Rate Of Net Protein Catabolism Research Articles

Growth hormone therapy initiated before starvation ameliorates the catabolic state and enhances the protein-sparing effect of total parenteral nutrition.

The effect of 7 days of subcutaneously administered bovine growth hormone (bGH) (0.2 mg kg-1 day-1; n = 4) or an equivalent volume of 0.15 mol l-1 saline (n = 3) on protein metabolism was assessed in lambs. The catabolic response to 48 h of starvation and subsequent hypocaloric total parenteral nutrition (TPN) was measured using primed constant intravenous infusions of [15N]urea and [14C]leucine. Following 48 h of starvation and 7 h of TPN, bGH-treated animals had a significantly decreased rate of net protein catabolism compared with controls (mean(s.e.m.) 2.4(0.2) versus 3.2(0.3) g kg-1 day-1, P < 0.01). The mean(s.e.m.) rate of whole-body protein catabolism was also significantly decreased in bGH-treated animals at 10.9(0.3) g kg-1 day-1 compared with 12.9(0.7) g kg-1 day-1 in saline-treated controls (P < 0.05). In addition, the rates of net and whole-body protein catabolism decreased significantly (P < 0.05) during the period of hypocaloric parenteral feeding to mean(s.e.m.) values of 2.3(0.2) and 8.6(0.6) g kg-1 day-1 respectively in bGH-treated animals. By contrast, in saline-treated controls net and whole-body protein catabolism continued to increase during hypocaloric parenteral feeding. There was a significant decrease (P < 0.05) in the rate of [14C]leucine uptake in tissues of the gastrointestinal tract, heart and diaphragm in bGH-treated animals compared with controls. These results demonstrate that daily administration of growth hormone decreases the catabolic response to a metabolic stress, resulting in the conservation of protein in the heart, diaphragm, gastrointestinal tract and musculoskeletal system by a primary anticatabolic action. In addition, growth hormone therapy initiated before induction of the catabolic state enhances the protein-sparing effects of TPN. Further study is justified to determine whether growth hormone therapy initiated before elective or urgent surgery in the nutritionally depleted patient may have a role in reducing the severity of the postoperative catabolic state, particularly in the patient in whom a complicated course is anticipated.

Mechanisms of host wasting induced by administration of cytokines in rats

This study determined the effects of chronic administration of the two principal proximate cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), on host wasting in rats. The effects were compared with those observed in a matched pair-fed group to distinguish the contribution from anorexia. Both TNF and IL-1 produced weight loss, net nitrogen loss, and skeletal muscle catabolism and increased liver weight. Such effects were independent from and additive to those resulting from semistarvation. However, under equivalent nutritional conditions, TNF infusion led to a greater effect on muscle protein catabolism and liver weight and caused liver protein anabolism, whereas only the group receiving IL-1 had altered glucose metabolism in the postabsorptive state. Tachyphylaxis was seen in the response of food intake over time after administration of IL-1. These actions define the two principal mechanisms for the development of protein calorie malnutrition that occur because of cytokine action, anorexia producing semistarvation and an increased net protein catabolic rate reducing anabolic efficiency.

Pretreatment with bovine growth hormone is as effective as treatment during metabolic stress to reduce catabolism in fasted lambs.

