Ulrich Wachter

Glucose metabolism and catecholamines.

Until now, catecholamines were the drugs of choice to treat hypotension during shock states. Catecholamines, however, also have marked metabolic effects, particularly on glucose metabolism, and the degree of this metabolic response is directly related to the &bgr;2-adrenoceptor activity of the individual compound used. Under physiologic conditions, infusing catecholamine is associated with enhanced rates of aerobic glycolysis (resulting in adenosine triphosphate production), glucose release (both from glycogenolysis and gluconeogenesis), and inhibition of insulin-mediated glycogenesis. Consequently, hyperglycemia and hyperlactatemia are the hallmarks of this metabolic response. Under pathophysiologic conditions, the metabolic effects of cate-cholamines are less predictable because of changes in receptor affinity and density and in drug kinetics and the metabolic capacity of the major gluconeogenic organs, both resulting from the disease per se and the ongoing treatment. It is also well-established that shock states are characterized by a hypermetabolic condition with insulin resistance and increased oxygen demands, which coincide with both compromised tissue microcirculatory perfusion and mitochondrial dysfunction. This, in turn, causes impaired glucose utilization and may lead to inadequate glucose supply and, ultimately, metabolic failure. Based on the landmark studies on intensive insulin use, a crucial role is currently attributed to glucose homeostasis. This article reviews the effects of the various catecholamines on glucose utilization, both under physiologic conditions, as well as during shock states. Because, to date (to our knowledge), no patient data are available, results from relevant animal experiments are discussed. In addition, potential strategies are outlined to influence the catecholamine-induced effects on glucose homeostasis.

Impact of exogenous beta-adrenergic receptor stimulation on hepatosplanchnic oxygen kinetics and metabolic activity in septic shock.

OBJECTIVE To investigate the impact of exogenous beta-adrenergic receptor stimulation on splanchnic blood flow, oxygen kinetics, glucose-precursor flux, and liver metabolism in septic shock. DESIGN Prospective trial. SETTING University hospital intensive care unit. PATIENTS Six patients with hyperdynamic (cardiac index >4.0 L/min/m2) septic shock, all requiring norepinephrine to maintain blood pressure >65 mm Hg. INTERVENTIONS We compared norepinephrine and phenylephrine titrated to achieve similar systemic hemodynamics and gas exchange. Splanchnic hemodynamics, oxygen kinetics, and metabolic parameters were measured before, during, and after replacing norepinephrine with phenylephrine. MEASUREMENTS AND MAIN RESULTS Splanchnic blood flow and oxygen kinetics were derived from the steady-state indocyanine-green clearance based on hepatic dye extraction and arterial and hepatic venous blood gases. Endogenous glucose production rate was derived from the plasma appearance rate of stable-isotope-labeled glucose using a primed-constant infusion. Splanchnic lactate, alanine (high-performance liquid chromatography) uptake, and hepatic monoethylglycinexylidide (MEGX) (fluorescence polarization immunoassay) formation rates were calculated from splanchnic blood flow and arterial-hepatic venous concentration differences. Replacing norepinephrine with phenylephrine induced no change in systemic hemodynamics or gas exchange. While splanchnic oxygen consumption and alanine uptake rate remained unaffected, splanchnic blood flow, oxygen delivery, and lactate uptake rate were significantly decreased. Glucose production rate also decreased significantly. A return to norepinephrine restored splanchnic blood flow, oxygen delivery, and lactate uptake rate to baseline values, while glucose production rate remained depressed. Hepatic MEGX formation rate was not influenced during the investigation. CONCLUSIONS Exogenous beta-adrenergic receptor stimulation determines splanchnic blood flow, oxygen delivery, and glucose precursor flux but not splanchnic oxygen utilization in septic shock. Gluconeogenesis is not directly affiliated to hepatosplanchnic oxygen kinetics. The different response of glucose and MEGX production rates, metabolic pathways of the periportal and perivenous region, may document intrahepatic heterogeneity associated with hepatocellular metabolic compartmentation.

