Annabel E. Barber

Bacterial translocation and intestinal atrophy after thermal injury and burn wound sepsis.

Bacterial translocation (BT) occurs after thermal injury in rodents in association with intestinal barrier loss. Infection complicating thermal injury may also affect the intestine producing bowel atrophy. To study these relationships, Wistar rats received either 30% scald followed by wound inoculation with Pseudomonas; 30% scald with pair feeding to infected animals; or sham injury as controls. On days 1, 4, and 7 after injury animals were killed with examination of the bowel and culture of the mesenteric lymph nodes (MLN), livers, spleens, and blood. All burned animals demonstrated BT to the MLN on day 1 after injury, but only burn-infected animals had continued BT on days 4 and 7, with progression of BT to the abdominal organs and blood. Burn injury and infection also resulted in significant atrophy of small bowel mucosa temporally associated with continued BT. Thus injury complicated by infection results in prolonged and enhanced bacterial translocation, perhaps due to failure to maintain the mucosal barrier.

Glutamine or fiber supplementation of a defined formula diet: Impact on bacterial translocation, tissue composition, and response to endotoxin

Despite provision of adequate calories, defined formula diets in rats lead to bacterial translocation (BT), fatty infiltration of the liver, and an increased susceptibility to endotoxin. These deleterious effects may be due in part to a loss of intestinal barrier integrity resulting from bowel atrophy. Defined formula diets lack both glutamine and fiber, substances which may help maintain intestinal mass. To determine whether supplementation of defined formula diets with either glutamine or fiber might prevent bowel atrophy and, thus, BT, hepatic steatosis, and the altered response to endotoxin, Wistar rats were fed (1) defined formula diet ad libitum (DFD), (2) (DFD + 2% (w/v) glutamine, (GLUT), or (3) DFD + 2% (w/v) psyllium (FIBER). Rats given standard food isocalorically pair-fed to DFD were used as controls. Nutritional status was assessed by daily weight gain, as well as the ability to maintain serum albumin, hematocrit and white blood counts. After 2 weeks of these feeding regimens, animals were sacrificed, and organ weights and composition were determined, with rates of bacterial translocation determined by mesenteric lymph node, abdominal viscera, and cecal cultures. Additional animals receiving the same experimental diets were subsequently challenged with endotoxin and observed for mortality with rates of post-endotoxin BT and the responses of acute phase proteins and cytokines measured. All dietary regimens resulted in equivalent weight gain and other nutritional parameters. Both glutamine and fiber supplementation maintained small bowel mass, but only GLUT preserved normal jejunal mucosal architecture. Neither fiber nor glutamine supplementation prevented cecal bacterial overgrowth or BT, resulting from the DFD.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of hypercortisolemia on soluble tumor necrosis factor receptor II and interleukin-1 receptor antagonist responses to endotoxin in human beings

BACKGROUND We have previously reported that the antecedent administration of glucocorticoids altered both the hormonal and proinflammatory cytokine responses to lipopolysaccharide (LPS) when administered to human volunteers. In that study, subjects with vastly exaggerated levels of tumor necrosis factor (TNF) and interleukin (IL)-6 12 and 144 hours after cortisol infusion exhibited hemodynamic and hormonal responses no different from those of untreated subjects after endotoxin. The current study examined levels of the antiinflammatory cytokines interleukin-1 receptor antagonist (IL-1ra) and soluble receptors to tumor necrosis factor (sTNF-R) in the same setting of the previous report. METHODS Hydrocortisone succinate was infused into healthy volunteers. LPS was then injected immediately or was delayed by 6, 12, or 144 hours (C, C-6, C-12, and C-144, respectively). Subjects receiving LPS alone served as controls. Plasma was analyzed to determine levels of TNF, sTNF-R and IL-1ra by enzyme-linked immunosorbent assay before administration of LPS and at 30-minute intervals after administration of LPS for 6 hours. RESULTS Levels of sTNF-R increased after LPS administration in all groups (p < 0.05 versus baseline) with a significantly higher level recorded in the subjects having received hydrocortisone 144 hours before (C-144, p < 0.05 versus all other groups). TNF levels remained undetectable in association with immediate infusion of LPS (C) and the relatively short delay group (C6). This cytokine peaked 90 minutes after LPS in all other groups, with a significantly higher peak in the C-144 subjects when compared with controls. IL-1ra levels rose in all groups but to a lesser extent in the C group (p < 0.05). CONCLUSIONS These data confirm that glucocorticoids influence the production of both sTNF-R and IL-1ra. The potential for an exaggerated response of sTNF-R exists for an extended period of time after exposure to glucocorticoids.