The effects of recombinant bovine GH (rbGH) treatment on the insulin-like growth factor (IGF) axis and protein metabolism during fasting induced metabolic stress were evaluated in young lambs. To explore whether rbGH pretreatment alone might offer a degree of protection against nutritional stress, we compared the effects of rbGH given only before or during the fasting-induced metabolic stress with that given over the whole period. The animals were fed ad libitum for 5 days (well fed phase) and then fasted for 70 h (fasted phase). The rbGH was administered during either the well fed and the fasted phase (G-G), only during the well fed phase (G-S), or only during the fasted phase (S-G), and the effects were compared with those of saline treatment throughout both phases (S-S; n = 7/group). The rate of net protein catabolism, analyzed on the final day of the study, was reduced (P < 0.001) to a similar degree in all rbGH-treated groups compared with that in the S-S group. rbGH pretreatment was as effective as rbGH administered during the catabolic phase. Plasma IGF-I was increased (P < 0.001) in the well fed phase by rbGH treatment and decreased in the fasted phase in all groups. The rbGH treatment during the fasted phase resulted in a smaller fall in plasma IGF-I levels than saline treatment (P < 0.05, G-G vs G-S and S-G vs. S-S), but no difference was observed in the specific binding of [125I]ovine GH to the hepatic membranes from animals of the different groups. There was a negative correlation between net protein catabolism and plasma IGF-I levels (r = -0.48; P < 0.01) and specific binding of [125I]ovine GH to hepatic membranes (r = -0.56; P < 0.001). Plasma IGF-II levels were decreased by rbGH treatment during the well fed phase, but the responses to treatment during the fasted phase were variable, suggesting that plasma IGF-II is regulated in a different manner than plasma IGF-I. The fasting-induced fall (P < 0.05) in plasma concentrations of IGF-binding protein (IGFBP)-3 was reduced with rbGH treatment, and plasma concentrations IGFBP-2 were altered in an inverse manner. This study suggests that fasting-induced GH resistance can be alleviated by rbGH treatment independent of whether treatment is commenced before or after the onset of catabolic stress. Our observation of prolonged anticatabolic action of prophylactic rbGH treatment supports the proposal that prophylactic use of GH may reduce the degree of catabolism associated with subsequent interventions and, thus, improve clinical outcome.

Anabolic and cardiovascular effects of recombinant human growth hormone in surgical patients with sepsis

The clinical and metabolic effects of 7 days of recombinant human growth hormone (rhGH) and total parenteral nutrition (TPN) in surgical patients with sepsis were determined in a randomized controlled trial. In patients with a mean(s.e.m.) pretreatment rate of net protein catabolism (NPC) of 1.5 g per kg per day or less rhGH treatment decreased NPC from 0.93(0.14) to -0.20(0.24) g per kg per day (n = 5; P < 0.0005) and rendered these patients anabolic. TPN alone decreased NPC from 1.12(0.11) to 0.61(0.11) g per kg per day (n = 5; P < 0.001). In patients with an initial NPC of more than 1.5 g per kg per day rhGH treatment decreased NPC from 2.72(0.12) to 1.08(0.24) g per kg per day (n = 5; P < 0.001) while TPN alone decreased it from 2.41(0.32) to 1.28(0.28) g per kg per day (n = 5; P < 0.005). Use of rhGH was not associated with any adverse effects or improvement in clinical course but did decrease the mean systolic and diastolic pressures during the study period. Thus rhGH is a useful anabolic agent and may have a role in the haemodynamic management of the catabolic patient with sepsis.

Peritoneal dialysis kinetics.

Traditionally, for patients maintained with peritoneal dialysis (PD), the level of blood urea nitrogen (BUN), creatinine, and other clinical and laboratory data have been used to judge the adequacy of treatment. Because of the relatively high mortality rates in patients maintained with continuous PD, in the United States and the high failure rate of PD itself, concern has been raised about both the adequacy of PD and its measurement. Underdialysis could be a cause of morbidity and mortality that may be masked by a reduction in protein intake that also lowers the BUN, giving a false sense of security. The peritoneal equilibration test (PET) is widely applied to classify an individual patient's peritoneal membrane permeability but when used alone, the PET is not a measure of adequacy. Currently, for both hemodialysis and PD, the near universally accepted method of quantification is Kt/Vurea, an index of small molecule clearance also known as the fractional urea clearance per dialysis. The continuous or near continuous nature of PD requires a different interpretation of Kt/V, which is usually expressed on a weekly basis using a different set of standards. The currently accepted minimum is 1.7 per week for continuous dialysis (CAPD) with somewhat higher values for intermittent PD. Measurement of Kt/V for PD patients is more direct than for hemodialyzed patients but also more tedious and subject to some pitfalls. A representative clearance must be obtained from dialysate collected preferably over a 24-hour period, and an independent measure of the patient's urea volume or total body water is required. The latter is usually estimated from anthropometric data. The average rate of net protein catabolism, an index of protein nutrition, can be calculated from the urea generation rate obtained from the same 24-hour dialysate collection and normalized to the patient's urea volume, similar to PCRn measured in hemodialyzed patients. An allowance for loss of protein in the dialysate is accomplished by application of the Randerson equation, which is similar to the Borah equation used for hemodialysis. Prospective controlled trials are necessary to examine the relationship between nutrition and dialysis dosage. The hope of the future is that prospective studies of dialysis adequacy, including a full clinical assessment of each patient, will help to establish the optimal dose of PD that will eliminate both the short-term and the long-term complications of uremia and allow a proper focus on other common causes of morbidity and mortality that are associated with the loss of kidney function.

