Wolfgang Geisser

Effects of a dobutamine-induced increase in splanchnic blood flow on hepatic metabolic activity in patients with septic shock

Background: Septic shock leads to increased splanchnic blood flow (Qspl) and oxygen consumption (VO2 spl). The increased Qspl, however, may not match the splanchnic oxygen demand, resulting in hepatic dysfunction. This concept of ongoing tissue hypoxia that can be relieved by increasing splanchnic oxygen delivery (DO2 spl), however, was challenged because most of the elevated VO2 spl was attributed to increased hepatic glucose production (HGP) resulting from increased substrate delivery. Therefore the authors tested the hypothesis that a dobutamine‐induced increase in Qspl and DO2 spl leads to increased VO sub 2 spl associated with accelerated HGP in patients with septic shock. Methods: Twelve patients with hyperdynamic septic shock in whom blood pressure had been stabilized (mean arterial pressure greater or equal to 70 mmHg) with volume resuscitation and norepinephrine received dobutamine to obtain a 20% increase in cardiac index (CI). Qspl, DO2 spl, and VO sub 2 spl were assessed using the steady‐state indocyanine green clearance technique with correction for hepatic dye extraction, and HGP was determined from the plasma appearance rate of stable, non‐radioactive‐labeled glucose using a primed‐constant infusion approach. Results: Although the increase in CI resulted in a similar increase in Qspl (from 0.91 +/‐ 0.21 to 1.21 +/‐ 0.34 l [center dot] min sup ‐1 [center dot] m2; P < 0.001) producing a parallel increase of DO2 spl (from 141 +/‐ 33 to 182 +/‐ 44 ml [center dot] min sup ‐1 [center dot] m2; P < 0.001), there was no effect on VO2 spl (73 +/‐ 16 and 82 +/‐ 21 ml [center dot] min sup ‐1 [center dot] m2, respectively). Hepatic glucose production decreased from 5.1 +/‐ 1.6 to 3.6 +/‐ 0.9 mg [center dot] kg sup ‐1 [center dot] min sup ‐1 (P < 0.001). Conclusions: In the patients with septic shock in whom blood pressure had been stabilized with volume resuscitation and norepinephrine, no delivery‐dependency of VO2 spl could be detected. Oxygen consumption was not related to the accelerated HGP either, and thus the concept that HGP dominates VO2 spl must be questioned in well‐resuscitated patients with septic shock.

Propofol/sufentanil anesthesia suppresses the metabolic and endocrine response during, not after, lower abdominal surgery.

We investigated the influence of propofol/sufentanil anesthesia on metabolic and endocrine responses during, and immediately after, lower abdominal surgery. Twenty otherwise healthy patients undergoing abdominal hysterectomy for benign myoma received either continuous infusions of propofol supplemented with sufentanil (0.01 &mgr;g · kg−1 · min−1, n = 10) or enflurane anesthesia (enflurane, n = 10). Plasma concentrations of glucose, lactate, free fatty acids, triglycerides, insulin, glucagon, cortisol, epinephrine, and norepinephrine were measured before, during, and 2 h after surgery. Pre- and postoperative endogenous glucose production (Ra glucose) was analyzed by an isotope dilution technique by using [6,6-2H2] glucose. Propofol/sufentanil anesthesia prevented the increase in plasma cortisol and catecholamine concentrations and attenuated the hyperglycemic response during surgery without showing any difference after the operation. Mediated through a higher glucagon/insulin quotient (propofol/sufentanil 15 ± 7 versus enflurane 8 ± 4 pg/&mgr;U, P < 0.05), the Ra glucose postoperatively increased more in the propofol/sufentanil than in the enflurane group (propofol/sufentanil 15.6 ± 2.0 versus enflurane 13.4 ± 2.2 &mgr;mol · kg−1 · min−1, P < 0.05). Implications The concept of stress-free anesthesia using propofol combined with sufentanil is valid only during surgery. The metabolic endocrine stress response 2 h after the operation is more pronounced than after inhaled anesthesia.

