Heiner Greten

Oxygen consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic shock

ObjectiveTo test the hypothesis that variations in oxygen consumption (Vo2) and resting metabolic rate reflect the severity of bacterial infections and reflect the development of sepsis syndrome and septic shock. DesignObservational study with sequential measurements of Vo2 and resting metabolic rate by expiratory gas analysis. SettingMedical intensive care unit. PatientsThirty patients, treated primarily for presumed bacterial infection, were examined on 118 treatment days. InterventionsNone. Measurements and Main ResultsVo2 and resting metabolic rate were measured by expiratory gas analysis. For mechanically ventilated patients, a measurement system was developed, based on a paramagnetic oxygen sensor, an infrared CO2 sensor, and digital signal averaging. Measurements in spontaneously breathing patients were performed with a metabolic monitor. Patients were assigned by clinical criteria to the following groups: sepsis, sepsis syndrome, and septic shock. The lowest Vo2 value of each patient in each stage was evaluated. Mean Vo2 in 15 patients with sepsis was 180 ± 19 (SD) mL/min/m2, in 11 patients with sepsis syndrome 156 ± 22 mL/min/m2, and in eight patients with septic shock 120 ± 27 mL/min/m2 (p < .001). Mean resting metabolic rate in sepsis was +55 ± 14%, in sepsis syndrome +24 ± 12%, and in septic shock +2 ± 24% (p < .001). Mean oxygen delivery (Do2) was 501 ± 116 mL/min/m2 in sepsis, 515 ± 186 mL/min/m2 in sepsis syndrome, and 404 ± 96 mL/min/m2 in septic shock. Oxygen extraction (Vo2/Do2) was highest in sepsis (0.39 vs. 0.33 in sepsis syndrome and 0.29 in septic shock). During recovery from sepsis syndrome or septic shock, a significant increase in resting metabolic rate to +61 ± 22% was measured in nine patients. ConclusionsIn sepsis syndrome, Vo2 and resting metabolic rate are enhanced by 30% compared with normal basal metabolism, but they are markedly reduced compared with uncomplicated sepsis. The higher Vo2 in uncomplicated sepsis is flow independent. The noninvasive measurement of Vo2 and resting metabolic rate by expiratory gas analysis therefore can be used as a quantitative staging and monitoring parameter for the development of sepsis syndrome and septic shock.

Selective Deficiency of Hepatic Triglyceride Lipase in Uremic Patients

To investigate the pathogenesis of hypertriglyceridemia in patients with renal disease we measured plasma lipoprotein composition as well as hepatic triglyceride lipase and lipoprotein lipase in post-heparin plasma. Three groups with renal disease were studied: conservatively treated chronic uremia; patients undergoing maintenance hemodialysis; and renal-allograft recipients. A selective decrease of hepatic triglyceride lipase with normal lipoprotein lipase was found in conservatively treated uremia and in patients undergoing hemodialysis. Elevated levels of very-low-density lipoproteins and increased triglycerides in low-density lipoproteins occurred in these patients. In contrast, hepatic triglyceride lipase and lipoprotein lipase were both normal in patients after renal transplantation who had Type II hyperlipoproteinemia as a common lipoprotein pattern with increased low-density-lipoprotein cholesterol and decreased high-density-lipoprotein cholesterol concentrations. The accumulation of a triglyceride-rich low-density lipoprotein in the majority of patients with renal disease may be the consequence of low hepatic triglyceride lipase.

Central Nervous System Effects of Corticotropin-Releasing Factor on Gastrointestinal Transit in the Rat

