Amelioration of the protein metabolic response in spermidine-supplemented trauma rats.

Polyamines are biologically active, small, positively charged ubiquitous compounds that play an important role in initiating adaptive changes in cell proliferation, cell growth, and synthesis of proteins and nucleic acids. The potential for exogenous dietary polyamine to significantly contribute to whole-body growth and health has not been explored. This study evaluates the efficacy of feeding a liquid diet supplemented with 0.05% spermidine in injured rats. Rats traumatized by bilateral femur fracture (n = 12) and pair-fed uninjured controls (n = 12) were starved for 2 days and then refed for 4 days with a liquid diet containing 0.05% spermidine or an isonitrogenous control diet. Daily urine and body weight data were collected. At the end of refeeding, the rats were killed, and blood, cerebrospinal fluid (CSF), muscle, and brain tissue were collected. Spermidine supplementation (0.05%) was found to be tolerated well by the rats and (1) did not affect voluntary food intake by traumatized rats, (2) did not alter the growth rate, (3) increased protein utilization efficiency, and (4) decreased leucine, isoleucine, and valine levels in plasma and muscle. The profound effect of trauma on plasma amino acid metabolism seen in rats fed the basal diet was absent in spermidine-supplemented rats. Depletion of plasma glutamine (GLN) levels due to trauma was significantly less in rats with spermidine supplementation (11% v 33%), indicating a beneficial effect to counteract trauma responses. The results suggest that spermidine supplementation improves protein utilization efficiency and ameliorates trauma effects on amino acid levels.

Nutritional efficacy of a spermidine supplemented diet.

Polyamines (PA) are ubiquitous cell components essential for growth. Dietary PAs are directed preferentially to tissues and organs that have been stimulated to grow by metabolic signals. Nutritional efficacy and growth potential of an oral PA supplement, spermidine (SD), was examined in growing rats. A group of 24-male Sprague-Dawley rats (200-220 g) was adapted to our vivarium conditions for 3 d, then fed ad libitum continuously for 14 d. During feeding they received either a basal diet (n = 8) or a test diet containing the basal diet with 0.05% SD (test diet 1, n = 8) or 0.10% SD (test diet 2, n = 8). This dose of SD corresponds to an intake of 54 and 108 mumol of SD per rat per day. At the end of 14 d of feeding, the animals were sacrificed and plasma, cerebral spinal fluid (CSF) and tissues (muscle, brain, and liver) were harvested for amino acid analysis. Voluntary food intake, body weight gain, and nitrogen excretion and balance were significantly decreased in test diet 2 fed rats compared to test diet 1. The opposing trends in the accumulation/depletion of free amino acids (AA) in muscle and plasma suggests that the exogenous supply of SD blocks the transport of amino acids, as well as PAs from the cells, since AA and PA share the same transport systems. A trend toward decreased weight gain and feeding efficiency was observed when high concentrations of SD were fed. It was concluded that feeding of SD at moderate intake is not toxic and does not retard growth. Oral administration of a smaller dose (<0.05%) of SD may promote further growth. The optimal level of SD dietary supplementation has thus yet to be established.

Nutritional and metabolic effects and significance of mild orotic aciduria during dietary supplementation with arginine or its organic salts after trauma injury in rats.

The effects of acute food deprivation and subsequent refeeding with isonitrogenous oral liquid diets supplemented with arginine (ARG), ARG alpha-ketoglutarate (AKG), or ARG alpha-ketoisocaproate (AKIC) were examined in a Sprague-Dawley rat trauma model (bilateral femur fracture). Both control and trauma rats were starved for 2 days and then pair-fed for 4 days with one of four liquid isonitrogenous diets: diet 1 was a basal casein-based diet, and diets 2, 3, and 4 were the basal diet in which 10% of the nitrogen was replaced by ARG, AKG, or AKIC nitrogen. Two days of starvation resulted in a 13% loss of body weight and also a 27% decrease in the excretion of orotic acid (OA) in control and trauma rats. Although the ARG content of diets 2, 3, and 4 was the same, ARG- and AKIC-supplemented rats excreted significantly (P < .05) more OA than AKG-fed rats. The low level of OA excretion in AKG-fed rats indicates greater use of ARG for metabolic purposes, including efficient urea cycle operation. The metabolic adaptation and nutritional efficacy, i.e., Increased nitrogen retention, larger weight gain, and altered amino acid (AA) metabolism, of AKIC rats seem to be better than in ARG- or AKG-fed rats.

