Evaluation of [Formula: see text] enrichment values obtained with an oral breath test under conditions of impaired gastric functioning.

Gastric emptying can be assessed by an oral administration of a 13C labeled substrate and its response in the expiratory release of the oxidation product [Formula: see text]. Impaired gut function, reflected, for example, in an intolerance against enteral nutrition may delay or discontinue gastric emptying, potentially leading to multiple peaks in the time profile of expiration. The resulting profile cannot be analyzed by the usual data evaluation that is based on a 'beta exponential' (BEX) function. We developed a new approach that better reflects the underlying physiology. It allows a flexible time profile of gastric release and considers a transient [Formula: see text] retention in different compartments as well as an incomplete recovery of [Formula: see text] in the expiration. Parameters that describe the distribution/retention kinetics cannot be determined based on the same breath data that were used to estimate emptying. To enable the determination of the kinetic parameters, they were constrained to match published data using a Bayesian statistical analysis. The applicability of the new model was compared with BEX for healthy subjects. BEX fails to explain the observed data and, compared to the new approach, overestimates the speed of emptying. Predictive accuracy under impaired gastric motility was explored using synthetic data. Only the new approach can reproduce a multiphase absorption profile. When routine benchtop equipment was used for measurements, then the rate-limiting step for precision in the estimate of emptying is the quality in the a priori estimate for kinetic parameters rather than precision in measurements. Only about 80% of the absorbed [Formula: see text] has to be released by expiration. With these features, the new approach promises to widen the applicability of breath tests for gastric emptying.

[The Ulm trauma track : Trauma care and research as focal points for medical students]. / Der Ulmer Trauma-Track : Traumaversorgung und -forschung als Schwerpunktsetzung im Medizinstudium.

BACKGROUNDS AND OBJECTIVES: As part of the expansion of the site-specific education profile of the medical curriculum MED@ULM of the University of Ulm, a new track "trauma care and trauma research" was established in the winter semester 2012/2013. The acceptance of the track was evaluated during the winter semester 2013/2014. MATERIAL AND METHODS: The 6-semester track extends the existing curriculum by offering subjects in trauma management and trauma research to students of human medicine. A central aim of the track is to promote medical professional competence, expertise in emergency care and competence in trauma-related scientific work and research. Central learning contents could be intensified in newly established emergency simulation training. Additionally, participating students have to perform a doctoral thesis on an obligatory trauma-related experimental subject. A first analysis study focusing on the learning style of the participating students (n = 17) and a control group consisting of members of the same semester (n = 20) was performed using the Kolb learning style inventory. In a validated evaluation in the winter semesters 2013/2014 and 2014/2015, the students were asked about their expectations and experience with the track, criticisms, suggestions and satisfaction with the study conditions. The data were analyzed using descriptive statistics. RESULTS: The analysis of the students' preferred learning styles revealed no differences between track students and the control group. Most of the students considered the track as a form of personal further education. The students had high expectations of practical skills with relevance to the clinical daily routine, learning scientific methods and preparing their thesis. The track students were more critical with regard to the study conditions than the control group students, although the track students of the third semester still judged their studies to be more interesting than the track students of the first semester and the control group. CONCLUSION: With the introduction of the new trauma track into the curriculum of the medical curriculum MED@ULM of the University of Ulm, a further possibility for medical students to focus on their own individual options was established. At least half of the track students wanted to be later active in the triad of patient care, teaching and research. Further investigations are necessary to determine whether the establishment of the trauma track has a positive influence on the number of new recruits in trauma surgery and anesthesiology.

Sulfide-inhibition of mitochondrial respiration at very low oxygen concentrations.

