Effect of posttraumatic hypoventilation on cerebral energy metabolism

Cerebral energy metabolism was studied in cats subjected to fluid-percussion brain trauma followed immediately by 30 minutes of controlled hypoventilation for the purpose of simulating a more realistic model of human head injury. The cerebral blood flow (CBF) and cerebral metabolic rates of oxygen (CMRO2) and glucose (CMRGl) were measured, with simultaneous phosphorus-31 magnetic resonance spectroscopy quantifications of cerebral tissue pH, phosphocreatine (PCr), and inorganic phosphate (Pi). Hypoventilation alone did not produce marked changes in CMRGl, tissue pH, or PCr:Pi ratios. When hypoventilation was combined with trauma, marked alterations in CBF, CMRGl, PCr:Pi ratio, and tissue pH were seen, indicating relative ischemia. The alterations of cerebral energy metabolism produced by combining trauma and hypoventilation are more severe than those caused by fluid-percussion trauma alone, and may provide a more realistic model of human head injury.     

Effect of chronic uraemia on skeletal muscle metabolism in man

Fatigue and lethargy, common symptoms in uraemia, have beenattributed to many factors. To assess possible bioenergeticcontributions to this, we examined the forearm muscle of fivepatients in end-stage renal failure using ³¹P-magnetic resonancespectroscopy. There was a small increase in the ratio of intracellularinorganic phosphate to ATP in resting muscle, suggesting anincreased cytosolic phosphate concentration. During exercise,increased phosphocreatine breakdown was accompanied by rapidintracellular acidification and an increase in calculated lacticacid accumulation in the muscle of the uraemic subjects, suggestingglycolysis dominating over oxidative phosphorylation as a sourceof ATP. After exercise, the half-time of phosphocreatine (PCr)recovery was longer in the uraemic subjects, suggesting diminishedmitochondrial function. The initial rate of PCr resynthesiswas not significantly decreased, but when account was takenof the high cytosolic ADP concentration (which drives mitochondrialoxidative ATP synthesis) the calculated maximum oxidative capacitywas significantly reduced in the uraemic subjects. Thus therewas evidence of mitochondrial dysfunction in uraemia due eitherto limitation of oxygen supply, reduced mitochondrial content,or an intrinsic mitochondrial defect. This resulted in increasedphosphocreatine depletion and increased glycolytic ATP productionduring exercise and there was partial compensation of the mitochondrialabnormality by increased ADP concentration. In three of thesepatients studied after elevation of haemoglobin with erythropoeitin(from 8 to 12g/dl), initial phosphocreatine breakdown and lacticacid accumulation during exercise were normalized, while exerciseduration and calculated maximum oxidative capacity remainedsignificantly abnormal. This suggests that anaemia contributesto these metabolic abnormalities but does not fully explainthem.     

Effect of sodium D-3-hydroxybutyrate on amino acidemia in hemorrhagic hypotension.

The effect of sodium D-3-hydroxybutyrate (3-OHB) on the amino acidemia caused by hemorrhagic stress was studied. Rats were infused 3-OHB (3-OHB group, n = 11) at a rate of 30 mumol/min.kg or the same volume of saline (control group, n = 11) for 1 h prior to hemorrhage. Mean arterial pressure was maintained at 40 mm Hg using reserved bottle for 30 min. While ketosis was suppressed in control group, plasma ketone body concentration increased from 2,062.9 +/- 223.7 to 3,151.4 +/- 794.8 mumol/l in the 3-OHB group during hemorrhage. Although significant difference in plasma concentrations of amino acids were not shown between two groups at the onset of shock, it was shown after 30 min of shock in alanine, proline, and threonine. Particularly severity of hyperalaninemia was clear. In the control group plasma alanine concentration increased as shock proceeded (p less than 0.01), and no significant change was shown in the 3-OHB group. These results indicate that pretreatment with 3-OHB suppress the hyperalaninemia seen in hemorrhagic hypotension. Ketone body administration may inhibit the protein catabolism in stressed states, such as hemorrhagic hypotension.     

Effect of isoflurane anaesthesia and surgery on carbohydrate metabolism and plasma cortisol levels in man.

