Glutamine kinetics in critically ill patients

Critical illness, defined as a life-threatening organ failure, entails an extreme stress that results in a pathophysiology of its own. The abnormal metabolism of these patients causes a severe muscle wasting that is poorly understood. One hypothesis is that the muscle is sacrificed to provide the body with key metabolic substrates, such as the amino acid glutamine. Both low and high plasma glutamine concentrations at Intensive Care Unit (ICU) admission are associated with a higher mortality. However, the mechanisms behind these associations are unknown. It has been suggested that there is an increased demand for glutamine in critical illness and that its availability is crucial for proper function of the immune system and the intestine. Hence, several intervention studies on glutamine supplementation in the ICU have been conducted. However, design and included patients varies widely and thus the results are heterogenous and problematic to compare. In order to explore the hypothesis that low plasma glutamine concentration in critical illness represents a shortage that may motivate glutamine supplementation, glutamine kinetics in these patients needs to be characterized. The first step was to establish and validate a bolus injection method to measure glutamine endogenous rate of appearance (endoRa) for studying endogenous glutamine production in the ICU setting. When this method was applied, a positive correlation was detected, where 35% of variability in plasma glutamine concentration could be related to endoRa during critical illness. The second part of the thesis consists of observational studies on plasma glutamine concentrations in connection to outcome and specific diagnoses. In the post ICU period, plasma glutamine concentration was within the reference range and was not related to mortality. In liver failure, regardless of aetiology, severity and course of illness, a high plasma glutamine concentration was a common finding, although most frequent in patients with acute fulminant and acute-on-chronic liver failure. There was a positive correlation between the severity of liver failure and plasma glutamine concentration. Admission hyperglutaminemia (≥930 μmol/L) was an independent predictor for high mortality. A majority of the hyperglutaminemic patients had a liver condition, although hyperglutaminemia was also observed in patients without signs of liver affection. The role of glutamine in critical illness is still not settled. Our observations give no indication that a high plasma glutamine per se is toxic. The finding that low plasma concentrations correlates with a lower endogenous production keeps the possibility open that there is a cohort of critically ill patients with too low glutamine availability, who would benefit from exogenous glutamine supplementation. The ultimate question if plasma glutamine concentration is just a biomarker or if it also gives signal of a deficit and/or an impaired handling of glutamine is still pending. Therefore, glutamine kinetics in critical illness needs to be further clarified

Characteristics of women who continue smoking during pregnancy: A cross-sectional study of pregnant women and new mothers in 15 European countries

Background: Some women continue smoking during pregnancy despite the extensive information available on the dangers smoking poses to their fetus. This study aimed to examine the prevalence and determinants of smoking before and during pregnancy and the extent of smoking during pregnancy from a European perspective in relation to maternal sociodemographic characteristics, health literacy, morbidity, and pregnancy-related factors. Methods: This multinational, web-based study evaluated pregnant women and new mothers in 15 European countries recruited from October 2011 to February 2012. Data were collected via an anonymous online questionnaire. Results: Of 8344 women included, 2944 (35.3%) reported smoking before pregnancy, and 771 (26.2%) continued smoking during pregnancy, 88 (11.4%) of whom smoked more than 10 cigarettes per day. There was a wide variation among the 15 European countries in smoking rates before and during pregnancy, ranging from 25.0% (Sweden) to 50.0% (Croatia) before and 4.2% (Iceland) to 18.9% (Croatia) during pregnancy. Women who lived in Eastern Europe, without a spouse/partner, with a low education level and unplanned pregnancy, who did not take folic acid, and consumed alcohol during pregnancy were the most likely to smoke before pregnancy. Women who lived in Eastern or Western Europe, without a spouse/partner, with a low education level and health literacy, being a housewife, having previous children and unplanned pregnancy, and who did not take folic acid were the most likely to continue smoking during pregnancy. Women who smoked more than 10 cigarettes per day during pregnancy were the most likely to be living in Eastern Europe and to have a low education level. Conclusion: Women with fewer resources living in Western or Eastern Europe are more likely not only to smoke before pregnancy but also to continue smoking during pregnancy. These high-risk women are characterized as living alone, having high school or less as highest education level, having low health literacy, being a housewife, having previous children, having unplanned pregnancy, and no use of folic acid. Our findings indicated that focus on smoking cessation is important in antenatal care in Europe as many women smoke before pregnancy, and still continue to do so in pregnancy

Plasma Glutamine Concentrations in Liver Failure.