Reprioritization of liver protein synthesis resulting from recombinant human growth hormone supplementation in parenterally fed trauma patients: the effect of growth hormone on the acute-phase response.

BACKGROUND: One of the major components of the metabolic response to severe trauma is the alteration in concentrations of a large number of plasma proteins referred to as acute-phase proteins (APP). The principle mediators of these liver-synthesized APP are mainly the cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). METHODS: We have measured the plasma levels of IL-6, TNF alpha, and 20 APP in 24 adult, severely injured, hypermetabolic and highly catabolic patients with multiple injuries within 48-60 hours after injury, when they were receiving maintenance fluids without calories or nitrogen, and subsequently during 7 days of total parenteral nutrition with (n = 12) or without (n = 12) recombinant human growth hormone supplementation (rhGH, 0.15 mg/kg/d). RESULTS: Baseline positive APP due to severe trauma include C-reactive protein (CRP), alpha-1 antichymotrypsin, alpha-1 acid glycoprotein, alpha-1 antitrypsin, fibronectin, and factor B. Negative APP include IgG, IgM, complement-3, prealbumin, transferrin, ceruloplasmin, and albumin. Except for CRP, alpha-1 antichymotrypsin, and albumin, all the APP levels increase during 7 days of nutritional support. Plasma levels of cytokines IL-6 and TNF-alpha, although initially markedly increased after injury, decrease with parenteral refeeding. There is a linear correlation between CRP and IL-6 levels and also between the transport proteins prealbumin and transferrin. Trauma-induced increases in CRP and IL-6 levels decreased with nutrition alone, but did not change with rhGH supplementation. An immunosuppressed state of injury is evident from the decreased immunoglobulin levels (IgG, IgM, IgA) in the trauma patients. Total parenteral nutrition alone increases the immunoglobulin levels to normal. However, with adjuvant rhGH, only IgA levels are normalized. CONCLUSIONS: Adjuvant rhGH therapy does not attenuate the reprioritization of acute liver protein synthesis and results in only limited restoration of host defenses. The clinical implications of these findings await further study.

Integrated nutritional, hormonal, and metabolic effects of recombinant human growth hormone (rhGH) supplementation in trauma patients.