The present study was undertaken to investigate in nine male surgical patients the effects of isoflurane anaesthesia alone on the carbohydrate metabolism by determining plasma growth hormone (GH), insulin, blood glucose, and cortisol, and to compare them with the effects of anaesthesia associated with surgical operations. Determination of plasma GH, insulin, cortisol, and blood glucose were made simultaneously before induction of isoflurane anaesthesia, after maintenance of anaesthesia for 15 minutes and 30 minutes and during and after conclusion of the operation. Plasma GH concentrations showed a significant elevation during isoflurane anaesthesia, and maintained a similar high level one hour after the start of the operation. An insignificant elevation in plasma insulin level and significant increases in blood glucose were noted during anaesthesia and operation. Plasma cortisol levels increased insignificantly during anaesthesia, but increased markedly during operation. Our observations would suggest that the increased blood level of GH and elevated blood cortisol play a part in the increase of blood glucose during isoflurane anaesthesia and surgical operations in man.     

Isoflurane inhibits enflurane metabolism in man

Halogenated inhalation anaesthetics interfere with each other's hepatic microsomal metabolism. The increase in plasma inorganic fluoride concentration, caused by the metabolism of a standardised dose of enflurane, was attenuated by isoflurane given either before or after the enflurane exposure. It is concluded that isoflurane inhibits the metabolism of enflurane in man, a fact that might be advantageous in certain clinical situations.     

Influence of arginine on splanchnic glucose metabolism in man.

To examine the mechanism of the arginine-induced rise in blood glucose concentration, splanchnic glucose output (SGO) and precursor uptake were studied during i.v. infusion of arginine (30 g/30 min) with and without somatostatin infusion (500 microgram/h, 90 min) in postabsorptive and in 60-h fasted healthy subjects. The hepatic venous catheter technique was employed. In the postabsorptive state, arginine infusion was accompanied by an eightfold and a fivefold increment, respectively, in the hepatic venous concentration of insulin and glucagon; SGO doubled and blood glucose increased by 30%. After cessation of arginine infusion, SGO and blood glucose returned to basal levels within 30 min. When both arginine and somatostatin were administered, glucagon rose threefold, whereas the insulin response was abolished. And while the rise in SGO during arginine infusion and its subsequent decline were uninfluenced by the simultaneous infusion of somatostatin, the rise in blood glucose was more pronounced and the glucose concentration remained elevated longer than in control studies without somatostatin. Splanchnic uptake of glucogenic precursors was uninfluenced by arginine infusion, with or without simultaneous somatostatin administration. In the 60-h fasted group, arginine infusion was accompanied by a minimal increase in insulin but a fivefold elevation of the glucagon level. Combined arginine and somatostatin infusion did not boost insulin significantly but the glucagon level rose threefold above the basal value. Basal SGO was 55% lower than in the postabsorptive state, and it rose in response to arginine administration (+50%) as well as during combined arginine and somatostatin infusion (+80%). No significant change in splanchnic uptake of glucogenic precursors was observed during arginine infusion with or without somatostatin administration. We conclude that (1) arginine infusion is accompanied by a rise in SGO and blood glucose due to arginine-induced stimulation of glucagon secretion, (2) the rise in SGO is caused primarily by glucagon-stimulated hepatic glycogenolysis, and (3) combined somatostatin and arginine administration is accompanied by a more marked rise in blood glucose due to hypoinsulinemia and reduced peripheral glucose utilization.     

Cholecystokinin metabolism in man and dogs.

We have developed a sensitive, specific and reproducible radioimmunoassay for cholecystokinin (CCK) with which basal levels of CCK of between 400-800 pg/ml have been measured in normal man, in patients with diabetes and with duodenal ulcer disease, and in normal dogs. After a meal, circulating levels of CCK rose to 1000-1200 pg/ml in human subjects. Release of CCK was more rapid in diabetic and duodenal ulcer patients than in normal subjects, but elevated postprandial levels persisted much longer in normal subjects. Patients with the Zollinger-Ellison syndrome had elevated values of cholecystokinin which rose after a meal. Lack of correlation between elevated basal levels of gastrin and CCK in patients with the Zollinger-Ellison syndrome suggest that the hypercholecystokininemia may be absolute. The disappearance half-time of exogenous CCK was about 21/2 minutes in normal subjects as well as in diabetic and duodenal ulcer patients. Studies in dogs demonstrated no uptake of basal levels of cholecystokinin by the kidney; on infusion of exogenous CCK-33, the kidney extracted 43% of the total CCK presented and 56% of the integrated CCK. We conclude that: 1) circulating basal and postprandial levels of CCK may be measured in a reproducible fashion; 2) postprandial release of CCK is more rapid in diabetic and duodenal ulcer patients than in normal man; 3) the disappearance half-time of exogenous CCK in man and dogs is about 21/2 minutes; 4) the kidney is a major site for uptake of CCK.     

