Posttraumatic hypermetabolism is associated with increased catabolism and loss of lean body mass in proportion to the severity of the injury. It is well established that an increased intake of protein is required for wound healing and achievement of nitrogen balance. Patients with sepsis can lose up to 250 g of lean body mass per day if unfed . Muscle proteolysis, a hallmark of protein metabolism in sepsis and trauma, can result in compromised respiratory function and further immuno-suppression. Animal studies have shown that protein deficiency leads to decreased fibroblast proliferation, diminished collagen synthesis, remodeling of previously healed wounds , and increased TNF . Compared to other trauma, thermal injury represents a severe form of trauma, where loss of as much as 20% of the body protein may occur following the insult. The severity of loss of lean body mass is closely related to the increased risk of morbidity and mortality in the acute phase of injury [90-92]. It is recommended that burn patients receive 1.5 to 2.5 g protein per kilogram actual body weight per day or approximately 20 to 25% of calories as protein [93,94]. Assessment of protein status through monitoring of prealbumin, transferrin, and nitrogen balance should be done on a regular basis. However, nitrogen balance studies need to be interpreted carefully in view of factors affecting results, such as reliance on accurate 24-h urine collection and normal renal function. In addition, fluid status, blood urea nitrogen, and creatinine should be monitored on an ongoing basis to assess tolerance to the high nitrogen renal solute load.
In nonseptic severely burned children, Jahoor et al. found that the rate of pro-teolysis was elevated after injury and remained high throughout the entire acute or flow phase of injury as well as the convalescent phase, which lasted 40 to 90 d after the burn . However, the net protein loss, as demonstrated by the urea kinetics, was elevated only during the first 2 weeks after injury. This suggests that aggressive nutritional therapy in burn patients may increase protein synthesis but cannot ameliorate the prolonged elevation of protein breakdown.
Stable isotope turnover studies in 33 severely burned adults and 8 pediatric patients (range 2 to 15 yr) using either methionine  or leucine tracers [96-98] further confirmed that during the flow phase of injury, nutrition support improved whole body net protein balance by increasing the rate of protein synthesis but not by reducing the rate of protein breakdown, findings that also resemble those of Claugue et al. in postoperative surgical patients . Similarly, in endotoxin-induced sepsis, reductions in protein synthesis were combined with an increased rate of protein breakdown [100,101]. Recognition of these fundamental alterations in amino acid and nitrogen metabolism has led to a number of strategies to improve recovery and limit morbidity in the hypermetabolic and catabolic patient.
Thus many investigators have attempted to increase or optimize protein synthesis by providing the "ideal" compositions of both energy and protein which can be maximally utilized by patients to replenish tissue proteins despite the prolonged proteolysis. More recently, attention has focused on the role of specific amino acids in contributing to wound healing -- in particular, glutamine and arginine.
Glutamine is the most abundant free amino acid in the body, comprising 69% of the total muscle free amino acid pool , where it serves as an important modulator or intermediate in a number of metabolic pathways. Studies have demonstrated a direct inhibitory effect of glutamine on protein degradation in cultured muscle tissue . A correlation between intracellular glutamine level and muscle protein synthesis has also been shown both in vitro and in vivo [104-106].
In healthy humans, glutamine has been recognized as a nonessential amino acid, because it can be synthesized by glutamine synthetase from glutamate via a-ketoglutarate. It functions in the synthesis of nucleotides, is a precursor for the antioxidant glu-tathione, and like most other amino acids is gluconeogenic. However, glutamine is more important than other amino acids in gluconeogenesis in the postabsorptive state . Glutamine is a major transporter of nitrogen in the form of ammonia from glutamate; it functions in acid-base homeostasis and is present in blood and muscle in higher concentrations than other amino acids.