Corticotropin-releasing factor (CRF) administered into the lateral cerebral ventricle significantly inhibited gastric emptying and small bowel transit, but most markedly increased large bowel transit in a dose-related fashion in freely moving rats. Inhibition of gastric emptying induced by central administration of CRF was completely abolished by pretreatment of the animals with either the ganglionic blocking agent chlorisondamine or the opioid antagonist naloxone, or by noradrenergic blockade with bretylium, but not by truncal vagotomy. Either chlorisondamine, naloxone, or vagotomy--but not bretylium--reversed the inhibitory effect of central CRF on small bowel transit. Chlorisondamine or vagotomy, but neither bretylium nor naloxone, abolished the stimulatory effect of central CRF on large bowel transit. Neither hypophysectomy nor adrenalectomy altered the gastrointestinal motor responses induced by central administration of CRF. Intraperitoneal administration of CRF also significantly inhibited gastric emptying and stimulated large bowel transit but did not alter small bowel transit. These peripheral effects of CRF were not prevented by blockade of autonomic efferents with bretylium or chlorisondamine. It is concluded that (a) CRF acts within the central nervous system to delay gastric emptying, to inhibit small bowel transit, and to increase large bowel transit in freely moving rats and (b) CRF exerts these biological actions by modulation of the autonomic nervous system and, in part, by opioid pathways.

Living donor for liver transplantation

Since living related liver transplantation was first performed in 1989, more than 150 cases have been performed worldwide, mostly in the United States and Japan. This paper reports the first series of living related liver transplantation in Europe. Twenty living related liver transplantation surgeries were performed over a 13‐mo period, with an overall patient survival of 85%. For patients who underwent elective transplantation (n=13), the survival rate was 100%. Technical complications included one arterial thrombosis necessitating retransplantation and five bile leaks requiring surgical revision. The technical improvements that permit avoidance of these complications are discussed. A detailed description of the living related liver procurement is given. All procurements yielded grafts of excellent quality. No intraoperative complications occurred, and no reoperations were necessary. No heterologous blood transfusion was needed. In two patients, incisional hernias developed after wound infection. Living related liver transplantation does not absolve the transplant community of efforts to promote cadaveric organ procurement. Nevertheless, living related liver transplantation does have the advantage of a readily available graft of excellent quality, permitting transplantation with optimal timing under elective conditions. Several centers are now preparing living related segmental liver transplants, following the model of our protocol, for three reasons: (a) to obtain superior results compared with cadaveric liver transplantation; (b) to overcome cadaveric organ shortage and further reduce pretransplantation mortality and (c) to provide viable organs in countries where cadaveric organ procurement is not established. When performed by a team experienced in pediatric liver transplantation and in adult liver resection, living related liver transplantation is an excellent modality for the treatment of end‐stage liver disease in children. (Hepatology 1994;20:49S‐55S.)

Association of Metformin's Effect to Increase Insulin-Stimulated Glucose Transport With Potentiation of Insulin-Induced Translocation of Glucose Transporters From Intracellular Pool to Plasma Membrane in Rat Adipocytes

To examine the cellular mechanism of the antihyperglycemic action of metformin, we studied its effect on various functional and molecular parameters involved in the pathogenesis of insulin resistance. Isolated rat adipocytes were incubated with or without metformin (1–100 μg/ml) for 2 h at 37°C followed by an incubation with or without insulin (1.72 nM). Metformin treatment had no significant effect on basal 3-O-methylglucose uptake. In contrast, metformin increased insulin-stimulated glucose transport in a dose-dependent manner up to 43 ± 7%. This effect was neither associated with a significant effect of metformin on trace insulin binding (1.74 ± 0.20% without metformin vs. 1.89 ± 0.30% with metformin; P > 0.05) nor with an effect of metformin on insulin-receptor kinase activity as measured by 32P incorporation into the 95,000-Mr β-subunit of the insulin receptor and an exogenous substrate, histone 2B. Determination of glucose-transporter numbers in subcellular membrane fractions, plasma membranes (PMs), and low-density microsomes (LDMs) with cytochalasin B binding revealed that metformins effect to increase insulin-stimulated glucose transport is associated with a potentiation (38 ± 5%) of insulininduced translocation of glucose transporter from the LDM to the PM, whereas the basal state was not significantly affected (basal LDM 61.3 ± 4.2 vs. basal metformin LDM 63.6 ± 7.1, P < 0.05; basal PM 6.4 ± 2.1 vs. basal metformin PM 7.2 ± 2.8, P > 0.05; insulin LDM 32.7 ± 5.4 vs. insulin-metformin LDM 15.8 ± 3.7, P < 0.01; insulin PM 28.6 ± 4.6 vs. insulin-metformin PM 45.3 ± 4.9 pmol/mg membrane protein, P < 0.01). Immunodetection of glucose-transporter isoforms HepG2 erythrocyte (GLUT1) and muscle adipose tissue (GLUT4) in adipocyte membrane fractions separated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and blotted to nitrocellulose revealed that insulin-induced translocation of GLUT1 and GLUT4 is potentiated by metformin. Determination of specific GLUT1 and GLUT4 mRNA levels revealed that this metformin effect is not associated with an increase in glucose-transporter gene expression. We conclude that 1) metformin increases insulinstimulated 3-O-methylglucose transport by potentiating insulin-induced translocation of GLUT1 and GLUT4 glucose transporter from LDM to the PM without affecting glucose-transporter gene expression, and 2) because neither insulin binding nor activation of insulin-receptor kinase in intact cells was significantly altered by metformin, these results suggest that metformin acts at the level of glucose transport.