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.

Effects of ventilation with 100% oxygen during early hyperdynamic porcine fecal peritonitis.

Objective: Early goal-directed therapy aims at balancing tissue oxygen delivery and demand. Hyperoxia (i.e., pure oxygen breathing) has not been studied in this context, since sepsis increases oxygen radical production, which is believed to be directly related to the oxygen tension. On the other hand, oxygen breathing improved survival in various shock models. Therefore, we hypothesized that hyperoxia may be beneficial during early septic shock. Design: Laboratory animal experiments. Setting: Animal research laboratory at university medical school. Subjects: Twenty domestic pigs of either gender. Interventions: After induction of fecal peritonitis, anesthetized and instrumented pigs were ventilated with either 100% oxygen or supplemental oxygen as needed to maintain arterial hemoglobin oxygen saturation ≥90%. Normotensive and hyperdynamic hemodynamics were achieved using hydroxyethyl starch and norepinephrine infusion. Measurements and Main Results: Before and at 12, 18, and 24 hrs of peritonitis, we measured lung compliance; systemic, pulmonary, and hepatosplanchnic hemodynamics; gas exchange; acid-base status; blood isoprostanes; nitrates; DNA strand breaks; and organ function. Gluconeogenesis and glucose oxidation were calculated from blood isotope and expiratory 13CO2 enrichments during continuous intravenous 1,2,3,4,5,6-13C6-glucose. Apoptosis in lung and liver was assessed postmortem (TUNEL staining). Hyperoxia did not affect lung mechanics or gas exchange but redistributed cardiac output to the hepatosplanchnic region, attenuated regional venous metabolic acidosis, increased glucose oxidation, improved renal function, and markedly reduced the apoptotic death rate in liver and lung. Conclusions: During early hyperdynamic porcine septic shock, 100% oxygen improved organ function and attenuated tissue apoptosis without affecting lung function and oxidative or nitrosative stress. Therefore, it might be considered as an additional measure in the first phase of early goal-directed therapy.

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.

Effect of increased cardiac output on hepatic and intestinal microcirculatory blood flow, oxygenation, and metabolism in hyperdynamic murine septic shock

Objective:Septic shock-associated organ dysfunction is attributed to derangements of microcirculatory perfusion and/or impaired cellular oxygen utilization. The hepatosplanchnic organs are regarded to play a pivotal role in the pathophysiology of sepsis-related organ failure. In a murine model of septic shock, we tested the hypothesis whether achieving normotensive, hyperdynamic hemodynamics characterized by a sustained increase in cardiac output would allow maintenance of regional microvascular perfusion and oxygenation and, thus, hepatic metabolic capacity. Design:Prospective, controlled, randomized animal study. Setting:University animal research laboratory. Subjects:Male C57Bl/6 mice. Interventions:Fifteen hours after sham operation (n = 11) or cecal ligation and puncture (CLP) (n = 9), mice were anesthetized, mechanically ventilated, and instrumented (central venous and left ventricular pressure-conductance catheter, portal vein and superior mesenteric artery ultrasound flow probes). Animals received continuous intravenous hydroxyethylstarch and norepinephrine to achieve normotensive and hyperdynamic hemodynamics, and glucose was infused to maintain normoglycemia. Measurements and Main Results:Measurements were recorded 18, 21, and 24 hrs post-CLP. In CLP mice, titration of hemodynamic targets were affiliated superior mesenteric artery and portal vein flow. Using a combined laser-Doppler flowmetry and remission spectrophotometry probe, we found well-maintained gut and liver capillary perfusion as well as intestinal microcirculatory hemoglobin oxygen saturation, whereas hepatic microcirculatory hemoglobin oxygen saturation was even increased. At 24 hrs post-CLP, the rate of de novo gluconeogenesis as derived from hepatic 13C-glucose isotope enrichment after continuous intravenous 1,2,3,4,5,6-13C6-glucose infusion (condensation biosynthesis modeling after gas chromatography-mass spectrometry isotope measurements) was similar in the two experimental groups. Conclusions:During murine septic shock achieving normotensive hyperdynamic hemodynamics with fluid resuscitation and norepinephrine, exogenous glucose requirements together with the lack of norepinephrine-induced increase in the rate of gluconeogenesis mirror impaired metabolic capacity of the liver despite well-maintained hepatosplanchnic microvascular perfusion and oxygenation.