Higher than normal plasma glutamine concentration at admission to an intensive care unit is associated with an unfavorable outcome. Very high plasma glutamine levels are sometimes seen in both acute and chronic liver failure. We aimed to systematically explore the relation between different types of liver failure and plasma glutamine concentrations.Four different groups of patients were studies; chronic liver failure (n = 40), acute on chronic liver failure (n = 20), acute fulminant liver failure (n = 20), and post-hepatectomy liver failure (n = 20). Child-Pugh and Model for End-stage Liver Disease (MELD) scores were assessed as indices of liver function. All groups except the chronic liver failure group were followed longitudinally during hospitalisation. Outcomes were recorded up to 48 months after study inclusion.All groups had individuals with very high plasma glutamine concentrations. In the total group of patients (n = 100), severity of liver failure correlated significantly with plasma glutamine concentration, but the correlation was not strong.Liver failure, regardless of severity and course of illness, may be associated with a high plasma glutamine concentration. Further studies are needed to understand whether high glutamine levels should be regarded as a biomarker or as a contributor to symptomatology in liver failure

A Tracer Bolus Method for Investigating Glutamine Kinetics in Humans

<div><p>Glutamine transport between tissues is important for the outcome of critically ill patients. Investigation of glutamine kinetics is, therefore, necessary to understand glutamine metabolism in these patients in order to improve future intervention studies. Endogenous glutamine production can be measured by continuous infusion of a glutamine tracer, which necessitates a minimum measurement time period. In order to reduce this problem, we used and validated a tracer bolus injection method. Furthermore, this method was used to measure the glutamine production in healthy volunteers in the post-absorptive state, with extra alanine and with glutamine supplementation and parenteral nutrition. Healthy volunteers received a bolus injection of [1-¹³C] glutamine, and blood was collected from the radial artery to measure tracer enrichment over 90 minutes. Endogenous rate of appearance (endoR_a) of glutamine was calculated from the enrichment decay curve and corrected for the extra glutamine supplementation. The glutamine endoR_a of healthy volunteers was 6.1±0.9 µmol/kg/min in the post-absorptive state, 6.9±1.0 µmol/kg/min with extra alanyl-glutamine (p = 0.29 versus control), 6.1±0.4 µmol/kg/min with extra alanine only (p = 0.32 versus control), and 7.5±0.9 µmol/kg/min with extra alanyl-glutamine and parenteral nutrition (p = 0.049 versus control). In conclusion, a tracer bolus injection method to measure glutamine endoR_a showed good reproducibility and small variation at baseline as well as during parenteral nutrition. Additionally, we showed that parenteral nutrition including alanyl-glutamine increased glutamine endoR_a in healthy volunteers, which was not attributable to the alanine part of the dipeptide.</p></div

Endogenous glutamine R_a in healthy subjects given alanyl-glutamine supplementation and parenteral feeding.

<p>CON (n = 5) given no alanyl-glutamine or parenteral feeding, GLN (n = 5) given intravenous alanyl-glutamine only, and GLN+TPN (n = 6) given intravenous alanyl-glutamine and parenteral feeding.</p

Endogenous glutamine R_a in healthy subjects (n = 4) studied repeatedly on 2 occasions in the postabsorptive state 3–12 days apart.

<p>Endogenous glutamine R_a in healthy subjects (n = 4) studied repeatedly on 2 occasions in the postabsorptive state 3–12 days apart.</p

Plasma glutamine concentration over the initial 15(blue symbols), 3 (green symbols), or 6 (black and red symbols) mg/kg of [1-¹³C] glutamine in healthy subjects (n = 4).

<p>The decay-curve for 3 mg/kg reaches undetectable levels already after 60 minutes.</p

Glutamine APE (atom percent excess) over 90–120 min after bolus injection of 1.5 (blue symbols), 3 (green symbols), or 6 (black and red symbols) mg/kg of [1-¹³C] glutamine in healthy subjects (n = 4).

<p>Glutamine APE (atom percent excess) over 90–120 min after bolus injection of 1.5 (blue symbols), 3 (green symbols), or 6 (black and red symbols) mg/kg of [1-¹³C] glutamine in healthy subjects (n = 4).</p

Plasma glutamine concentration dichotomized above or below 930 μmol/L, the upper limit of the reference range, for the total group of patients with liver failure (n = 100).

<p>The high out-of-normal–range values were then related to symptoms of liver failure as reflected by the Child-Pugh and MELD scores by receiver operator characteristics curves (ROC curves).</p

Etiologies behind chronic liver failure in group A.

<p>Etiologies behind chronic liver failure in group A.</p