Continuous Ambulatory Peritoneal Dialysis with a High Flux Membrane

The standard peritoneal equilibration test (PET) was performed in 66 patients on CAPD. Patients were classified as low (n = 5), low average (n = 22), high average (n = 27), and high (n = 12) transporters based on the dialysate/plasma creatinine (D/P Cr) after 4 hour dwells. After an average time interval of 14 months on CAPD, indices of dialysis adequacy and nutrition were assessed. Based on monitoring of patient chemistries and drain volumes, peritoneal transport was considered stable during the interval. Instilled volumes and exchange tonicity were individualized in each patient to achieve combined renal and dialysis weekly creatinine clearance and KT/V urea that were not significantly different between groups. Overall, there were significant positive correlations of PET D/P Cr with dialysate albumin concentrations (r = 0.30, p < 0.02) and dialysate albumin losses (g/wk, r = 0.27, p < 0.04). There were significant inverse correlations with lean body mass (r = -0.26, p < 0.03), drain volumes (r = -0.025, p < 0.04), and KT urea by dialysis (L/wk, r = -0.24, p < 0.05). High transporters had significantly (p < 0.05) lower mean serum albumin, net protein catabolic rate (nPCR), lean body mass calculated from creatinine kinetics, and daily creatinine production (and presumably lower muscle mass) compared with one or more lower transport groups. In conclusion, we hypothesize that, in high transporters, use of more hypertonic exchanges with greater glucose absorption may inhibit appetite and nPCR; also, protein losses in drain volumes are increased. High transporters may require increased clearance and protein intake targets compared with other groups to maintain nutrition.(ABSTRACT TRUNCATED AT 250 WORDS)

Cross Sectional Assessment of Weekly Urea and Creatinine Clearances and Indices of Nutrition in Continuous Ambulatory Peritoneal Dialysis Patients

To perform a cross sectional analysis in 71 patients on continuous ambulatory peritoneal dialysis (CAPD) to identify significant correlations of weekly small solute clearances and indices of nutritional status with each other and with patient demographics and other commonly monitored clinical and laboratory parameters. This was a retrospective, cross sectional analysis in 71 patients on CAPD from less than 1 to 105 patient-months (average, 20 months). An outpatient CAPD program. All patients on CAPD in our program at the time of the study willing to undergo the clearance and nutritional status measurements. No interventions other than the monitoring of their status. Weekly small solute clearances, dietary protein intake, serum albumin, lean body mass, net protein catabolic rate, and urinary and dialysate nitrogen. Weekly Kt/V urea (weekly urea clearance normalized to total body water) of at least 1.7 and weekly total creatinine clearances (liter/week/1.7 m2) of at least 50 are associated with net protein catabolic rates (PCR) greater than 0.9 g/kg of normalized body weight in average CAPD patients. Kt/V urea and net PCR correlate significantly with serum albumin. High transporters identified by the peritoneal equilibration test have greater albumin losses and lower serum albumin concentrations. Estimates of lean body mass correlate significantly with serum albumin and net PCR; lean body mass correlates significantly and inversely with age. Greater small solute clearances are associated with better nutritional status.

Continuous Ambulatory Peritoneal Dialysis with a High Flux Membrane

The standard peritoneal equilibration test (PET) was performed in 66 patients on continuous ambulatory peritoneal dialysis (CAPD). Patients were classified as low (n = 5), low average (n = 22), high average (n = 27), and high (n = 12) transporters based on the dialysate/plasma creatinine (D/P Cr) after 4 hr dwells. After an average time interval of 14 months on CAPD, indices of dialysis adequacy and nutrition were assessed. Based on monitoring of patient chemistries and drain volumes, peritoneal transport was considered stable during the interval. Instilled volumes and exchange tonicity were individualized in each patient to achieve combined renal and dialysis weekly creatinine clearance and KT/V urea that were not significantly different between groups. High transporters had significantly (p < 0.05) lower mean serum albumin, net protein catabolic rate (nPCR), lean body mass calculated from creatinine kinetics, and daily creatinine production (and presumably lower muscle mass), and higher albumin clearances compared to one or more lower transport groups. In conclusion, we hypothesize that high transporters are prone to protein malnutrition related to increased dialysate protein losses, and perhaps suppression of appetite, with increased use of hypertonic exchanges. High transporters are candidates for protein supplementation on CAPD or transfer to nightly intermittent peritoneal dialysis where short cycles provide more ultrafiltration with less glucose absorption.