An anabolic stimulus is needed in addition to conventional nutritional support in the catabolic "flow" phase of severe trauma. One promising therapy appears to be rhGH infusion which has direct as well as hormonal mediated substrate effects. We investigated on a whole-body level, the basic metabolic effects of trauma within 48-60 h after injury in 20 severely injured (injury severity score [ISS] = 31 +/- 2), highly catabolic (N loss = 19 +/- 2 g/d), hypermetabolic (resting energy expenditure [REE] = 141 +/- 5% basal energy expenditure [BEE]), adult (age 46 +/- 5 y) multiple-trauma victims, before starting nutrition therapy and its modification after 1 wk of rhGH supplementation with TPN (1.1 x REE calories, 250 mg N.kg-1.d-1). Group H (n = 10) randomly received at 8:00 a.m. on a daily basis rhGH (0.15 mg.kg-1.d-1) and Group C (n = 10) received the vehicle of infusion. Protein metabolism (turnover, synthesis and breakdown rates, and N balance); glucose kinetics (production, oxidation, and recycling); lipid metabolism, (lipolysis and fat oxidation rates), daily metabolic and fuel substrate oxidation rate (indirect calorimetry); and plasma levels of hormones, substrates, and amino acids were quantified. In group H compared to group C: N balance is less negative (-41 +/- 18 vs -121 +/- 19 mg N.kg-1.d-1, P = 0.001); whole body protein synthesis rate is 28 +/- 2% (P = 0.05) higher; protein synthesis efficiency is higher (62 +/- 2% vs 48 +/- 3%, P = 0.010); plasma glucose level is significantly elevated (256 +/- 25 vs 202 +/- 17 mg/dL, P = 0.05) without affecting hepatic glucose output (1.51 +/- 0.20 vs 1.56 +/- 0.6 mg N.kg-1.min-1), glucose oxidation and recycling rates; significantly enhanced rate of lipolysis (P = 0.006) and free fatty acid reesterification (P = 0.05); significantly elevated plasma levels of anabolic GH, IGF-1, IGFBP-3, and insulin; trauma induced counter-regulatory hormone (cortisol, glucagon, catecholamines) levels are not altered; trauma induced hypoaminoacidemia is normalized (P < 0.05) and 3-methylhistidine excretion is significantly low (P < 0.001). Improved plasma IGF-1 levels in Group H compared with Group C account for protein anabolic effects of adjuvant rhGH and may be helpful in promoting tissue repair and early recovery. Skeletal muscle protein is spared by rhGH resulting in the stimulation of visceral protein breakdown. The hyperglycemic, hyperinsulinemia observed during rhGH supplementation may be due to defective nonoxidative glucose disposal, as well as inhibition of glucose transport activity into tissue cells. The simultaneous operation of increased lipolytic and reesterification processes may allow the adipocyte to respond rapidly to changes in peripheral metabolic fuel requirements during injury. This integral approach helps us to better understand the mechanism of the metabolic effects of rhGH.

Arterial-jugular vein free amino acid levels in patients with head injuries: important role of glutamine in cerebral nitrogen metabolism.

Traumatic brain injury is the single largest contributor of trauma center deaths. Injury to the brain cannot be considered as an isolated event, affecting only this organ. Profound hypoglutaminemia commonly seen in patients with head injuries may be caused by the diminished release of glutamine from the brain to the systemic circulation. To assess this hypothesis, we have simultaneously measured the free amino acid (AA) levels in systemic arterial (A, radial artery), cerebral venous (JV, jugular bulb), and systemic venous (PA, pulmonary artery) plasma in 11 adult patients with severe head injuries once within 48 hours of the initial injury before starting nutritional support and again after 3 to 4 days of enteral feeding. Cerebral organ (A-JV) changes of AA levels were compared with whole body systemic (A-PA) changes. Arterial total AA levels when compared with reported normal values are diminished by 46% in patients with isolated severe injuries. Cerebral outflow of glutamine is 6% of the total AA output compared with 73% in normals. The systemic outflow of glutamine in patients with brain injuries is 28% of total AA flow. Despite this high systemic output, significant hypoglutaminemia persists. Feeding for 3 days did not appreciably change the arterial plasma AA levels except that of glutamate and citrulline. A significant (p = 0.01) linear relationship between glutamine (product) and glutamate (precursor) was seen in JV samples but not in A or PA samples. The ratio of plasma glutamine to glutamate was decreased significantly only in JV during nutritional support, and this was caused mainly by an increase in glutamate levels. This may be owing to defective amidation to glutamine, inasmuch as gamma aminobutyric acid (GABA) levels were only minimally affected. Nutritional support improves the net release of glutamine from the brain. This suggests that supplementing the diet with glutamine may be beneficial to support systemic requirements in patients with severe head injuries.

Ornithine-alpha-ketoglutarate (OKG) supplementation is more effective than its component salts in traumatized rats.