During stress and burn injury, synthesis of glutamine is inadequate to meet metabolic demands , and it becomes conditionally essential. Parry-Billings  found in patients with major burn injury that plasma glutamine concentration was 58% lower than normal controls, and it remained low for at least 21 d postinjury. Although plasma concentrations of all amino acids were decreased after burn injury, glutamine levels did not return to normal, whereas concentrations of alanine and branched-chain amino acids did . The authors postulated that the decrease in glutamine concentration may be a contributing factor to the immunosuppression that occurs after major burn injury. Because glutamine is needed for lymphocyte proliferation, and because it is the main energy source for enterocytes, it may be important in the maintenance of gut barrier function . The effect of glutamine deficiency is also seen when in vitro glutamine supplementation of neutrophils isolated from burn patients results in increased bactericidal function . In addition, due to glutamine's role via citrulline as a precursor of arginine, some of the effects of deficiency in catabolic states may possibly be due to a reduction in arginine synthesis .
Studies by Newsholme and his colleagues have also shown an important role of glutamine in the immune system, where it is an extremely important fuel for macrophages and lymphocytes, as well as other immune system cells [113,114]. These cells possess high proliferation rates, resembling enterocytes and tumor cells, which also have high glutamine utilization rates. Newsholme et al. [115-118] revealed that utilization of glucose and glutamine by the cells of the immune system proceeds at a very high rate, estimated at 25% of the rate of the glucose utilized by the maximally working perfused heart . Most glucose and glutamine metabolized by immune cells appears to undergo partial oxidation in these tissues, which involves only the "left hand" of the Kreb's citric acid cycle (i.e., from a-ketoglutarate to oxaloacetate), despite possessing all the enzymes necessary for complete oxidation in the Kreb's cycle . In this way, the tricarboxylic acid (TCA) cycle is operated at a higher rate with a relatively lower level of citric acid concentration, which would otherwise inhibit glycolysis via a feedback mechanism. Therefore by utilizing glutamine as a fuel, both glycolysis and the TCA cycle can be maintained at a constantly higher rate to meet the high demand of energy for these actively proliferating cells. Thus the high uptake rate and partial oxidation of glucose and glutamine result in the partial metabolization of glucose to lactate and the conversion of glutamine to lactate, aspartate, and alanine. The physiological significance is that it may afford cells of the immune system a rapid and immediate response to the immune challenge (such as invasion of bacteria or endotoxin). Partial oxidation of these substrates may also provide intermediates for the biosynthesis of other substrates that are important for cell proliferation and immune function, for example, the product of glycolysis, glucose 6-phosphate, can be used for the formation of 5-ribose-phosphate, which is required for DNA and RNA synthesis. Similarly, glycerol 3-phosphate is necessary for phospholipid synthesis; glutamine itself and the products of its degradation, aspartate and ammonia, serve as direct precursors for purine and pyrimidine synthesis; and the amide nitrogen of glutamine is also utilized for the formation of glucosamine, GTP, and NAD+. Therefore, any significant decrease in glutamine and glucose utilization could be expected to decrease the rate of proliferation of these cells and impair the immune function of the host. Based on the factors regulating glutamine released from the muscle, it was proposed that the transport of glutamine out of the muscle acts as the flux-generating step for its utilization by the cells of the immune system , and it was suggested that burn and other trauma patients may require supplementation of glutamine to spare its loss from muscle tissue and to preserve host immune function. Although subsequent research has shown failure of glutamine supplementation to influence muscle protein metabolism , its effects on immune function remain promising .
Research has been done on the effects of glutamine supplementation in surgical and critically ill patients. Unfortunately, glutamine is not stable in solution and converts to the cyclic product, pyroglutamic acid (pGlu) and ammonia . This difficulty has been overcome by supplementing glutamine in its dipeptide form with other amino acids [123-125]. Clinical trials have confirmed the efficiency of dipeptide utilization by different tissues within the body [123,124]. Furthermore, in a series of dose response tests it was found that glutamine is readily metabolized and cleared from the bloodstream and no evidence was found of clinical toxicity or generation of toxic metabolites of glutamine in patients receiving continuous glutamine-containing parenteral feeding for up to 6 weeks [126-129]. These observations support the safety of glutamine in nutritional support formula.