Glucose and urea production and leucine, ketoisocaproate and alanine fluxes at supraphysiological plasma adrenaline concentrations in volunteers

ObjectiveTo determine the magnitude and time course of adrenergic effects on metabolism in volunteers and possible implications for the use of sympathomimetics in the critically ill.DesignDescriptive laboratory investigation.Subjects7 volunteers.InterventionPrimed continuous infusions of stable isotope tracers ([15N2]-urea, [6,6-D2]-glucose, [methyl-D3]-L-leucine, [15N]-L-alanine) were used. After isotopic steady state had been reached an infusion of adrenaline (0.1 μg/kg/min) was administered (4 h). Isotopic enrichment was measured using gas chromatography-mass spectrometry and the corresponding rates of appearance were calculated.Measurements and main resultsGlucose production increased from 14.1±1.2 to 21.5±2.0 μmol/kg/min (p<0.05) after 80 min of adrenergic stimulation and then decreased again to 17.9±1.2 μmol/kg/min after 240 min. Leucine and ketoisocaproate (KIC) fluxes were 2.3±0.2 and 2.6±0.2 μmol/kg/min, respectively, at baseline and gradually decreased to 1.8±0.2 and 2.2±0.1 μmol/kg/min, respectively, after 240 min of adrenaline infusion (bothp<0.05). Alanine flux increased from 3.7±0.5 to 6.9±0.9 μmol/kg/min (p<0.05) after 80 min of adrenergic stimulation. Urea production slightly decreased from 4.8±0.9 to 4.3±0.8 μmol/kg/min during adrenaline (p<0.05).ConclusionsAdrenaline induced an increase in glucose production lasting for longer than 240 min. The decrease in leucine and KIC flux suggests a reduction in proteolysis, which was supported by the decrease in urea production. The increase in alanine flux is therefore most likely due to an increase in de-novo synthesis. The ammonia donor for alanine synthesis in peripheral tissues and the target for ammonia after alanine deamination in the liver remain to be investigated. These results indicate that adrenaline infusion most probably will not promote already enhanced proteolysis in critically ill patients. Gluconeogenesis is an energy consuming process and an increase may deteriorate hepatic oxygen balance in patients.

Metabolic effects of norepinephrine and dobutamine in healthy volunteers.

The objective of the present study was to evaluate the effects of norepinephrine (n = 9) and dobutamine (n = 7) on carbohydrate and protein metabolism in healthy volunteers in comparison with a control group (n = 9). Norepinephrine (0.1 &mgr;g/kg min), dobutamine (5 &mgr;g/kg min), or placebo was infused for 240 min. The plasma concentration of glucose, lactate, epinephrine, norepinephrine, insulin, and glucagon were determined. Glucose and urea production and leucine flux were measured using a tracer technique. Norepinephrine caused a persisting rise in plasma glucose concentration, whereas the increase in glucose production was only transient. A minor increase in plasma lactate concentration was observed, but it did not exceed the physiological range. No change in leucine flux, urea production, or plasma concentration of insulin, glucagon, or epinephrine was found. Dobutamine slightly decreased glucose production, whereas the plasma concentration of glucose and lactate did not change. The reduction in leucine flux was paralleled by a decrease in urea production. No change in the plasma concentration of insulin, glucagon, or the catecholamines was observed. In conclusion, both norepinephrine and dobutamine have only minor metabolic effects. Because glucose production is enhanced by &agr;1- and &bgr;2-adrenoceptor stimulation, we conclude that dobutamine is only a weak agonist at these adrenoceptors. These minor metabolic actions may make both compounds suitable for critically ill patients because no further increase in metabolic rate should be caused.

Metabolic and calorigenic effects of dopexamine in healthy volunteers.

OBJECTIVE To evaluate metabolic and calorigenic effects of dopexamine in healthy volunteers. DESIGN Prospective, randomized trial. SETTING Laboratory of the University Department of Anesthesiology. SUBJECTS Eight volunteers. INTERVENTIONS After a control period, dopexamine was administered using four infusion rates (0.75, 1.5, 3.0, and 6.0 microg/kg/min). MEASUREMENTS AND MAIN RESULTS Blood pressure, heart rate, oxygen consumption (VO2), and the plasma concentration of potassium, glucose, lactate, and norepinephrine were measured. Typical hemodynamic responses were seen. VO2 increased from 122 +/- 11 (SD) to 150 +/- 9 mL/min/m2 during the highest dopexamine infusion rate. Plasma potassium concentration decreased only during the highest infusion rate. Plasma glucose concentration increased during infusion rates of 3 and 6 microg/kg/min of dopexamine, from 90 +/- 5 to 99 +/- 5 mg/dL (5.0 +/- 0.3 to 5.5 +/- 0.3 mmol/L), and from 87 +/- 7 to 103 +/- 11 mg/dL (4.8 +/- 0.4 to 5.7 +/- 0.6 mmol/L), respectively. Lactate did not increase during dopexamine infusion. Plasma norepinephrine concentration increased during all four infusion rates. CONCLUSION It was not possible to differentiate the adrenergic receptor subtype responsible for the calorigenic and metabolic effects, since the putative beta2 adrenergic-receptor agonist, dopexamine, caused an increase in the plasma concentration of the beta1 adrenergic-receptor agonist, norepinephrine. Since beta2 adrenergic receptor-mediated effects such as hypokalemia were found only at infusion rates > or = 3 microg/kg/min, the effects of dopexamine at infusion rates < 3 microg/kg/min may be mainly mediated by stimulation of dopaminergic receptors and the indirect sympathomimetic action.

