Intravenous feeding of the rat with short chain fatty acid esters. II. Monoacetoacetin.

Acetoacetic acid is oxidized independent of carnitine transport into the cell mitochondria and its monoglyceride is a water soluble compound. The latter was examined as an intravenous nutrient. The monoglyceride of acetoacetic acid was prepared from the acid anhydride, diketene, and glycerol and was found to be totally miscible with water. The nutritional properties of monoacetoacetin were investigated by continuous intravenous infusion of 25 or 50 g/kg body weight per day into ad libitum fed rats. The response of these animals was compared to normal and food restricted rats. All experimental animals survived the 7 day study period in good health and were free of detectable physiological and behavioral abnormalities. The test rats demonstrated weight gain dependent on the infusion rate while on an inadequate spontaneous oral food intake diet. Ketonuria, hyperketonemia and monoglyceride excretion in the urine accompanied the infusion of monoacetoacetin and were dependent on the infusion load. At 50 g/kg per day total plasma ketones were found to be comparable with the infusion load. At 50 g/kg per day total plasma ketones were found to be comparable with the maximum level obtained in fasted rats, but the acetoacetate concentration was relatively higher than in fasting. This was consistant with ketosis derived from the hydrolysis of the monoglyceride. It was concluded from these results that monoacetoacetin might be an asset for intravenous nutrition.

Intravenous feeding of the rat with short chain fatty acid esters. I. Glycerol monobutyrate.

Intravenous nutrition was investigated using butyric acid because it is oxidized independent of carnitine transport into the cell mitochondria. This carnitine independent fatty acid, in the form of water soluble monobutyrin, was continuously infused into rats for seven days at 27 g monobutyrin per kilogram of body weight per day and provided half the daily energy requirement. All experimental animals survived the alimentation in good health and were free of detectable physiological and behavioral abnormalities. The intravenous infusion depressed the test animals spontaneous food intake to half their preinfusion level. These experimental rats still demonstrated continuous weight pain in contrast to weight loss by pair-fed controls. At decapitation, the monobutyrin infused rats had hepatic glycogen levels three times that of the controls, along with lower soluble hepatic protein, and normal lipid and water content. The plasma acetoacetate was also elevated in experimental rats. It was inferred from these results that monobutyrin was hydrolyzed, and the metabolites were oxidized by the rat. It is concluded from these observations that monobutyrin produces no obvious toxic affects during short infusion periods and provides calories for the rat when given intravenously.

Carnitine levels in severe infection and starvation: a possible key to the prolonged catabolic state.

Tissue carnitine levels have been measured in man and the dog. Skeletal muscle carnitine levels rise in the dog with starvation to roughly twice the normal level. An equal degree of starvation plus peritonitis is associated with unchanged skeletal muscle carnitine levels. In the presence of peritonitis, sequential skeletal muscle biopsies show a progressive fall in the tissue carnitine levels with a subsequent rise in those animals which survive and clear their peritonitis. Normal human skeletal muscle levels are essentially the same as in the dog. A combination of sepsis and starvation in man is associated with essentially unchanged skeletal muscle carnitine levels, whereas pure sepsis without starvation is associated with decreased skeletal muscle carnitine levels. It is suggested that these changes are in the direction expected for a limitation of fat catabolism and, in the presence of a limited exogenous source of glucose, that this would result secondarily in a protein catabolic state to supply glucose for the body's energy needs.

Physiological and metabolic correlations in human sepsis. Invited commentary.

The septic response in man appears to be a disease in which the infecting agent induces a state of disordered metabolic control in the host. The abnormal regulation of metabolic pathways causes a diversion of substrate utilization toward gluconeogenesis and ketone body formation and a reduction in oxidative energy-producing metabolism. This state of metabolic insufficiency is reflected in the pattern of cardiorespiratory, vascular, and physiological compensation. The precise magnitude of the resultant physiological compensation and its rate and direction of change can be quantified by the use of physiological state trajectories which also reflect the magnitude of underlying metabolic derrangements. The prognostic and therapeutic implications of these changes are discussed.

