N(omega)-nitro-L-arginine methyl ester effects on neutrophil function and bacterial clearance.

Nitric oxide synthase (NOS) inhibitors are considered promising as a therapeutic option in severe septic shock. The aim of this study was to investigate the effects of N-nitro-L-arginine methyl ester (L-NAME) application on neutrophil (PMN) respiratory burst, phagocytosis, and elimination of Escherichia coli from blood and tissue in rabbits. Twenty-eight female chinchilla rabbits were randomized to a treatment and control group. To quantify the bacterial clearance process, 10 colony forming units (CFU) of E. coli were injected intravenously into anesthetized rabbits. Animals in the L-NAME group had a significantly higher mortality compared with controls. NOS inhibition resulted in a significant delay of bacterial clearance (P < 0.001). These findings correlated with a significant augmentation of all organ E. coli findings (P = 0.002-0.035). PMN phagocytosis activity was notably reduced by L-NAME treatment during the experimental observation. Neutrophil burst, on the other hand, was amplified by NOS inhibition (P = 0.008). Our findings point to an interference with the PMN-dependent immune mechanisms after L-NAME treatment. The augmented PMN burst reaction could be a compensatory mechanism, potentially leading to tissue damage. Therefore, in this model, we find sufficient evidence pointing to a possible cause for the deleterious effect of early nonselective NOS inhibition in critically ill patients.

Modulation of host defense by hydrocortisone in stress doses during endotoxemia.

OBJECTIVE: To investigate the effects of low-dose hydrocortisone (HC) on neutrophil respiratory burst, phagocytosis, and elimination of E. coli from blood and tissue under endotoxemic and non-endotoxemic conditions. DESIGN. Randomized, controlled trial. SETTING: Experimental laboratory, university hospital. SUBJECTS: Forty-eight female chinchilla rabbits ( n=8 in six groups A-F). INTERVENTIONS: In order to quantify the bacterial clearance process, defined numbers [10(8) colony forming units (CFU)] of Escherichia coli were injected intravenously into all anesthetized rabbits. Group A did not receive further intervention. Group B received bolus administration of HC 1.4 mg/kg and group C 14 mg/kg. Endotoxin (LPS, 40 microg/kg/h) was given to groups D, E, and F. Group E received additional bolus administration of HC 1.4 mg/kg and group F 14 mg/kg. All HC groups (B, C, E, and F) were continuously infused with HC 0.18 mg/kg/h. MEASUREMENTS: Monitored parameters were neutrophil respiratory burst and phagocytosis activity, rates of bacterial elimination from the blood, arterial blood pressure, serum lactate and LPS concentrations, as well as nitrite and nitrate levels. Tissue samples of liver, kidney, spleen, and lung were collected for bacterial counts. MAIN RESULTS: In controls HC significantly delayed elimination of injected E. coli from the blood (P<0.01). LPS also prolonged bacterial elimination but additional HC did not further delay removal of E. coli from the blood. Under endotoxemia HC depressed respiratory burst, whereas phagocytosis functions remained unaltered. Moreover, bacterial colonization of organs was reduced after HC in the LPS groups. Significance, however, was reached only in the liver (P<0.05). Due to HC, clearance from LPS (P<0.01) and lactate (P<0.05) were improved. Levels of nitrite and nitrate did not differ among the groups. CONCLUSION: HC demonstrated immunomodulatory effects even in stress doses. In endotoxemic states use of low-dose HC seems to be favorable, although not in non-septic conditions.

Omega-3 fatty acids improve the diagnosis-related clinical outcome.

OBJECTIVE: Supplementation of clinical nutrition with omega-3 fatty acid in fish oil exerts immune-modulating and organ-protective effects, even after short-term application. The aim of this study was to evaluate dose-dependent effects of parenteral supplementation of a 10% fish oil emulsion (Omegaven, Fresenius-Kabi, Bad Homburg, Germany) on diagnosis- and organ failure-related outcome. DESIGN: Prospective, open label, multiple-center trial. PATIENTS AND METHODS: A total of 661 patients from 82 German hospitals receiving total parenteral nutrition for > or =3 days were enrolled in this study. The sample included 255 patients after major abdominal surgery, 276 with peritonitis and abdominal sepsis, 16 with nonabdominal sepsis, 59 after multiple trauma, 18 with severe head injury, and 37 with other diagnoses. The primary study end point was survival; secondary end points were length of hospital stay and use of antibiotics with respect to the primary diagnosis and the extent of organ failure. Multiple quasi-linear and logistic regression models were used for calculating diagnosis-related fish oil doses associated with best outcome. RESULTS: The patients enrolled in this survey were (mean +/- sd) 62.8 +/- 16.5 yrs old, with a body mass index of 25.1 +/- 4.2 and Simplified Acute Physiology Score (SAPS) II score of 32.2 +/- 13.6. Length of hospital stay was 29.1 +/- 18.7 days (12.5 +/- 14.8 days in the intensive care unit). Total parenteral nutrition, including fish oil (mean, 0.11 g.kg(-1).day(-1)), was administered for 8.7 +/- 7.5 days and lowered hospital mortality as predicted by Simplified Acute Physiology Score II from 18.9% (95% confidence interval, 17.4-20.4%) to 12.0% (p < .001). The fish oil dose.kg.day did correlate with beneficial outcome (intensive care unit stay, hospital stay, mortality). Fish oil had the most favorable effects on survival, infection rates, and length of stay when administered in doses between 0.1 and 0.2 g.kg(-1).day(-1). Lower antibiotic demand by 26% was observed when doses of 0.15-0.2 g.kg(-1).day(-1) were infused as compared with doses of <0.05 g.kg(-1).day(-1). After peritonitis and abdominal sepsis, multiple quasi-linear regression models revealed a fish oil dose for minimizing intensive care unit stay of 0.23 g.kg(-1).day(-1) and an inverse linear relationship between dosage and intensive care unit stay in major abdominal surgery. CONCLUSION: Administration of omega-3 fatty acid may reduce mortality, antibiotic use, and length of hospital stay in different diseases. Effects and effect sizes related to fish oil doses are diagnosis dependent. In view of the lack of substantial study literature concerning diagnosis-related nutritional single-substrate intervention in the critically ill, the present data can be used in formulating hypotheses and may serve as reference doses for randomized, controlled studies, which may, for instance, confirm the value of omega-3 fatty acid in the adjunctive therapy of peritonitis and abdominal sepsis.