Randomized clinical trial of intravenous soybean oil alone versus soybean oil plus fish oil emulsion after gastrointestinal cancer surgery.

BACKGROUND: Specific immunonutrients may reduce the incidence of postoperative complications and shorten recovery time. This randomized trial evaluated the clinical efficacy of a fish oil emulsion on outcome and immune function after gastrointestinal cancer surgery. METHODS: A total of 206 patients with gastrointestinal or colonic cancer were randomized to receive isocaloric and isonitrogenous intravenous infusions of either soybean oil alone (1.2 g per kg bodyweight per day; control group, 103 analysed) or soybean plus fish oil emulsion (1.0 and 0.2 g per kg per day respectively; treatment group, 100 analysed) over 20-24 h daily for 7 days after surgery. RESULTS: Baseline data were comparable in the two groups. There were fewer infectious complications (four versus 12 on day 8; P = 0.066), systemic inflammatory response syndrome (SIRS) was significantly less common (four versus 13; P = 0.039) and hospital stay was significantly shorter (mean(s.d.) 15(5) versus 17(8) days; P = 0.041) in the treatment group. Total postoperative medical costs were comparable in the two groups (mean(s.d.) US $ 1269(254) and 1302(324) in treatment and control groups respectively; P = 0.424). The median (interquartile range) difference in CD4/CD8 between days 1 and 8 after surgery was + 0.30 (0.06 to 0.79) in patients receiving fish oil and + 0.20 (-0.19 to 0.55) in controls (P = 0.021). No severe adverse events occurred in either group. CONCLUSION: Fish oil emulsion-supplemented parenteral nutrition significantly reduced SIRS and length of hospital stay. These clinical benefits may be related to normalization of cellular immune functions and modulation of the inflammatory response.

Depressed reflex vasomotor control of the burn wound.

Total leg blood flow was measured by venous occlusion plethysmography in five normals and 14 burned patients before and after 30 min of external heating. Leg surface temperatures were held constant, but rectal temperatures increased on the average of 0.4 to 0.5 degrees C in all subjects following this heat load. Leg blood flow increased by 56.0% in the controls, 63.2% in five patients with essentially no leg burn (mean burn size = 1.5% leg surface), and 9.6% in nine patients with major leg injuries (mean burn size 55% leg surface). Failure of reflex vasodilatation in the burned leg was evident up to 107 days postinjury even when the wound was well-healed. All subjects sweated freely from the unburned skin. In two patients, where arm and leg blood flows were measured simultaneously, flow to the uninjured arm increased while that to the injured leg remained unchanged. This lack of reflex vasodilatation in the burned limbs suggests either that wound vessels are denervated or that they are so dilated in the basal state that further dilatation is limited. The bulk of this and other data would support the denervation concept. This physical or chemical denervation could occur at the time of injury, be localised to the area of the wound, and result in loss of both neurogenic vasoconstrictor tone and active reflex vasodilatation.

Heat loss in anhidrotic ectodermal dysplasia.

The dynamics of heat loss by 2 patients with classic anhidrotic ectodermal dysplasia were studied. Both were active in high school athletics and avoided heat injuries by various forms of behavior modification. Elevated core and skin temperature measurements were found at rest in comfortable environments. In a warm environment 35-45% of the heat generated was lost by radiation, 44-52% by conduction and convection, and only 4-6% by evaporation. Heat loss in control subjects was 9% by radiation, 17% by conduction/convection, and 67% by evaporation. The dry routes of heat dissipation used by the anhidrotic patients were inadequate to prevent a rise in core temperature.

The effect of insulin-induced hypoglycemia on gene expression in the hypothalamic-pituitary-adrenal axis of the rat.