The first studies were done with glutamine supplemented total parenteral nutrition, first with free glutamine and later with dipeptide glutamine . Improvements in nitrogen balance, immune function, infection reduction, and maintenance of total body water were noted . Supplementation of parenteral nutrition with glutamine in 84 critically ill patients reduced mortality from 67 to 43% at 6 months [131,132]. In a study of 26 burn patients fed enterally and parenterally, intravenous (IV) supplementation with 0.57 g/kg glutamine (40 g/70 kg man) resulted in a significant reduction in Gram-negative bacteria and improvement in serum transfer-rin and prealbumin at 14 d post-burn in comparison with isonitrogenous controls . In a study of 41 burn patients fed enterally and parenterally, Garrel and colleagues found that enterally administered glutamine, 26 g/d (0.4 g/kg for a 70 kg man) from the beginning of enteral feeding until wounds were healed, resulted in a significant reduction in blood infection, Pseudomonas aeruginosa infection, and mortality . The higher amount of enteral glutamine in Garrel's study may explain the positive result in contrast to previous studies of glutamine administered enterally to critically ill patients in amounts of 10 g/d with no effect . Due to the positive effects of glutamine and no documentation of adverse effects , it is recommended that enteral glutamine be considered in burn and trauma patients .
In adults, arginine is classified as a nonessential amino acid that becomes conditionally essential during growth, trauma, and wound healing. In healthy adults fed an Arg-free diet for 6 to 7 d, de novo arginine synthesis is not affected, unlike nutritionally essential amino acids . Arginine stimulates the secretion of insulin, glucagon, prolactin, catecholamines, corticosteroids, somatostatin, and growth hormone. Increased amounts of arginine are needed for growth for synthesis of collagen and connective tissue proteins . Collagen is composed primarily of glycine, proline, and hydroxyproline. The high arginase level found in wound tissues converts arginine to ornithine, which is a substrate for collagen synthesis (via proline) and polyamines (via ornithine decarboxylase), which are important for tissue growth and wound repair. Arginine can also be converted via nitric oxide synthase (NOS) to nitric oxide (NO).
Fibroblasts, which are important in the proliferative phase of wound healing, can take up citrulline from the circulation and convert it to arginine . In turn, fibroblasts can convert arginine to nitric oxide by both the constitutive and inducible pathways . This indicates that nitric oxide production and, thus, arginine, could be important in the proliferation stages of wound healing. Supplemental arginine was only effective in enhancing wound healing in normal but not knockout mice with the inducible nitric oxide synthase pathway removed, indicating that the production of nitric oxide is one mechanism by which arginine improves wound healing . Nitric-oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) significantly enhance collagen deposition at a wound site in comparison to regular NSAIDs . In hypertrophic scars, where excessive fibrosis has occurred, there is a reduced expression of nitric oxide synthase . Because nitric oxide has a role in vasodilation and inhibition of cell proliferation, it is thought that a lack of nitric oxide and perhaps its precursor arginine might be a contributing factor to the increased cellularity of abnormally healed hypertrophic scars . Vasodilation or increased blood flow to the wound is important, because collagen synthesis requires increased oxygen (PO2 of 200 torr) as compared with normal cell replication (PO2 of 40 torr) . While local vasodilation may be beneficial for immune defense and wound healing, the release of large quantities of NO may cause systemic vasodilation and hypotension and may be deleterious in a patient with sepsis.
Possible benefits of arginine supplementation in trauma patients may include promotion of wound healing [138,145] and improved patient immunity . Additionally, a beneficial effect of arginine on nitrogen metabolism has also been reported in clinical and laboratory experiments . Saito et al.  fed burned guinea pigs with different amounts of arginine in enteral diets and found that arginine supplementation at 2% of the total dietary energy intake reduced the mortality of the burn injury. Based on a series of laboratory experiments on thermally injured animals, Alexander et al.  proposed the composition of an "optimal" diet for burn patients, in which 2% of the dietary energy is derived from arginine. The diet was found to reduce the rate of wound infection, hospital length of stay, and mortality when compared to other "standard" enteral formulations. In surgical patients, a randomized, prospective trial conducted by Daly et al.  revealed that supplying 16 g/d of arginine to cancer patients undergoing major surgery resulted in enhancement of various parameters of the T-lymphocyte response, compared to a group of similar patients receiving isonitrogenous glycine supplements (25 g/d). Other studies also demonstrated improved thymic function in injured patients with an enhanced arginine supply ranging from 15 to 30 g/d [149-153].