The effect of tumor bulk on the metabolic response to cancer.

The aim of this study was to examine the association between tumor bulk and degree of metabolic abnormalities in patients with cancer. Patient data were obtained from a retrospective review of metabolic data collected from patients over a 5‐year period. Some of the data have been used in other previously published studies.1, 2, 3 Patients were included in this study if metabolic data had been collected preoperatively, if they had no “significant” sepsis and concurrent endocrine disease, and if they had not received total parenteral nutrition. Solid tumor volume was calculated based on the tumor dimensions recorded in the pathologic records of the patients reviewed. The authors made the assumption that solid tumors were uniformly spherical and 1 cm3 of tumor tissue weighed 1 g. The volume and weight of hepatic or pulmonary metastases were similarly calculated using dimensions obtained with ultrasound or computed tomographic scanning. The volume of myeloproliferative tumors was calculated assuming that all hematopoietic tissue, except the spleen, was uniformly malignant and the myeloid tissue composed 5.9% of the patient's body weight. The following metabolic parameters were measured: oxygen consumption, rates of plasma glucose appearance and clearance, rate of plasma glucose oxidation and recycling, and rate of net protein catabolism. Glucose kinetics were measured by using primed constant infusions of [14C]glucose and [6‐3H]glucose. The rate of protein catabolism was determined by using primed constant infusions of [14C]urea or [di‐15N]urea. Blood samples were drawn after 120 minutes of isotope infusion over a 60‐minute interval. Indirect calorimetry was performed and oxygen consumption determined.Eighty‐five patients were included in the study. Approximately 81% were patients with solid tumors. The majority of these patients had gastrointestinal and head and neck malignancies. The remaining 19% had leukemias or lymphomas. The rates of plasma glucose appearance and clearance were determined in all 85 patients as was the rate of net protein catabolism. However, the rates of plasma glucose oxidation and recycling were determined in only 52 patients (61%).A positive correlation was found between the rate of plasma urea appearance and the rate of net protein catabolism and tumor bulk (r 2 =.80). The bulk of tumor present was positively correlated with the rate of plasma glucose appearance (r 2 =.72) and the rate of plasma glucose clearance (r 2 =.70). However, a negative correlation was demonstrated when the percentage of glucose uptake oxidized by tissue was compared to tumor bulk (r 2 =.75); this was associated with an increase in the percentage of tissue glucose uptake recycled to lactate (r 2 =.62). Oxygen consumption was also positively correlated with tumor bulk (r 2 =.79).Based on these data, the authors concluded that progressive increase in tumor size is associated with an increase in peripheral substrate mobilization, an increase in the rate of glucose production, an increase in the rate of tissue glucose uptake, and an increase in glucose recycling and protein loss.

Passive immunization against circulating insulin-like growth factor-I (IGF-I) increases protein catabolism in lambs: evidence for a physiological role for circulating IGF-I.

Primed constant infusions of [14C]urea were used to determine the acute effect of passive immunization against circulating free and protein-bound insulin-like growth factor-I (IGF-I) on the rate of net protein catabolism (NPC) in castrated male lambs fasted for 48 h. Following an intravenous bolus of 50 ml IGF-I antiserum, the rate of NPC increased to a peak 30 min after injection of 1.69 +/- 0.16 g/kg per day from a baseline value of 1.45 +/- 0.22 g/kg per day (P < 0.05, n = 4). In three animals given 50 ml equivalents of the purified immunoglobulin fraction, NPC increased from 1.31 +/- 0.20 to 1.59 +/- 0.16 g/kg per day (P < 0.05). A similar trend was observed in animals given 25 ml antiserum (n = 4). The rate of NPC did not increase following a bolus of non-immune serum in control animals and the rate of NPC in the treated lambs returned to control levels within 60 min of antibody injection. Plasma insulin and glucose concentrations in both the treated and control groups were unchanged throughout the study. These data suggest that circulating IGF-I has a physiological role in regulating whole body protein turnover during starvation and possibly other catabolic states. The effect of immunoneutralization of circulating IGF-I is transient and this suggests that while IGF-I has an endocrine role in the regulation of protein turnover, other regulatory mechanisms are involved.