Scavenger Receptor Class B Type I Mediates the Selective Uptake of High-Density Lipoprotein–Associated Cholesteryl Ester by the Liver in Mice

Objective— High-density lipoprotein (HDL) cholesteryl esters (CE) are taken up by liver and adrenals selectively, ie, independent from particle internalization. Class B type I scavenger receptor (SR-BI) mediates this uptake in vitro. The role of SR-BI in HDL metabolism was explored in mice. Methods and Results— Mice with a mutation in the SR-BI gene (SR-BI KO) and wild-type (WT) littermates were used. Mutants had increased HDL cholesterol. HDL was labeled with 125I (protein) and [3H] (CE). After HDL injection, blood samples were drawn and finally the mice were euthanized. In WT, the plasma decay of HDL-associated [3H] is faster compared with 125I and this represents whole-body selective CE uptake. In SR-BI KO, the decay of both tracers is similar, yielding no selective CE removal. In WT liver and adrenals, uptake of [3H] is higher than 125I, showing selective uptake. In SR-BI KO, liver uptake of [3H] and 125I are similar, proposing no selective HDL CE uptake. In SR-BI KO adrenals, selective uptake is reduced; however, even in the absence of SR-BI, this uptake is detected using WT-HDL. Conclusions— SR-BI mediates selective uptake of HDL CE by the liver. In adrenals, an alternative mechanism or mechanisms can play a role in selective CE uptake.

In vitro modulation of the distribution of normal human plasma high density lipoprotein subfractions through the lecithin: Cholesterol acyltransferase reaction☆

The effect of the lecithin: cholesterol acyltransferase reaction on the chemical composition, morphology and distribution of normal human plasma high density lipoprotein (HDL) subclasses was studied in vitro. Incubation of plasma in the presence of polyenephosphatidylcholine (PPC) resulted in a 45 +/- 11% (n = 6) decrease in unesterified cholesterol after 20 h. This effect was abolished by prior heating of the plasma at 56 degrees C or by the addition of diisopropyl fluorophosphate (DIFP). Plasma triacylglycerol levels were constant. Analysis of the plasma lipoproteins by zonal ultracentrifugation and isopycnic equilibrium banding revealed a bimodal distribution of the HDL of native plasma and both heat-inactivated or DIFP-treated samples with peak maxima at d = 1.084 g/ml and d = 1.110 g/ml. Following the lecithin:cholesterol acyltransferase reaction essentially all of the HDL material had flotation characteristics typical of HDL2. The peak maximum was d = 1.086 g/ml. There were no apparent changes in the distribution of the lipoproteins of d less than 1.063 g/ml. The newly formed HDL were poor in PC and unesterified cholesterol but rich in cholesteryl ester, sphingomyelin and lyso-PC. The HDL apolipoprotein pattern was unaltered. HDL morphology was not affected by the lecithin:cholesterol acyltransferase reaction. Similar results were obtained in the absence of PPC. However, under these conditions the total phospholipid content of the HDL was reduced and lyso-PC was not demonstrable as a product of the lecithin:cholesterol acyltransferase reaction after 20 h. The results are interpreted to indicate that lecithin:cholesterol acyltransferase is involved in the transformation of HDL3 into HDL2.