In burn-injured animals, elevated NO production has been found to last for months . Under these circumstances, inducible NO synthase (iNOS) is induced, and prolonged overproduction of NO [154-156] may contribute to hypotension and shock [157,158], free-radical-mediated tissue damage, and subsequent organ malfunction [159,160] and, thus, multiple organ dysfunction syndrome (MODS).
From a nutritional perspective, it is important to determine if the NO production can be modulated by arginine supply. A number of studies have demonstrated that a bolus IV injection of arginine to healthy [161,162] and septic human subjects  at a level above 0.2 g/kg resulted in an increased level of NO in the expired air  and increased urinary excretion of nitrite, nitrate, and cyclic GMP . In some cases, such increased production of NO was accompanied by immediate but transient vasodynamic changes . Because NO is a short-lived paracrine mediator, regulation of its production is potentially important for burn and trauma patients. Merely enhancing the arginine content in the nutritional support may not be sufficient, and a combined nutritional-pharmacological approach with arginine as well as combinations of NOS agonist and antagonist may be required. The design of highly selective inhibitors of NO production  will likely improve the understanding of the function of NO and lead to the development of therapeutic strategies for manipulating NO synthesis for the benefit of severely injured patients. The reported "therapeutic" dose of arginine is from 0.2 to 0.5 g/kg/d of oral intake [149,151-153] or parenteral feeding , and the reported bolus arginine infusion that exerts an effect on modulating NO production and hemodynamic change in human subjects are similar (above 0.2 g/kg) [161,162]. Such amounts of arginine given chronically via enteral or parenteral feeding may benefit trauma patients; however, the same dose given by rapid IV infusion or bolus injection would cause an immediate "surge" of NO production and subsequent hemodynamic change in human subjects. However, Beaumier et al.  did not demonstrate an increase in urinary nitrate excretion or the conversion of plasma L-[15^2-guanidino] arginine to NO3 in healthy human subjects receiving a therapeutic intake of arginine 0.56 g/kg/d in the diet for 6 d.
NO has also been shown to be important in healing tendons and fractures, with increased NOS activity following injury [166,167]. Studies done in rats indicate that all three NOS isoforms are expressed in a coordinated sequence  during healing [168,169], and suppression of NOS impairs fracture healing .
Due to the possible role of NO in the pathogenesis of septic shock syndrome and the role of NO in mediating the hypotensive effect of TNF , there has been concern that arginine supplementation might not be indicated in critically ill patients . A study of the metabolic effects of supplementing enterally fed critically ill patients with arginine indicated that arginine is mainly metabolized into ornithine by the arginase enzyme rather than into NO [172,173]. In a study of 50 burn patients Saffle et al.  reported no differences in mortality in patients randomized to receive an immune-enhancing enteral formula containing arginine as compared with patients received a standard high-protein formula. However, in a review of immunonutrition in critically ill patients, there was increased mortality with immunonutrition, especially in patients with sepsis . In a randomized multicenter clinical trial, mortality was 44% in patients with severe sepsis receiving enteral nutrition (containing additional L-arginine, omega-3 fatty acids) as compared to 14% in those given parenteral nutrition resulting in ending the recruitment of patients with severe sepsis .
It was postulated that providing an arginine-containing immunoenhancing formula during compensatory anti-inflammatory response syndrome (CARS) and immunosuppression might stimulate the immune system and be beneficial, whereas in sepsis and systemic inflammatory response syndrome (SIRS), arginine-containing enteral products should not be used . This remains an area for further investigation, and although arginine is important for wound healing, routine supplementation of arginine in critically ill patients cannot be recommended at this time .
Research has also been done on the effects of ornithine a-ketoglutarate, a precursor to glutamine, arginine, and proline. In a prospective, double-blind randomized trial of 47 patients with 25 to 95% total body surface area burns, 20 g of ornithine a-ketoglutarate added to enteral feeding significantly reduced wound healing time and improved nutritional status .