Synergistic effect of insulin-like growth factor-I administration on the protein-sparing effects of total parenteral nutrition in fasted lambs.

Using primed constant isotopic infusions, we investigated the effects of recombinant human insulin-like growth factor-I (IGF-I) infusion on protein kinetics in both fasted and parenterally fed (TPN) lambs. Infusion of IGF-I at a dose of 50 micrograms/kg.h in fasted animals increased (P less than 0.005) the mean plasma IGF-I concentration from 77.5 +/- 9.7 to 454.4 +/- 51.4 ng/ml. During IGF-I infusion the rate of net protein catabolism (NPC) was decreased (P less than 0.005) by 17% from 3.5 +/- 0.2 to 2.9 +/- 0.2 g/kg.day, and the rate of appearance (Ra) of leucine in plasma decreased (P less than 0.01) from 5.0 +/- 0.4 to 3.4 +/- 0.4 mumol/kg.min. In addition, the fractional synthetic rate of protein in cardiac and diaphragmatic muscle increased by 100% (P less than 0.05) during the same period. After 3 h of TPN, the rate of NPC was decreased (P less than 0.01) in the TPN animals compared to that in their fasted counterparts (1.89 +/- 2.27 vs. 4.1 +/- 0.2 g/kg.day, respectively). The rate of NPC was further decreased after another 300 min of TPN to 0.76 +/- 0.27 g/kg.day. However, the Ra of leucine was not changed compared to the initial value. Infusion of IGF-I concurrently with TPN reversed (P less than 0.001) the rate of NPC from 1.02 +/- 0.21 g/kg.day after 180 min of TPN alone to a state of net protein gain of 0.14 +/- 0.19 g/kg.day after a further 300 min of combined IGF-I and TPN infusion. The Ra of leucine decreased (P less than 0.01) from 3.9 +/- 0.8 to 2.5 +/- 0.47 mumol/kg.min during IGF-I and TPN infusion. Similarly, the fractional synthetic rates of protein in cardiac muscle, diaphragm, adductor muscle, psoas muscle, and hepatic tissue were increased (P less than 0.05) compared to those in animals that received only TPN. The protein-sparing effects of IGF-I and TPN were synergistic, and the infusion of both agents resulted in the induction of a protein anabolic state within 60 min of commencing IGF-I infusion. In contrast, neither IGF-I nor TPN alone resulted in a state of net protein anabolism, and neither had an effect on protein kinetics until 120 min into the infusion. Consequently, IGF-I shows considerable potential as an anticatabolic agent when used synergistically with nutritional support.

A possible role for IGE-II: evidence in sheep for in vivo regulation of IGF-I mediated protein anabolism.

Using primed constant infusions of [14C]urea we assessed the effects in castrate male lambs of insulin-like growth factor (IGF) II infusion on protein metabolism during concurrent IGF-I infusion. A 300 minute infusion of IGF-I at 15 micrograms/kg.hour (n = 4) increased (p less than 0.001) the plasma IGF-I concentration from 72.5 +/- 6.4 ng/ml to 213.6 +/- 17.4 ng/ml and decreased (p less than 0.01) the rate of net protein catabolism (NPC) from 1.48 +/- 0.28 g/kg.day to 1.02 +/- 0.18 g/kg.day. Infusion of IGF-II at a dose of 50 micrograms/kg.hour concurrently with IGF-I at 15 micrograms/kg.hour (n = 4) was associated with a similar rise (p less than 0.01) in plasma IGF-I concentration from 79.4 +/- 4.1 ng/ml to 225.2 +/- 32.8 ng/ml. Plasma IGF-II increased (p less than 0.05) from 350.6 +/- 41.6 ng/ml to 746.7 +/- 165.5 ng/ml over the infusion. Coadministration of IGF-II completely blocked (p less than 0.01) the anabolic effect of IGF-I and the rate of NPC remained unchanged throughout the combined IGF-I and IGF-II infusion at a level comparable to saline infused controls (n = 4). This study suggests that IGF-II may play a physiological role as a circulating modulator of the anabolic effects of IGF-I.

The effect of tumor bulk on the metabolic response to cancer.