Our aim was to study the ability of an immortalized cell line (AMJ2-C11) to sustain aerobic cell respiration at decreasing oxygen concentrations under continuous sulfide exposure. We assumed that the rate of elimination of sulfide through the pathway linked to the mitochondrial respiratory chain and therefore operating under aerobic conditions, should decrease with limiting oxygen concentrations. Thus, sulfide's inhibition of cellular respiration would occur faster under continuous sulfide exposure when the oxygen concentration is in the very low range. The experiments were performed with an O2K-oxygraph (Oroboros Instruments) by suspending 0.5-1×10(6) cells in 2 ml of continuously stirred respiration medium at 37 °C and calculating the oxygen flux (JO2) as the negative derivative of the oxygen concentration in the medium. The cells were studied in two different metabolic states, namely under normal physiologic respiration (1) and after uncoupling of mitochondrial respiration (2). Oxygen concentration was controlled by means of a titration-injection pump, resulting in average concentration values of 0.73±0.05 µM, 3.1±0.2 µM, and 6.2±0.2 µM. Simultaneously we injected a 2 mM Na2S solution at a continuous rate of 10 µl/s in order to quantify the titration-time required to reduce the JO2 to 50% of the initial respiratory activity. Under the lowest oxygen concentration this effect was achieved after 3.5 [0.3;3.5] and 11.7 [6.2;21.2]min in the uncoupled and coupled state, respectively. This time was statistically significantly shorter when compared to the intermediate and the highest O2 concentrations tested, which yielded values of 24.6 [15.5;28.1]min (coupled) and 35.9 [27.4;59.2]min (uncoupled), as well as 42.4 [27.5;42.4]min (coupled) and 51.5 [46.4;51.7]min (uncoupled). All data are medians [25%, and 75% percentiles]. Our results confirm that the onset of inhibition of cell respiration by sulfide occurs earlier under a continuous exposure when approaching the anoxic condition. This property may contribute to the physiological role of sulfide as an oxygen sensor.

CTLA-4 regulates the murine immune response to Trypanosoma cruzi infection.

Infection with Trypanosoma cruzi causes a profound suppression of T cell responsiveness to polyclonal or antigenic stimuli. In this study, we quantified expression of the negative T cell regulatory molecule CTLA-4 in T. cruzi infected mice and analysed its influence on the immune suppression. Levels of splenic CTLA-4 expression were highest around day 10 after infection, reaching 5% in resistant B6D2F1 mice, but exceeding 10% of CD4(+) T cells in C57BL/6 mice that were susceptible to mortal disease. The proliferative response of explanted splenocytes to CD3-mediated stimulation was strongly suppressed in both the susceptible and the resistant strains. Blockade of CTLA-4 in vitro with a monoclonal antibody affected neither proliferative response nor cytokine production (IFN-gamma, IL-4 and IL-2) by splenic T cells from infected C57BL/6 mice. Treatment of mice with anti-CTLA-4 antibody on the day of infection decreased IFN-gamma production and reduced mortality by about 50%. We conclude that high CTLA-4 expression is a hallmark of severe disease in murine T. cruzi infection, and that CTLA-4 has a regulative influence at the early stages during priming of the immune reaction to the parasite, augmenting a strong Th1-biased response.

Xenon incorporated in a lipid emulsion inhibits NMDA receptor channels.

BACKGROUND: Over the past decade hyperpolarized (129)xenon incorporated in lipid emulsions has been studied for the purpose of imaging enhancement in radiology. Xenon (Xe), a NMDA (N-methyl-D-aspartate)-receptor antagonist, has neuroprotective properties even at subanesthetic concentrations. Thus, its intravenous administration for this purpose deserves further evaluation. In this study, we investigated in an in vitro model the effect of Xe, incorporated in a lipid emulsion (Lipofundin MCT(R) 20%), on the NMDA receptor channel of cortical neurons of the mouse. METHODS: Pulses of 50 micro M of NMDA solution were extracellularly applied to the cells for 10 s, and the elicited membrane currents (I) were recorded while the membrane potential (V) was clamped at -80 mV. Either Lipofundin MCT(R) 20% or aqueous solution was loaded with Xe and applied simultaneously with the NMDA pulses by means of a multibarreled pipette attached to a battery of infusion-pumps. RESULTS: Xenon equilibrated in Lipofundin(R) caused a concentration-dependent and reversible inhibition of NMDA-induced currents (maximal Xe content [Xemax]: 190 micro l ml-1). The inhibitory effect was equivalent compared with the effect of Xe dissolved in aqueous solution (Xemax: 89 micro l ml-1) even though the Xe content of the lipid solution was almost doubled. Further enhancement of the Xe content by saturating both the lipid emulsion and the aqueous solutions with Xe (Xemax: 256 micro l ml-1) did not increase the inhibitory action on NMDA-receptors. CONCLUSION: The data demonstrate that Xe dissolved in Lipofundin MCT(R) 20% inhibits NMDA-receptors. Lipid emulsions enriched with Xe may serve as a carrier and a reservoir for Xe.

