Catabolic Patients Research Articles

Alanyl-glutamine infusions to patients with acute pancreatitis

In this study we infused different amounts of glutamyl-dipeptides (group 1: 1.5 g ALA-GLN + 3.5 g GLY-GLN, group 2: 20 g ALA-GLN, group 3: 40 g ALA-GLN) for a period of five days into patients with acute pancreatitis. In spite of this high amount of ALA-GLN administration we were not able to normalise the depleted glutamine pool of skeletal muscle in these catabolic patients.

Energy cost of fat-fuel mobilization in geriatric trauma

Age-related changes in body composition may result in varied responses to acute accidental injury. Gaining fat as age advances is common and therefore the mobilization of fat fuel resources in traumatized geriatric patients needs closer examination. We have measured in six elderly (age, 60 to 74 years) and seven young (age, 18 to 46) traumatized, hypermetabolic, and highly catabolic patients, in the “flow phase” of the metabolic response to injury, the rates of whole-body lipolysis and net fat oxidation. This enabled us to calculate the rate of triglyceride/free fatty acid ( TG FFA ) cycling in the whole body and to assess its contribution to energy expenditure. Energy metabolism in general and the fat metabolism in particular were found to be somewhat slowed in elderly trauma patients compared with equally injured young individuals, although the aged patients had more total body fat. The energy cost of TG FFA cycling is significantly ( P < .025) lower in elderly trauma victims (0.28 ± 0.06 kcal/kg/d) compared with young patients (0.63 ± 0.1 kcal/kg/d). This can account for approximately 3% to 4% of the elevation in metabolic rate over that predicted in the uninjured state.

A Reappraisal of the Peptide‐Based Enteral Formulas: Clinical Applications

The development of peptide-based enteral formulas is a significant milestone in the advancement of nutritional care of the nutritionally compromised patient. Although previously limited to specific gastrointestinal mucosal diseases, the use of peptide-based formulas has been extremely useful in the critically ill patient with impaired gastrointestinal absorption associated with hypoalbuminemia resulting from hypermetabolic states. Based on previous animal studies, several investigators have noted improved nitrogen absorption, greater nitrogen utilization, higher branched chain amino acid levels, and increased insulin secretion with the use of peptide-based formulas compared with intact protein or free amino acid diets. Recent studies have indicated an improved gastrointestinal tolerance with peptide-based diets, with the rate of absorption and the degree of tolerance dependent on the presence of small molecular weight peptides. In addition, we have found that the critically ill patient suffering from severe hypoalbuminemia frequently develops a protein-losing enteropathy, which can be attenuated by the use of a peptide-based formula. Thus, peptide-based formula may attenuate albumin turnover in the intestine and thus be efficacious in patients with a protein-losing enteropathy from a variety of etiologies (table 2). We therefore recommend that enteral support with a peptide-based diet is safe and extremely useful in the catabolic, critically ill patient or in patients with significant gastrointestinal malabsorption associated with a protein-losing enteropathy. Tolerance of these formulas is dependent on the catabolic state of the patient, with more catabolic patients needing higher concentrations of nitrogen in the form of peptides and/or supplemental parenteral branched chain amino acids.(ABSTRACT TRUNCATED AT 400 WORDS)

Endogenous protein-synthesis efficiency in trauma victims

Hyperglycemia despite increased glucose oxidation and hypoaminoacidemia despite increased rate of protein breakdown are frequently seen in hypermetabolic and highly catabolic patients with major trauma. The extent of reutilization of endogeneously produced amino acids in the synthesis of new proteins (protein recycling) by the traumatized human is poorly understood. The protein synthesis efficiency was measured in ten multiple trauma patients during the early “flow” phase of injury, and these data were compared with normal and depleted patients. In acute trauma the synthetic efficiency of protein is significantly ( P = .01) low (61% ± 4%) compared with other pathologic states (78% ± 1%). This suggests that the priority is preferentially set to meet the increased demands of glucose production, and a major portion of the amino acids are utilized for purposes other than synthesis of body proteins. This observation should be taken into account in the early management of acute trauma patients before the body adapts to accept the exogenous supply of amino acids.