Addition of an anabolic stimulus during nutritional support seems to be a reasonable adjunct to augment protein synthesis. Ornithine-alpha-ketoglutarate (OKG) has been used for this purpose in many pathological situations, but the mechanism of action is poorly understood. We have evaluated the relative metabolic efficacy of four isonitrogenous diets with or without the addition of alpha-ketoglutarate (alpha KG) or ornithine (ORN), in a rat trauma (bilateral femur fracture) model. Both control and traumatized rats were starved for 2 d. Then for 4 d, the control rats were pair-fed to the traumatized rats, one of the four isonitrogenous diets: the basal diet was a casein-based liquid diet; the ORN and OKG diets were the basal diet in which 10% of the dietary nitrogen was replaced by ORN- or OKG-nitrogen, respectively; the alpha KG diet contained equivalent amounts of alpha KG as were present in the OKG diet. Body weight gain per gram of nitrogen intake was similar in all four diet groups of both control and traumatized rats. The fraction of nitrogen intake that was retained in the body was significantly higher in OKG-fed traumatized rats (23%) than in the corresponding basal diet-fed rats. Plasma and muscle free amino acid concentrations were comparable in OKG- and ORN-fed rats but not in OKG- and alpha KG-fed rats. Our data suggest that the mechanism of OKG action may be associated with increases in growth hormone and insulin, as well as the production of metabolites of ORN and alpha KG. OKG has better metabolic benefits than its two components given separately in the nutritional support of injured rats.

Adjuvant recombinant human growth hormone does not augment endogenous glucose production in total parenteral nutrition-fed multiple trauma patients.

Hyperglycemia and insulin resistance are well-known, consistent responses to severe injury. The purpose of this study was to investigate the mechanism for the further exaggerated hyperglycemia due to adjuvant recombinant human growth hormone (rhGH) treatment in multiple trauma patients. We have measured in 20 adult severely injured, highly catabolic, hypermetabolic multiple trauma patients, the glucose kinetics (appearance, clearance, oxidation, and recycling) once in the basal state (study I), 48 to 60 hours after injury but before starting nutritional therapy, and again (study II) after 7 days of intravenous nutrition (1.1 times resting energy expenditure, 250 mg nitrogen [N]/kg/d) with or without adjuvant rhGH. Group H (n = 10) randomly received daily (8 AM) rhGH (0.15 mg/kg/d) and group C (n = 10) received the vehicle of infusion. Adjuvant rhGH treatment in intravenously fed trauma patients (1) increases plasma insulin-like growth factor-1 (IGF-1) and insulin concentrations, (2) improves N balance, and (3) exaggerates the hyperglycemic response without affecting endogenous glucose output, glucose oxidation, or recycling. The mechanism for the hyperglycemic hyperinsulinemia in trauma may be due to a defective nonoxidative glucose disposal, as well as inhibition of glucose transport activity into tissue cells.

Altered brain and muscle amino-acid levels due to remote injury during glutamine supplementation.

Glutamine (GLN) has aroused considerable interest among clinicians and nutritionists after studies demonstrated conclusively profound GLN depletion during critical illness. Although the brain plays an important role in GLN metabolism, little is known concerning changes in cerebral handling of GLN following injury. We have evaluated in a rat trauma (bilateral femur fractures) model, the nutritional efficacy of GLN-rich diet and the remote injury-induced changes in amino-acid (AA) contents of brain and muscle tissues. Both control and traumatised rats were starved for 2 days and then pair-fed for 4 days, either a basic liquid diet (BioServ # F1259) or an isonitrogenous test diet which contained the same basic diet from which 10% nitrogen (N) was replaced by GLN-N. Protein efficiency ratio as well as plasma levels of anabolic growth hormone and insulin did not change due to GLN-enriched diet. Remote injury-induced changes in GLN and glutamic acid (GLU) during GLN-rich diet were minimal in brain tissues; whereas GLN levels were decreased in plasma and muscle, GLU levels were increased in plasma and decreased in muscle tissues. The AA levels of brain tissues, in general, were maintained within narrow limits during GLN supplementation in control and injured rats. An increased influx of tryptophan and increased synthesis of the neurotransmitter serotonin were suggested due to GLN-enriched diet.