[Catabolic stress response during and after abdominal surgery. Comparison between two anaesthesia procedures]. / Katabole Stressantwort während und nach abdominalchirurgischen Eingriffen. Ein Vergleich zwischen zwei Anästhesieverfahren.

BACKGROUND: The purpose of the study was to investigate the effect of modified neuroleptanesthesia (NLA) with fentanyl/midazolam on the catabolic responses during and after abdominal surgery. METHODS: A total of 13 patients undergoing cystoprostatectomy received either modified NLA ( n=7) or inhaled anesthesia with isoflurane (ISO, n=6). Glucose and urea production rates were assessed before, during and 1 day after the operation. Plasma concentrations of glucose, urea, lactate, insulin, glucagon and cortisol were also determined. RESULTS: In contrast to isoflurane anesthesia, modified NLA prevented an increase in plasma glucose concentration and glucose production during ( P<0.05), but not after surgery. There were no differences in perioperative urea production rates or plasma concentrations of urea, insulin, glucagon and lactate between the two groups. Modified NLA suppressed the intraoperative increase in plasma cortisol concentration as observed in the ISO group ( P<0.05). CONCLUSION: Modified NLA inhibits the increase in plasma glucose concentration and glucose production as seen during isoflurane anesthesia. However, NLA does not influence the catabolic response on the first postoperative day.

Sevoflurane versus isoflurane--anaesthesia for lower abdominal surgery. Effects on perioperative glucose metabolism.

BACKGROUND: The aim of this study was to determine the impact of sevoflurane anaesthesia on metabolic and endocrine responses to lower abdominal surgery. METHODS: A prospective randomized controlled study in 20 patients undergoing abdominal hysterectomy. Patients were randomly assigned to receive either sevoflurane (S) or isoflurane anaesthesia (I). Using a stable isotope dilution technique, endogenous glucose production (EGP) and plasma glucose clearance (GC) were determined pre- and postoperatively (6,6-2H2-glucose). Plasma concentrations of glucose, insulin, cortisol, epinephrine and norepinephrine were measured preoperatively, 5 min after induction of anaesthesia, during surgery and 2 h after the operation. RESULTS: EGP increased in both groups with no intergroup differences (preop. S 12.2 +/- 1.6, I 12.4 +/- 1.6; postop. S 16.3 +/- 1.9*, I 19.0 +/- 3.1* micromol kg(-1) min(-1), all values are means +/- SD, *P < 0.05 vs. preop.). Plasma glucose concentration increased and GC decreased in both groups. There were no differences between groups. (Glucose conc. mmol l(-1) preop.: S 4.1 +/- 0.3, I 3.9 +/- 0.5; 5 AI S 5.1 +/- 0.6*, I 5.1 +/- 1.0*, postop. S 7.0 +/- 1.0*, I 7.1 +/- 1.4*; * = P < 0.05 vs. preop.; GC ml kg(-1)min(-1) preop. S 3.0 +/- 0.4, I 3.2 +/- 0.4; postop. S 2.4 +/- 0.3*, I 2.7 +/- 0.3*; *=P < 0.05 vs. preop.) Insulin plasma concentrations were unchanged. Cortisol plasma concentrations increased intra- and postoperatively with no changes between the groups. Norepinephrine plasma concentration increased in the S group after induction of anaesthesia. I group norepinephrine was increased 2 h after operation and showed no intergroup differences. CONCLUSION: Sevoflurane, as well as isoflurane, does not prevent the metabolic endocrine responses to surgery.