This study has examined the effects of insulin-induced hypoglycemia on expression of the CRH, arginine vasopressin, and POMC genes and corresponding peptides in freely moving, unanesthetized, male Sprague-Dawley rats. Animals were infused with 150 mM NaCl for 3 days before the experimental day and were then administered insulin (4 U/kg) or saline iv. In one experiment animals were killed 0, 30, 60, or 90 min after insulin or saline, and RNA was isolated from anterior pituitary, cerebral cortex, and punches of the hypothalamic paraventricular and supraoptic nuclei. In a second experiment, animals were killed 90 min after insulin or saline treatment, and RNA was isolated from whole hypothalami. RNA was analyzed by Northern blot. Plasma glucose fell from 106 +/- 5 to 38 +/- 2 mg/dl after insulin administration and remained low for the duration of the experiment. Plasma levels of ACTH, corticosterone, and vasopressin were 10-, 6-, and 4-fold higher, respectively, in the insulin-treated vs. control animals (by analysis of variance, P less than 0.0001 in all cases), while plasma CRH was unchanged. During hypoglycemia POMC mRNA levels were 1.8-fold higher in the insulin-treated group (by analysis of variance, P less than 0.025). In contrast, paraventricular nucleus, whole hypothalamic, and parietal cortex CRH mRNA and vasopressin mRNA were unchanged. These data support previous studies which indicated that POMC gene expression is increased by hypoglycemia. However, we found no evidence for an increase in paraventricular nucleus or cerebral cortex CRH mRNA expression during hypoglycemia-associated stimulation of the hypothalamic-pituitary-adrenal axis, suggesting that another factor(s) may mediate the observed increase in POMC gene expression.

Recombinant human growth hormone enhances the metabolic efficacy of parenteral nutrition: a double-blind, randomized controlled study.

This multicenter, randomized, double-blind study was performed to investigate whether recombinant GH improves the efficacy of total parenteral nutrition (TPN). Fifteen stable patients requiring parenteral feeding due to gastrointestinal/pancreatic disease were studied. Constant maintenance TPN providing approximately 30 kcal/kg day and approximately 1.6 g protein/kg.day was administered during an initial 7-day baseline period. After randomization, daily sc injections of saline (control, n = 9) or GH (10 mg/day, n = 6) were administered a 14-day treatment period as nutrient intake remained constant. Elemental balances for nitrogen (N), potassium (K), phosphorus (P), and sodium (Na) were determined daily and serial blood indices, vital signs, and other clinical parameters were monitored. Nutrient balances approached equilibrium during the baseline week in both groups. With GH administration, a significant increase in N, K, and P balance occurred; in contrast, nutrient balances did not change significantly from baseline values in control patients. The cumulative change (delta) in nutrient balances from the baseline week was also significantly greater in the GH-treated patients (delta N: control+2 +/- 7 g vs. GH+36 +/- 6. g, P less than 0.005; delta K:+57 +/- 45 mmol vs.+199 +/- 19 mmol, P less than 0.03; delta P: -27 +/- 30 mmol vs. +91 +/- 69 mmol, P less than 0.02). Plasma insulin-like growth factor-I concentrations rose 5-fold and serum cholesterol rose slightly with GH; no other significant change in group mean blood values occurred. One patient receiving GH and chronic prednisone therapy developed moderate hyperglycemia and mild peripheral edema; no other deleterious effects attributable to GH were observed. GH was well tolerated and significantly enhanced nutrient retention compared to standard parenteral feeding alone. GH improves the efficacy of parenteral nutrient utilization in patients requiring TPN.

Impaired gluconeogenesis in extensively injured patients with gram-negative bacteremia.

Glucose kinetics and gluconeogenic precursors were studied in burned patients with or without gram-negative bacteremia. Gram-negative sepsis in burned patients impairs the increased rate of hepatic glucose production which characteristically occurs after thermal injury.

Newer products and formulas for alimentation.

Adequate nutritional support for the critically ill patient has evolved over the past 150 years from a time when starvation was accepted practice for patients with fever. Three to four thousand calories and other essential nutrients can now be safely provided each day to patients with infection or other critical illness. Nutrients may be provided in meals, administered by specialized enteral feedings, or infused intravenously. Nutrient mixtures with a high proportion of carbohydrate and protein appear the best dietary therapy to maintain body protein and support other organ systems and and cellular functions. New products and formulas offer the physician a wide variety of techniques for providing adequate nutrition to all patients with critical illness.

