The metabolic effects of thermal injury.

World J. Surg. 16, 68-79, 1992

World Journal of Surgery 0 1992 by the Soci~t~ lnternationale de Chirurgie

The Metabolic Effects of Thermal Injury Edward E. Tredget, M.Sc., M.D. and Yong Ming Yu, M.D., Ph.D. Firefighters' Burn Treatment Unit, University of Alberta Hospital, Alberta, Canada and Massachusetts General Hospital, Boston, Massachusetts, U.S.A. Major thermal injury is associated with extreme hypermetabolism and catabolism as the principal metabolic manifestations encountered following successful resuscitation from the shock phase of the burn injury. Substrate and hormonal measurements, indirect calorimetry, and nitrogen balance are biochemical metabolic parameters which are useful and more readily available biochemicalparameters worthy of serial assessment for the metabolic management of burn patients. However, the application of stable isotopes with gas chromatography/mass spectroscopy and more recently, new immunoassaysfor growth factors and cytokines has increased our understanding of the metabolic manifestations of severe trauma. The metabolic response to injury in burn patients is biphasic wherein the initial ebb phase is followed by a hypermetabolic and catabolic flow phase of injury. The increased oxygen consumption/metabolic rate is in part fuelled by evaporative heat loss from wounds of trauma victims, but likely also by a direct central effect of inflammation upon the hypothalamus. Although carbohydrates in the form of glucose appear to be an important fuel source following injury, a maximum of 5-6 mg/kg/min only is beneficial. Burn patients have accelerated gluconeogenesis, glucose oxidation, and plasma clearance of glucose. Additionally, considerable futile cycling of carbohydrate intermediates occurs which includes anaerobic lactate metabolism and Cori cycle activity arising from wound metabolism of glucose and other substrates. Similarly, accelerated lipolysisand futile fatty acid cycling occurs following hum injury. However, recent evidence suggests that lipids in the diet of burned and other injured patients serve not only as an energy source, but also as an important immunomodulator of prostaglandin metabolism and other immune responses. Amino acid metabolism in burn patients is characterized by increased oxidation, urea synthesis, and protein breakdown which is prolonged and difficult to reduce with current nutritional therapy. However, the current goal of nutritional support is to optimize protein synthesis. Specific unique requirements may exist for supplemental glutamine and arginine following burn injury but further research is needed before enhanced branched chain amino acids supplements can be recommended for burn patients. Recent research investigations have revealed the importance of enteral feeding to enhance mucosal defense against gut bacteria and endotoxin. Similarly, research has demonstrated that many of the metabolic perturbations of burns and sepsis may be due, at feast in part, to inflammatory cytokines. Investigation of their pathogenesis and mechanism of action both at a tissue and a cellular level offer important prospects for improved understanding and therapeutic control of the metabolic disorders of burn patients.

Thermal injury is a post-traumatic inflammatory disease in which the magnitude of the injury and the cardiopulmonary and

metabolic reserve, in part reflected in age of the patient, are the principal components in determining the probability of survival (Figure 1) [1]. In the past 2 decades, substantial improvements in the initial emergent and subsequent resuscitative stages of major burn injuries have occurred. This has allowed patients to survive into a postinjury hypermetabolic phase of wound care [2, 3], in which the immunometabolic reserve of the patient appears critical to successful local defense in wounded tissues and subsequent healing. Although many modalities for nutritional and metabolic support of injured patients now exist, rapid increases in the understanding of the whole body, regional, and cellular responses to injury and sepsis continue to dictate refinements in application of nutritional and other forms of therapy for burn patients [4]. Methodologic Approaches to Immunometabolic Manifestations of Burned Patients Traditionally standard metabolic measurements within most burn care centres include serial measurements of body weights as illustrated in Figure 2, which demonstrate rapid accretions with fluid resuscitation during the burn resuscitative phase (day 1) or with sepsis (day 10). However, continual erosion of body mass typically leads to loss of lean body weight proportional to the extent of the injury but up to 30% to 40% in its extreme [5, 6]. Measurements of urinary nitrogen excretion principally as urea or other ammonia-containing substrates are important routines for burn patients which are readily available, relatively inexpensive and remain as a persistent clinical standard of protein degradation and nutritional balance. Additionally, losses of nitrogen from burn wounds may account for 20% to 25% of total daily nitrogen losses [7]. Similarly, the refinement of indirect calorimetry [8] coupled with in vitro calibration [9] has allowed accurate measurement of total energy expenditure in most burn patients at different phases of injury except at extremes of FiO2 where measurement error can exceed 5% as compared to 2% to 3% overall errors achievable in the lower ranges of oxygen consumption and carbon dioxide production

[tO]. Reprint requests: Edward E. Tredget, M.D., 2D3.82 Walter Mackenzie Centre, University of Alberta Hospital, Edmonton, Alberta, T6G 2B7, Canada.