Phenylalanine kinetics in healthy volunteers and liver cirrhotics: implications for the phenylalanine breath test.

Expired 13CO2 recovery from an oral l-[1-13C]phenylalanine ([13C]Phe) dose has been used to quantify liver function. This parameter, however, does not depend solely on liver function but also on total CO2 production, Phe turnover, and initial tracer distribution. Therefore, we evaluated the impact of these factors on breath test values. Nine ethyl-toxic cirrhotic patients and nine control subjects received intravenously 2 mg/kg of [13C]Phe, and breath and blood samples were collected over 4 h. CO2 production was measured by indirect calorimetry. The exhaled 13CO2 enrichments were analyzed by isotope ratio mass spectrometry and the [13C]Phe and l-[1-13C]tyrosine enrichments by gas chromatography-mass spectrometry. The cumulative 13CO2 recovery was significantly lower in cirrhotic patients (7 vs. 12%; P < 0.01), in part due to lower total CO2 production rates. Phe turnover in cirrhotic patients was significantly lower (33 vs. 44 micro mol. kg(-1). h(-1); P < 0.05). When these extrahepatic factors were considered in the calculation of the Phe oxidation rate, the intergroup differences were even more pronounced (3 vs. 7 micro mol. kg(-1). h(-1)) than those for 13CO2 recovery data. Also, the Phe-to-Tyr conversion rate, another indicator of Phe oxidation, was significantly reduced (0.7 vs. 3.0 micro mol. kg(-1). h(-1)).

Intraoperative epidural blockade prevents the increase in protein breakdown after abdominal surgery.

BACKGROUND: The aim of this study was to investigate the effect of epidural blockade with bupivacaine, restricted to the intraoperative period, on protein catabolism after major abdominal surgery. METHODS: Fourteen patients undergoing cystoprostatectomy were randomly assigned to receive either general anaesthesia with isoflurane (control group, n=7) or a combination of general anaesthesia and epidural blockade with bupivacaine from segment T4 to S5 (epidural group, n=7). Rates of urea (Ra urea) and glucose production (Ra glucose) were measured three days before and three days after the operation using stable isotope tracers ([15N2]urea, [6,6-2H2]glucose). Protein breakdown was calculated from the urea production rate. Plasma concentrations of metabolic substrates (urea, glucose, lactate, glycerol, amino acids) and hormones (insulin, glucagon, cortisol, adrenaline, noradrenaline) were also determined. RESULTS: Protein breakdown significantly increased after surgery in the control group (P<0.05), while it remained unaltered in the epidural group (control; 66 (54-76), epidural; 43 (29-58) mg x kg(-1) x h(-1), P<0.05, median (range)). Glucose plasma concentration and Ra glucose increased in both groups to a similar extent (P<0.05). Plasma concentration of branched chain amino acids decreased after epidural analgesia to a value significantly lower than in the control group (P<0.05). Glutamine plasma concentration decreased in the control group (P<0.05), but did not change in the epidural group. There were no differences in plasma concentrations of insulin, cortisol and catecholamines between the two groups. Glucagon plasma concentration in the epidural group was significantly lower than in the control group (P<0.05). CONCLUSION: Intraoperative epidural blockade inhibits the increase in protein breakdown after abdominal surgery.

Laparoscopic-assisted vaginal hysterectomy and the hyperglycemic response to surgery: an observational study.