Plasma levels of insulin-like growth factor binding protein-3 in acute trauma patients.

Insulin-like growth factors (IGFs) are a family of polypeptides that regulate cell growth. Their action and bioavailability are modified by binding proteins such as IGF binding protein-3 (IGFBP-3). Plasma IGFBP-3 level was found to be growth hormone (GH)-dependent, which makes detection of IGFBP-3 useful in the evaluation of GH secretion. In the early catabolic flow phase of severe injury, when plasma levels of GH and IGF-1 are low versus uninjured levels, the role of IGFBP-3 has not been investigated. We have measured basal levels of these polypeptide hormones in 16 adult (13 men and three women aged 47 +/- 7 years) severely injured (Injury Severity Score, 32 +/- 2), hypermetabolic resting energy expenditure [REE] to basal energy expenditure [BEE] ratio, 1.30 +/- 0.05), ventilator-dependent, multiple-trauma patients within 48 to 60 hours of injury when the patients were receiving maintenance fluids without calories or nitrogen. These basal values were compared with those of 16 age-matched postabsorptive normals. In the catabolic flow phase of injury, plasma levels of GH, IGF-1, and IGFBP-3 were significantly reduced by 50%, 46%, and 45%, respectively. There was a significant linear inverse relationship between IGFBP-3 and age and also a positive correlation between IGFBP-3 and IGF-1 in both control and injured subjects. The ratio of IGFBP-3 to IGF-1 was not changed in trauma victims. Measurement of plasma IGFBP-3 levels has potential as a marker for monitoring GH therapeutic efficacy.

Adjuvant recombinant human growth hormone stimulates insulin-like growth factor binding protein-3 secretion in critically ill trauma patients.

The early catabolic phase of severe injury is associated with acute growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-30 deficiency. The metabolic half-life of circulating IGF-1 is prolonged by its binding to IGFBP-3. The role of this binding protein in nutritionally repleted multiple-injury patients has not been previously evaluated. We have measured plasma levels of these polypeptides and nitrogen (N) balance in 18 adult (15 males/3 females; mean age, 45 years), severely injured, hypermetabolic, and highly catabolic trauma patients within 48 to 60 hours after injury, when they were receiving maintenance fluids without calories or N and during 6 days of total parenteral nutrition (TPN). Before instituting TPN, the patients were randomized to receive (group H, n = 9) or not to receive (group C, n = 9) daily recombinant human growth hormone (rhGH), 0.15 mg/kg IM. Adjuvant rhGH significantly increases plasma levels of GH, IGF-1, IGFBP-3, and insulin. In addition, it shows better improvement in N balance. The bioavailability of IGF-1 is increased, as indicated by the decrease in IGFBP-3:IGF-1 ratio. A significant correlation between IGF-1 and IGFBP-3 levels is present in the trauma patients who received TPN and rhGH. A GH/IGF-1/IGFBP-3 axis that closely regulates the metabolic status of the patient is established in trauma.

Efficacy of a mixture of medium-chain triglyceride (75%) and long-chain triglyceride (25%) fat emulsions in the nutritional management of multiple-trauma patients.