Comparison of 80 versus 10 mg of Atorvastatin on Occurrence of Cardiovascular Events After the First Event (from the Treating to New Targets [TNT] Trial)

Analyses of randomized clinical trials are usually restricted to examination of time to first event. However, because many patients have multiple events, this approach precludes much potentially useful clinical and economic data. To assess the effect on overall disease burden in the Treating to New Targets (TNT) study, we evaluated the effect of treatment with atorvastatin 80 versus 10 mg in the period after the occurrence of a first cardiovascular event. In TNT, 10,001 patients with stable coronary heart disease received double-blind therapy with atorvastatin 80 or 10 mg and were followed for 4.9 years. Post hoc time-to-event analysis was used to estimate separate hazard ratios for time to any first, second, third, fourth, and fifth recurrent cardiovascular events. During TNT, 3,082 patients had a first recurrent cardiovascular event, with 1,516, 698, 345, and 197 developing second, third, fourth, and fifth recurrent events, respectively. In patients receiving atorvastatin 80 mg, the relative risk of a first recurrent event was significantly decreased compared to those receiving atorvastatin 10 mg. Significant benefit with the 80-mg dose was also observed for second, third, fourth, and fifth recurrent events. Similar findings were recorded in 5,854 patients with type 2 diabetes mellitus and/or metabolic syndrome and in 3,809 patients > or = 65 years of age compared to younger patients. In conclusion, treatment with atorvastatin 80 mg continued to significantly decrease the risk of any cardiovascular event over time compared to atorvastatin 10 mg in patients who had survived previous events. In TNT, analyses limited to the primary end point significantly underestimated the decrease in total cardiovascular disease burden achieved by intensive low-density lipoprotein cholesterol lowering.

Opposite effects of insulin and catecholamines on LDL-receptor activity in human mononuclear leukocytes.

The mechanisms by which insulin and catecholamines affect low-density lipoprotein (LDL)-receptor activity were studied in freshly isolated human mononuclear leukocytes. Incubation of cells for up to 24 h in a lipid-free medium resulted in an increase in the specific binding, accumulation, and degradation of 125I-labeled LDL. Insulin stimulated the ability of the cells to bind, accumulate, and degrade the lipoprotein with high affinity, which may be caused by an increase in the LDL-receptor number without altering binding affinity. (–)-Epinephrine inhibited the specific binding, accumulation, and degradation of 125I-LDL. This effect appears to be mediated by a decrease in the number of LDL receptors and not by a change in the binding affinity. (–)-Norepinephrine, the unspecific β-adrenergic agonist (–)-isoproterenol, and the β2-specific agonist terbutaline mimicked the effect of epinephrine on LDL-receptor activity. Catecholamines and β-adrenergic agonists yielded sigmoidal log-concentration effect curves. The action of epinephrine was attenuated by the β-antagonist (dl)-propranolol. These results demonstrate that insulin stimulates and catecholamines suppress the specific binding, accumulation, and degradation of 125I-LDL in human mononuclear leukocytes. The catecholamine action appears to be mediated by β2-adrenergic receptors. A suppression of LDL-receptor activity resulting from deficiency of insulin and elevated plasma catecholamine concentrations in uncontrolled insulin-dependent diabetic patients may contribute to the increased levels of LDL cholesterol observed in these patients.

Neonatal Fulminant Hepatitis B: Structural and Functional Analysis of Complete Hepatitis B Virus Genomes from Mother and Infant

Transmission of hepatitis B virus (HBV) from anti-hepatitis B e (anti-HBe)-positive carrier mothers to their infants may result in neonatal fulminant hepatitis B (FHB). We investigated whether HBV variants with a particular DNA sequence and functional phenotype, responsible for FHB, are selected during transmission. Full-length HBV genomes from a mother-infant pair were completely sequenced and transfected into human hepatoma cells. The dominant neonatal and maternal HBV populations were nearly identical (homology 99.8%) and showed a precore stop codon mutation, T-1762 and A-1764 substitutions in the core promoter region, and pre-S2 start codon mutations. Cells transfected with variants from mother and child, compared with wild-type virus, synthesized and released a similar number or fewer HBV DNA-containing particles. In conclusion, no particular HBV strain emerged during neonatal FHB. In this case, a de novo infection with variants showing a defect in HBe antigen and pre-S2 protein synthesis but not a high replication competence probably contributed to the fulminant disease course.