Peripheral tissue metabolism in cancer-bearing man.

Whole-body tracer studies have documented abnormal glucose and amino acid kinetics in cancer-bearing man. Whether these abnormalities are related to systemic or local tumor effects is questioned. Forearm metabolism was examined in six patients with localized squamous cell carcinoma of the distal esophagus and six healthy normal male volunteers. Substrate arterio-venous differences and blood flow across forearm tissues were determined and substrate flux calculated. The mean forearm blood flow (ml min-1 100 ml forearm-1) was not significantly different between cancer patients (3.67 +/- 0.12) and normal subjects (2.80 +/- 0.40). The uptake of glucose (mumol min-1 100 ml forearm-1) was significantly higher in cancer patients (1.99 +/- 0.45) compared to control subjects without weight loss (0.47 +/- 0.18). Lactic acid release (mumol min-1 100 ml forearm-1) was significantly higher in cancer patients (-1.15 +/- 0.35) compared to control subjects (-0.26 +/- 0.14). There was no significant difference in the flux of individual amino acids between the groups, although the mean total nitrogen released from forearms of cancer-bearing patients was greater than that from normal controls. The arterial serum insulin level was significantly lower and the arterial plasma glucagon level significantly higher in cancer patients compared to control subjects. These data cannot be explained by weight loss alone and suggest a peripheral defect in metabolism in this group of cancer-bearing patients.     

Influence of parenteral nutrition on phospholipid metabolism in the rat lung in the posttraumatic period

Most experimental studies in the field of parenteral nutrition following trauma are aimed at a reduction of catabolism and therefore an improvement of the N-balance. The aim of this study was to investigate the influence of PN on PHL composition in the posttraumatic lung, especially in the surfactant fraction. We compared a carbohydrate - amino acid formula with a formula containing carbohydrate - amino acid - lipid. Polytrauma was performed by single femur fracture plus laparotomy with eventeration of the intestines for 30 minutes and hypovolemia (2 ml/100 g bw). After an adaption phase with reduced caloric supply, full caloric support was given from the 4th to the 14th day (100 Kcal/kg bw/day). The following metabolic parameters were used: N-balance; phospholipid total, -classes, -molecular species and fatty acid pattern of lecithin in lung tissue and lavage (using special HPLC and GC techniques). There were small differences between the groups using standard metabolic parameters (such as nitrogen balance). In contrast, we found significantly altered phospholipid patterns in the lung. With lipid emulsion there was an increased fraction of saturated lecithins (mainly dipalmitoyl phosphatidylcholine). From our data we conclude that it is possible to influence surfactant phospholipid composition by parenteral nutrition through the use of lipid emulsion. This might be useful for posttraumatic lung treatment.     

The effects of glucagon on protein metabolism in normal man.

Plasma glucagon rises after major injury and could act to increase gluconeogenesis and ureagenesis in the post-traumatic state. This study documents the effect of prolonged glucagon infusion on ureagenesis and nitrogen excretion, as well as possible sources of the increased ureagenesis, in normal man. Four healthy men fasted for 6 days during intravenous infusion of glucose (750 gmday), establishing a steady state of minimal ureagenesis. Glucagon (1 mg/day) then was added to the infusion for 5 days. Glucose alone was given for the final 2 days. Forearm muscle flux of metabolites was determined by standard arterial-deep venous sampling and capacitance plethysmography. Glucagon concentration was suppressed during glucose infusion (11 +/- 13 pg/ml) and rose to levels seen in subjects with major trauma during glucagon infusion (669 +/- 138 pg/ml). Glucose infusion stabilized urine nitrogen excretion at 1.54 +/- 0.42 gm of N/sq m/day. Nitrogen excretion increased to 2.40 +/- 0.53 gm of N/sq m/day with glucagon infusion, with urea accounting for the increased excretion. Excretion of 3-methylhistidine was unchanged. Plasma amino acid concentration was strikingly reduced on the first day of glucagon infusion, where it stabilized. Forearm flux showed a slight net release of amino acid nitrogen during glucose infusion. Addition of glucagon to the glucose infusion resulted in a net uptake of nitrogen by forearm skeletal muscle. These evidences strong suggest that glucagon infusion in normal man increases ureagenesis, not only at the expense of the free amino acid pool, but by the hydrolysis of visceral protein as well, with muscle protein being maintained.