Ten severely injured patients who were admitted to the intensive care unit and who needed total parenteral nutrition (TPN) were randomly enrolled in a prospective double-blind study comparing two 20%-fat intravenous emulsions: one (MCT-LCT) containing a physical mixture of 75% medium-chain triglyceride (MCT) and 25% long-chain triglyceride (LCT) and another containing 100% LCT. TPN (30 kcal.kg-1.day-1) was given continuously as amino acids (20% of energy) and glucose (50% of energy) over 7 days with the respective lipid emulsion (30% of energy) provided from 0800 to 1600 each day. Plasma substrate concentrations, nitrogen balance, resting energy expenditure, substrate net oxidation rates, whole-body lipolysis rates, and fatty acid reesterification rates were measured or calculated. Plasma concentrations of lipid metabolites (glycerol, triglycerides, and fatty acids) indicated rapid hydrolysis and efficient use of the MCT-LCT emulsion. Whole-body lipolysis rate decreased by 53% in the MCT-LCT group and by 34% in the LCT group. Net fat oxidation was greater and FFA reesterification less with MCT-LCT than with LCT, indicating more efficient and rapid fuel utilization in the post-traumatic period with the MCT-LCT emulsion. In critically ill patients dependent on intravenous nutrition, an MCT-LCT mixture may be useful as an obligate fuel and to limit net hepatic lipogenesis.

Pulsatile nature of growth hormone levels in critically ill trauma victims.

BACKGROUND: Circulating growth hormone (GH) levels in normal persons fluctuate widely because of pulsatile GH secretion. It is not known whether this pulsatile nature and rhythmicity exist in severe injury. These data become necessary to decide the timing of supplementary GH administration for its optimal utilization. The purpose of this study was to investigate the GH circadian variation with respect to that of insulin-like growth factor-1 (IGF-1), insulin, C-peptide, and cortisol in the early flow phase of injury. METHODS: Plasma GH, IGF-1, insulin, C-peptide, and cortisol levels were measured at 1-hour intervals during 24 hours (8 AM to 8 AM) in 10 severely injured adults with multiple trauma during the early catabolic flow phase 24 to 48 hours after injury, when patients received maintenance fluids without calories or nitrogen. RESULTS: The 24-hour integrated GH concentration is not different from either 12-hour mean diurnal or 12-hour mean nocturnal or mean 8 AM GH concentration. Pulsatile GH bursts persist in injured patients during both day and night. Pulsatile bursts do not exist for IGF-1, insulin, and C-peptide. The plasma levels of cortisol show time-dependent daily maximum and minimum levels. CONCLUSIONS: Pulsatile GH bursts persist in injured patients but less frequently than seen in normal persons. The time of bolus administration of GH to augment the anabolic GH action in patients with trauma does not matter; however, for convenience morning administration may be preferable for patients in the intensive care unit.

Adjuvant recombinant human growth hormone normalizes plasma amino acids in parenterally fed trauma patients.

BACKGROUND: The addition of an anabolic stimulant during intensive nutrition therapy in trauma patients seems to be a reasonable adjuvant for minimizing muscle-mass erosion. The plasma free amino acid pattern is the mirror of the net amino acid metabolism, and we have measured the progressive changes resulting from recombinant human growth hormone therapy in trauma victims during nutritional repletion in the early catabolic flow phase of injury. METHODS: In 20 severely injured (injury severity scale = 31 +/- 2), highly catabolic, and hypermetabolic adult multiple-trauma patients, we have measured the fasting (day 0) plasma amino acid levels (48 to 60 hours after injury before starting the nutrition therapy) and their progressive changes during 7 days of IV nutrition support (total parenteral nutrition, 1.1 x resting energy expenditure calories, 250 mg of nitrogen per kilogram per day) with or without adjuvant recombinant human growth hormone. Group H (n = 10) randomly received daily recombinant human growth hormone (0.15 mg of Somatropin per kilogram per day) and Group C (n = 10) received the vehicle of infusion. RESULTS: Hypoaminoacidemia of trauma is normalized by infusion of recombinant human growth hormone, which indicates its anabolic nature, and this is confirmed in the cumulative nitrogen balance (-281 +/- 139 mg of nitrogen per kilogram per 7 days compared with -809 +/- 151 mg of nitrogen per kilogram per 7 days without recombinant human growth hormone; p < or = .005). This improved nitrogen retention is also reflected in the significantly low blood urea nitrogen levels in the recombinant human growth hormone group, which represents the efficient utilization of the infused amino acids for synthesis of proteins. Elevated plasma insulin-like growth factor-1 levels in Group H compared with those in Group C may also account for this altered amino acid metabolism. CONCLUSIONS: Recombinant human growth hormone treatment in combination with conventional total parenteral nutrition in the immediate posttraumatic period improved nitrogen metabolism and normalized the plasma free amino acid levels.