PURPOSE: To test the hypothesis that laparoscopic-assisted vaginal hysterectomy (LAVH) attenuates the hyperglycemic response to surgery when compared to vaginal hysterectomy (VH). METHODS: Fourteen patients received either LAVH (n=7) or VH (n=7). Whole body glucose production was measured before and three hours after surgery using [6.6-2H2] glucose. Before, during and after the operation, plasma concentrations of glucose, insulin, glucagon, cortisol, epinephrine and norepinephrine were determined. RESULTS: Plasma glucose concentration increased in both groups during and after surgery showing a significantly higher value after VH than after LAVH (VH: 8.3 +/- 1.4 mmol x L(-1); LAVH: 6.6 +/- 0.9 mmol x L(-1), P <0.05). The postoperative increase in glucose production was comparable in both groups. While plasma concentrations of insulin and glucagon remained unchanged, intra- and postoperative plasma cortisol concentrations were significantly higher in the VH group than in the LAVH group. Plasma catecholamine concentrations significantly increased after both types of surgery to the same extent. CONCLUSION: In this observational study, LAVH appears to blunt the hyperglycemic and cortisol response to surgery when compared to VH.

Hepato-splanchnic metabolic effects of the stable prostacyclin analogue iloprost in patients with septic shock.

OBJECTIVE: To evaluate the effects of the stable prostacyclin analogue iloprost on hepato-splanchnic blood flow, oxygen exchange and metabolism in patients with septic shock. DESIGN: Prospective clinical study. SETTING: Intensive care unit in a university clinic. PATIENTS: Eleven patients with septic shock requiring norepinephrine to maintain mean arterial pressure above 70 mmHg. INTERVENTIONS: Iloprost was incrementally infused to increase cardiac index by 15%. MEASUREMENTS AND MAIN RESULTS: Splanchnic blood flow (Qspl) was measured using the steady-state indocyanine-green infusion technique and endogenous glucose production rate (EGP) using a stable isotope approach. Systemic and splanchnic oxygen consumption (VO2), the hepato-splanchnic uptake rates of the glucose precursors lactate, pyruvate, alanine and glutamine, the hepatic venous redox state and gastric mucosal-arterial PCO2 gradients were determined. After a baseline measurement, iloprost infusion was started. After 90 min all measurements were repeated and a third measurement was obtained after another 90 min following iloprost withdrawal. Qspl (baseline I: 0.82/0.75-1.08 l x min x m2; iloprost: 0.94/0.88-1.29 l x min x m2; baseline II: 0.87/0.74-1.09 l x min x m2) and splanchnic oxygen delivery (baseline I: 122/103-166 ml x min x m2; iloprost: 134/117-203 ml x min x m2; baseline II: 130/98-158 ml x min x m2) significantly increased. While systemic VO2 significantly increased (baseline I: 139/131-142 ml x min x m2; iloprost: 147/136-164 ml x min x m2; baseline II: 143/133-154 ml x min x m2) splanchnic VO2 increased in 9 of 11 patients which, however, did not reach statistical significance. EGP significantly decreased (baseline I: 23/16-26 micromol x kg x min; iloprost: 16/14-21 micromol x kg x min; baseline II: 18/12-20 micromol x kg x min), whereas all other parameters of energy metabolism remained unchanged. CONCLUSION: In patients with septic shock an iloprost-induced increase in cardiac index increased splanchnic blood flow and shifted oxygen utilization from the energy requiring de novo glucose production rate to other oxygen-demanding metabolic pathways.

Effects of selective iNOS inhibition on gut and liver O2-exchange and energy metabolism during hyperdynamic porcine endotoxemia.