Applying Ockham's Razor to Pancreatitis Prognostication: A Four-Variable Predictive Model

Objective:We sought to develop a simple yet accurate prognostic scoring system to determine the severity of acute pancreatitis at admission. Summary Background Data:Because acute pancreatitis has a variable and frequently unpredictable course, identifying individuals at greatest risk for significant, life-threatening complications and stratifying their care appropriately remain a concern. Previous prognostic scoring systems predict severity reasonably well but are limited by time constraints, are unwieldy to use, or both. Methods:Data from the international phase III trial of the platelet-activating factor receptor-antagonist Lexipafant were used to develop a 4-variable prognostic model. We then compared the models ability to predict the severity of acute pancreatitis with the Ranson, Glasgow, and APACHE II systems. Results:The model (BALI), which included BUN ≥25 mg/dL, Age ≥65 years, LDH ≥300 IU/L, and IL-6 ≥300 pg/mL, measured at admission, was similar to the Ranson, Glasgow, and APACHE II systems in its ability to identify increased mortality from acute pancreatitis. The receiver operating characteristic curve area for the BALI model was ≥0.82 ± 0.03 (mean ± SD) versus 0.75 ± 0.04 (Ranson), 0.80 ± 0.03 (Glasgow), and 0.79 ± 0.03 (APACHE II). Furthermore, at a prevalence of 15%, the positive and negative predictive values for increased mortality were similar for all systems. Conclusion:The prognostic ability of the BALI 4-variable model was similar to the Ranson, Glasgow, and APACHE II systems but is unique in its simplicity and ability to accurately predict disease severity when used at admission or anytime during the first 48 hours of hospitalization.

Differential pathophysiology of bacterial translocation after thermal injury and sepsis

Bacterial translocation (BT) occurs transiently after thermal injury and may result from an ischemic intestinal insult. To evaluate continued intestinal ischemia in the ongoing BT associated with sepsis after injury, rats were randomized to (1) 30% burn injury with Pseudomonas wound infection (BI), (2) BI + fluid resuscitation (BI + Fluid), (3) BI after allopurinol pretreatment to inhibit xanthine oxidase (BI + Allo), or (4) BI after azapropazone pretreatment to inhibit neutrophil degranulation (BI + Aza). On postburn days (PBD) 1, 4, and 7, animals were studied for evidence of BT and intestinal lipid peroxidation. BI + Fluid, BI + Allo, and BI + Aza significantly (p less than 0.05) reduced rates of BT and ileal lipid peroxidation acutely after thermal injury (PBD 1) compared to BI. All four groups had equally high rates of BT associated with the onset of sepsis (PBDs 4 and 7), without evidence of further intestinal lipid peroxidation. These data indicate that the chronic gut barrier failure associated with sepsis after injury occurs independently of continued intestinal ischemia.

Antibiotic prophylaxis diminishes bacterial translocation but not mortality in experimental burn wound sepsis

Pseudomonas (PSA) burn wound sepsis results in prolonged bacterial translocation (BT) of enteric organisms such as E. coli to the mesenteric lymph nodes (MLN) and organs in rats. Intestinal decontamination with oral antibiotics may improve mortality after burn injury, perhaps due to decreased BT. To determine the effect of oral antibiotic prophylaxis effective against E. coli but not PSA on BT and subsequent mortality in a model of PSA burn wound sepsis, rats were given a 30% scald burn and wound inoculation with 10(8) PSA followed by randomization to either ampicillin (50 mg/kg/d) or saline gavage. Cultures of MLN, organs, blood, and cecal contents were obtained on days 1, 4, and 7 after injury, with additional animals observed for 14-day mortality. Although oral antibiotic prophylaxis resulted in increased cecal colony counts, the incidence of BT was unchanged. The number of organisms present in both the MLN and organs, however, was significantly reduced with prophylaxis, indicating cecal overgrowth by non-translocating bacteria. Reduction of the number of translocating organisms did not result in improved mean survival time after injury, suggesting that mortality from PSA burn wound sepsis occurs independently of bacterial translocation.

Effect of cyclosporine on adrenocortical response to injury and infection

The effects of cyclosporine administration on the adrenocortical response to the severe stress of burn wound sepsis were studied in Wistar rats. Animals were treated with cyclosporine (10 mg/kg/day) or saline by gavage for 10 days, then subjected to 30% scald burns with wound inoculation with Pseudomonas. Animals were sacrificed on Postburn Days (PBDs) 1, 4, and 7 for determination of serum corticosterone and ACTH levels and adrenal weights and histology. Adrenal glands from animals sacrificed on PBD 7 were also analyzed for DNA, RNA, and protein content. Cyclosporine treatment without injury had no significant effect on body weight gain, adrenal mass, or baseline ACTH or corticosterone levels. During sepsis, cyclosporine-treated animals demonstrated a significantly diminished adrenocortical response compared to those given only saline. Serum corticosterone levels in the cyclosporine group were 45, 53, and 62% lower on PBDs 1, 4, and 7, respectively, than in saline-treated controls (P < 0.01 on each day). ACTH levels were 43 and 36% lower in cyclosporine-treated animals on PBDs 4 and 7, respectively, compared to the saline-treated group (P < 0.05 on each day). Adrenal hyperplasia occurred in both groups by PBD 7, but increases in adrenal mass and in histologic changes associated with hyperplasia (lipid depletion, vascular dilation) were less pronounced in cyclosporine-treated animals compared to those receiving saline, while adrenal composition remained similar between the two groups. Thus, cyclosporine administration is associated with an attenuated adrenocortical response to the stress of sepsis due to diminished circulating levels of ACTH.