Parenteral nutrition including amino acids fails to increase creatinine clearance in catabolic patients

A 70% increase in creatinine clearance (Ccr) has been reported previously in patients receiving parenteral nutrition (P.N.) with amino acids compared with P.N. without amino acids.We have investigated 10 male catabolic patients who got P.N. with and without amino acid solution. Twelve-hour Ccr was done on two consecutive days during infusion of P.N. On the second day 1000 ml of isotonic saline was replaced by 1000 ml of amino acid solution (Vamin® 14g N/1).We found a statistically non-significant increase in Ccr (median: 1.6%, 95% confidence interval: -8.5% to 11.3%).In conclusion, no clinically important change in Ccr occurs in catabolic patients during P.N. with amino acids.

Infusion of dipeptides as nutritional substrates for glutamine, tyrosine, and branched-chain amino acids in patients with acute pancreatitis

In this study we investigated the effect of a total parenteral nutrition supplemented with synthetic dipeptides on plasma and muscle amino acid metabolism in four patients with acute pancreatitis. We infused an amino acid solution containing alanylglutamine, glycylglutamine, glycylvaline, glycylisoleucine, glylcylleucine, and glycyltyrosine for a period of five days in daily dosages of 10.3, 22.1, 68.8, 37.2, 42.5, and 15.7 mmol, respectively. The plasma levels remained below 100 μmol/L for all infused dipeptides. The plasma concentrations of alanylglutamine were not measurable. Mean peptide urine excretion remained below 5%, with the exception of glycylglutamine (8.5% ± 5.1%). Arteriovenous concentration differences of the dipeptides across the leg were not significantly different from zero, indicating that the infused dipeptides have no important role in the nitrogen exchange of skeletal muscle. A marked intracellular glutamine deficiency in skeletal muscle was found in all four patients (5.1 ± 0.6 mmol/L v 19.5 ± 0.8 in healthy subjects) before infusion. Intracellular glutamine concentration was significantly higher after the infusion period (5.1 ± 0.7 v 9.5 ± 1.8 mmol/L, P > .05), but no normalization of the intracellular glutamine levels was achieved by the infusion of the two glutamine-containing peptides. We conclude that peptides are well metabolized as substrates for parenteral nutrition in catabolic patients. Furthermore, the infusion of glutamine peptides caused a significant increase of intracellular glutamine levels; however, the dosage of glutamine peptides was too low to normalize the muscular glutamine concentrations.

Addition of Glutamine to Total Parenteral Nutrition After Elective Abdominal Surgery Spares Free Glutamine in Muscle, Counteracts the Fall in Muscle Protein Synthesis, and Improves Nitrogen Balance

Twenty-two patients undergoing elective abdominal surgery were given total parenteral nutrition (TPN) after the operation. The TPN contained either a conventional amino acid solution supplemented with glutamine or a conventional amino acid solution without supplementation. To study amino acid and protein metabolism, muscle biopsy specimens were taken before surgery and on the third postoperative day. The postoperative decrease in the intracellular concentration of free glutamine was less pronounced in the glutamine group (21.8 +/- 5.5%) than in the control group (38.7 +/- 5.1%; p less than 0.05). The protein synthesis was reflected in the concentration and size distribution of ribosomes. No significant changes in these parameters were seen in the glutamine group after the operation. In the control group, the total concentration of ribosomes fell by 27.2 +/- 8.5% (p less than 0.05), and the relative proportion of polyribosomes fell by 10.6 +/- 2.9% (p less than 0.01). Although there were significant changes in the control group, no significant differences in the changes of these parameters between the two groups were detected. The cumulative nitrogen loss was significantly less in the glutamine group as compared to the control group during the period studied--2.3 +/- 1.4 g versus 8.5 +/- 1.5 g, respectively (p less than 0.01). Administration of glutamine to catabolic patients is advocated.