The interpretation of serial measurements of energy substrates such as plasma glucose, triglycerides, free fatty acids, and amino acids following trauma have been enhanced greatly

E.E. Tredget and Y.M, Yu: Metabolic Effects of Thermal Injury

69

160

6Q

/'k / ~

t

o;

Weight (kg Nitrogen (gm/Oay)

U

O~ O

;

.-

,

.........

8°1

y

',

-

•

N[

:N

t

o Oxygen O_

0

Consumption

~_

I

10

20

n

~3400 ~ 2 9 8 t

80

0

40

50

Day Fig. 2. Changes in body weight, urinary urea nitrogen, and oxygen consumption in a typical 38 year old male with a 45% total body surface area burn complicated by Pseudomonas aeruginosa sepsis at 14 days postburn. Fig. 1. The probability of survival of burn patients given total body surface area burned and age based on multifactorial analysis of 1706 patients.

by the research application of stable, nonradioactive isotopes which are quantitated by mass spectroscopy [11]. They have allowed investigation and understanding of the dynamic flow of SUbstrates through enzymatic pathways leading to degradation, synthesis, and oxidation of various labelled substrates previOusly not possible. This technology is limited by its expense and requires refinement of the mathematical models employed for measuring net movement of labelled substrates in the whole body or for complicated pools, such as the plasma bicarbonate pool [12]. However, such approaches offer the potential for safe, highly sensitive, and specific investigation for healthy and InjUred individuals including burn patients [13]. Finally, exciting immunologic and molecular biologic advances have allowed identification of previously unrecognized prostanoids and growth factors in burn patients and animal models allowing an emerging understanding of their role in altered metabolism at a Cellular level as well as in local and distant tissues in burn Patients [14]. Metabolic Response to Thermal Injury

Cuthbertson [15] originally characterized the metabolic reSponse to injury as a biphasic response in which the initial .resuscitative or ebb phase was characterized by decreased mtravascular volume, poor tissue peffusion, and low cardiac OUtput accompanied by a hypometabolic state in which total body oxygen demands are below normal levels. With complete resuscitation~ a physiologic state of increased cardiac output, elevated energy expenditure, erosion of lean body mass, and abnormal substrate production and utilization termed the flow Phase persists not until wound closure, but well after, until remodelling of healing wounds is completed [16]. •Increased metabolic rate reflected by oxygen consumption V~aindirect calorimetry, rises in a linear fashion with the extent of the total body surface area (TBSA) burned, until increases of 100% above the resting energy expenditure (REE) are reached With injuries of >-60% TBSA [5, 8, 10, 16, 17]. Twenty-four hour

daily monitoring of burn patients also demonstrates additional, substantial increases in oxygen consumption associated with cold stress or painful stimuli prompting the establishment of thermoneutral patient care environments to control heat and evaporative water loss as well as adequate analgesic relief policies in modern burn care centers [17]. As such, most patients prefer thermoneutral environments of 31°C to 33°C [18], but provision of such environments or limitation of evaporative water loss from the wounds does not reduce the elevations in oxygen consumption to normal [19]. Although not as yet demonstrated in burn patients, inflammatory growth factors known to be released in burn and other wounds [20, 21] are capable of altering body temperature through interactions with specialized endothelial cells in the region of the hypothalamus, resulting in many complex physiologic and behavioral changes including elevation of core body temperature [22, 23]. Despite many formulations which exist for estimation of total energy expenditure of burn and trauma patients [16, 24], the wide range of approaches attests to the individuality which exists within patients, as well as the unique environments and wound care approaches characterizing different institutions. Thus, accurate estimation of energy expenditure and caloric support for requirements is most accurately based on indirect calorimetry measurements made on calibrated instruments with the patients in a steady state, i.e., at rest and on enteral tube feedings only to allow accurate REE measurements accounting for the specific dynamic action of feeding-induced thermogenesis [16]. As illustrated in Figure 2, hypermetabolism after trauma is seen in its extreme in burn patients in whom losses of urinary nitrogen may exceed 40 gm per day, 80% to 90% of which is urea [25]. Skeletal muscle, 40% of body weight, is the principal protein store undergoing proteotysis after burn injury in which increased release of the amino acids into the plasma occurs principally as alanine and glutamine [26] for hepatic synthesis of acute phase proteins and other proteins of higher biologic priority [27]. Carbohydrate Metabolism in Thermal Injury

Glucose, a 6 carbon sugar, is metabolized anaerobically by a series of enzymatic steps, three of which are allosteric, rate-

70

World J. Surg. Vol. 16, No. 1, Jan./Feb. 1992

METABOLIC PATHWAYS OF ENERGY SLIBSTRATES

CYTOPLASM

Z G6P,, :

...... - GIF'°gen

T

Pep O~loocelote, c w ~ , o , ~

Glycer~de~de-5-P- = ~hydm=yoce~Jne,,.,-.--Glycerol NAu I, 3 BaPGycerote Prosp+l Ipyruvole cids

~4x;oneogemc"A A

A ~ c,A ®

. P) "uv=re~

Loctote

/

.............