Safety of glutamine-enriched parenteral nutrient solutions in humans.

To determine the safety of glutamine-enriched parenteral nutrition, seven normal volunteers were admitted to the Clinical Research Center for three 5-d study periods. The subjects received infusions of parenteral nutrients containing increasing doses of glutamine (0, 0.285, and 0.570 g.kg body wt-1.d-1) substituted for alanine and glycine. Each study period was preceded by greater than or equal to 2 wk of normal food intake. The diets were isocaloric (1.2X estimated basal metabolic rate) and isonitrogenous (1.5 g protein.kg-1.d-1) with nonprotein calories given as dextrose (38%) and fat emulsion (62%). The diets were all well tolerated and there were no untoward effects. Plasma glutamine concentrations increased significantly with glutamine administration but plateaued at concentrations approximately 25% above control values. Ammonia and glutamate, potentially toxic metabolites of glutamine, did not change significantly with glutamine enrichment. Nitrogen balance and hormonal concentrations were unchanged during the three dietary periods. Results of mental-status examinations and continuous performance testing were normal and unchanged throughout the three periods. Glutamine-enriched parenteral nutrient solutions are well tolerated with no associated signs of toxicity in normal humans.

The systemic inflammatory response: perspective of human endotoxemia.

Improvements in detection of cytokines and other intermediary substances has allowed a new wave of investigations to determine the role that endotoxin plays in initiating these mediators. We have reviewed all studies of endotoxin administration (Escherichia coli, Lot EC-5, 4 ng/kg) to healthy humans in an effort to collate the currently available data that describes mediator elaboration and therapy directed against them. More than 60 studies included descriptions of the effects of administering endotoxin alone and with pretreatments, such as antiendotoxin molecules (n = 8), mediator receptor antagonist (n = 9), antimediator therapy (n = 5), and anti-inflammatory agents (n = 49), which were given in an attempt to modify the inflammatory response. Endpoints that were monitored included vital signs and symptoms, leukocyte and platelet patterns, alterations in coagulation, hormonal secretion, plasma enzyme activities, plasma cytokine and anticytokine concentrations, plasma metabolic substrates, and ex vivo mononuclear cell responses. Analysis of investigations of human endotoxemia with and without pretreatments suggests that such trials a) are safe, b) are unable to achieve the success of small animal studies using pretreatments of endotoxemia, and c) have results similar to antimediator therapy administered recently to patients with Gram-negative bacteremia. Establishment of endotoxemia in humans may provide a valuable screening method to determine which antimediator treatments should be submitted to carefully constructed clinical trials.

Is glutamine a conditionally essential amino acid?

The nonessential amino acid glutamine has recently been the focus of extensive scientific interest because of its importance in cell and tissue cultures and its physiologic role in animals and humans. Glutamine appears to be a unique amino acid, serving as a preferred respiratory fuel for rapidly proliferating cells, such as enterocytes and lymphocytes; a regulator of acid-base balance through the production of urinary ammonia; a carrier of nitrogen between tissues; and an important precursor of nucleic acids, nucleotides, amino sugars, and proteins. Abundant evidence suggests that glutamine may become a "conditionally essential" amino acid in the critically ill. During stress the body's requirements for glutamine appear to exceed the individual's ability to produce sufficient amounts of this amino acid. Provision of supplemental glutamine in specialized enteral or parenteral feeding may enhance nutritional management and augment recovery of the seriously ill while minimizing hospital stay.

Positive nitrogen balance with human growth hormone and hypocaloric intravenous feeding.