Proposal of a new formula to calculate total urinary nitrogen from urea urinary nitrogen

Urea urinary nitrogen (UUN) and total urinary nitrogen (TUN) were determined in 15 patients to study their relationship mainly in highly catabolic patients. The subjects were: 7 multiple trauma, 3 autologous bone-marrow transplant, 1 tetanus, 4 postcholecystectomy patients; 180 determination were made, 111 of which in highly catabolic phase (TUN > 15 g/day). TUN and UUN are well correlated (r = 0.9742; p < 0.001) in the range 3 to 52 g/ day of TUN. Urea represents the 83.2 ± 9.4% (M ± SD). A double-linear formula to calculate TUN from UUN is proposed (for UUN ⩽ 15 g/ day: TUN = UUN × 1.17 + 0.7; for UUN > 15 g/ day: TUN = UUN + 4). The least square procedure was used to compare the differences between measured and calculated TUN, and the results obtained with the proposed double-linear formula were compared with that obtained employing pre-existing formulas (Lee's and Mackenzie's). Considering all ranges of values studied (3–52 g of TUN) the results obtained were significantly different (p < 0.005); dividing the levels of TUN in ⩽ 15 g; 16–29 g and ⩾ 30 g, the results were always better, but the statistical significancy was not always reached.

Parenteral nutrition including amino acids fails to increase creatinine clearance in catabolic patients

A 70% increase in creatinine clearance (Ccr) has been reported previously in patients receiving parenteral nutrition (P.N.) with amino acids compared with P.N. without amino acids. We have investigated 10 male catabolic patients who got P.N. with and without amino acid solution. Twelve-hour Ccr was done on two consecutive days during infusion of P.N. On the second day 1000 ml of isotonic saline was replaced by 1000 ml of amino acid solution (Vamin 14g N/l). We found a statistically non-significant increase in Ccr (median: 1.6%, 95% confidence interval: -8.5% to 11.3%). In conclusion, no clinically important change in Ccr occurs in catabolic patients during P.N. with amino acids.

Splanchnic and peripheral release of 3-methylhistidine in relation to its urinary excretion in human infection

The present investigation was undertaken in order to determine the release of 3-methylhistidine (3MH) from the splanchnic region and from the leg, and the contributions these make to the increase in urinary 3MH excretion in infection. Thirteen febrile patients with infection were investigated. After an overnight fast, hepatic vein, femoral vein, and radial artery catheterizations were performed. Splanchnic and leg blood flows were determined by dye dilution technique. Plasma 3MH was analyzed by a modified HPLC method. The release of 3MH from the leg was 0.064 ± 0.007 μmol/min (±SE) and from the splanchnic region 0.012 ± 0.013 μmol/min. These releases of 3MH constitute 27% ± 2% and 8% ± 6% of the individual urinary excretions, respectively. With increasing degree of catabolism, measured as individual 3MH increase above baseline excretion or as the 3MH to creatinine ratio (3MH:Cr), the relative contribution to urinary excretion from the leg was increased (individual increase, P = 0.08; 3MH:Cr, P < 0.01). Since this contribution was not decreased in the more catabolic patients, as would have been expected if the increase in urinary 3MH originated elsewhere, it is concluded that skeletal muscle is the source, and these results thus validate the use of urinary 3MH excretion as a marker of myofibrillar protein catabolism in infected patients.

Medium chain triglycerides in septic patients on total parenteral nutrition

The object of this study was to compare the metabolic effects of a 10% long chain triglyceride (LCT) emulsion with those produced by a 10% emulsion of medium and long chain triglycerides, MCT/LCT. During 7 days, 20 septic patients received total parenteral nutrition. Daily between 9:00 and 21:00 hours, 0.14 ± 0.01 triglycerides/kg body weight/h was infused. Nine received an LCT emulsion, 11 an MCT/LCT emulsion. Venous blood samples were taken on each of the 7 days at 09:00 and 17:00 hours. No signs of complications attributable to the lipid infusion were observed. The plasma concentrations of phospholipids, triglycerides, free glycerol, non-esterified fatty acids, and sometimes cholesterol, rose during the lipid infusion. Blood ketone body levels did not increase. With both emulsions a day by day acumulation of phospholipids (at09:00 and 17:00 hours) in the plasma was observed. Cholesterol also accumulated but only with the LCT emulsion. The nitrogen balance and urinary excretion of creatinine and of 3-methylhistidine/creatinine ratio was lower with the MCT/LCT emulsion, which suggests less muscular catabolism in patients receiving that emulsion.