The derangements in energy/substrate metabolism seen in oncology patients are similar regardless of the tumor's site of origin, and in advanced disease these metabolic derangements can be manifested as cancer cachexia. The relationship between tumor size and the degree of metabolic abnormality, however, remains unclear. Using primed constant infusions of stable and radiolabeled isotopes and indirect calorimetry, the authors have determined the rates of net protein catabolism (NPC), glucose oxidation, Cori cycling of glucose, and oxygen consumption in 85 patients with cancer. They have assessed the association between bulk of tumor and metabolic abnormality using regression analysis. A positive correlation was found between tumor bulk and the rates of NPC (r2 = 0.8), plasma glucose appearance (r2 = 0.72), plasma glucose clearance (r2 = 0.70), the percentage of tissue glucose uptake recycled to lactate (r2 = 0.62), and oxygen consumption (r2 = 0.79). The percentage of tissue glucose uptake oxidized was negatively correlated with tumor bulk (r2 = 0.75). The data indicate that the degree of metabolic abnormality seen in cancer patients is closely related to the quantity of malignant tissue present. Progressive increase in tumor size is associated with an increase in peripheral substrate mobilization, an increase in the rate of hepatic glucose production, an increase in tissue glucose uptake, an increase in energy-expensive glucose cycling to lactate, and an increase in protein loss.

Studies in the Basal State and the Response to Total Parenteral Nutrition

A series of isotopic infusions were performed in 43 severely ill patients suffering from blunt trauma (mean injury severity score of 31). The patient data have been compared with data obtained from 32 normal volunteers, and in addition the metabolic response of the trauma patient to total nutritional support (TPN) has been assessed. The rate of VO2 was elevated in the trauma patients compared with that of the volunteers (160 mumol/kg/minute vs. 103 mumol/kg/minute). Glucose production was significantly increased in the patients compared with the volunteers (21 +/- 2 mumol/kg/minute vs. 14 +/- 1 mumol/kg/minute), but the trauma patients had an impaired capacity to directly oxidize plasma glucose. The percentage of glucose uptake oxidized in the volunteers was 36 +/- 2%, and the percentage of glucose uptake recycled was 10 +/- 1%. By contrast, in the trauma patients, 23 +/- 4% of the glucose uptake was directly oxidized, and 29 +/- 11% was recycled. The rate of glycerol turnover in the trauma patients (5.3 +/- 0.3 mumol/kg/minute) was significantly elevated compared with the volunteer value (2.2 +/- 0.1 mumol/kg/minute), and the basal rate of fat oxidation was twice as high in the patients as in the volunteers (2 mg/kg/minute vs. 1 mg/kg/minute). The rate of whole body protein catabolism was significantly higher in the patients (5.8 +/- 0.7 g/kg/day vs. 4.3 +/- 0.3 g/kg/day), and as a result, the rate of net protein catabolism was significantly elevated in the patients. The response to TPN (amino acids and a 50:50 mixture of glucose and fat) included an increase in the percentage of glucose uptake oxidized (up to 45 +/- 12%), a decrease in the oxidation of fat (up to 0.8 mg/kg/minute), and a significant increase in whole body protein synthesis (up to 6.1 +/- 1.1 g/kg/day) so that the rate of net protein loss was minimized but not prevented. (The rate of net protein catabolism during TPN was 1.3 +/- 0.5 g/kg/day.) There was no correlation between the injury severity score (ISS) and the degree of metabolic abnormality. The rate of NPC in the patients with ISS less than 20 was higher than in the volunteers (ISS = 0), but the values for NPC in patients with ISS 21-40, and ISS greater than 40 were virtually identical to the corresponding values in patients with ISS less than 20. It is concluded from these studies that: 1) Trauma patients have a high rate of VO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of stress, depletion, and/or malignant disease on the responsiveness of surgical patients to total parenteral nutrition