Cardiac and metabolic effects of hypothermia and inhaled hydrogen sulfide in anesthetized and ventilated mice.

Objective: To test the hypothesis whether inhaled hydrogen sulfide amplifies the effects of deliberate hypothermia during anesthesia and mechanical ventilation as hypothermia is used to provide organ protection after brain trauma or circulatory arrest. Awake mice inhaling hydrogen sulfide exhibit reduced energy expenditure, hypothermia, and bradycardia despite unchanged systolic heart function. In rodents, anesthesia alone causes decreased metabolic rate and thus hypothermia and bradycardia. Design: Prospective, controlled, randomized study. Setting: University animal research laboratory. Subjects: Male C57/B6 mice. Interventions: After surgical instrumentation (central venous, left ventricular pressure-conductance catheters, ultrasound flow probes on the portal vein and superior mesenteric artery), normo- or hypothermic animals (core temperature = 38°C and 27°C) received either 100 ppm hydrogen sulfide or vehicle over 5 hrs (3 hrs hydrogen sulfide during normothermia). Measurements and Main Results: During normothermia, hydrogen sulfide had no hemodynamic or metabolic effect. With or without hydrogen sulfide, hypothermia decreased blood pressure, heart rate, and cardiac output, whereas stroke volume, ejection fraction, and end-diastolic pressure remained unaffected. Myocardial and hepatic oxidative deoxyribonucleic acid damage (comet assay) and endogenous glucose production (rate of appearance of 1,2,3,4,5,6-13C6-glucose) were similar in all groups. Hypothermia comparably decreased CO2 production with or without inhaled hydrogen sulfide. During hypothermia, inhaled hydrogen sulfide increased the glucose oxidation rate (derived from the expiratory 13CO2/12CO2 ratio). This shift toward preferential carbohydrate utilization coincided with a significantly attenuated responsiveness of hepatic mitochondrial respiration to stimulation with exogenous cytochrome-c-oxidase (high-resolution respirometry). Conclusions: In anesthetized and mechanically ventilated mice, inhaled hydrogen sulfide did not amplify the systemic hemodynamic and cardiac effects of hypothermia alone. The increased aerobic glucose oxidation together with the reduced responsiveness of cellular respiration to exogenous cytochrome-c stimulation suggest that, during hypothermia, inhaled hydrogen sulfide improved the yield of mitochondrial respiration, possibly via the maintenance of mitochondrial integrity. Hence, inhaled hydrogen sulfide may offer metabolic benefit during therapeutic hypothermia.

Understanding the mechanisms by which isoflurane modifies the hyperglycemic response to surgery.