Inhibition of prostaglandin synthesis improves post-operative nitrogen balance

The metabolic response to injury includes net breakdown of skeletal muscle protein and negative nitrogen balance. Prostaglandins have been shown to mediate muscle protein breakdown in vitro. To examine the role of prostaglandins in post-operative protein catabolism in vivo, 15 dogs underwent a standard abdominal operation under general anaesthesia during which, catheters were implanted in the aorta and vena cava. Seven of the animals were given Ibuprofen to prevent prostaglandin synthesis during the operation and through the post-operative period, whilst the other eight served as controls. Inhibition of prostaglandin synthesis led to a significant improvement in nitrogen balance due mainly to a decreased excretion of urea (plasma urea levels were unaffected). This may be due to a diminished breakdown of skeletal muscle protein in response to injury, as there was an apparent reduction in efflux of amino-nitrogen and phenyl alanine from hindquarter muscle as compared to post-operative controls. In conjunction with nutritional therapy, inhibition of prostaglandin synthesis may be beneficial in improving nitrogen balance in catabolic patients.

Methionine, cystathionine and cystine increased urinary losses during total parenteral nutrition of adult patients

Amino-acids involved in transsulphuration pathway were studied in the plasma and urine of 49 depleted surgical patients and 36 critically ill, injured patients who received total parenteral nutrition. A minimum B6 intake of 5 mg day −1 was provided to all patients; nitrogen intake was supplied with different amino-acid solutions. A daily methionine load higher than 15–24 mg kg −1, resulted in increased methionine plasma levels and increased urinary loss, both linearly related to methionine intake and notwithstanding the metabolic status of the patients. The increase of methionine load caused the appearance of traces of cystathionine in plasma and the increase of cystathionine urinary loss that were always higher than reference. This increase was linearly related to methionine intake in both patient groups, the slope being significantly higher in the depleted group. It suggests a limiting role of cystathioninase in the transsulphuration pathway. Its activity seems lower in depleted than in catabolic patients. During total parenteral nutrition, in spite of lower than normal cystine plasma values, cystine urinary output was always 2–10 times higher than reference in both patient groups, although cystine urinary loss was linearly related to methionine intake. Taurine and amino-butyrate were not significantly affected by total parenteral nutrition.

Peripheral, visceral and body nitrogen balance of catabolic patients, without and with parenteral nutrition.

The effect of major trauma and sepsis on skeletal muscle, central tissue and whole body nitrogen (N) metabolism was investigated in 5 patients before and during TPN (30 kcal, 0.30 g N kg-1 day-1). Fasting 3-methylhistidine (MEH) urinary excretion was elevated (407.9 +/- 67.6 mumol m-2 day-1), muscle and body N balances (NB) were markedly negative (-28.2 +/- 4.6 g m-2 day-1 and -15.7 +/- 3.1 g m-2 day-1), while central tissue NB was positive (13.0 +/- 2.4 g m-2 day-1). TPN effected a reduction in MEH excretion (261.8 +/- 27.5 mmol m-2 day-1 - p less than 0.05) and decreased the release of almost all amino acids from muscle tissue, some of them acting as catabolic markers. Muscle (-7.2 +/- 1.2 g m-2 day-1 - p less than 0.01) as well as body NB (-4.8 +/- 1.4 g m-2 day-1 - p less than 0.01) improved, whilst central tissue NB worsened, even though still positive (3.1 +/- 1.6 g m-2 day-1 - p less than 0.05). Gathering fasting and TPN data MEH excretion was significantly related to both body (r = 0.89) and muscle (r = 0.73) NB, that were highly related to each other (r = 0.93), being muscle always worse than body NB. In conclusion, the anticatabolic activity of TPN is confirmed, although our setting did not achieve muscle NB, it was consistently improved and seems to be the major determinant of body NB, in contrast central NB and central N utilization (46.4% +/- 5.4 vs 15.8% +/- 8.4 - p less than 0.05) worsened.

