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Rationale: 1. To characterise and quantify the cytokine response to critical illness and relate this response to common metabolic features of the illness; 2. To determine whether these immunologic and metabolic responses can be modified using enteral immunonutrition. Methods: Circulating cytokine concentrations (TNFα, IL-6, IL-10, TGF-β1, IL-lra, sTNF-RI and sTNF-RII), c-reactive protein and cortisol levels were determined using the ELISA technique. Cytokine genotypes (IL-10, TNFα and TNFβ) were determined following the amplification of DNA using polymerase chain reaction (PCR) then by using sequence specific oligonucleotide probes (SSOP) or Ncol restriction digest. Energy expenditure was measured continuously in mechanically ventilated patients by indirect calorimetry. The modified enteral formula, supplemented with glutamine, arginine, fish oil, nucleotides, fibre and antioxidants, was compared with an isocaloric, isonitrogenous control feed as part of a prospective, randomised, double-blind, controlled trial. Results: The frequency of IL-10, TNFα and TNFβ genotypes, between the ICU population and controls differed significantly. There were fewer high IL-10 producers in the ICU population (6% versus 30%, p1000pg/ml) or an increase in IL-6 concentration during ICU admission was associated with an increased risk of mortality (p=0.005 and p=0.036, respectively). Elevated admission levels of IL-1ra, sTNF-RI and sTNF-RII were also associated with increased mortality risk (p=0.039, p=0.05 and p=0.05, respectively). Soluble TNF-RI was significantly correlated with measures of protein catabolism; urinary nitrogen (adj r²=0.166, p=0.002) and percentage energy derived from protein oxidation (adj r²=0.138, p=0.009). Both cortisol and c-reactive protein levels were weakly, but statistically highly significantly, correlated with anti-inflammatory cytokines IL-10 and TGFβ. Immunonutrition did not influence either pro- or anti-inflammatory cytokine responses in this ICU population. There was however a tendency to reduced mortality rate (32% versus 22%, p=0.522); reduced ICU length of stay (10 days versus 12 days, p=0.915) and reduced number of MODS days (5.5 days versus 7 days, p=0.843) with the trial formula. Conclusions: Genetic variation in IL-10 and/or TNFα production may be protective of admission to the ICU. Admission levels of the pro-inflammatory cytokine, IL-6, and to a lesser extent soluble receptors and the receptor antagonist (sTNF-RI, sTNF-RII and IL-1ra) can provide an indication of patient outcome. Overall cytokines correlate weakly (but statistically highly significantly) with metabolic and clinical features of critical illness. A randomised controlled trial of enteral immunonutrition has failed to demonstrate any statistically significant benefits in this general ICU population with MODS. |
