of patients NEC was panintestinal. Median small intestinal loss was 25% in NEC and 4.0% in SIP (p < 0.001). Ileocecal valve was resected in 29% of NEC and 14% of SIP patients (p = 0.01). Enterostomy was performed in 78% of patients and primary anastomosis in 18%; 4% died of extensive NEC without definitive surgery. Overall survival was 74% (NEC 73%, SIP 77%, p = 0.48; NICU A 82%, NICU B 65%, p = 0.003). From 1986-2000 to 2001-2014 overall survival increased from 69 to 81% (p = 0.04). Treating NICU was the strongest predictor of survival, RR = 2.8 (95% CI = 1.4-5.1), p = 0.003. CONCLUSIONS: Overall survival improved significantly from the early (1986-2000) to the late (2001-2014) study period. Strongest predictor of mortality was the treating neonatal intensive care unit. LEVEL OF EVIDENCE: III.

Matrilysins-1 and -2 (MMP-7 and -26) and metalloelastase (MMP-12), unlike MMP-19, are up-regulated in necrotizing enterocolitis.

OBJECTIVES: Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of premature infants characterized histologically by extensive tissue injury and inflammation. Matrix metalloproteinases (MMP) are involved in tissue remodeling and cell migration, both being important aspects of inflammatory disease. The aim of this study was to investigate whether MMPs play a role in the pathogenesis of NEC. METHODS: Expression of MMP-1, -7, -9, -10, -12, -19 and -26 was studied using in situ hybridization/immunohistochemistry in samples intestinal tissue removed from 15 patients with NEC; in 7 of them control samples were obtained at closure of stomas. Six intestinal samples from patients with intestinal atresia and four samples of necrosis were also included in the material examined. Laminin-5 was immunostained to find migrating enterocytes and cytokeratin to delineate mucosal epithelium. RESULTS: MMP-7 protein was upregulated in the epithelium of 12/18 NEC samples. MMP-26 was induced in stromal cells of 12/17 NEC specimens. Stromal expression was found for MMP-1 and -12 mRNAs in 7/18 samples. MMP-1 was also detected in the epithelium of regenerating areas. Both NEC and stoma samples expressed MMP-9 in inflammatory cells. Epithelial MMP-19 was downregulated in NEC. CONCLUSIONS: Our results suggest that several MMPs may be major factors in tissue destruction and remodeling in NEC. Targeted inhibition of matrilysins, using synthetic MMP inhibitors or blockers of their signal transduction pathways, may represent a novel therapeutic option for the treatment of intestinal inflammation associated with NEC.