Preliminary results of a prospective randomized trial of restrictive versus standard fluid regime in elective open abdominal aortic aneurysm repair.

BACKGROUND: Open abdominal aortic aneurysm (AAA) repair is associated with a significant morbidity (primarily respiratory and cardiac complications) and an overall mortality rate of 4% to 10%. We tested the hypothesis that perioperative fluid restriction would reduce complications and improve outcome after elective open AAA repair. METHODS: In a prospective randomized control trial, patients undergoing elective open infra-renal AAA repair were randomized to a "standard" or "restricted" perioperative fluid administration group. Primary outcome measure was rate of major complications (MC) after AAA repair and secondary outcome measures included: Sequential Organ Failure Assessment Score; FiO2/PO2 ratio; Urinary Albumin/Creatinine Ratio; Length-of-stay in, intensive care unit, high dependency unit, in-hospital. This prospective Randomized Controlled Trial was registered in a publicly accessible database and has the following ID number ISRCTN27753612. RESULTS: Overall 22 patients were randomized, 1 was excluded on a priori criteria, leaving standard group (11) and restricted group (10) for analysis. No significant difference was noted between groups in respect to age, gender, American Society Anesthesiology class, Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity scores, operation time, and operation blood loss. There were no in-hospital deaths and no 30-day mortality. The cumulative fluid balance on day 5 postoperative was for standard group, 8242 +/- 714 mL, compared with restricted group, 2570 +/- 977 mL, P < 0.01. MC were significantly reduced in the restricted group (n = 10), 1 MC, compared with standard group (n = 11), 14 MC, P < 0.024. Total and postoperative length-of-stay in-hospital was significantly reduced in the restricted group, 9 +/- 1 and 8 +/- 1 days, compared with standard group, 18 +/- 5 and 16 +/- 5 days, P < 0.01 and P < 0.025, respectively. CONCLUSIONS: Serious complications are common after elective open AAA repair, and we have shown for the first time that a restricted perioperative fluid regimen can prevent MC and significantly reduce overall hospital stay.

The use of antiendotoxin peptides in obstructive jaundice endotoxemia.

BACKGROUND: Two novel antiendotoxin peptides, P6 and C1, may reduce the inflammatory response. This study aimed to determine the effect of endotoxin on hepatic cytokine response and to assess P6 and C1-related attenuation of the proinflammatory response to endotoxemia, in experimental biliary obstruction. MATERIALS AND METHODS: 15 Male Wistar rats were randomized to one of three groups: bile duct ligation (BDL)+P6 (n=5), BDL+C1 (n=5), and BDL+no peptide (n=5). Rats were weighed and underwent BDL surgery on day 1. On day 8, the rats were reweighed and isolated hepatic perfusion was carried out. P6 or C1 peptide (10 µmol/l) was preincubated with 300 ml of endotoxin-containing Krebs perfusate. After perfusion of 10 min with endotoxin-free perfusate, the livers were perfused for another 10 min with 300 ml of perfusate-containing endotoxin on its own or endotoxin plus peptide. This was followed by a further 100 min of perfusion with endotoxin-free perfusate. Effluent perfusate was collected at 20-min intervals for subsequent biochemical and cytokine analyses. RESULTS: Perfusion with endotoxin+P6 or endotoxin+C1 resulted in no significant difference in weight loss, or interleukin-6 response compared with perfusion with endotoxin alone. However, perfusion with endotoxin+P6 or endotoxin+C1 significantly reduced the tumor necrosis factor-α response to portal endotoxemia compared with perfusion with endotoxin alone. CONCLUSION: This study demonstrates that novel antiendotoxin peptides may attenuate the hepatic inflammatory response in portal endotoxemia. In obstructive jaundice, preoperative peptide administration may reduce endotoxin-related postoperative complications.

Ischemic preconditioning before lower limb ischemia--reperfusion protects against acute lung injury.

OBJECTIVE: Prolonged limb ischemia followed by reperfusion (I/R) is associated with a systemic inflammatory response syndrome and remote acute lung injury. Ischemic preconditioning (IPC), achieved with repeated brief periods of I/R before the prolonged ischemic period, has been shown to protect skeletal muscle against ischemic injury. The aim of this study was to ascertain whether IPC of the limb before I/R injury also attenuates systemic inflammation and acute lung injury in a fully resuscitated porcine model of hind limb I/R. METHODS: This prospective, randomized, controlled, experimental animal study was performed in a university-based animal research facility with 18 male Landrace pigs that weighed from 30 to 35 kg. Anesthetized ventilated swine were randomized (n = 6 per group) to three groups: sham-operated control group, I/R group (2 hours of bilateral hind limb ischemia and 2.5 hours of reperfusion), and IPC group (three cycles of 5 minutes of ischemia/5 minutes of reperfusion immediately preceding I/R). Plasma was separated and stored at -70 degrees C for later determination of plasma tumor necrosis factor-alpha and interleukin-6 with bioassay as markers of systemic inflammation. Circulating phagocytic cell priming was assessed with a whole blood chemiluminescence assay. Lung tissue wet-to-dry weight ratio and myeloperoxidase concentration were markers of edema and neutrophil sequestration, respectively. The alveolar-arterial oxygen gradient and pulmonary artery pressure were indices of lung function. RESULTS: In a porcine model, bilateral hind limb (I/R) injury significantly increased plasma interleukin-6 concentrations, circulating phagocytic cell priming, and pulmonary leukosequestration, edema, and impaired gas exchange. Conversely, pigs treated with IPC before the onset of the ischemic period had significantly reduced interleukin-6 levels, circulating phagocytic cell priming, and experienced significantly less pulmonary edema, leukosequestration, and respiratory failure. CONCLUSION: Lower limb IPC protects against systemic inflammation and acute lung injury in lower limb I/R injury.

Modulation of N-methyl-N-nitrosourea-induced crypt restricted metallothionein immunopositivity in mouse colon by a non-genotoxic diet-related chemical.

Red meat consumption is associated with endogenous metabolic generation of mutagenic N-nitroso compounds (NOC) and may be implicated in causation of colorectal cancer. Assessment of a biologically relevant dose of NOCs is hampered by imperfect understanding of NOC interactions with other dietary components. This study tests the hypothesis that NOC effects upon mutational biomarkers in mouse colon may be modulated by a non-genotoxic diet-related compound. N-methyl-N-nitrosourea (MNU) and undegraded lambda carrageenan (lambdaCgN) were selected as test chemicals, representing a NOC and a non-genotoxic agent, respectively. Study end-points included (i) DNA adduct formation and (ii) metallothionein (MT) crypt restricted immunopositivity indices (MTCRII) which are considered representative of crypt stem cell mutations. Frequency and size of MT immunopositive foci as well as total number of MT immunopositive crypts were assessed. Biologically effective doses of MNU and lambdaCgN were determined in model validation studies and the agents were then tested alone and in combination. Continuous lambdaCgN treatment for 10 weeks induced significantly greater colonic mucosal injury than a drinking water control. In combined treatment regimens, lambdaCgN treatment did not significantly affect MNU-induced DNA adduct formation. However, combinations of lambdaCgN with MNU significantly increased MTCRII in excess of those induced by MNU alone. Recurrent or continuous lambdaCgN regimens had greater interactive effects with MNU upon MTCRII than short-term lambdaCgN treatment. This study has shown that exposure to a non-genotoxic diet-related compound (lambdaCgN) modulates the effective NOC dosimetry for induction of MT crypt restricted immunopositivity.