Clh.ole

// //

$ e

CYCLE

i

Fumorote

I \

"~c"a.A----~

d~eloglutomte:

S ~

"C~c~eogenic"AA.

./c: ° Fig. 3. The metabolic steps in glucose metabolism.

limiting, and reversible in the cytoplasm of all cells to either the 3 carbon moiety, pyruvate, or its oxidized form, lactate (Fig. 3) [28]. Progressive oxidation of the carbon hydrogen bonds of these glucose intermediates in the mitochondria of most but not all cells results in the donation of electrons to nicotinamide adenine dinucleotide (NAD) or other electron carriers and release of COz, Metabolism of NAD occurs via contribution of its electrical/chemical energy to produce a proton gradient in the inner membrane of mitochondria which is coupled to the production of ATP and the reduction of oxygen to water, i.e., oxidative phosphorylation [29]. Arteriovenous difference and whole body isotopic investigations have demonstrated that in addition to oxidation of glucose for energy, much of glucose metabolism occurs glycolytically, i.e., in the cytoplasm of celts, without oxygen consumption [30], and with considerable futile substrate cycling within the cytoplasm [31]. In contrast to hypothyroidism in which substrate cycling is very low [32], burn patients appear to metabolize glucose and consume ATP through substrate cycling, the net result of which is heat production, increased thermogenesis, and oxygen consumption [31]. Provision of glucose for oxidative purposes has been demonstrated to be useful only to a limit of approximately 5-6 mg/kg/min which appears optimal for protein synthesis, but beyond which further oxidation fails to occur [33, 34]. Excessive provision of glucose is now well recognized to increase carbon dioxide production principally due to fat synthesis, most of which occurs within the liver. Practically, this limit has important implications for weaning burn patients from respira-

tors and can contribute to the development of cholestatic jaundice [35]. More recently, regional glucose metabolism has confirmed earlier findings suggesting that burn wounds in humans [30, 36] or animal models [37] metabolize glucose primarily by glycolysis, despite the presence of oxygen, with the subsequent release of lactate'locally and into the systemic circulation. Hepatic metabolism of lactate to produce new glucose (gluconeogenesis) functions potentially to control systemic pH in burn patients (2 lactate + 2 H + = 1 glucose) and completes the Cori cycle activity in which wounded tissue consumes glucose and releases lactate despite the presence of adequate oxygen stores [38, 39]. Although the survival value of accelerated Cori cycle activity is difficult to understand, local release of lactic acid in wounded tissues has antibacterial effects associated with low wound pH and lactate is a known stimulant of collagen metabolism as a potential reducing substance for prolyl hydroxylase [40, 41]. Clinically, the chronic elevations in plasma glucose and the normal or elevated levels of insulin have lead investigators to propose that both septic and burn patients are resistant to the normal effects of insulin [42, 43] such as increased cellular uptake of glucose, reduced protein breakdown, and stimulated protein synthesis via enhanced cellular uptake of amino acids [44]. Evidence for a post-receptor defect in insulin metabolism has supported this concept [42, 45], however ample stable isotope data has demonstrated that glucose metabolism including turnover, plasma clearance, and oxidation, are enhanced in

E.E. Tredget and Y.M. Yu: Metabolic Effects of Thermal Injury

71

burn patients as compared to normal, bed-rested control patients [46]. Wolfe and coworkers [47] augmented glucose disposal pathways in burn patients by infusions of insulin during Which plasma concentrations of potassium and glucose are maintained stable. This stimulation of energy substrate availability to counteract a potential cellular energy deficit, via enhanced glucose utilization during hyperinsulinemic, euglycemic conditions or via activation of the initial oxidative step in glucose metabolism catalyzed by pyruvate dehydrogenase, did reduce protein breakdown and utilization for energy purposes V~'hen urea and leucine kinetic studies were conducted. H o w ever, the magnitude of the reductions did not approach that of the control resting or hyperinsulinemic state, further suggesting that the abnormalities of substrate metabolism seen after burns and/or sepsis are not correctable by provision of excessive amounts of exogenous substrates such as glucose nor administration of a single hormone, such as insulin, at supraphysiologic dOSes.

TAG which contain FFA in which the first double bond is located 3 carbons from the methyl terminus (omega-3), have reduced weight loss, skeletal muscle wasting and energy expenditure in a burned guinea pig model [62]. Similarly, dietary augmentation offish oil derived omega-3 fatty acids has reduced monocyte production of the cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF) in normal human subjects [63], and such approaches have begun to be applied in the burn population [62]. Alternatively, provision of medium chain triglycerides which have the theoretical advantages of preferential oxidation [63] with little tendency for deposition in adipose tissue [64] or incorporation into membranes to serve as prostanoid precursors [65] have avoided RES blockage, but have not as yet demonstrated protein-sparing features [66]. Finally, structured TAG containing both medium chain fatty acids and fish oil have improved hepatic protein synthesis, reducing protein catabolism as well as decreasing total energy expenditure in similar animal models of thermal injury [67].

