ObjectiveTo determine whether gut-derived factors leading to organ injury and increased endothelial cell permeability would be present in the mesenteric lymph at higher levels than in the portal blood of rats subjected to hemorrhagic shock. This hypothesis was tested by examining the effect of portal blood plasma and mesenteric lymph on endothelial cell monolayers and the interruption of mesenteric lymph flow on shock-induced lung injury. Summary Background DataThe absence of detectable bacteremia or endotoxemia in the portal blood of trauma victims casts doubt on the role of the gut in the generation of multiple organ failure. Nevertheless, previous experimental work has clearly documented the connection between shock and gut injury as well as the concept of gut-induced sepsis and distant organ failure. One explanation for this apparent paradox would be that gut-derived inflammatory factors are reaching the lung and systemic circulation via the gut lymphatics rather than the portal circulation. MethodsHuman umbilical vein endothelial cell monolayers, grown in two-compartment systems, were exposed to media, shamshock, or postshock portal blood plasma or lymph, and permeability to rhodamine (1 OK) was measured. Sprague-Dawley rats were subjected to 90 minutes of sham or actual shock and shock plus lymphatic division (before and after shock). Lung permeability, pulmonary myeloperoxidase levels, alveolar apoptosis, and bronchoalveolar fluid protein content were used to quantitate lung injury. ResultsPostshock lymph increased endothelial cell monolayer permeability but not postshock plasma, sham-shock lymph/plasma, or medium. Lymphatic division before hemorrhagic shock prevented shock-induced increases in lung permeability to Evans blue dye and alveolar apoptosis and reduced pulmonary MPO levels. In contrast, division of the mesenteric lymphatics at the end of the shock period but before reperfusion ameliorated but failed to prevent increased lung permeability, alveolar apoptosis, and MPO accumulation. ConclusionsGut barrier failure after hemorrhagic shock may be involved in the pathogenesis of shock-induced distant organ injury via gut-derived factors carried in the mesenteric lymph rather than the portal circulation.Gut barrier failure, with the ensuing translocation of bacteria and endotoxin from the gut, has been proposed as a major contributor to the development of systemic infec- April 23, 1998. 518 tion and multiple organ failure (MOF) after shock.' Evidence of the association between gut injury and the subsequent development of a septic state and distant organ failure2-4 continues to increase. There are abundant clinical and experimental data that trauma and hemorrhage are associated with elevated systemic cytokine levels.7 In fact, MOF, including acute lung injury, after hemorrhagic shock appears to result from an overwhelming systemic inflammatory response driven by the release, activation, and interaction of endogenous cytokines.8'9 Thus, gut-derived cy-

Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal emergency encountered in the neonatal intensive care unit. Despite advances in neonatal care, NEC remains a leading cause of morbidity and mortality among premature infants. Epidemiologic studies have identified multiple factors that increase an infant's risk for the development of NEC, although premature birth, bacterial colonization, and enteral feeding are thought to play central roles in disease pathogenesis. Appreciating factors that underlie the susceptibility of prematurely born infants to NEC is important for the development of new strategies aimed at the prevention and treatment of disease. In this review, we discuss defense mechanisms in the intestine and discuss how these systems may be insufficient in the prematurely born infant and thereby further contribute to initiation of NEC. In addition, based on a review of the literature, we suggest that, although numerous bacterial and viral pathogens have been associated with NEC, no individual organism is known to be responsible for disease. Finally, we comment on the possible role for probiotics in promoting maturation of intestinal defense mechanisms thereby attenuating or preventing the sequence of events that lead to NEC. (Pediatr Res 63: 117-123, 2008)

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The purpose of our study was to describe children with life-threatening bleeding. DESIGN:We conducted a prospective observational study of children with life-threatening bleeding events. SETTING: Twenty-four childrens hospitals in the United States, Canada, and Italy participated. SUBJECTS:Children 0-17 years old who received greater than 40 mL/kg total blood products over 6 hours or were transfused under massive transfusion protocol were included. INTERVENTIONS:Children were compared according bleeding etiology: trauma, operative, or medical. MEASUREMENTS AND MAIN RESULTS:Patient characteristics, therapies administered, and clinical outcomes were analyzed. Among 449 enrolled children, 55.0% were male, and the median age was 7.3 years. Bleeding etiology was 46.1% trauma, 34.1% operative, and 19.8% medical. Prior to the life-threatening bleeding event, most had age-adjusted hypotension (61.2%), and 25% were hypothermic. Children with medical bleeding had higher median Pediatric Risk of Mortality scores (18) compared with children with trauma (11) and operative bleeding (12). Median Glasgow Coma Scale scores were lower for children with trauma (3) compared with operative (14) or medical bleeding (10.5). Median time from bleeding onset to first transfusion was 8 minutes for RBCs, 34 minutes for plasma, and 42 minutes for platelets. Postevent acute respiratory distress syndrome (20.3%) and acute kidney injury (18.5%) were common. Twenty-eight-day mortality was 37.5% and higher among children with medical bleeding (65.2%) compared with trauma (36.1%) and operative (23.8%). There were 82 hemorrhage deaths; 65.8% occurred by 6 hours and 86.5% by 24 hours. CONCLUSIONS: Patient characteristics and outcomes among children with life-threatening bleeding varied by cause of bleeding. Mortality was high, and death from hemorrhage in this population occurred rapidly.

SUMMARY Necrotizing enterocolitis (NEC) is an inflammatory intestinal disorder that affects 2–5% of all premature infants. Enterobacter sakazakii (ES), a common contaminant in milk-based powdered infant formula, is implicated as a causative agent of sepsis, meningitis, and NEC in newborn infants with high mortality rates. However, the role of ES in the pathogenesis of NEC is not known to date. Here, we demonstrate for the first time that ES is able to induce clinical and histological NEC in newborn rats. ES was found to bind to enterocytes in rat pups at the tips of villi and to intestinal epithelial cells, IEC-6, in culture with no significant invasion. Exposure to ES induced apoptosis and increased the production of interleukin-6 in IEC-6 cells and in the animal model. These data suggest that ES could be a potential pathogen that induces NEC, and triggers intestinal disease by modulating enterocyte intracellular signaling pathways.

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CSI in patients younger than 3 years is uncommon. Four simple clinical predictors can be used in conjunction to the physical examination to substantially reduce the use of radiographic imaging in this patient population.