Assessment of perioperative glycerol metabolism by stable isotope tracer technique

The aim of this study was to investigate metabolic changes during and after abdominal hysterectomy with specific regard to glycerol metabolism. Seven otherwise healthy patients with benign uterine myoma were enrolled in this study. Glycerol turnover and hepatic glucose production were measured before and after the operation by using stable-isotope technique ([1,1,2,3,3-2H5]-glycerol, [6,6-2H2]-glucose). Metabolic substrates (glycerol, nonesterified fatty acids, β-hydroxybutyrate, glucose, lactate) and hormones (insulin, glucagon, cortisol, catecholamines) were determined pre-, intra-, and postoperatively. Hysterectomy was associated with an increase of postoperative glycerol turnover from 3.56 ± 1.28 to 6.46 ± 2.44 μmol · kg−1 · min−1 (P < 0.05). This increment was inversely related to the age of the patients (r = 0.872, P < 0.05). Glycerol concentration tended to increase perioperatively. These changes, however, were not of statistical significance. Hepatic glucose production and glucose plasma levels increased postoperatively from 9.75 ± 1.61 to 12.79 ± 1.45 μmol · kg−1·min−1 (P < 0.05) and 4.6 ± 0.9 to 6.2 ± 0.9 mmol/L (P < 0.05), respectively. Cortisol and catecholamine levels rose during and after surgery, while insulin and glucagon remained unchanged. The enhanced rate of lipolysis after hysterectomy was not detectable from plasma glycerol levels alone. The results of this study showed that using stable isotope technique allowed a more differentiated look at metabolic pathways than static plasma substrate concentrations, especially under perioperative conditions.

Integrated analysis of glucose, lipid, and urea metabolism in patients with bladder cancer. Impact of tumor stage.

OBJECTIVE The aim of the study was to characterize the metabolic changes in non-weight-losing patients with cancer of the bladder and to investigate the effect of tumor stage. The kinetics of glucose, glycerol, and urea metabolism were assessed in 22 weight-stable patients with non-metastatic bladder cancer (tumor stage p </= T2, n = 8; tumor stage p > T2, n = 14) and 10 patients with benign uterine myoma (controls). METHODS The kinetics of glucose, glycerol, and urea metabolism were assessed by [6,6-(2)H(2)]glucose, [1,1,2,3,3-(2)H(5)]glycerol, and [(15)N(2)]urea. Plasma concentrations of glucose, glycerol, urea, lactate, free fatty acids, insulin, glucagon, cortisol, epinephrine, and norepinephrine also were determined. RESULTS Plasma concentrations of glucose, urea, and insulin were higher in cancer patients than in controls (P < 0.05). Whereas glucose production was similar in both groups, glucose clearance was lower in patients with bladder cancer (P < 0.05). Glycerol turnover rate was comparable between groups. Whole-body urea synthesis rate was higher in the cancer group than in the control group (P < 0.05), but there was no difference in urea synthesis when calculated per kilogram of fat-free body mass. Plasma concentrations of glycerol, lactate, free fatty acids, glucagon, cortisol, epinephrine, and norepinephrine were similar in both groups. There was no difference in any parameter between patients with an early tumor stage (p < T2) and patients with a later tumor stage (p > T2). CONCLUSION Patients with bladder cancer had a lower rate of glucose clearance than did control subjects. Lipid metabolism was not affected, whereas urea synthesis rate was elevated in cancer patients. However, when expressed per kilogram of fat-free body mass, no difference in protein breakdown could be observed. The tumor stage had no effect on glucose, lipid, or protein metabolism.

[Parenteral nutrition therapy. Energy and non-energy actions of carbohydrates and fats].