Although fat is a necessary component of nutritional support, providing excessive lipid is not beneficial. Clinical studies of burn patients have shown an improved outcome when patients are enterally fed lower amounts of fat. Burn patients fed a diet containing 15 to 20% fat (in comparison with a 37 to 50% fat diet) had reduced incidence of pneumonia and wound infections and reduced length of hospital stay [179,180]. Gottschlich  also reported an association between dietary lipid content and diarrhea and recommended a low fat diet to promote tolerance to enteral feeds. Following burn injuries and in critical care, prolonged elevation of triglycerides may be associated with increased mortality , although it is not clear whether the increase in triglycerides is due to increased lipid administration with propofol or an indication of hypermetabolism. Propofol, a widely used sedative due to its rapid onset and quick recovery, is based in a 10% lipid emulsion and can provide a significant amount of calories from IV lipid that needs to be accounted for in the provision of nutrition support to prevent overfeeding and elevation of serum triglycerides.
Absorbed triacylglycerol (TAG) from the systemic circulation may be stored as fat or alternatively oxidized as an energy source depending on the physiological state of the host. However, utilization of circulating TAG is dependent on the enzyme lipoprotein lipase, which is bound to the endothelial surface of capillaries in all but central nervous system tissues , and if its capacity to hydrolyze circulating TAG is exceeded, clinical lipemia develops [183-185]. Inhibition of lipoprotein lipase is known to occur after endothelial exposure to the cytokine TNF or cachectin, which appears to limit TAG metabolism in sepsis, severe inflammatory states including trauma, and in cancer cachexia [11,186], whereas heparin stimulates lipoprotein lipase activity in relatively low doses [186,187]. Mobilization of TAG represents an important endogenous source of stored energy in adipocytes, hepatocytes, and other tissues. Intracellularly, hormone-sensitive lipase metabolizes stored TAG into free fatty acids (FFAs) and glycerol. Using stable isotope tracers of glycerol and FFA [188,189], this process has been found to be sensitive to stimulation by circulating epinephrine or inhibition by insulin via signal transduction through their respective receptors on the cell surface of adipocytes [190-192]. The synthesis of TAG by FFA esterification requires energy. Therefore, the accelerated lipolysis-TAG synthesis cycle is part of the substrate recycling in severe burn patients, which contributes to increased energy expenditure in the hypermetabolic state.
During trauma and sepsis, the catabolic hormones epinephrine, norepinephrine, and glucagons stimulate lipase, resulting in lipolysis of stored triglycerides and increased FFAs. The intracellular transport of long-chain FFAs into mitochondria via carnitine is impaired. FFA accumulate and inhibit pyruvate dehydrogenase and glycolysis, resulting in anaerobic metabolism and increased lactate, pyruvate, and acidosis .
Based on investigations by Mildred and George Burr , it is now recognized that normally a group or family of polyunsaturated fatty acids essential for growth and development cannot be synthesized in humans but instead must be present in the diet [195-197], and these FFA are defined as essential fatty acids (EFAs). With the introduction of IV nutrition, Collins  and Holman  described clinical features of EFA deficiency, which occurs in adults and infants after prolonged feeding of a diet deficient in EFA. EFA deficiency occurs not only due to the lack of exogenous supply of EFA from the diet, but also due to elevated plasma insulin levels stimulated by high glucose intakes, which inhibit the release of fatty acids from the adipose tissue stores within the body. Lineolenic, linoleic, and arachidonic acids are recognized precursors of the prostanoid family, important diverse fatty acids involved in cell signal transduction in many immunometabolic functions. Eczematous skin lesions, sparse hair growth, poor wound healing, thrombocytopenia, and hypermetabolism are recognized clinical features of EFA deficiency, described initially by Holman . Subsequently, IV lipid emulsions have been formulated with very high proportions of arachidonic and other EFA between 50 and 70% of total FFA, whereas normally, EFAs comprise only 8 to 10% of adipose tissue [193,200]. Thus, only small amounts of linoleic acid in the form of 500 ml per week of 20% IV fat emulsions will prevent EFA deficiency (EFAD ) [201,202]. Conversely, adverse changes in membrane fluidity , stimulation of nonphysiologic prostaglandin synthesis [187,204], and impairment of reticuloendothelial clearance of bacteria due to the release of a nonphysiologic lipoprotein X carrier [205,206] are important, potentially deleterious effects of excessive EFA provision in the diet.