Enhancement of protein synthesis efficiency in parenterally fed trauma victims by adjuvant recombinant human growth hormone.

In the early catabolic phase of severe injury, conventional nutritional support is inadequate to reverse negative nitrogen balance and an anabolic stimulus may be beneficial. The utilization efficiency of body energy sources after injury could be improved by adjuvant recombinant human growth hormone (rhGH) therapy. We measured the protein kinetic response to exogenous rhGH in trauma patients fed parenterally (TPN). Severely injured (mean ISS, 31 +/- 2), highly catabolic (mean nitrogen loss, 19 +/- 2 g/day), and hypermetabolic (mean BEE/REE, 1.41 +/- 0.05), adult (mean age, 46 +/- 5 years), multiple trauma victims (n = 20, 17 men/3 women) were investigated. Rates of whole-body protein kinetics (turnover [WBPT], synthesis [WBPS], breakdown [WBPB], and protein synthesis efficiency [PSE]--the fraction of nitrogen turnover utilized for protein synthesis) were measured using a primed-constant infusion of 18N glycine 48 to 60 hours after injury when the patients were receiving only maintenance fluids without calories or nitrogen. The patients were then fed glucose-based TPN (1.1 x REE; 250 mg N/kg/day) and randomized to receive or not to receive rhGH. Group H (n = 10) received daily rhGH (0.15 mg/kg/day, Somatropin, Genentech, Inc.) intramuscularly at 8 am and group C (n = 10) received only the vehicle of infusion. Protein kinetic measurements were repeated at the end of 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Nutritional influence on the recovery of 14CO2 in critically ill trauma patients.

Several factors, including age, nutritional and metabolic status, and underlying pathological conditions, should be considered in estimating the correction factor for labeled CO2 retention. We have evaluated the nutritional influence of this correction factor in a group of severely injured (injury severity score = 33 +/- 5), hypermetabolic, and highly catabolic adult trauma patients. Primed-constant infusion of NaH14CO3 was used, and the breath 14CO2 radioactivity was measured. The experiment was conducted once in the fasting condition during the early catabolic "flow" phase of injury and again during and after a week of intravenous feeding. The mean value of the 14CO2 recovery (85.2 +/- 2.7%) in the basal fasting condition was higher than the value of 81% commonly used in normal subjects. During intravenous nutritional support the recovery was 100.8 +/- 1.7%. Recovery of tracer increased linearly with O2 uptake and CO2 production. The linear expression obtained between recovery and CO2 production could estimate the recovery within 3% in trauma patients, and that obtained by multiple regression with CO2 production and O2 uptake would predict the recovery within 1.5%.

Posttraumatic hormonal environment during total parenteral nutrition.

Hormonal responses to major trauma trigger a cascade of metabolic adjustments leading to catabolism and substrate mobilization. Energy deficit and energy surfeit have profound effects on hormone levels. To characterize the course of changes in regulatory hormone levels after multiple injury, we measured the plasma levels of eight hormones, once within 48-60 h after injury in the fasting state and then daily for 5 days during the administration of total parenteral nutrition in 10 hypermetabolic, highly catabolic, and severely injured adult patients. Acute deficiency in anabolic insulinlike growth factor 1 (IGF-1) and growth hormone levels and elevated levels of counterregulatory stress hormones and insulin were seen as a result of trauma. Provision of nutrition on the 1st day has no effect on IGF-1 and cortisol levels. However, growth hormone levels are raised to normal, and the nitrogen balance is improved. Over the next 4 days, there were no appreciable changes in these parameters. The persistent low levels of IGF-1 reflect the altered nutrition status of the patients, as characterized by the continued negative nitrogen balance and elevated cortisol levels in the early posttrauma period. Anabolic IGF-1 and insulin levels showed significant negative correlation with the catabolic indicators 3-methylhistidine and catecholamine excretion. The results suggest that IGF-1 is regulated by nutritional intake independently of growth hormone and may be a better nutrition indicator.