We have previously demonstrated that non-selective nitric oxide synthase (NOS) inhibition did not reverse the LPS-induced deterioration of hepato-splanchnic energy status in porcine endotoxic shock. Therefore, this study investigated the effect of selective inducible NOS (iNOS) inhibition using 1400 W on intestinal and liver perfusion, O2 kinetics, and energy metabolism during hyperdynamic porcine endotoxemia. Intravenous E. Coli LPS was continuously infused over 24 h concomitant with fluid resuscitation. After 12 h of endotoxemia, continuous intravenous infusion of 1400 W was started until the end of the experiment and was titrated to maintain mean blood pressure (MAP) at baseline levels. Twelve, 18, and 24 h after starting LPS, we measured hepatic arterial and portal venous blood flow, ileal mucosal-arterial PCO2 gap, portal as well as hepatic venous lactate/pyruvate ratios, and endogenous glucose production rate. Expired NO and plasma nitrate levels were assessed as a measure of NO production. 1400 W decreased LPS-induced increase in expired NO and allowed for the maintenance of MAP without modification of cardiac output. Despite unchanged regional macrocirculation, 1400 W prevented the progressive rise of ileal mucosal-arterial PCO2 gap, significantly improved the LPS-induced impairment of hepato-splanchnic redox state, and blunted the decline in liver lactate clearance. Increased glucose production rate was not influenced. Thus, the selective iNOS inhibition with 1400 W prevented circulatory failure and largely attenuated otherwise progressive LPS-induced deterioration of intestinal and hepatocellular energy metabolism.

Arterial and mixed venous xenon blood concentrations in pigs during wash-in of inhalational anaesthesia.

There are no data available on the kinetics of blood concentrations of xenon during the wash-in phase of an inhalation anaesthesia aiming at 1 MAC end-expiratory concentration. Therefore, we anaesthetized eight pigs with continuous propofol and fentanyl and measured arterial, mixed venous and end-expiratory xenon concentrations by gas chromatography-mass spectrometry 1, 2, 3, 4, 5, 7, 10, 15, 20, 30, 60 and 120 min after starting the anaesthetic gas mixture [67% xenon/33% oxygen; 3 litre x min(-1) during the first 10 min, thereafter minimal flow with 0.48 (SD 0.03) litre x min(-1)]. End-expiratory xenon concentrations plateaued (defined as <5% change from the preceding value) at 64 (6) vol% after 7 min, and arterial and mixed venous xenon concentrations after 5 and 15 min respectively. The highest arterio-venous concentration difference occurred after 3 min. Using the Fick principle, we calculated a mean xenon uptake of 3708 (829) and 9977 (3607) ml after 30 and 120 min respectively.

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

UNLABELLED: 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 micromol. 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 micromol. kg(-1). min(-1); during surgery, 10.1 +/- 0.5 micromol. 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 micromol. kg(-1). min(-1) to 12.4 +/- 1.0 micromol. 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. IMPLICATIONS: Epidural analgesia combined with general anesthesia prevented the hyperglycemic response to surgery by decreasing endogenous glucose production. The increased glucose plasma concentration in patients receiving fentanyl/midazolam anesthesia was caused by a decrease in whole-body glucose clearance. The hyperglycemic response observed during inhaled anesthesia with isoflurane was a consequence of both impaired glucose clearance and increased glucose production.

Effect of dopexamine on hepatic metabolic activity in patients with septic shock.

Hepato-splanchnic metabolic activity is seen to be related to regional blood flow and oxygen/substrate availability in patients with sepsis. Catecholamines, which may modulate metabolic activity perse, are common to stabilize hemodynamics. We studied the effect of a dopexamine-induced increase in splanchnic blood flow (Qspl) on regional metabolic rate in 10 patients with septic shock requiring norepinephrine to maintain mean arterial pressure (>60 mmHg). Splanchnic blood flow was determined using the indocyanine-green method with hepatic venous sampling. We determined the hepato-splanchnic lactate, pyruvate, alanine, and glutamine turnover and the lactate/pyruvate and ketone body ratio as well as the endogenous glucose production (EGP) using the stable isotope approach. Qspl increased from 0.86 (0.79-1.15) to 0.96 (0.92-1.33) L/min/m2, not influencing any parameter of metabolic activity. We speculate that this finding is due to altered beta-adrenoreceptor-mediated thermogenic effects due to the interplay of different beta-sympathomimetics at the receptor site.