Fat Metabolism in Burn Patients

Burn Injury, Protein and Amino Acid Nutrition

As reviewed earlier [351 48], metabolism of free fatty acids !FFA) and triacylglycerides/triglycerides (TAG) is complicated In that although these substrates can function as an efficient nergy source, they are also important components of the lipid !layer of cell walls. FFA and TAG are also precursors to the elcosanoid family of fatty acids which possess diverse effects on Cellular and whole body metabolism in addition to their role in lmmUnomodulation. Although highly variable FFA concentrations are found in burn patients, FFA turnover, measured by ~3C-palmitate is rapidly accelerated in proportion to the extent of burn injury [49]. Similarly, release of FFA from TAG stored in adipocytes (lipolysis) is accelerated. However, a large proPortion of FFA turnover is recycled through resynthesis of TAG (reesterification) both intracellularly and by interorgan lipolysis and reesterification, representing an additional futile SUbstrate cycle [31,50]. Increases in TAG-FFA cycling of 450% have been documented in burn patients which appear due to the lipolytjc effects of circulating catecholamines and were partially abolished by beta blockade, in contrast to glycolytic substrate cycling in the same patients [31, 50]. Indirect calorimetry in burn patients suggests that a large proportion of endogenous energy substrates is derived from fat oxidation, and thus numerous protocols for feeding burn patients propose inclusion of Substantial proportions of lipid as a nonprotein energy source [51, 52]. Although most burn patients can be fed enterally, Considerable controversy arises in regard to the immunologic effects of FFA [53] when lipid emulsions which are extraordinarily high in the eicosanoid FFA precursor, linoleic acid (18:2w6) [54], are infused intravenously into burn and other traumatized and septic patients. Potential changes in membrane .flUidity [55], stimulation of prostaglandin synthesis [56, 57], Impairment of reticuloendothelial clearance of bacteria [58, 59], and release of a lipoprotein X carrier at the endothelial surface [60, 61] which is metabolized likely in the reticuloendothelial System (RES), are important potentially deleterious effects for burn patients which have just begun to be recognized in animal models [58] and other human systems [59]. Attempts to ameliorate the detrimental metabolic effects of trauma mediated in Part through eicosanoid precursors, by the provision of dietary

As discussed earlier, burn injury probably represents the greatest stimulus to muscle protein catabolism. The severity of nitrogen loss is closely related to the increased risk of morbidity and mortality in the acute phase [68-70]. In a recent longitudinal study of severely burned children, Wolfe and associates [71] used multiple tracers to determine the kinetics of several essential amino acids and urea at different stages of burn injury. Since the essential amino acids are not synthesized de novo within the body, the flux of these amino acids at fasting state likely represents the absolute rate of protein breakdown within the body, and the rate of urea synthesis an indicator of net protein catabolism. Based on this stable isotope study in burn patients, proteolysis became elevated soon after injury and remained elevated throughout the flow and convalescent phase, lasting from 40 to 90 days after the burn [71]. However, net protein catabolism, as indicated by the urea kinetics was only elevated during the flow phase, i.e., the first several days to 2 weeks after the injury. Although the observed effects of nutritional support of these burn patients appeared to be in shortening the duration of the catabolic state, improvements in the nitrogen balance of the traumatized patients was achieved by increasing the rate of protein synthesis and not by reducing protein degradation. Thus, the development of optimal amino acid solutions for nutritional support has been based on the importance of optimizing protein synthesis through the application of the expanding knowledge of the nutritional biochemistry of various amino acids and other substrates after burn injury. This has led to the development of many new nutritional support formulas with selective enrichment of specific nutrients to optimize protein metabolism following trauma.

~

Branched Chain Amino Acids in Burn Trauma

In the late 1970's numerous in vitro studies revealed that branched chain amino acids (BCAA), leucine, iso-leucine and valine, had the effect of promoting protein synthesis and inhibiting protein breakdown in cultured muscle tissues, in particular, leucine and its keto acid alpha-keto-isocaproate [72]. Subsequently, many in vivo studies indicated that the peripheral

