B. J. Rowlands

The presence of tumour necrosis factor in CSF and plasma after severe head injury

In a cohort of victims of traumatic brain injury, 18 out of 50 patients had a plasma tumour necrosis factor (TNF) concentration above 2 pg/ml within 24 h of injury (mean 12.19, SD 45.96 pg/ml). Twenty-six had CSF samples available of which 17 demonstrated TNF concentrations above 1 pg/ml (mean 3.98, SD 3.61 pg/ml). We conclude that traumatized brain parenchyma is a significant source of TNF activity and implicate the cytokine in cellular metabolic derangements following head injury.

Changes in gastrointestinal morphology associated with obstructive jaundice.

Bacterial translocation has been consistently demonstrated in experimental models of obstructive jaundice. An important factor which promotes this phenomenon is physical injury of the intestinal mucosa. Some previous studies have presented suggestive evidence of this, following bile duct ligation. The aims of this study were to analyse objectively intestinal mucosal morphometric characteristics, to examine for evidence of bacterial translocation, and to assess enterocytes for ultrastructural abnormalities. Adult female Wistar rats were assigned to one of three groups: control (n=8), bile duct ligation (BDL; n=11), or sham operation (n=10). One week later, portal blood, mesenteric lymph nodes, liver, and spleen were harvested and cultured aerobically and anaerobically for evidence of bacterial translocation. Segments of jejunum, ileum, caecum, and large bowel were examined histologically, using light microscopy and morphometrically, using an image analysis system. Electron microscopy was performed on regions of the gastrointestinal tract where significant morphometric alterations had been identified. Significant bacterial translocation was identified following BDL (63.6% BDL vs. 0% sham vs. 0% control, p<0.01, Fishers exact test). There was a significant reduction in total mucosal thickness (standard error) [650u2009µm (23) BDL vs. 731u2009µm (27) sham vs. 744u2009µm (95) control] and villous height [451u2009µm (20) BDL vs. 515u2009µm (18) sham vs. 559u2009µm (79) control] in jaundiced animals, compared with sham‐operated and control animals (p<0.02, Mann–Whitney U‐test). Electron microscopy revealed oedematous change associated with mild inflammation, disruption of desmosomes, and the formation of lateral spaces between enterocytes. In addition, enterocytes showed vacuolation of their cytoplasm and mitochondrial swelling. Increased numbers of bacteria appeared to be attached to the mucosa. These data provide evidence of physical disruption of intestinal mucosa in jaundiced animals, most marked in the distal ileum. Significant bacterial translocation occurs following bile duct ligation and this supports the hypothesis of gut barrier dysfunction with obstructive jaundice. Copyright

Mortality following Lower Limb Ischemia-Reperfusion: A Systemic Inflammatory Response?

Abstract. Restoration of blood flow to an acutely ischemic lower limb may paradoxically result in systemic complications and unexpected mortality. It has been suggested that lower limb ischemia reperfusion alters gut permeability. In this study, using a rat model, we determined the effect of acute lower limb ischemia-reperfusion on mortality rate, bowel morphology, and circulating concentrations of endotoxin and the proinflammatory cytokine interleukin-6. Survival rate was compared in two groups of adult Wistar rats: (1) control group (n = 10); and (2) animals subjected to 3 hours of bilateral hind limb ischemia followed by reperfusion (n = 10). Both groups were observed under standard conditions for 4 days. In a second experiment three groups of animals were studied: (I) control (n = 12); (II) 3 hours of bilateral hind limb ischemia alone (n = 12); and (III) 3 hours of bilateral hind limb ischemia followed by 2 hours of reperfusion (n = 12). Animals subjected to bilateral hind limb ischemia followed by reperfusion had a significantly higher mortality rate (70%) than controls (0%) (p < 0.005). Morphometric assessment of the small bowel showed a significant decrease in mean mucosal thickness in the ischemia-reperfusion group compared with that in the group of controls and the ischemia-alone group (p < 0.05). Bilateral hind limb ischemia followed by reperfusion was associated with significantly increased plasma concentrations of endotoxin (p < 0.05) and interleukin-6 (p < 0.0001) compared with that of controls and ischemia alone. These results indicate that reperfusion of the acutely ischemic lower limb is accompanied by structural changes in the gut mucosa associated with increased systemic endotoxin concentrations and cytokine activation. Mortality following reperfusion of the acutely ischemic limb may be related to a systemic inflammatory response triggered by endotoxin of gut origin.

Early and Long-Term Results of Surgery for Severe Necrotising Pancreatitis

Background: Necrotising pancreatitis is a challenging problem for the surgeon, as it is associated with considerable morbidity and mortality. The indications, timing of surgical intervention and type of procedure continue to be debated in an effort to improve the outcome of this devastating disease process. Methods: A retrospective analysis of early and long-term results in a series of 44 consecutive patients (34 men, 10 women, median age 46.5, range 13–74 years) who underwent necrosectomy for severe necrotising pancreatitis. In 16 patients necrosectomy and primary abdominal closure with drains was performed, 14 patients had planned staged necrosectomy and delayed abdominal closure with drains, and in 14 patients necrosectomy with open laparostomy was undertaken. Results: There were 8 deaths (18%) and 14 cases (32%) of significant hospital morbidity (fistula 10, pseudocyst 2, renal failure 2). Variables which correlated with mortality were: high APACHE II score, acute renal failure requiring dialysis, and requirement for surgical intervention at an early stage (within the first two weeks). A total of 28 late complications occurred in 21 of the surviving patients (endocrine pancreatic insufficiency 10, exocrine pancreatic insufficiency 2, pseudocyst 2, chronic renal failure 2, incisional hernia 10, recurrent pancreatitis 1, and chronic pain 1). Conclusions: Low mortality can be achieved in patients with severe necrotizing pancreatitis with aggressive surgical intervention and careful perioperative management. Long-term morbidity remains high, and emphasises the need for prolonged follow-up.

