Garrett-Cox, R; (2008) Effects of glutamine in neonatal endotoxaemia. Doctoral thesis , UCL (University College London).

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Abstract

Background: Neonatal sepsis increases systemic inflammation, which may lead to multiple organ failure and death. Glutamine has been suggested to have beneficial effects during neonatal sepsis, but its effects on systemic inflammation and systemic metabolism are unknown. Methods: Suckling rat pups were given intraperitoneal endotoxin alone (E) or with glutamine (EG). Controls were administered saline (C) alone or with glutamine (CG). Sepsis score and rectal temperature were monitored. Oxygen consumption (V02, ml/kg/h) was measured by indirect calorimetry. Animals were sacrificed exsanguinated and plasma separated. Liver was resected and hepatocytes and liver mitochondria were isolated for in vitro experiments. Oxygen consumption and glutathione levels in hepatocytes and hepatocyte mitochondria were measured. Plasma glutamine and tumour necrosis factor alpha (TNF-a, pg/ml) were measured. Results: Endotoxic (E) rats had lower V02 than C rats from 90 minutes post injection to 210 minutes (V02 150-210 minutes: C 671+/-45 E 429+A36, p<0.0004 n=8). V02 was higher (p<0.05) in EG rats than E rats (E 460+/-29 EG 654+/-68 n=10). EG rats were significantly less hypothermic between 90-210 minutes (58/132 measurements) compared with E (95/147 p=0.0007). Sepsis score was significantly lower in the EG group than the E group (E 4.9+/-0.3 EG 3.6+/-0.3 n=40 p<0.01). Endotoxaemia caused a rapid significant decrease in plasma glutamine concentration at 2h (C vs. E p<0.001), which was prevented by intraperitoneal glutamine (EG p<0.05 vs. E). TNF-a levels were greatly increased by endotoxaemia and this increase was partly prevented by glutamine (At 6h C 32+/-27, E 799+/-193, EG 219+/-75, E vs. C p<0.001, vs. EG p<0.01). In isolated hepatocytes there was reduced oxygen consumption in endotoxin (E) group but increased oxygen consumption in endotoxin glutamine (EG) group. There was shown to be no statistical difference between all groups in the hepatocyte isolated mitochondrial oxygen consumption. Glutathione levels in the liver were reduced in both E and EG groups compared to controls. Glutathione in liver mitochondria showed an increase in the groups treated with glutamine at 4 hours post injection. Conclusions: Neonatal endotoxaemia lowers V02, heat production, and body temperature. Glutamine restores V02 of endotoxic animals. Glutamine additionally increases rectal temperature and improves clinical signs of endotoxic rats. Glutamine administration prevents the endotoxin-induced fall in plasma glutamine levels, and reduces the concentration of both pro- and anti inflammatory cytokines, supporting its use as a potential therapeutic agent in neonatal sepsis.

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