ZusammenfassungZiel dieser Arbeit ist es, die nicht-energetische Bedeutung der klassischen Energieträger Kohlenhydrate und Fette im Rahmen parenteraler Ernährungskonzepte darzustellen. Basierend auf der pharmakologischen Funktion dieser Nährsubstrate im Kontext der pathophysiologischen Veränderungen des Organ- und Intermediärstoffwechsels definiert sich eine Ernährungsstrategie, die versucht, eine differenzierte, auf einzelne Krankheitsbilder abgestimmte Nährstoffzufuhr durchzuführen. Kohlenhydratzufuhr: Dabei werden als wesentliche Ziele einer parenteralen Kohlenhydratgabe die Vermeidung von Hyperglykämie, die Normalisierung der nach Trauma und während Sepsis gesteigerten hepatischen Glukoseproduktion sowie die Reduktion der Proteinkatabolie genannt. Bei der Realisierung dieser Zielgrößen sind der Zufuhr von Glukose in Abhängigkeit vom vorliegenden Krankheitsbild und der verwendeten Dosierung metabolische Grenzen gesetzt. Der Zuckeraustauschstoff Xylit repräsentiert aufgrund günstiger Effekte auf den hepatischen Glukose- und Proteinstoffwechsel eine metabolisch sinnvolle Alternative zur alleinigen Verwendung von Glukose. Fettapplikation: Die nicht-energetische Ernährungstherapie mit Fetten beinhaltet einerseits die Zufuhr der essentiellen Fettsäuren Linolsäure und α-Linolensäure und berücksichtigt andererseits das immunmodulatorische Potential verschiedener Fettsäuren als Präkursoren im Eikosanoidstoffwechsel. Am Beispiel der Organsysteme Leber und Lunge wird aufgezeigt, daß wegen dieser pharmakologischen Bedeutung einzelner Fettsäuren jede Lipidinfusion prinzipiell einen Einfluß auf spezifische Organfunktionen nehmen kann.AbstractThe object of this review is to demonstrate the non-nutritional importance of carbohydrates and fat as they represent the classic energy carriers in parenteral nutrition. Concerning the pathophysiological changes of organ metabolism and intermediary metabolism as well as the pharmacological function of this nutritive substrates it is necessary to adjust parenteral nutrition strategy to various clinical pictures. The major goals of parenteral applicated carbohydrates are to avoid hyperglycemia, to return the increased hepatic glucose production during trauma and sepsis back to normal, and to reduce protein catabolism. Realizing this goals the dosage of glucose infusion underlies close metabolic borders depending on the present disease. Because of favourable effects of hepatic glucose and protein metabolism, xylitol, a non-glucose polyol, represents a useful alternative energy source to glucose. The non-energetic nutrition therapy with fat consists of application of the essential fatty acids linolic and linloeic acid and considers the immunmodulatory effects of various fatty acids as precursors in the eicosanoid metabolism. As demonstrated at the organ systems of liver and lung this pharmacological effects of any lipid infusion might influence specific organ functions.

Die parenterale ErnährungstherapieEnergetische und nicht-energetische Wirkungen von Kohlenhydraten und Fetten: Energetische und nicht-energetische Wirkungen von Kohlenhydraten und Fetten

ZusammenfassungZiel dieser Arbeit ist es, die nicht-energetische Bedeutung der klassischen Energieträger Kohlenhydrate und Fette im Rahmen parenteraler Ernährungskonzepte darzustellen. Basierend auf der pharmakologischen Funktion dieser Nährsubstrate im Kontext der pathophysiologischen Veränderungen des Organ- und Intermediärstoffwechsels definiert sich eine Ernährungsstrategie, die versucht, eine differenzierte, auf einzelne Krankheitsbilder abgestimmte Nährstoffzufuhr durchzuführen. Kohlenhydratzufuhr: Dabei werden als wesentliche Ziele einer parenteralen Kohlenhydratgabe die Vermeidung von Hyperglykämie, die Normalisierung der nach Trauma und während Sepsis gesteigerten hepatischen Glukoseproduktion sowie die Reduktion der Proteinkatabolie genannt. Bei der Realisierung dieser Zielgrößen sind der Zufuhr von Glukose in Abhängigkeit vom vorliegenden Krankheitsbild und der verwendeten Dosierung metabolische Grenzen gesetzt. Der Zuckeraustauschstoff Xylit repräsentiert aufgrund günstiger Effekte auf den hepatischen Glukose- und Proteinstoffwechsel eine metabolisch sinnvolle Alternative zur alleinigen Verwendung von Glukose. Fettapplikation: Die nicht-energetische Ernährungstherapie mit Fetten beinhaltet einerseits die Zufuhr der essentiellen Fettsäuren Linolsäure und α-Linolensäure und berücksichtigt andererseits das immunmodulatorische Potential verschiedener Fettsäuren als Präkursoren im Eikosanoidstoffwechsel. Am Beispiel der Organsysteme Leber und Lunge wird aufgezeigt, daß wegen dieser pharmakologischen Bedeutung einzelner Fettsäuren jede Lipidinfusion prinzipiell einen Einfluß auf spezifische Organfunktionen nehmen kann.AbstractThe object of this review is to demonstrate the non-nutritional importance of carbohydrates and fat as they represent the classic energy carriers in parenteral nutrition. Concerning the pathophysiological changes of organ metabolism and intermediary metabolism as well as the pharmacological function of this nutritive substrates it is necessary to adjust parenteral nutrition strategy to various clinical pictures. The major goals of parenteral applicated carbohydrates are to avoid hyperglycemia, to return the increased hepatic glucose production during trauma and sepsis back to normal, and to reduce protein catabolism. Realizing this goals the dosage of glucose infusion underlies close metabolic borders depending on the present disease. Because of favourable effects of hepatic glucose and protein metabolism, xylitol, a non-glucose polyol, represents a useful alternative energy source to glucose. The non-energetic nutrition therapy with fat consists of application of the essential fatty acids linolic and linloeic acid and considers the immunmodulatory effects of various fatty acids as precursors in the eicosanoid metabolism. As demonstrated at the organ systems of liver and lung this pharmacological effects of any lipid infusion might influence specific organ functions.