Nitrogen equilibrium cannot be achieved in surgical patients without adequate nitrogen and calorie intake, frequently requiring central venous feedings. To investigate the hormonal environment under which nitrogen retention might be achieved during hypocaloric feedings, we administered peripheral vein nutrition with growth hormone (GH) to four healthy male patients. The intravenous diets provided 50% of estimated energy requirements (mean 566 kcal/m2/day) and adequate nitrogen (6 gm/m2/day). Each subject was studied for two 7-day periods; 10 mg of GH was given daily during one period and placebo during the other. Administration of GH decreased weight loss, caused retention of nitrogen, potassium, and phosphorus in amounts closely matching their proportions in skeletal muscle, and stimulated insulin production. GH also raised serum levels of free fatty acids and glycerol, increased urinary excretion of ketones, and favored fat oxidation in the postabsorptive state. Hyperinsulinemia and increased lipolysis and ketogenesis may augment the primary effects of GH. Further studies at adequate and approximately 30% of adequate calorie intake confirmed these findings. Maintenance of body protein with GH may allow improved nutritional care of catabolic patients that was previously unrecognized.

Postoperative alteration of arteriovenous exchange of amino acids across the gastrointestinal tract.

Nitrogen flux across the splanchnic bed is altered following operation, injury, and sepsis, but the individual contributions of gut and liver and their interrelationships remain undefined. Since more than 60% of whole blood amino acid nitrogen is transported as glutamine and alanine, we determined the flux of these amino acids across the gastrointestinal tract and liver in splenectomized, awake dogs during a control period and a 2 and 4 days following a standard laparotomy. Blood flow was measured in all studies and substrate flux calculated from flow and arteriovenous and portovenous concentration differences. Portal blood flow decreased by 25% following operation from a control value of 26 +/- 2 ml/kg body weight . min to 19 +/- 2 (P less than 0.05). Total hepatic blood flow did not change significantly after operation, but the individual contributions of the hepatic artery and portal vein were altered; hepatic artery flow increased from a control value of 10 +/- 1 ml/kg . min to 23 +/- 3 (P less than 0.001). Glutamine uptake by teh gastrointestinal tract nearly doubled from a control value of 0.75 +/- 0.16 microM/kg . min to 1.31 +/- 0.13 (P less than 0.05) on postoperative day 2. This increase in flux occurred despite a diminished arterial concentration and a reduced portal blood flow, indicating that extraction of glutamine by the gastrointestinal tract was not primarily dependent on increased arterial concentration. Alanine, on the other hand, was released by the gut at a rate of 1.97 +/- 0.37 microM/kg . min in controls and decreased to 0.81 +/- 0.13 microM/kg . min (P less than 0.05) in dogs that had operation. Glutamine was released by the liver in control dogs at a rate of 1.59 +/- 0.59 microM/kg . min but switched to an organ of slight glutamine uptake (0.31 +/- 0.31, P less than 0.01) on postoperative day 2. Alanine uptake by the liver doubled from 2.94 +/- 0.29 to 5.46 +/- 0.63 microM/kg . min (P less than 0.05) following surgical stress. The gastrointestinal tract plays an active metabolic role in the processing of amino acids following operation and may be a key regulatory of interorgan substrate flux following injury and infection.

Increased peripheral amino acid release following burn injury.

Turnover rates of 10 amino acids were determined in four normal subjects and 18 burned patients (mean burn size, 41% of total body surface) by measuring leg blood flow by venous occlusion plethysmography and arterial (A) and femoral venous (FV) amino acid concentrations. Patient arterial plasma amino acid concentrations generally were low or normal, although phenylalanine was elevated. Only alanine demonstrated significant A-FV concentration difference (-9 +/- 2 mumole/100 ml in patients vs -5 +/- 1in controls, mean +/- SEM). Leg blood flow was 6.26 +/- 0.57 ml/100 ml of leg volume . min in the patients and 2.62 +/- 0.57 in controls. While the net peripheral release of the 10 amino acids was accelerated following injury, only alanine release was consistently greater in the patients (0.27 plus or minus 0.05 mumole/100 ml in leg volume . min) as compared with that of controls (0.08 +/- 0.02). The increased alanine release from legs of patients generally was related to the extent of total body surface injury and oxygen consumption of the patient, but was unrelated to size of limb burn or leg blood flow. The accelerated rate of alanine release from limbs of burn patients relates to the generalized catabolic effects of injury rather than to local inflammatory or metabolic events which may occur in the injured extremity.

Limited effects of prostaglandin inhibitors in Escherichia coli sepsis.

