Intestinal dysfunction in the critical trauma patients - An early and frequent event.

BACKGROUND: Small-bowel dysfunction exerts a relevant prognostic impact in the critically ill patients. Citrullinemia has been used in the evaluation of the intestinal function and it is considered an objective parameter of the functional enterocyte mass. Present study proposes to determine the intestinal dysfunction prevalence and the citrullinemia kinetic profile in severe trauma patients and to investigate its correlation with severity indicators and clinical outcome. METHODS: A prospective study including 23 critical trauma patients was performed. Aminoacidemias were quantified, by ion exchange chromatography, at the admission and at the first and third days. Severity and outcome parameters were registered. RESULTS: In severe trauma patients, severe hypocitrullinemia (< 20 µmol/L) prevalence at admission was high (69.6%) and mean citrullinemia was low (19.5 ± 11.1 µmol/L). Baseline citrullinemia was inversely and significantly correlated with shock index (r = -55.1%, p = 0.008) and extent of invasive ventilation support (r = -42.7%, p = 0.042). Citrullinemia < 13.7 µmol/L at admission, observed in 17.4% of patients, was associated with higher shock index (1.27 ± 0.10 versus 0.75 ± 0.18, p = 0.0001) and longer duration of invasive ventilation support (20.3 ± 7 versus 11.2 ± 7.1 days, p = 0.029) and intensive care unit stay (22 ± 5.9 versus 12.2 ± 8.8 days, p = 0.048). A citrullinemia decrease in the first day after admittance superior to 12.7% constituted a significant predictive factor of in-hospital mortality (75 versus 14.3%, p = 0.044; odds ratio = 7.8; accuracy = 65.2%; specificity = 92.3%; negative predictive value = 85.7%] and lower actuarial survival (69.8 ± 41.6 versus 278.1 ± 37.4 days, p = 0.034). CONCLUSIONS: Those results confirm the high prevalence and the prognostic relevance of hypocitrullinemia, considered a biomarker of enterocyte dysfunction, in severe trauma patients.

Changes in arginine metabolism during sepsis and critical illness in children.

Arginine is an important amino acid during disease and healing because of functions in the immune system and as precursor of nitric oxide (NO). In critically ill adults and children, plasma arginine and citrulline concentrations are substantially decreased, indicating an arginine-deficient state. Arginine availability is reduced because of increased arginine disposal in combination with reduced de novo arginine synthesis. The latter is most likely caused by reduced citrulline availability. As a result, NO synthesis may be impaired, which might compromise microcirculation. These metabolic changes seem to be dependent on the severity of inflammation. Arginine or citrulline supplementation in severe inflammation might therefore be beneficial. Possibly, the use of protein-energy-enriched formulas may be a first step to improve arginine availability and NO synthesis. In critically ill children, arginine metabolism and supplementation is however a virtually unexplored field. Since pediatric sepsis is a significant health problem, which differs in epidemiology and pathophysiology from sepsis in adults, and because of the scarcity of data in this population, studies focused on pathophysiological mechanisms and possible interventions in arginine metabolism in pediatric critical illness are warranted.

Low citrulline in Leigh disease: still a biomarker of maternally inherited Leigh syndrome.

Two siblings presented with encephalopathy, lactic acidosis, and hypocitrullinemia. Muscle and liver biopsies were considered for respiratory chain studies, but because of hypocitrullinemia, molecular analysis for maternally inherited Leigh syndrome was first performed, revealing in both siblings the mitochondrial DNA T8993G mutation (95% heteroplasmy), allowing to avoid tissue biopsies. Hypocitrullinemia, an occasional finding in mitochondrial diseases, has been specifically associated with T8993G mutation. However, only few patients have been reported, and the prevalence of hypocitrullinemia in 8993 mitochondrial DNA mutations is unknown. In a small series of 16 Leigh syndrome patients, sensitivity and specificity of hypocitrullinemia (< or = 12 micromol/L) for 8993 mitochondrial DNA mutations were 66% and 85%, respectively. Although studies in larger cohorts are necessary, we suggest considering T8993G mutation early in the diagnostic evaluation of infantile mitochondrial diseases with hypocitrullinemia, which minimizes the need for invasive procedures associated with a small but nonnegligible risk of complications and incorrect diagnosis.

Hypocitrullinemia in patients with MELAS: an insight into the "MELAS paradox".

L-citrulline, classified as a nonessential amino acid, is synthesized predominantly via Delta-1-pyrroline carboxylate synthase in the endothelial cells of the small intestine. In mammals, small quantities of citrulline are also produced in nitric oxide synthase-expressing cells. Considering the fact that the enzymes involved in the endogenous synthesis of L-citrulline are all located in the mitochondria and the fact that citrulline is a component of the citrulline-nitric oxide (NO) cycle, we hypothesized that the distinct clinical, biochemical, and morphological characteristics of MELAS, a maternally inherited mitochondrial disorder, might be due to alterations in nitric oxide homeostasis. Analysis of serum from MELAS patients showed that levels of plasma arginine were similar in both patients and in controls. However, levels of citrulline in MELAS patients were significantly lower than in controls, and there was a clear inverse correlation between arginine and citrulline levels in these patients. We found no correlation between the level of heteroplasmy and the plasma levels of either arginine or citrulline. We discuss the depressed citrulline levels in MELAS patients, who have an unusual and paradoxical pattern of vascular respiratory chain expression, in the context of NO homeostasis.

Urinary metabolites characteristic of urea-cycle amino acid deficiency.

Experiments with 45-75-g male rats gave conclusive evidence that the simultaneous absence from the diet of arginine, ornithine, or citrulline caused an immediate and persistent elevation of orotic and citric acids in the urine. The experiments also demonstrated that a deficiency of no other individual amino acid increased urinary citrate and orotate. Elevated urinary excretion of orotic and citric acid occurred independently of the form of nonessential nitrogen. Replacement of arginine isonitrogenously with ornithine or citrulline prevented the rise in urinary orotic acid, but had different effects on growth, urinary citrate, and urinary urea. These differences were probably due to differential uptake of arginine, ornithine, and citrulline by tissues; In the reported experiments employing L-amino acids as sources of dietary nitrogen, a deficiency of any amino acid indispensable for growth and nitrogen balance or a deficiency of arginine, ornithine, or citrulline retarded growth, increased urinary urea, and decreased urinary ammonia. It is concluded that the severe loss of orotic acid during urea-cycle amino acid deficiency arises from a decreased capacity of the urea cycle to detoxify ammonia, thereby causing increased shunting of intramitochondrial carbamyl phosphate into pyrimidine synthesis. The similarities in metabolism during arginine deficiency and ammonia intoxication are discussed. The evidence shows that urinary orotic acid may be a valuable measure of arginine nutrition in mammals.