Plasma concentrations and tissue uptake of free amino acids in dogs in sepsis and starvation: effects of glucose infusion--some effects of low alimentation.

The plasma concentrations of substrates, together with transhepatic and transgut balances, have been studied in six control and eight septic awake fasted dogs. Four severely ill septic dogs (typically fluid in chest and/or abdomen, extensive peritonitis, respiratory difficulties) had high concentrations of threonine, glycine, tyrosine, lysine, histidine, tryptophan, and triglycerides (p less than or equal to 0.05). The other septic dogs (less severely ill) showed fewer and less pronounced alterations in the plasma substrates (aspartate and tryptophan were elevated, p less than or equal to 0.05). The infusion of glucose increased the concentration of glucose, lactate, and pyruvate and depressed the concentrations of most amino acids in both normal and septic dogs. Threonine, asparagine, glutamine, leucine, isoleucine, alpha-aminobutyrate, and tyrosine were significantly depressed in the severely ill septic dogs (p less than or equal to 0.05). In the normal dogs most amino acids were removed by the liver, with alanine accounting for approximately 40% of the total. Glutamine removal was negligible. In the septic dogs hepatic removal of amino acids was variable; livers of two severely ill septic dogs did not remove amino acids. In the control dogs glucose infusion (0.015--0.017 g/kg/min) tended to lower hepatic removal of amino acids. Hepatic dye removal in the septic dogs was always very poor. In the gut glutamine was removed and alanine, glutamate, glycine, and ammonia produced, but the overall sum of amino acid uptake was negligible in both the control and septic dogs. The ratio of tryptophan to the sum of valine, isoleucine, leucine, tyrosine, and phenylalanine concentrations was greatly elevated in all septic dogs in which it was measured. The free concentrations of amino acids in the liver, heart, and muscle tissues were grossly elevated in the low intravenous alimented septic state relative to the fasted normal state, whereas the tissue concentrative ability as measured by nonmetabolizable amino acids, alpha-aminoisobutyrate and cycloleucine, was not similarly increased. Sepsis clearly alters plasma and tissue concentrations, and in some instances hepatic uptake of amino acids.

Feeding studies in weanling rats with dorsomedial hypothalamic lesions: maintenance of competence to compensate for additional calories.

Weanling rats received bilateral electrolytic lesions in the dorsomedial hypothalamus primarily destroying the dorsomedial hypothalamic nuclei (DMN). Sham-operated rats served as controls. After a 14 day postoperative period during which food intake (lab chow) and body weight were recorded, each of the above groups were subdivided into 2 groups. One DMN group and one sham-operated control group were continued on lab chow alone throughout the remainder of the study. The other DMN group and the second control group were given additional calories in the form of a liquid diet by stomach tube during 2 separate periods of 10 and 14 days, respectivly, to increase their caloric intake beyond that taken in spontaneously. Both tube-fed groups reduced their ad lib caloric intake from chow considerably and to the same extent. Body weight gains were similar in tube-fed versus non-tube-fed rats, whether with or without DMN lesions. After the second, 14-day-long tube feeding period, however, DMN rats regulated their body weight somewhat less precisely than the controls. This may be related to their reduced food intake during that time period. The data indicate that weanling rats with DMN lesions, despite their basic hypophagia, do not show a deficit in caloric metering and gross body weight regulation.

Open reduction and internal fixation of acetabular fractures: heterotopic ossification and other complications of treatment.

Open reduction and internal fixation was performed on 50 displaced acetabular fractures in 49 patients by nine different attending surgeons over a 10-year period. At an average follow-up of 38 months, poor results were noted clinically in 38% and radiographically in 40%. The incidence of short- and long-term complications was greater than in other studies. Particularly distressing was the 58% incidence of heterotopic ossification (HO). Twenty-four percent had grade III or IV; five hips were autofused and the remainder had 40-60% loss of motion. There was no correlation of HO with age, sex, fracture type, degree of comminution, associated femoral head fracture or dislocation, delay to surgery, or operative time. However, 26 of 28 patients who had a trochanteric osteotomy as part of the operative exposure developed HO. Other complications included wound infection (12%), avascular necrosis of the femoral head (10%), nerve palsy (8%), and deep vein thrombosis/pulmonary embolism (8%). The data suggest formulation of specific treatment protocols, an awareness of surgical risks, and that staff specialization may reduce complications and improve outcome. Avoiding a trochanteric osteotomy at surgery and using prophylactic postoperative irradiation or indomethacin are suggested to reduce HO.