72

uptake or clearance of BCAA was significantly increased after trauma, suggesting an increased requirement for oxidation in the muscle tissue [73-75]. Thus, it was hypothesized that trauma patients may have an enhanced consumption of BCAA as an alternative fuel and depletion of the intracellular BCAA pool may reduce their availability for protein synthesis. However, marked variability within trauma patients in whom the nitrogen balance technique was applied has led to conflicting results [73-75]. Using ~3C-leucine, Wolfe and colleagues [76] demonstrated that the burn patients had both an increased rate of leucine oxidation and an increased rate of leucine utilization for protein synthesis, although the increase of the latter was much less than the elevation in protein breakdown. By comparing the effect of BCAA-enriched enteral feeding with a conventional enteral diet, Yu and coworkers [77] found that the increased BCAA intake resulted only in an increased rate of leucine oxidation with minimal stimulation of protein synthesis. Similar findings were also reported by Miltiken and associates [78] in liver cirrhosis patients receiving BCAA feeding. As such these observations suggest that BCAA availability is not a rate limiting factor for protein synthesis in traumatized patients and the burn patients do not use the enriched BCAA supply for synthesizing more proteins. Furthermore, it has been estimated that total BCAA oxidation accounts for only 2% to 5% of total energy expenditure [12]. Therefore, in spite of the observed two fold increase in leucine oxidation following BCAA feeding [79], the BCAA likely do not serve as a major fuel for burn patients. As Brennan and coworkers [80] summarized, it appears that greater benefits must be demonstrated in humans before any wide-spread application of the use of BCAA enriched formulation can be recommended. However, Garlick and colleagues [81] have found that increased BCAA supply can enhance insulin sensitivity for muscle protein synthesis. Additionally, a close relationship between BCAA metabolism and gtutamine release from muscle tissue exists [82]. Thus, further carefully designed clinical trials will be required as the importance of glutamine and its interrelationships with other amino acids is studied in the immune and metabolic functions of trauma patients. Giutamine-Enriched Nutritional Support

Glutamine is the most abundant free amino acid in the body, comprising 69% of the total free amino acid pool of muscle [83]. Investigations of the intracellular concentration of glutamine have demonstrated a direct inhibitory effect of glutamine on protein degradation in cultured muscle tissue [84]. A correlation between the intracellular glutamine level and muscle protein synthesis has also been shown in in vivo and in vitro studies [85-87]. Additionally, large and rapid losses of muscle glutamine consistently occur after burn injury and other types of trauma, amounting to 60% of the free pool [88, 89]. Using a membrane vesicle preparation, Rennie and colleagues [85, 90, 91] have proposed that glutamine transport is impaired due to the rise in intramuscular Na + and Ca ++ and depression of K + ion concentrations which are known to occur after trauma. Since the transport of glutamine is sodium dependent, glutamine will be lost from the skeletal muscle. In view of the relationship between protein turnover and the glutamine pool size within the muscle, Rennie and associates [85] suggested


that depletion of glutamine in the muscle pool plays a crucial role in governing post-traumatic muscle protein loss. Studies by Newsholme and colleagues [92-96] have revealed the importance of glutamine for the immune system. Recent work has identified gtutamine as an extremely important fuel for macrophages and lymphocytes, and possibly many of the cells of the immune system [96]. Studies have revealed that the utilization of both glucose and glutamine by the cells of the immune system proceeded at a very high rate, estimated as 25% of the rate of glucose utilization by maximally working perfused heart [95]. Most of this glucose and glutamine underwent partial oxidation in these tissues, which involved only the "left hand" biochemical reactions of the Kreb's citric acid cycle, i.e., from alpha-ketoglutarate to oxaloacetate, despite the fact that the enzymes for the operation of the complete Kreb's cycle are present in these cells [95]. Thus, high uptake rate and partial oxidation of these substrates are characteristic for such cells, including lymphocytes, thymocytes, enterocytes, and tumor cells. As a consequence, glucose was metabolized to lactate and glutamine is converted to lactate, aspartate and alanine. As proposed by Newsholme [95, 96], partial oxidation of these substrates may provide for optimal regulation of these intermediates which are biosynthetic substrates important for cell proliferation and the immune function. For example, glucose 6-phosphate, a product of glycolysis, can be used for the formation of 5-ribose-phosphate, which is required for DNA and RNA synthesis. Similarly, glutamine itself and the products of its degradation, aspartate and ammonia, serve as direct precursors for purine and pyrimidine synthesis. The nitrogen atoms of glutamine are also utilized for the formation of glucosamine, GTP, and NAD. Therefore, it seems likely that any significant decrease in glutamine and glucose utilization would be expected to decrease the rate of proliferation of these and other rapidly turning over, gtutamine dependent cells and impair the immune functions of the host. Analysis of the kinetics of glutamine transport out of muscle suggests that this process acts as the flux-generating step for glutamine utilization by the cells of the immune system. Thus, supplementation of extra glutamine is theorized to spare its loss from muscle tissue and to preserve the immune function of the host [95, 96]. Based on the above projections, initial clinical trials have been conducted to test if glutamine enriched total nutrition could replete the intracellular glutamine pool, lessen the nitrogen loss from the host and preserve the gut mucosa mass while maintaining immune competence for the burn patients. Unfortunately, glutamine is not stable in water and the decomposition of free gtutamine in solution occurs in a quantitative fashion producing a cyclic product pyroglutamic acid (pGlu) and ammonia [97]. This difficulty has been solved in recent years by supplementing glutamine in its dipeptide form with other amino acids [98-100]. Clinical trials have confirmed the efficiency of dipeptide utilization by different tissues within the body [101, 102]. Importantly, recent investigations of the safety of glutamine for human use have failed to demonstrate any evidence of clinical toxicity or generation of toxic metabolites of glutamine within the blood of patients receiving continuous glutamine-containing parenteral feeding for up to 6 weeks [103-106]. Conversely, glutamine was found to be readily metabolized and cleared from the bloodstream. Currently nutritional-immunological benefits of glutamine