Fatty acid levels vary much more widely than glucose in normal uninjured man (0.1 mM in the fed state to 1.0 to 1.5 mM in nonstressed starvation) [184,207,208]. Similarly, FFA concentrations in plasma following major trauma, such as thermal injury, are highly variable; however, FFA turnover measured by 13C palmitate is significantly elevated in proportion to the severity of the injury, as is the release of FFA from stored TAG (lipolysis) . However, as in carbohydrate metabolism, burn and trauma victims demonstrate substantial futile cycling in lipid metabolism, in that a larger proportion of FFA turnover is recycled through resynthesis of TAG (reesterification), both intracellularly and by interorgan transfer via lipolysis and reesterification [64,209]. Increases of 450% in TAG-FFA recycling in burn patients appear to be due to the lipolytic effects of high circulating catecholamines that are partially attenuated by P-blockade [64,209]. This increase in FFA released by lipo-lysis appears to be well in excess of their oxidation rate, and as much as 70% of the FFA released undergo reesterification [189,201]. Although increased plasma glucose increases the rate of glucose oxidation, the oxidation of FFA is reduced and reesterification increased by increased glucose availability, a nonmetabolic cycle described by Randle as the glucose-fatty acid cycle . The principal site of plasma FFA clearance and reesterification is the liver, where TAG in the form of very low-density lipoprotein (VLDL) is synthesized and released into the plasma normally for storage in peripheral adipocytes or as an energy source for other tissues. In critically ill patients, secretion of VLDL by the liver appears limited by impaired lipoprotein synthesis (apoprotein B), representing another mechanism by which accumulation of intracellular hepatic TAG may occur, in addition to excessive carbohydrate feeding as discussed earlier [189,211]. Clinically, hepatic steatosis appears most closely correlated with the severity of illness and, to a lesser extent, the nature of the nutritional support .
In addition, the eicosanoid family of fatty acids exerts diverse effects in modulating the inflammatory and metabolic response in traumatized patients. Attempts have been made to attenuate the untoward inflammatory effects of some eicosanoids by altering the type of exogenous FFA supply. Provision of TAG containing n-3 FFA, in which the first double bond is located at the third carbon from the methyl end of the FFA, was found to reduce the extent of weight loss, skeletal muscle wasting, and energy expenditure in a burned guinea pig model . Dietary augmentation of fish-oil-derived n-3 FFA has reduced monocyte production of the cytokines, IL-1, and TNF in normal human subjects  and has led to similar approaches in the burn and trauma population [179,213]. Attempts to provide structured lipids as TAG manufactured with both medium-chain fatty acids and n-3 FFA have been shown to improve hepatic protein synthesis, reduce protein catabolism, and decrease TEE in animal models of thermal injury . Reductions in infection rate and immunosuppressive eicosanoids have been demonstrated by others [216,217].
Dietary fatty acids can also affect lymphocyte function through changes in the membrane phospholipid composition and function as well as a precursor for eicosanoids. In burn patients receiving enteral formula containing 29% fat (mainly MCT and 18:2 n-6 fatty acids), there was a reduction in arachadonic acid in lymphocyte phospholipids early after burn injury, indicating either increased metabolism of arachidonic acid metabolites involved with the inflammatory process or inhibition of the 8-6-desaturase enzyme slowing conversion of 18:2 n-6 to 20:4 n-6, and was associated with reduced NK cytotoxicity . Because n-3 fatty acids compete with n-6 fatty acids for composition of cell membranes and for metabolism, and n-3 produce anti-inflammatory metabolites, n-3 fatty acids are less inflammatory.