Prophylactic antibiotics in trauma: the hazards of underdosing

Prophylactic antibiotic regimens in trauma patients may be significantly altered by large fluid shifts and hyperdynamic physiologic responses. We prospectively studied prophylactic amikacin and clindamycin in 150 abdominal trauma patients requiring laparotomy, analyzing the effects of duration of coverage, dosing interval, and dose. No difference in infection rates was noted when 72-hour coverage was compared with 24-hour coverage (19% vs. 21%). Clindamycin dosed at 1,200 mg every 12 hours achieved acceptable serum concentrations; infection rates were not significantly higher than seen with 600 mg every 6 hours (21% vs. 12%, p greater than 0.05). High-dose (11 mg/kg) amikacin reduced infection rates in patients with high blood loss (p less than 0.025), high Injury Severity Scores (p less than 0.025), and no colon penetration (p less than 0.005). These data suggest that high doses are more effective than long courses of antibiotics in reducing infections in trauma patients undergoing laparotomy.

Novel Substrates to Maintain Gut Integrity

CONTENTS INTRODUCTION . . 4 4 EVIDENCE FOR G U T MUCOSAL BARRIER DYSFUNCTION . . 4 4 CLINICAL SIGNIFICANCE OF G U T MUCOSAL BARRIER DYSFUNCTION . . 46 GUT DERIVED SEPSIS: THERAPEUTIC STRATEGIES. . . 41 NOVEL SUBSTRATES A N D G U T INTEGRITY . . 48 GLUTAMINE . . 48 Metabolism of glutamine . . 48 Glutamine and the gut mucosa . . 48 Glutamine and experimental disease models . . * 49 Glutamine supplemented TPN and experimental disease models . . . 49 Glutamine supplemented enteral nutrition and experimental disease models . . 49 Rationale for clinical use of glutamine . . . 50

Effect of Supplemental L-Arginine in a Chemical-Induced Model of Colorectal Cancer

Abstract. l -Arginine inhibits the development of spontaneous, transplantable solid tumors and chemically induced mammary tumors. The aim of the present study was to investigate the effect of l -arginine on chemically induced colorectal cancer in male Wistar rats. Colorectal cancer was induced in all animals by weekly subcutaneous injections of the colonic procarcinogen 1,2-dimethyhydrazine (DMH) at a dosage of 20 mg/kg body weight. Arginine was given in a 1% solution of drinking water. Group I was the DMH control; group II, arginine for 22 weeks; group III, arginine for the first 10 weeks only. Lymphocyte function was evaluated by measuring the thymic lymphocyte proliferative response to the T cell mitogen phytohemagglutinin. The results show that tumor incidence and tumor burden (tumors/rat and tumors/tumor-bearing rat) were significantly reduced in both groups of animals receiving arginine compared to DMH controls ( p < 0.05). The tumor areas and volumes were also reduced in both arginine groups ( p < 0.05). Thymic lymphocyte stimulation indices were significantly increased by arginine supplementation ( p < 0.05). These results would be in keeping with the reduction in colorectal tumor production due to a “nonspecific” stimulation of the host immune system by l -arginine.

Host immune responses and intestinal permeability in patients with jaundice.

Systemic endotoxaemia is implicated in the development of complications associated with obstructive jaundice. The aims of these studies were to assess the systemic immune response to intervention in patients with jaundice and to compare the effects of surgical and non‐surgical biliary drainage on host immune function and gut barrier function.

Endotoxaemia in Obstructive Jaundice

Surgical procedures in patients with obstructive jaundice are associated with significant morbidity and mortality1. This is due, to a large extent, to the development of postoperative complications such as sepsis, bleeding disorders and renal failure24. Clinical and experimental studies have suggested several aetiological factors for these complications including hypotension, impaired nutritional status, impaired immune function and the presence of potential toxic substances in the circulation such as bilirubin and bile acids1’5’6. However, in recent years, there has been an increasing recognition of the role of circulating endotoxins in the development of complications in obstructive jaundice4’7-9. The focus of this review will be the proposed association between the presence of systemic endotoxaemia in obstructive jaundice and the subsequent development of systemic complications. The experimental and clinical evidence for the existence of portal and systemic endotoxaemia in obstructive jaundice will be reviewed, followed by an outline of the current theory on the origin and mechanisms of development of endotoxaemia. The effects of endotoxaemia in jaundiced animals and patients, and the mechanisms by which these may be produced, will then be reviewed. The recognition of endotoxaemia as a possible cause of complications in obstructive jaundice and other pathological situations has led to the development of a variety of therapeutic strategies, including the use of anti-endotoxin agents, and these will be discussed.

NUTRITIONAL MODULATION OF GUT INFLAMMATION

Nutritional therapy is an important component of the management of gastrointestinal inflammation, which disrupts the gut mucosal barrier leading to sepsis, SIRS and MODS. Future studies will be needed to define the role of specific nutrients in enhancing mucosal barrier function and supporting general immune function, and how this affects morbidity and mortality of critically-ill patients.