Hypoalbuminemia as an indicator of diarrheal incidence in critically ill patients.

Recently, we noted that substantial numbers of critically ill patients admitted to a medical ICU developed diarrhea. We checked them for infectious, metabolic, and untoward medication effects, which were negative. We next considered a possible causal relation between reduced serum albumin and diarrhea. To document the frequency of diarrhea in this population, explore the relation between hypoalbuminemia and diarrhea, and make a preliminary assessment of a peptide-based, chemically defined diet in these catabolic patients, a study of consecutive medical ICU patients was begun. For each patient, we recorded the principal diagnosis, type of diet received, the frequency and volume of stool, and the serum albumin concentration at admission. When diarrhea developed, attention was paid to the serum albumin levels as well as the effects of various diets. Overall, 12 (34%) of 35 study patients developed diarrhea. No patient had a previous history of diarrhea, malabsorption, weight loss, or GI symptoms that may precede the onset of diarrhea. The stools from each patient with diarrhea were examined for enteric pathogens, ova and parasites, Clostridium difficile culture and cytotoxin assay, and qualitative stool fat, which were all negative. Every patient with a serum albumin level less than 2.6 g/dl developed diarrhea. No patient with a serum albumin level of 2.6 g/dl or greater developed diarrhea, regardless of the type of nutritional support received. Four of the 12 patients with hypoalbuminemia and diarrhea were placed on a peptide-based, chemically defined diet, after which their diarrhea resolved and their serum albumin concentrations increased.

Use of serum CPK-MM to monitor response to nutritional intervention in catabolic surgical patients

Nutritional status of surgical patients is widely assessed using anthropometrics, visceral proteins, and urinary nitrogen losses. Since assay of muscle-specific marker 3-methylhistidine (3MH) is currently limited to research laboratories, routine use of serum creatinine phosphokinase (CPK) and myoglobin is potentially useful in monitoring nutritional repletion of stressed patients. An acute and a temporal phase human studies were done to test this hypothesis. After an overnight fast, nondiabetic, noncardiac patients were given an IVGTT (0.5 g/kg) 3 days after a standard abdominal midline operation. Glucose, insulin, total CPK, myoglobin, and 3-methylhistidine were measured serially. Baseline CPK was elevated threefold above normal range of upper limits, whereas myoglobin was at the upper limit of normality. After the IVGTT insulin rose, ( P < 0.005) and CPK and 3MH fell ( P < 0.005) whereas myoglobin rose and remained elevated throughout the study ( P < 0.05). As long as insulin levels remained elevated, CPK remained depressed. With sufficient TPN to induce positive nitrogen balance (35 kcal and 0.2 g N/kg/day), elevated CPK levels fell and remained depressed in direct correlation with elevated insulin. Greater than 95% of total serum CPK consisted of the isoenzyme CPK-MM. These initial studies indicate that total serum CPK is useful in monitoring the short-term responses of postoperative catabolic patients who receive nutritional repletion.

Region-specific immunoassays for human myelin basic protein

Three monoclonal antibodies reactive with human myelin basic protein have been used to develop immunoradiometric assays for this protein. Clone 1, a mouse IgG2a, is reactive with an epitope in the region 129–138. Clone 2, a mouse IgG1, is reactive with the region 119–131. Clone 12, a rat IgG, is reactive with the region 86–96. Competition experiments show that the reactions of Clone 1 and Clone 2 are mutually exclusive, probably because of steric effects. In contrast, when either Clone 1 or Clone 2 react they cause minimal interference with the subsequent binding of Clone 12. Less than 1 ng/ml of myelin basic protein can be detected in each of the two immunoradiometric assays developed. Clone 12 can also be used on its own in a competitive immunoassay to detect around 2 ng/ml. Using an extraction technique before the assay, serum or plasma can also be investigated. Assays for defined regions of myelin basic protein should prove valuable in identifying the products of myelin catabolism in patients with demyelinating disease.