Responses to bacteremia include fever, leukocytosis, elaboration of acute-phase proteins, hypoferremia, and increased protein catabolism. To evaluate the role of prostaglandins in the mediation of these responses, the effects of intravenous ibuprofen (12.5 mg/kg X dose) were studied in eight dogs infused with live Escherichia coli. Thirteen dogs served as noninfected controls. Two of the eight animals that received ibuprofen died during the study, whereas all control animals with sepsis survived. Prostaglandin inhibition prevented the rise in temperature resulting from sepsis, while alterations in white cell count, C-reactive protein, and serum iron levels were unaffected. In addition, protein catabolism appeared to be similar in both groups. This minimal metabolic effect coupled with observed renal side effects makes the use of nonsteroidal, anti-inflammatory agents in sepsis of questionable benefit.

The effect of exogenous substrate on hepatic metabolism and membrand transport during endotoxemia.

Endotoxemia in dogs reduced hepatic uptake and biliary excretion of indocyanine green dye. This diminished active membrane transport was associated with reduced hepatocyte membrane potential difference. Studies of arteriovenous concentration differences and flow across the liver demonstrated that endotoxemia increased hepatic glucose and lactate production and decreased oxygen consumption. Correction of this energy deficit occurred following infusion of glucose and insulin, but not after administration of isocaloric quantities of intravenous amino acids. The glucose-insulin infusion during endotoxemia shifted the liver back to an organ of glucose uptake, improved oxygen consumption, and provided the necessary energy for normal dye transport and maintenance of the normal membrane potential difference.

Epinephrine acutely mediates skeletal muscle insulin resistance.

Alterations in carbohydrate metabolism and insulin resistance are major features of the metabolic response to injury. The mediators of these changes are not defined. In this study we investigated the influence of epinephrine on insulin-mediated glucose uptake by peripheral tissue. Forearm blood flow and substrate exchange were determined during insulin clamp studies with and without epinephrine infusion in normal persons. During control studies insulin concentration was raised to 103 +/- 5 microU/ml. Whole body glucose disposal was 9.23 +/- 1.01 mg/kg . min. At a comparable level of hyperinsulinemia (93 +/- 4 microU/ml), epinephrine reduced glucose disposal to 4.54 +/- 0.39 mg/kg . min (P less than 0.01). Forearm glucose uptake was reduced from 0.66 +/- 0.08 to 0.18 +/- 0.13 mg/100 ml . min (P less than 0.05) despite a doubling of forearm blood flow. Epinephrine reduces whole body glucose disposal in part by reducing glucose uptake in peripheral tissue, primarily muscle. Epinephrine-induced skeletal muscle insulin resistance may play a major role in insulin-resistant states and may contribute to accelerated protein catabolism seen following injury.

The induction of interleukin-1 in humans and its metabolic effects.

To investigate the metabolic effects of interleukin-1 and its role as a mediator of host responses to trauma and sepsis, we injected seven healthy male subjects with etiocholanolone, an inflammatory agent that stimulates systemic responses thought to be mediated by interleukin-1. The subjects were fed a constant diet during each 4-day study and received three daily intramuscular injections of etiocholanolone, 0.10 mg/kg. Etiocholanolone injection resulted in inflammation, fever, leukocytosis, increased serum C-reactive protein, hypoferremia, and increased plasma activity of interleukin-1/lymphocyte-activating factor. Plasma concentrations of the counterregulatory hormones were normal. Protein metabolism, as reflected in nitrogen balance, 15N turnover, and forearm flux of alanine and glutamine, was unaltered. Serum glucose and insulin levels and tissue responsiveness to insulin were normal. This dissociation of acute-phase and catabolic responses may reflect the magnitude of the stimulus; higher levels of interleukin-1 may initiate catabolic responses. Alternatively, other mediators such as the counterregulatory hormones may direct the catabolic responses that occur after injury and sepsis.

Sepsis alters skeletal muscle energetics and membrane function.