Hepatic oxygen exchange and energy metabolism in hyperdynamic porcine endotoxemia: effects of the combined thromboxane receptor antagonist and synthase inhibitor DTTX30.

OBJECTIVE: We compared the effects of thromboxane receptor antagonist and synthase inhibitor DTTX30 on systemic and liver blood flow, oxygen (O2) exchange and energy metabolism during 24 h of hyperdynamic endotoxemia with untreated endotoxemia. DESIGN: Prospective, randomized, experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: Twenty-seven domestic pigs: 16 during endotoxemia with volume resuscitation alone; 11 with endotoxemia, volume resuscitation and treatment with DTTX30. INTERVENTIONS: Continuous infusion of Escherichia coli lipopolysaccharide (LPS) for 24 h together with volume resuscitation. After 12 h of endotoxemia, DTTX30 was administered as a bolus of 0.12 mg kg-1 followed by 12 h continuous infusion of 0.29 mg kg-1 per h. MEASUREMENTS AND RESULTS: DTTX30 effectively counteracted the endotoxin-associated increase in TXB2 levels and increased 6-keto-PGF1 alpha with a significant shift of the thromboxane/prostacyclin ratio towards predominance of prostacyclin. DTTX30 prevented the significant progressive endotoxin-induced decrease of mean arterial pressure (MAP) below baseline while maintaining cardiac output (CO), and increased the fractional contribution of liver blood flow to CO without an effect on either hepatic O2 delivery or O2 uptake. The mean capillary hemoglobin O2 saturation (HbO2) on the liver surface and HbO2 frequency distributions remained unchanged as well. CONCLUSIONS: DTTX30 significantly attenuated the endotoxin-induced derangements of cellular energy metabolism as reflected by the diminished progressive decrease in hepatic lactate uptake rate and a blunted increase in hepatic venous lactate/pyruvate ratios. While endotoxin significantly increased the endogenous glucose production (EGP) rate, EGP returned towards baseline levels in the DTTX30-treated group. Thus, in our model DTTX30 resulted in hemodynamic stabilization concomitant with improved hepatic metabolic performance.

Glucose infusion does not suppress increased lipolysis after abdominal surgery.

The purpose of this study was to investigate the effect of glucose infusion on lipid metabolism after abdominal surgery. Patients (n = 6) with non-metastasized colorectal carcinoma were investigated on the second day after surgery and healthy volunteers were studied after an overnight fast. The rates of glycerol appearance (R(a) glycerol), i.e., lipolysis rates, were assessed by primed continuous infusion of [1,1,2,3,3,-5H2]glycerol before and after 3 h of glucose infusion (4 mg x kg(-1) x min(-1)). Plasma concentrations of glycerol, free fatty acids, glucose, lactate, insulin, and glucagon were determined. Fasting R(a) glycerol was higher in patients than in volunteers (7.7 +/- 1.8 versus 1.9 +/- 0.3 micromol x kg(-1) x min(-1), P < 0.05). Glucose infusion suppressed the R(a) glycerol in volunteers to 1.0 +/- 0.2 micromol x kg(-1) x min(-1) (P < 0.05), whereas lipolysis was not affected in patients. Plasma concentrations of glycerol and free fatty acids similarly decreased during glucose administration by 50% in both groups (P < 0.05). In contrast to the patients, a significant correlation (r = 0.78, P < 0.05) between the R(a) glycerol and plasma glycerol concentration was observed in normal subjects. The hyperglycemic response to glucose infusion was significantly more pronounced (P < 0.05) in patients (10.7 +/- 0.7 mmol/L) than in volunteers (7.1 +/- 0.4 mmol/L), whereas the plasma insulin increased to the same extent in the two groups (P < 0.001). In conclusion, lipolysis rates are increased after abdominal surgery and glucose administration, most likely due to insulin resistance, and fail to inhibit stimulated whole-body lipolysis.