Polyribosome concentration in human skeletal muscle after starvation and parenteral or enteral refeeding

Posttraumatic and septic states cause a loss of body proteins resulting in a negative nitrogen balance. The major part of the excreted nitrogen is derived from the proteins of skeletal muscle. The loss in proteins is due to a decrease in protein synthesis rather than an increase in protein degradation. Nutritional support may increase protein synthesis, and determination of its activity in skeletal muscle will give information on the utilization of nutrients in catabolic patients. The effect of nutritional support on healthy subjects was studied to achieve a background for future clinical studies. Male volunteers between 20 and 40 years old were refed parenterally or enterally after three days of starvation. Muscle biopsies (50 mg) were analyzed for the size distribution of ribosomes in a sucrose density gradient, and the ribosome concentration was determined per mg of DNA. Changes in the percentage content of polyribosomes preceded those of the total ribosome concentration. The total polyribosome concentration per gram wet weight of skeletal muscle decreased significantly during starvation. After one and two days of refeeding, a significant increase was observed, but the original level of the nonstarved subjects was not reached. The total ribosome concentration increased upon refeeding, but was not significantly different from that of the starved condition. The nitrogen balance was negative during starvation but attained equilibrium after two days of refeeding. Nutrition administered by the parenteral or enteral route were equally effective in restoring protein synthesis.

Forms of Malnutrition in Stressed and Unstressed Patients

PCM can be usefully considered in terms of edematous (kwashiorkor-like) and nonedematous (marasmic) forms, as long as the limitations of the traditional terms are kept in mind. The body composition of subjects with undernutrition, or total starvation, both appear to maintain an extracellular fluid volume at a normal level, which increases as a percentage of the shrinking body weight. This is in contrast to patients with hospital malnutrition, in whom there is often an absolute increase in the extracellular volume while the body cell mass is shrinking. Data from the starvation literature suggest that the adult subject must gain approximately 10% of his or her body weight as extracellular expansion before edema is clinically evident. Preliminary evidence indicates that the hospitalized patient with the edematous form of malnutrition is at greater risk for complications and death when undergoing an operation, or requiring intensive care. The depleted patient who shows a rise in a depressed serum albumin after 7 to 10 days of TPN will have an improved prognosis when undergoing the stress of an elective operation. This improvement appears to be more the result of decreasing the expanded extracellular fluid volume than achieving a major increase in protein stores. The severely catabolic patient, particularly during episodes of major infection, can be expected to benefit by a nutritional intake that is carefully designed to provide calorie and nitrogen equilibrium. Nutritional intake high enough to guarantee positive balances of calories and nitrogen should be delayed until the acute catabolic stimulus has subsided, at which time the nutritional objective is to rebuild lost tissue.

Nutritional and Metabolic Consequences of Thermal Injury

Major burns produce a variety of metabolic and nutritional consequences. The patient's metabolic rate is often doubled, and caloric demands of 3000 to 5000 calories per day are not uncommon. There are marked hormonal changes characterized by an increase in secretion of catecholamine and glucagon and a reversal of the normal insulin-to-glucagon ratio. Serum glucose increases primarily through hepatic gluconeogenesis to meet the increased demands of the burn wound and of the increased metabolic rate. Lipids may be available but they are an inefficient source of calories. Skeletal and visceral proteins are mobilized to meet the increased nutritional demands. The overall result is a severely catabolic patient in negative nitrogen balance, with decreased immunologic function and all of the wound-healing problems associated with protein and calorie malnutrition. Aggressive nutritional support (using enteral feeding whenever possible) is essential. Supplemental feedings should be started on all patients unable to reach their recommended calorie and protein requirements through regular oral diet. An increase in protein intake (calorie-to-nitrogen ratio of 100:1) may be beneficial. By establishing nutritional goals and monitoring daily weight, calorie count, protein intake, and biochemical parameters, the physician can significantly improve the chances of survival of even the most seriously injured patients.