We studied the effect of anesthesia on the kinetics of perioperative glucose metabolism by using stable isotope tracers. Twenty-three patients undergoing cystoprostatectomy were randomly assigned to receive epidural analgesia combined with general anesthesia (n = 8), fentanyl and midazolam anesthesia (n = 8), or inhaled anesthesia with isoflurane (n = 7). Whole-body glucose production and glucose clearance were measured before and during surgery. Glucose clearance significantly decreased during surgery independent of the type of anesthesia. Epidural analgesia caused a significant decrease in glucose production from 10.2 ± 0.4 to 9.0 ± 0.4 &mgr;mol · kg−1 · min−1 (P < 0.05), whereas the plasma glucose concentration was not altered (before surgery, 5.0 ± 0.2 mmol/L; during surgery, 5.2 ± 0.1 mmol/L). Glucose production did not significantly change during fentanyl/midazolam anesthesia (before surgery, 10.5 ± 0.5 &mgr;mol · kg−1 · min−1; during surgery, 10.1 ± 0.5 &mgr;mol · kg−1 · min−1), but plasma glucose concentration significantly increased from 4.8 ± 0.1 mmol/L to 5.3 ± 0.2 mmol/L during surgery (P < 0.05). Isoflurane anesthesia caused a significant increase in plasma glucose concentration (from 5.2 ± 0.1 mmol/L to 7.2 ± 0.5 mmol/L) and glucose production (from 10.8 ± 0.5 &mgr;mol · kg−1 · min−1 to 12.4 ± 1.0 &mgr;mol · kg−1 · min−1) (P < 0.05). Epidural analgesia prevented the hyperglycemic response to surgery by a decrease in glucose production. The increased glucose plasma concentration during fentanyl/midazolam anesthesia was caused by a decrease in whole-body glucose clearance. The hyperglycemic response observed during isoflurane anesthesia was a consequence of both impaired glucose clearance and increased glucose production.

Breath analysis with broadly tunable quantum cascade lasers.

With the availability of broadly tunable external cavity quantum cascade lasers (EC-QCLs), particularly bright mid-infrared (MIR; 3-20 μm) light sources are available offering high spectral brightness along with an analytically relevant spectral tuning range of >2 μm. Accurate isotope ratio determination of (12)CO2 and (13)CO2 in exhaled breath is of critical importance in the field of breath analysis, which may be addressed via measurements in the MIR spectral regime. Here, we combine for the first time an EC-QCL tunable across the (12)CO2/(13)CO2 spectral band with a miniaturized hollow waveguide gas cell for quantitatively determining the (12)CO2/(13)CO2 ratio within the exhaled breath of mice. Due to partially overlapping spectral features, these studies are augmented by appropriate multivariate data evaluation and calibration techniques based on partial least-squares regression along with optimized data preprocessing. Highly accurate determinations of the isotope ratio within breath samples collected from a mouse intensive care unit validated via hyphenated gas chromatography-mass spectrometry confirm the viability of IR-HWG-EC-QCL sensing techniques for isotope-selective exhaled breath analysis.

Effects of intravenous sulfide during porcine aortic occlusion-induced kidney ischemia/reperfusion injury.

In rodents, inhaled H2S and injection of H2S donors protected against kidney ischemia/reperfusion (I/R) injury. During porcine aortic occlusion, the H2S donor Na2S (sulfide) reduced energy expenditure and decreased the noradrenaline requirements needed to maintain hemodynamic targets during early reperfusion. Therefore, we tested the hypothesis whether sulfide pretreatment may also ameliorate organ function in porcine aortic occlusion-induced kidney I/R injury. Anesthetized, ventilated, and instrumented pigs randomly received either sulfide or vehicle and underwent 90 min of kidney ischemia using intraaortic balloon-occlusion, and 8 h of reperfusion. During reperfusion, noradrenaline was titrated to maintain blood pressure at baseline levels. Sulfide attenuated the fall in creatinine clearance and the rise in creatinine blood levels, whereas renal blood flow and fractional Na+ excretion were comparable. Sulfide also lowered the blood IL-6, IL-1&bgr;, and nitrite + nitrate concentrations, which coincided with reduced kidney oxidative DNA base damage and iNOS expression, and attenuated glomerular histological injury as assessed by the incidence of glomerular tubularization. While expression of heme oxygenase 1 and cleaved caspase 3 did not differ, sulfide reduced the expression Bcl-xL and increased the activation of nuclear transcription factor &kgr;B. During porcine aortic occlusion-induced kidney I/R injury, sulfide pretreatment attenuated tissue injury and organ dysfunction as a result of reduced inflammation and oxidative and nitrosative stress. The higher nuclear transcription factor &kgr;B activation was probably due to the drop in temperature.