Hepatic O2 exchange and liver energy metabolism in hyperdynamic porcine endotoxemia: effects of iloprost.

OBJECTIVE: To compare the effects of a 12 h continuous infusion of iloprost, a stable prostacyclin analogue, on hepatic blood flow (Qliv), O2 exchange, and energy metabolism during a 24 h hyperdynamic, porcine endotoxemia with volume resuscitation alone. DESIGN: Prospective, randomized, experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: Twenty-eight domestic pigs: 16 animals during endotoxemia with volume resuscitation alone (ETX), 12 with endotoxemia, volume resuscitation, and treatment with iloprost (ILO). INTERVENTIONS: Endotoxemia was initiated by continuous infusion of E. coli lipopolysaccharide. Animals were resuscitated with hetastarch, aimed at maintaining a MAP of > 60 mmHg. After 12 h of endotoxemia, iloprost was administered for 12 h in the treatment group, titrated to avoid pharmacologically induced hypotension (MAP < 60 mmHg). MEASUREMENTS AND RESULTS: Iloprost significantly increased Qliv, with no effect on hepatic O2 delivery. Mean capillary hemoglobin O2 saturation (HbScO2) on the liver surface, as well as HbScO2 frequency distributions--a measure of microcirculatory O2 availability--remained unchanged. Treatment with iloprost, however, significantly attenuated the endotoxin-induced derangements of cellular energy metabolism as reflected by the diminished progressive decrease in hepatic lactate uptake rate and a blunted increase in hepatic venous lactate/pyruvate ratios. While endotoxin significantly increased endogenous glucose production (EGP) rate, iloprost restored EGP to normal at the end of the experiment. CONCLUSIONS: Thus, in a clinically relevant model of human sepsis, iloprost did not produce potential adverse effects but rather ameliorated hepatic metabolic disturbances and, thereby, hepatic energy balance.

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

UNLABELLED: 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 microg. 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 (R(a) glucose) was analyzed by an isotope dilution technique by using [6,6-(2)H(2)] 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/microU, P < 0.05), the R(a) 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 micromol. 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.

Norepinephrine and nomega-monomethyl-L-arginine in porcine septic shock: effects on hepatic O2 exchange and energy balance.

We compared the effects of norepinephrine (NOR; n = 11) and the nonselective nitric oxide synthase inhibitor Nomega-monomethyl-L-arginine (L-NMMA; n = 11) on hepatic blood flow (Q liv), O2 exchange, and energy metabolism over 24 h of hyperdynamic, normotensive porcine endotoxic shock. Endotoxin (ETX; n = 8) caused a continuous fall in mean arterial pressure (MAP) despite a sustained 50% increase in cardiac output (Q) achieved by adequate fluid resuscitation. NOR maintained MAP at preshock levels owing to a further rise in Q, while the comparable hemodynamic stabilization during L-NMMA infusion resulted from systemic vasoconstriction, increasing the systemic vascular resistance (SVR) about 30% from shock level after 6 h of treatment concomitant with a reduction in Q to preshock values. Whereas NOR also increased Q liv and, hence, hepatic O2 delivery (hDO2), but did not affect hepatic O2 uptake (hVO2), L-NMMA influenced neither Q liv nor hDO2 and hVO2. Mean capillary hemoglobin O2 saturation (HbScO2) on the liver surface as well as HbScO2 frequency distributions, which mirror microcirculatory O2 availability, remained unchanged as well. Neither treatment influenced the ETX-induced derangements of cellular energy metabolism reflected by the progressive decrease in hepatic lactate uptake rate and increased hepatic venous lactate/pyruvate ratios. ETX nearly doubled the endogenous glucose production (EGP) rate, which was further increased with NOR, whereas L-NMMA nearly restored EGP to preshock levels. Nevertheless, despite the different mechanisms in maintaining blood pressure neither treatment influenced ETX-induced liver dysfunction.