E.E, Tredget and Y.M. Yu: Metabolic Effects of Thermal Injury

enriched nutritional support, either in its free form or dipeptide form, are undergoing extensive clinical trials. Numerous rePOrts [103-106] have demonstrated that supplementing glutarnine in total parenteral nutrition could replete the plasma and muscular free glutamine pool and improve limb amino acid balance and whole body nitrogen balance [103, 104]. Other StUdies also revealed that glutamine-enriched parenteral feeding Could ameliorate the loss of gut protein in stressed surgical patients as well as in patients with primary gastrointestinal disease or those receiving radiation therapy [103, 106-108]. However, further investigation of the metabolic and immunological benefits of glutamine enriched nutritional therapy and of the optimal content of glutamine in the diet of burn and traumatized patients is required before its routine use can be advocated.

73

wound increasing the consumption of arginine. Such enhanced arginase activity in the wounds could also increase regional d e n o v o synthesis of proline leading to higher hydroxyproline formation in the healing wound. Teleologically, activated macrophages and other phagocytes in the open wound of the burn patients would likely consume sizable amounts of arginine for immune function and prevention of bacterial invasion [122, 123]. Other studies have suggested that the mechanism of arginine enhancement of wound healing occurs by stimulation of pituitary release of growth hormone [124, 125]. However, in a recent wound healing study of human subjects receiving 30g/day of arginine supplementation, no strong evidence of increased plasma levels of growth hormone, insulin-like growth factor, or somatomedin was consistently found [126]. Thus, the underlying mechanisms of arginine stimulation of wound healing requires further investigation.

Arginine supplementation in nutritional therapy

The major beneficial effects of arginine supplementation for burn patients may include promotion of wound healing [109, 1113]and improved immune function [110]. In addition, a modest benefit of arginine on nitrogen balance has also been reported in clinical and laboratory experiments. Saito and coworkers [111] SUpplied varying amounts of arginine to burned guinea pigs and fOUnd reduced mortality only in groups receiving arginine SUpPlementation to 2% of total dietary energy intake. Based on the results of a series of laboratory experiments on thermally injured animals, Alexander and colleagues [1 t2] proposed the COmposition of an "optimal" diet for burn patients, which Included 2% of the dietary energy derived from arginine. Such diets were found to reduce the rate of wound infection, shorten hospital stay, and reduce mortality when compared to other "standard" dietary formulations. In surgical patients, a randomized, prospective trial conducted by Daly and associates [113] revealed that supplying 16g per day of arginine to cancer Patients undergoing major surgery enhanced T-lymphocyte response as compared to the group of similar patients receiving 25g per day of glycine supplement isonitrogenously. Other similar studies have also demonstrated an improvement of thyrn'ic function in injured patients [114-116]. In spite of these clinical observations, the underlying biologic naechanism by which arginine supplementation in stressed conditions mediates beneficial effects is only recently becoming Understood. In 1987, Hibbs and coworkers [117] reported their findings of an arginine-dependant biochemical pathway, the .deaminase pathway, by which synthesis of citrulline and nitrate in macrophages is coupled to the release of a highly reactive nitric oxide. As such, this arginine-derived metabolic product exerts an inhibitory effect on activated cytotoxic macrophages, I)NA synthesis, mitochondrial respiration, and aconitase activity in tumor target cells [117]. Recently, a series of well designed studies by Ganger and associates [118, 119] examined all the major pathways of arginine metabolism in inactivated rnurine macrophages and confirmed that only the deaminase Pathway is closely related to the bacteriostatic capability of tnUrine macrophages [118, 119]. Subsequent studies revealed that this arginine dependent metabolic pathway also exists in certain human cells [120, 121]. In addition, the effect of arginine xn WOund healing may also be related to the release of both arginase and arginine de aminase activity by macrophages in the