We performed a series of 14C[urea] infusions to assess the effect of depletion (greater than 15% decrease in body weight), stress (VO2 greater than 130 mumol.kg-1.min-1), and cancer on the basal rate of net protein catabolism (NPC) and the response of patients to total parenteral nutrition (TPN). Depleted patients had low rates of NPC (0.8 +/- 0.1 g.kg-1.d-1) compared with nondepleted patients (p less than 0.05) and during TPN anabolism was achieved (0.5 +/- 0.2 g.kg-1.d-1). Gastrointestinal (GI) cancer patients had rates of NPC similar to those of normal volunteers; during TPN, NPC approximated zero. Severely stressed (SS) nondepleted patients had high rates of NPC (2.7 +/- 0.2 g.k-1.d-1) whereas SS-depleted patients had lower (p less than 0.05) rates of NPC (1.9 +/- 0.3 g.kg-1.d-1); both groups of SS patients remained catabolic despite TPN (1.2 +/- 0.3 and 0.5 +/- 0.2 g.kg-1.d-1, respectively). In response to TPN, depleted patients become anabolic, GI cancer patients stop losing protein but do not become anabolic, and stressed patients remain catabolic and continue to loss protein.

Whole-body protein kinetics in patients with early and advanced gastrointestinal cancer: the response to glucose infusion and total parenteral nutrition.

We have isotopically determined rates of whole-body protein synthesis and catabolism in a group of normal volunteers and in two groups of cancer patients: 20 patients with advanced weight-loss (AWL) upper gastrointestinal cancer and 7 patients with early non-weight-loss (ENWL) lower gastrointestinal cancer. In both patients and volunteers we determined protein kinetics in the basal state and during glucose infusion at 4 mg/kg/min. In addition, in the AWL patients the effect of total parenteral nutrition (TPN) on protein dynamics was also assessed. The rate of net protein breakdown was determined with the primed constant infusion of either 15N-urea or 14C-urea, the rate of whole-body protein catabolism was measured with the primed constant infusion of 15N-lysine, and the rate of whole-body protein synthesis was deduced from the above two values. The basal rates of net protein catabolism, whole-body protein catabolism, and whole-body protein synthesis were similar in the volunteers and ENWL cancer patients. The basal values for net protein catabolism in the volunteers and ENWL patients were 1.46 +/- 0.18 and 1.34 +/- 0.08 gm/kg/min, respectively. In both volunteers and ENWL patients glucose infusion resulted in a significant decrease in net protein catabolism. In the ENWL patients this decrease was due to a significant decrease in whole-body protein catabolism (p less than 0.05); the rate of whole-body protein synthesis did not change significantly. In the AWL cancer patients the rate of net protein catabolism was significantly higher than in either the volunteer or ENWL group (p less than 0.05), and glucose infusion did not result in a decrease in net protein catabolism. However, when the AWL group was studied during TPN there was a significant decrease in net protein catabolism from 2.24 +/- 0.30 to 0.17 +/- 0.09 gm/kg/day (p less than 0.01). This decrease was due to the combined effect of a significant decrease in whole-body protein catabolism coupled with an increase in whole-body protein synthesis. From these studies we conclude the following: (1) ENWL cancer patients and normal volunteers have similar protein dynamics, and in both groups glucose infusion resulted in a significant decrease in protein loss. (2) AWL cancer patients have an elevated rate of net protein catabolism, and this is not sensitive to glucose infusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Whole body protein kinetics in severely septic patients. The response to glucose infusion and total parenteral nutrition.

Rates of whole body protein synthesis and catabolism in normal volunteers and in a group of severely septic patients were isotopically determined. In addition, the effect in the patients of either glucose infusion or total parenteral nutrition (TPN) on protein dynamics was assessed. The basal rate of net protein catabolism (NPC) was significantly higher in the septic patients than in the volunteers (p less than 0.05). The values obtained in the volunteers and patients were 1.44 +/- 0.18 and 2.20 +/- 0.10 g/kg/day, respectively. This increase in NPC was primarily due to a major increase in whole body catabolism that was partially counteracted by a modest increase in protein synthesis. When the patients were infused with glucose (4 mg/kg/min), NPC decreased significantly (p less than 0.001) to 1.96 +/- 0.08 g/kg/day, and during TPN the value was significantly lower again (p less than 0.04) (0.63 +/- 0.28 g/kg/day). In each instance the conservation of host tissue was due to an increase in protein synthesis: the accelerated rate of whole body protein catabolism continued irrespective of the nutritional status. The following conclusions were reached from these data: severely ill septic patients have an accelerated rate of NPC compared with normal volunteers, and this is primarily due to a large increase in whole body protein catabolism; TPN is an effective means of conserving host tissue in severely septic patients via the promotion of whole body protein synthesis; despite the beneficial effect of TPN in these patients, whole body protein catabolism continues unabated, and as a result, protein losses still occur at approximately one fourth the rate seen in the absence of TPN; and there is no obvious advantage in terms of protein-sparing when protein is provided in amounts exceeding 1.5 g/kg/day.