The effects of sepsis on skeletal muscle energetics and membrane function are poorly understood, and the time course of changes in energy metabolism are unclear. To clarify these relationships, high energy phosphate ratios, intracellular pH, and phosphocreatine breakdown rates were measured in vivo in the gastrocnemius muscle of adult male Wistar rats after cecal ligation and puncture or sham operation with 31P magnetic resonance spectroscopy. Adenosine triphosphate (ATP) concentration and Na(+)-K+ ATPase and creatine kinase activities were determined in vitro. Within 24 hours, Na(+)-K+ ATPase activity increased by 60% in rats with cecal ligation and puncture, all of which had positive bacterial cultures, as compared to none of the sham-operated controls. Phosphocreatine/ATP ratios decreased by 20% in association with a quantitatively similar increase in phosphocreatine breakdown (9.7 +/- 0.5 vs 11.9 +/- 0.5 mumoles/gm wet wt/sec; p = 0.01). ATP concentrations were maintained, and intracellular pH did not change significantly. In this model, changes in phosphocreatine breakdown were not related to total creatine kinase activity, which did not change significantly, or increases in adenosine 5'-diphosphate (ADP) concentration (62 +/- 8 vs 92 +/- 8 mumols/L; p = 0.02). Thus, in early sepsis before a measurable decrease in pH occurs, ATP is utilized at an increased rate to help maintain ionic balance and/or to support other metabolic processes. Phosphocreatine stores are used to buffer ATP concentrations.

Both cyclooxygenase-dependent and cyclooxygenase-independent pathways mediate the neuroendocrine response in humans.

The neuroendocrine response that occurs after operation, trauma, or infection is essential for maintaining homeostasis within the host. Corticotropin-releasing hormone, (CRH), arginine vasopressin (AVP), and products of the cyclooxygenase pathway have been proposed as possible mediators of the pituitary-adrenal response. We studied the relationship between the induction of these mediators and the onset of the neuroendocrine response in healthy male volunteers receiving one of two standard provocative stimuli: (1) Escherichia coli endotoxin (4 ng/kg intravenously) and (2) hypoglycemia induced by insulin (0.15 units/kg intravenously). Additional subjects receiving these stimuli were pretreated with the cyclooxygenase inhibitor ibuprofen, 1600 mg orally. Serial measurements were made of circulating concentrations of CRH, AVP, adrenocorticotropic hormone, cortisol, and catecholamines. A sudden rise in circulating AVP (but not CRH) concentrations preceded the onset of all other responses after both stimuli. The prevention of this surge of AVP after endotoxin by ibuprofen was associated with blockade of the neuroendocrine response. These data demonstrate that two independent pathways are available for stimulation of the stress response. After both stimuli, peripheral AVP (but not CRH) levels may mirror alterations that occur within the central nervous system.

Glutathione deficiency increases organ dysfunction after hemorrhagic shock.

BACKGROUND: Reactive oxygen metabolites contribute to tissue destruction in a wide variety of diseases. Glutathione, a potent endogenous antioxidant, neutralizes the destructive potential of free radicals, but this tripeptide may be depleted during illness. We hypothesized that glutathione deficiency would amplify organ dysfunction after shock in rats. METHODS: Rats received either diethyl maleate to deplete tissue glutathione or a control solution intraperitoneally. The animals were subsequently bled to and maintained at a mean arterial pressure of 40 mm Hg for 30 minutes and then fully resuscitated. Sham animals underwent blood pressure monitoring only. Tissue glutathione, liver and renal function tests, organ bacterial content, and mortality rates were determined 4 and 24 hours after shock. RESULTS: Normal rats subjected to shock and sham animals had similar laboratory chemistry results, organ culture results, and mortality rates. However, glutathione-depleted animals subjected to shock had elevated liver and renal function tests, increased organ bacteria, and a dramatic increase in mortality rates compared with control shock and sham animals. CONCLUSIONS: We conclude that glutathione deficiency predisposes animals to organ failure and death after an otherwise nonlethal period of hypotension. Because glutathione deficiency is associated with severe injury and sepsis, treatment strategies that maintain glutathione stores may decrease the incidence of multisystem organ failure.