Die parenterale ErnährungstherapieEnergetische und nicht-energetische Wirkungen von Kohlenhydraten und Fetten

ZusammenfassungZiel dieser Arbeit ist es, die nicht-energetische Bedeutung der klassischen Energieträger Kohlenhydrate und Fette im Rahmen parenteraler Ernährungskonzepte darzustellen. Basierend auf der pharmakologischen Funktion dieser Nährsubstrate im Kontext der pathophysiologischen Veränderungen des Organ- und Intermediärstoffwechsels definiert sich eine Ernährungsstrategie, die versucht, eine differenzierte, auf einzelne Krankheitsbilder abgestimmte Nährstoffzufuhr durchzuführen. Kohlenhydratzufuhr: Dabei werden als wesentliche Ziele einer parenteralen Kohlenhydratgabe die Vermeidung von Hyperglykämie, die Normalisierung der nach Trauma und während Sepsis gesteigerten hepatischen Glukoseproduktion sowie die Reduktion der Proteinkatabolie genannt. Bei der Realisierung dieser Zielgrößen sind der Zufuhr von Glukose in Abhängigkeit vom vorliegenden Krankheitsbild und der verwendeten Dosierung metabolische Grenzen gesetzt. Der Zuckeraustauschstoff Xylit repräsentiert aufgrund günstiger Effekte auf den hepatischen Glukose- und Proteinstoffwechsel eine metabolisch sinnvolle Alternative zur alleinigen Verwendung von Glukose. Fettapplikation: Die nicht-energetische Ernährungstherapie mit Fetten beinhaltet einerseits die Zufuhr der essentiellen Fettsäuren Linolsäure und α-Linolensäure und berücksichtigt andererseits das immunmodulatorische Potential verschiedener Fettsäuren als Präkursoren im Eikosanoidstoffwechsel. Am Beispiel der Organsysteme Leber und Lunge wird aufgezeigt, daß wegen dieser pharmakologischen Bedeutung einzelner Fettsäuren jede Lipidinfusion prinzipiell einen Einfluß auf spezifische Organfunktionen nehmen kann.AbstractThe object of this review is to demonstrate the non-nutritional importance of carbohydrates and fat as they represent the classic energy carriers in parenteral nutrition. Concerning the pathophysiological changes of organ metabolism and intermediary metabolism as well as the pharmacological function of this nutritive substrates it is necessary to adjust parenteral nutrition strategy to various clinical pictures. The major goals of parenteral applicated carbohydrates are to avoid hyperglycemia, to return the increased hepatic glucose production during trauma and sepsis back to normal, and to reduce protein catabolism. Realizing this goals the dosage of glucose infusion underlies close metabolic borders depending on the present disease. Because of favourable effects of hepatic glucose and protein metabolism, xylitol, a non-glucose polyol, represents a useful alternative energy source to glucose. The non-energetic nutrition therapy with fat consists of application of the essential fatty acids linolic and linloeic acid and considers the immunmodulatory effects of various fatty acids as precursors in the eicosanoid metabolism. As demonstrated at the organ systems of liver and lung this pharmacological effects of any lipid infusion might influence specific organ functions.