Glucose, fatty acid, and urea kinetics in patients with severe pancreatitis. The response to substrate infusion and total parenteral nutrition.

Rates of glucose turnover and oxidation in normal volunteers (N = 16) and in severely ill patients with pancreatitis (N = 9) were isotopically determined. Glucose turnover was determined using primed constant infusions of either 6-3H-glucose or 6-d2-glucose, and glucose oxidation with either U-14C-glucose or U-13C-glucose after appropriate priming of the bicarbonate pool. Urea kinetics were determined using primed constant infusions of either (15N2)-urea or U-14C-urea, whereas free fatty acid (FFA) kinetics were determined by the constant infusion of 1,2-13C palmitate. Basal rates of glucose production and plasma glucose clearance were significantly higher in the patients than in the volunteers. During glucose infusion (4 mg/kg/min) endogenous glucose production was virtually totally suppressed in the volunteers (94 +/- 4%). There was significantly less suppression in the patients, however (44 +/- 1%). In addition, the percentage of available glucose oxidized (i.e., percentage of uptake oxidized) was significantly less in the patients than in the volunteers. The basal rate of urea production was significantly higher in the patients; however, in both patients and volunteers, glucose infusion resulted in a significant decrease. The rate of FFA turnover was similar in the patients and volunteers, and the patients and volunteers were equally sensitive to the suppressive effects of glucose infusion. When the patients were studied during total parenteral nutrition (TPN), there was no further suppression of endogenous glucose turnover than that seen during 2 hours of glucose infusion, and the mean rate of urea turnover measured during TPN (7.0 +/- 1.9 mumol/kg/min) was also not significantly different than the value determined during glucose infusion (8.9 +/- 1.8 mumol/kg/min). It was concluded from these studies that patients with pancreatitis are metabolically similar to septic patients, have an impairment in their ability to oxidize infused glucose when compared with normal volunteers, have an elevated rate of net protein catabolism, and have FFA kinetics similar to those seen in normal humans.

Net protein catabolic rate after kidney transplantation: impact of corticosteroid immunosuppression.

Protein catabolic rate (PCR) was measured during the first 3 to 7 weeks after kidney transplantation in nine nondiabetic patients (16-52 yr old) who were receiving azathioprine and corticosteroid immunosuppression. Five of the patients received additional amounts of corticosteroids to treat rejection episodes. The PCR paralleled the amounts of corticosteroids administered initially as prophylactic immunosuppression and later as treatment for rejection episodes. In spite of a diet containing 1.2 g of protein per kg ideal body weight, net urea generation reflected severe lean body mass breakdown, roughly equivalent in magnitude to a 50% body surface area full-thickness burn. This catabolism was accompanied by a fall in serum albumin without significant weight loss. Hypercatabolism in the early posttransplant period is severe. After transplantation diet should be modified to try to satisfy these nitrogen demands.

Nitrogen balance during intermittent dialysis therapy of uremia

Daily measurements of nitrogen balance were made at two levels of protein intake in five patients undergoing chronic intermittent dialysis therapy. During ingestion of high (1.4 g/kg of body wt) protein intake, nitrogen balance was positive on nondialysis days and negative on dialysis days, so that cumulative balance for the week of study was not different from zero. During ingestion of low (0.5 g/kg) protein intake, nitrogen balance was approximately zero on nondialysis days but was again negative on dialysis days, so that cumulative balance for this period was negative. The negative nitrogen balance observed on dialysis days was associated with a higher rate of urea nitrogen generation (Gu, g/24 hr, determined by a kinetic model of urea nitrogen in dialysis patients) that was most evident in the hours immediately following dialysis. Net protein catabolic rate (PCR, g/24 hr), derived from total nitrogen mass balance equations, correlated very closely with Gu:Gu = 0.154 PCR - 1.7, r = 0.96. This relationship agreed well with previous observations made in nondialyzed uremic patients under more steady-state conditions. These studies demonstrate that nitrogen balance is negative on dialysis days regardless of protein intake, and that Gu is higher on dialysis days. The negative nitrogen balance could result from amino acid loss in dialysate and from increased protein catabolism stimulated by loss of glucose into dialysate.