Recent advances in the management of trauma.

Delivery of the most up-to-date trauma care requires a well-trained team of four physicians and four nurses to carry out the initial management of a single major injury patient (Border et al, 1975). Ventilatory insufficiency, circulatory insufficiency, and wounds must all be treated promptly and simultaneously.

Food intake of weanling rats with lesions in the ventromedial and dorsomedial hypothalamic nuclei in response to intragastric loading and caloric density manipulation.

Male rats received bilateral electrolytic lesions shortly after weaning in the ventromedial (VMN) and dorsomedial (DMN) hypothalamic nuclei, respectively. A third group of rats served as sham-operated controls. The animals were subjected to intragastric preloading with 33% d-glucose and egg-white solutions and a 33% corn-oil suspension, and ad libitum feeding was assessed hourly for the first 7 hr after preloading. The pattern of food-intake depression was similar in all groups but the quantitative greatest depression was found in the DMN rats. The response of these three groups of animals to a diet diluted with 20% alpha cell, a nonnutritive bulker, showed an initial failure to meter calories by both VMN and DMN rats which, however, was compensated for during the remainder of the 24-hr test period. In response to a 50% glucose-chow mixture, both VMN and DMN rats, as well as the controls, showed the same pattern and behaved like mature dynamic hyperphagic rats inasmuch as they did not eat more of this mix than of the standard diet. After a 48-hr fast, both VMN and DMN rats showed refeeding hypophagia rather than hyperphagia. The data suggest that Panksepp's contention that the VMN in the mature rat is involved in long-term satiety regulation may be extended to the weanling rat with VMN destruction. Thus, this controlling role appears established early in ontogeny.

Glucose preference and caloric regulation in weanling rats with ventromedial and dorsomedial hypothalamic lesions.

Weanling male rats received electrolytic lesions in the ventromedial (VMN) and dorsomedial (MDN) hypothalamic nuclei, respectively. A third group served as sham-operated controls (CON). After the two hypothalamic syndromes had been well established, the animals were subjected to (1) a glucose preference test assessing the choice between a 10% w/v and a 35% w/v d-glucose solution, and (2) a test examining the anorexigenic effect of intraperitoneally injected glucose. Weanling rats with VMN lesions, like their mature counterparts, consistently preferred the stronger over the weaker glucose solution throughout the experiment (16 days). Weanling DMN rats, on the other hand, showed a bimodal response, initially like that of the CON rat, toward the end of the experiment, like that of the VMN rats. The weanling CON animals behaved differently from their mature counterparts, inasmuch as their preference for the dilute solution became evident only toward the latter part of the test. An analysis of the calorie intake shows that calories from glucose are similar in all three groups of rats, that the pattern and magnitude of caloric intake in DMN and CON rats are almost identical, and that the total caloric intake (from chow plus glucose) is reduced in the DMN rats because the calorie component from chow is profoundly reduced. In response to intraperitoneally injected glucose, VMN rats show a longer depression of food intake than has been reported for mature VMN rats. The CON and DMN rats recovered quicker and reached preinjection levels of food intake sooner than the VMN rats. The data indicate that in the weanling VMN rat, as in its mature counterpart, the VMN are involved in long-term feeding behavior and do respond to the metabolic signal arising from administered glucose. Nevertheless, the principle factor in their preference seems to be taste rather than solely a metabolic signal. The data show that the DMN are less involved in this sensing and integrating mechanism. In essence, the DMN rat functions quite normally, but its control system is set at a subnormal level.