Relative nutritional efficacy of arginine and ornithine salts of alpha-ketoisocaproic acid in traumatized rats.

The relative dietary efficacy of arginine alpha-ketoisocaproate (AKIC) and ornithine alpha-ketoisocaproate (OKIC) is evaluated in a rat (Sprague-Dawley) trauma (bilateral femur fracture) model. Both control and traumatized rats were starved for 2 d and then pair-fed for 2 or 4 d one of three liquid diets: diet 1 was a basic casein diet; diets 2 and 3 were the basic diet in which 10% of nitrogen was replaced by AKIC or OKIC nitrogen, respectively. Irrespective of the diet, the protein-efficiency ratio, defined as the gain in body weight per grams nitrogen consumed, was 27% less in traumatized rats than in control rats. More improvement in apparent nitrogen balance, particularly in traumatized rats, was seen with the AKIC supplement. Plasma amino acid patterns demonstrated stimulation of net protein synthesis with AKIC and not with OKIC. Dietary supplementation with AKIC may be beneficial to promote nitrogen economy in trauma victims.

Acute IGF-1 deficiency in multiple trauma victims.

The circulating levels of IGF-1 in the catabolic flow phase of injury were measured in multiple trauma victims once before nutritional support and again after 4 days of intravenous feeding. The hypermetabolic and highly catabolic state of injury is characterized by a diminished level of IGF-1 along with increased levels of stress hormones. Inverse relationships of adiposity and aging on IGF-1 levels are seen both in injured and uninjured subjects. Feeding could restore the IGF-1 levels in non-obese, young patients but it is delayed in obese or elderly subjects. This diminished responsiveness to feeding of IGF-1 hormone deficiency in obese and elderly subjects should be taken into consideration in their post-trauma treatment and may warrant adjuvant administration in these types of patients.

Altered tissue polyamine levels due to ornithine-alpha-ketoglutarate in traumatized growing rats.

All cells contain significant amounts of polyamines (PA), and their concentrations are highly regulated. Metabolic activity within a tissue may be reflected in the amount of intracellular PA. Since trauma involves accelerated death and regeneration of tissues, the related levels of PA in extracellular and intracellular fluids may reflect altered protein metabolism. Trauma induces an increased excretion of urinary PA, and the tissues responsible for this whole-body activity are not known. During posttraumatic nutritional management, supplementation with ornithine-alpha-ketoglutarate (OKG) seems to improve nitrogen economy. The present study evaluates the significance of muscle, liver, and intestine PA responses in traumatized (bilateral femur fractures) rats to the feeding of an isonitrogenous liquid diet supplemented with or without OKG. Uninjured control rats were pair-fed with respective traumatized rats. After 2 days of starvation and 4 days of feeding, the traumatized and control rats were killed and the tissues were excised and analyzed. Starvation decreases and refeeding increases urinary PA excretion. Trauma-induced PA response is predominantly seen in muscle tissues, and this may be responsible for parallel increases in PA excretion. Liver PA responses show a varying tendency confirming the increased protein synthetic activity due to trauma. Intestine has the highest intracellular PA levels, and there is a general smaller (statistically insignificant) increase in all the individual PA contents due to trauma. OKG supplementation augments tissue and urine PA responses in control rats; however, in trauma rats muscle PA levels show very little change, although nitrogen retention is significantly better (88% to 77%). Mechanistic studies are needed to evaluate the significances of the time-dependent, injury-induced, individual intracellular PA levels.