Patients with acute respiratory distress syndrome (ARDS) randomized to receive a 55% fat enteral formula rich in omega-3 fatty acids (40% of fat source as borage and fish oil) or a formula rich in omega-6 fatty acids (97% corn oil) had significant improvements in oxygenation, lower ventilation requirements, reduced length of stay in the ICU, and decreased pulmonary inflammation . In healthy humans, supplementation of the diet with 18 g of fish-oil-derived omega-3 fatty acids daily for 6 weeks reduced IL-1 and TNF-a production by monocytes ex vivo  up to 50% of controls and persisted for up to 4 months following supplementation. Similar reductions in IL-1, TNF, and IL-6 found in women whose diets were supplemented with eicosapentaenoic and docosahexaenoic acid  have led to dietary formulations enriched in omega-3 fatty acids for burn patients . In 24 elective abdominal surgery patients randomized to receive perioperative parenteral nutrition supplemented with 10 g fish oil or regular parenteral nutrition support, there was a reduction in inflammatory response and IL-6 levels . Also, in 21 critically ill patients intolerant of enteral nutrition randomized to received n-3 vs. n-6 lipid infusion, a reduction in proinflammatory cytokines TNF-a and IL-1 was seen . In an animal model of pancreatitis, n-3 fatty acid supplementation increased IL-10, antiinflammatory cytokine . In 23 adult burn patients, there was an improvement in insulin-like growth factor (IGF) when patients were enterally fed formula containing of 15% fat (rich in omega-3 fatty acids, 50% of the fat source was fish oil), in comparison to patients fed 15% fat (mainly omega-6 fatty acids), or 35% fat, mainly omega-6 fatty acids . It is thought that higher levels of IGF-1 promote wound healing and protein balance .
In contrast to beneficial effects on inflammation, in rats fed a diet high in menhaden oil (omega-3 fatty acids) in comparison to those fed corn oil (omega-6 fatty acids) for 30 d, there was a significant reduction in wound strength, indicating that omega-3 fatty acids may adversely change the maturational phases of wound healing . Thus, providing a formula with n-3 fatty acids may be appropriate during the inflammatory phase and may not be beneficial during the proliferative and maturation phase .
Isotopic tracer studies have shown that glucose is oxidized as an energy substrate up to a rate of about 5 mg/kg/min. In hypermetabolic states, a large portion of oxidized glucose is derived from endogenous lipid and amino acid substrates via gluconeogensis, providing approximately 2 mg/kg/min. Excess glucose is used for lipogenesis and results in increased CO2 production and RQ. The RQ for the oxidation of glucose is 1, whereas lipogenesis results in an RQ greater than 1. Theoretically, RQ could be as high as 8 with lipogenesis; however, physiologically, RQs rarely exceed 1.3, perhaps due to the stress response preventing lipogenesis . It has been thought that the hypercapnic effect of excess glucose calories was due to an excess proportion of carbohydrates. However, a study by Talpers and colleagues in 1992 showed that total calories affect CO2 production more than the proportion of carbohydrate. In this study, 20 stable mechanically ventilated patients were randomized to receive isocaloric TPN as 40% CHO/40% fat/20% protein, 60% CHO/20% fat/20% protein, and 75% CHO/5% fat/20% protein. The VCO2 did not change with increasing CHO proportion (205, 203, and 211 ml/min, respectively); however, the VCO2 did increase when the patients received increased total calories (1.0, 1.5, and 2.0 times REE) from 181 to 244 ml/min (p < 0.01). Thus, although the proportion of carbohydrates is important, it is more important to avoid overfeeding critically ill patients, because the respiratory workload will be increased and may interfere with ventilator weaning.
Glucose is the principal carbohydrate fuel source with plasma levels that vary normally within a narrow range . Its storage form, glycogen, is in limited supply, with 80 to 100 g total stored in liver and muscle, and it is depleted quickly after injury, within 24 to 48 h, by tissues that are predominately carbohydrate utilizing (brain, kidney, heart, red blood cells, and muscle) and that metabolize up to 300 g/d of glucose [27,29,30]. As illustrated in Figure 11.3, glucose undergoes anaerobic or oxygen-independent metabolism in the cytoplasm at a cellular level.
Fatty Acid Oxidation
ADP Glycolysls ATP
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