Neonatal gut barrier and multiple organ failure: role of endotoxin and proinflammatory cytokines in sepsis and necrotizing enterocolitis

Abstract

Background/Purpose Failure of the gut barrier and endotoxemia have been implicated in sepsis and multiple organ failure (MOF) syndromes in adults. The contributions of endotoxin (ETX) and proinflammatory cytokines (CKs) to the pathophysiology of disease and the outcomes of infants in the neonatal intensive care unit (NICU) are not clear. We measured ETX and CK concentrations in infants who presented with clinical signs of sepsis and/or necrotizing enterocolitis (NEC) to study their impact on MOF and outcomes. Methods Blood samples from infants with signs of NEC and/or sepsis were collected for culture and determination of complete blood cell counts and concentrations of CKs (interleukin [IL]-1 β, tumor necrosis factor [TNF] α, and IL-6) and ETX at the onset of illness. Infants with signs of sepsis but without those of NEC were classified by blood culture results into a confirmed sepsis group (ie, positive culture) or a control group (ie, negative culture). Endotoxin concentrations were determined by chromogenic Limulus amebocyte lysate assay, and CK levels were quantitated by enzyme-linked immunoassay. Data are expressed as mean ± SD and as odds ratios (ORs) with 95% confidence intervals (CIs). P values lower than .05 were considered to be significant. Results There was no demographic or clinical difference among the NEC (n = 27), sepsis (n = 44), and control (n = 56) groups, except that fewer ( P = .02) infants in the NEC group (11%) had received maternal milk feedings as compared with infants in the sepsis group (23%) and those in the control group (39%). Endotoxin concentrations were higher ( P < .0001) in the NEC group (3.30 ± 2.11) as compared with the sepsis group (0.67 ± .86) and the control group (0.09 ± 0.24). Generalized linear regression analysis using formula feeding, mechanical ventilation, and Gram-negative bacteremia as covariates demonstrated that NEC increased ETX concentrations independently ( r = .80; P < .0001). Endotoxemia correlated with higher concentrations of all 3 CKs ( P < .0001). There was an inverse association between ETX and both platelet count ( r = −0.30; P = .0003) and absolute neutrophil count ( r = −0.29; P = .0009). Infants who died of MOF had higher concentrations of ETX (2.83 ± 3.04 vs 0.67 ± 1.04 EU/mL; P < .0001), IL-1β (509 ± 493 vs 106 ± 223 pg/mL; P < .0001), IL-6 (416 ± 308 vs 99 ± 165 pg/mL; P < .0001), and TNF- α (503 ± 449 vs 126 ± 237 pg/mL; P < .0001) as compared with those without MOF. Eighty-six percent of the infants with MOF died. Multivariate logistic regression analysis demonstrated that higher ETX concentrations (OR = 2.47; 95% CI = 1.39-4.40; P = .002) and lower gestational age (OR = 1.41; 95% CI = 1.12-1.77; P = .003) predicted mortality. Conclusions Neonatal endotoxemia and release of proinflammatory CKs are important contributors to MOF and mortality in the NICU. Endotoxemia was most severe at the onset of illness among the infants with NEC, suggesting that gut barrier failure plays an important role in adverse outcomes in the NICU.