The Role of Nutrition and the Gastrointestinal Tract

Early studies by Windmueller and colleagues [127, 128] have demonstrated that the gut extracts a large amount of both parenterally and enterally administered glutamine, which serves as a major respiratory fuel for the enterocytes, with the majority of glutamine nitrogen disposed of in the form of ammonia, citrulline, and alanine. More recently, it has been well recognized that the gastrointestinal tract plays a very active role in mediating the host response in trauma, infection, and other stressed conditions [129]. Studies have shown that in the flow phase of trauma, there is an accelerated release of alanine and glutamine from the skeletal muscle coupled with an active extraction of glutamine by gut tissue which exceeded muscle release [130-132] and contributed to the reduced plasma glutamine level. Since glutamine has been found to be a major fuel for the enterocytes and the interorgan fate of glutamine metabolism has revealed a substantial increase of its extraction by the intestine in the flow phase of trauma [132] it has been hypothesized that supplementation of glutamine could preserve the enterocyte function and mucosal defense. In healthy subjects, the mucosa of the gastrointestinal tract represents a first barrier to invasion of gut bacteria and curiotoxin within its lumen. The integrity of this barrier function appears to be maintained physically by the lining of normal epithelial cells and the preservation of tight junctions between these cells of the intestinal wall [133, 134]. This barrier function appears to be supported by a variety of other immunological mechanisms of the gut-associated lymphatic tissue (GALT). The GALT includes the abundantly distributed lymphocytes, rnacrophages, and Peyer's patches on the gut wall, the regional lymph nodes in the mesentery, and the intraluminal secretion of IgA as a specialized defense system to aid in recognition of appropriate antigens for gut absorption [135]. Finally, the Kupffer cells of the liver and the spleen also serve as a backup barrier to trap and detoxify bacteria or endotoxin which escapes the gut into the portal circulation. As such, trauma and sepsis are known to be associated with altered permeability of the intestinal mucosa, decreased mucosal defense, and an increased number of bacteria within the intestinal lumen [136]. Thus, Wilmore and coworkers have proposed the concept of gut origin sepsis wherein bacteria or their toxic products pass through the gut wall and approach the extraintestinal organs,

74

triggering the release of toxic mediators and cytokines locally and systematically [129, 137]. Based on clinical experience and experimental observations, long term parenteral nutrition has been shown to cause gut atrophy. Provision of nutrients via the intestinal tract appears to serve as a t r o p h i c stimulus for maintaining gut mucosal mass and other defense systems [138140]. Recent observations have shown that animals on parenteral feeding developed an 80% reduction of secretory IgA (s-IgA) in the bile as compared to those receiving enteral feeding with identical nutrients. Furthermore, the IgA level in these animals showed an immediate rise following the change of the route of nutrient administration [141]. Therefore, the intraluminal presence of the nutrients is essential for maintaining its protein mass as well as s-IgA production. Examination of the gut lamina propria plasma cell population further demonstrated that the marked depletion of IgA-producing plasma cells was selective, since it was not accompanied by a similar reduction of IgG and IgM-producing cell population [142]. The close relevance of lgA level and the incidence of bacteria translocation is further demonstrated by the observation that 66% of animals receiving parenteral nutrition developed positive bacterial cultures of their mesenteric lymph nodes as compared to only 33% in the group receiving enterat feeding [141]. These findings also agree well with the clinical observations that the patients on enteral feeding showed fewer septic complications than those receiving parenteral feeding [t42], and that gut-origin sepsis in intensive care unit patients is better combatted by enteral feeding [143]. The Role of Inflammation on Burn Metabolism

Early studies of the role of the classical endocrine hormones including catecholamines, glucagon, cortisol, and insulin have documented elevations and are fundamentally accepted perturbations typical seen in major burn patients [144]. Simulation of the hormonal milieu and metabolic response of burn patients in normal humans by exogenous infusions of such hormones individually or in combinations [145, 146] are capable or reproducing a portion of the substrate and metabolic perturbations seen after severe trauma such as burns. However, such approaches were not capable of reproducing the magnitude of responses in protein and carbohydrate metabolism nor the hepatic synthesis of acute proteins which required the presence of an inflammatory agent such as etiocholanolone [147]. Presently, rapidly emerging evidence exists for the generation of polypeptide cytokines which have been isolated in burn patients' wounds and serum and have profound effects upon regional and whole body metabolism. IL-I has been isolated from blister fluid in burned tissue [t48] and likely is released by damaged epithelial cells directly [149] or by indirect stimulation of heat denatured tissue after activation of the classical and alternative pathways of the complement system [150, 151]. Similarly, tumor necrosis factor has been isolated from the plasma of burned patients [152], levels of which closely correlate with the severity of injury. More recently, elevated levels of interleukin-6 [153] have been demonstrated in the burn patient population. Each of these cytokines when infused into animal models or administered to humans directly have potent metabolic effects on basic energy substrate metabolism and hormonal profiles [154-157]. They possess many similar and


related properties, behave in synergistic fashion when administered simultaneously, and are capable of inducing the secretion of each other as welt as additional cytokines and eicosanoids [158]. Increased plasma glucose, glucose turnover, oxidation and recycling typical of burn patients can be reproduced by the infusion of recombinant IL-1 and TNF [154, 159]. Elevations of classical counter-regulatory hormones including catecholamines, ACTH, cortisol, glucagon, and insulin have been demonstrated following infusion of these cytokines in small animals, primates, and humans [154-159]. Direct effects of IL-I on ACTH secretion in the hypothalamus [160], insulin release via pancreatic islet cells [161], and acute phase protein synthesis by hepatocytes [156] suggest that many of the earlier poorly understood hormonal profiles are likely compensatory and are designed to localize inflammation to the site of wounding. For example, in the central nervous system circulating TNF and IL-1 or endotoxin induce ACTH and cortisol elevation directly by cells of the anterior pituitary in vitro [162] and in vivo [161], thereby reducing cytokine synthesis and release, likely in part, by reduction of cytokine gene transcription by circulating glucocorticoids [161]. Such involvement in the anterior pituitary strengthens the neuroendocrine role of immunoregulatory molecules after inflammatorY diseases such as burns, and offers explanations for the reduced capacity of anesthetized animals or central nervous system compromised patients to respond metabolically to major stress such as burns or sepsis [154, 160-163]. Although earlier reports suggest the muscle proteolysis of major injury may be due to IL-1 [164], subsequent studies suggest that TNF more likely has a direct effect on muscle membrane potential [159] and induces the release of amino acids from muscle, principally alanine and glutamine, when administered to humans [157], Although the direct effects of cytokines on endothelium [165] may be responsible for some of the metabolic effects in nearby tissues, such as connective tissue matrix in wounds or muscle [166], direct effects of TNF and other cytokines upon muscle and other tissues have been demonstrated, for example, increased glucose transport and anaerobic fiaetabolism with lactate production and release [167]. Currently, it remains important for further research to demonstrate the subcellular mechanism of action whereby cytokines or endotoxin directly mediate profound changes in substrate metabolism. Alterations in key Kreb's cycle allosteric enzymes such as pyruvate dehydrogenase have been demonstrated in septic animal models whose regulatory phosphatase subunits are themselves regulated by intracellular calcium flux [154, 168]. Alterations of subcellular calcium and other ions are a common intracellular event following inflammation and sepsis [t69]. Similarly, signal transduction by many growth factors including IL-I and TNF, as well as endotoxin, induce changes in intracellular calcium together with alterations in certain cytoplasmic enzyme functions including glycogen phosphorylase [170-172]. Importantly, suggestions by Granger and Leninger [173, 174] that products of inflammatory cells can uncouple the transport of electrons derived by oxidative substrate metabolism in mitochondria from the formation of ATP offer a hypothesis for a key subcellular metabolic defect in inflamed tissues which may account for the marked increase in anaerobic metabolism seen following burns or sepsis. Finally, the increased availability of recombinant growth

E.E. Tredget and Y.M. Yu: Metabolic Effects of Thermal Injury factors and their inhibitors [175], human hormones such as growth hormone [176], and monoclonal antibodies [177] offer exciting new potential therapies which may allow control of the basic abnormalities of cellular metabolism associated with inflammation and enhance biosynthetic processes [178, 179] leading to reduced morbidity and mortality following burns. R6sum6

Apr~s r6cup6ration de la premiere phase de choc survient un hypercatabolisme majeur. Des param~tres de surveillance de l'6volution et d'6valuation de I'efficacit6 du traitement sont facilement disponibles: dosages hormonaux et de diff6rents subtats, calorim6trie indirecte et bilan azot6 devraient ~tre dos6s de fa~0n r6guli6re chez les brfil6s. Notre compr6hension des perturbations m6taboliques chez le bless6 et chez la grand brfll6 s'est am61ior6e ces derni6res ann6es en raison de l'application de techniques isotopiques avec des dosages par la chromatographie gazeuse et la spectrophotom6trie de masse et plus rfcemment encore les dosages immunologiques des facteurs de croissance et des cytokines. La r6ponse m6tabolique ~t l'agression chez le br0t6 est biphasique. La phase initiale est descendante, suivie d'une phase ascendante d'hypercatabolisme. L'augmentation de la consommation en oxyg6ne et du rn6tabolisme est en pattie provoqu6e par la perte en chaleur au niveau des plaies, mais aussi, par un effet direct central, li6e l'inflammation qui agit sur l'hypothalamus. Bien que des hydrates de carbone, sous forme de glucose, semblent 6tre une SOUrce importante d'6nergie apr6s un traumatisme, l'apport de seuletnent 5-6 mg/kg/min est suffisant, La n6oglucog6n~se, I'o×Ydation du glucose et la clairance plasmatique du glucose du b~16 sont acc616r6es. Les cycles m6taboliques des hydrates de Carbone, y compris le m6tabolisme anaErobie des lactates et le Cycle de Coil sont inefficaces. De m6me, la lipolyse est accdl6r6e et le cycle des acides gras est inefficace. Cependant, il est 6vic!ent que les lipides chez le brt~16 et d'autres patients victimes du traumatisme ne sont pas seulement une source d'6nergie rnais.aussi un immunomodulateur du m6tabolisme des prostaglandines et d'autres voies de r6ponse immune. Le m6tabolisnae des acides aminfs chez le brtll6 est caract6ris6 par une °Xydation, une synth~3se d'urde et un catabolisme prot6ique accrus, ph6nom~nes prolong6s et difficiles g r6duire avec les rnoyens actuels de nutrition artificielle. Le but du soutien nUtritionnel est cependant d'optimiser la synth6se prot6ique. bes besoins sp6cifiques peuvent n6cessiter une suppl6mentation en glutamine e~ arginine apr6s brOlures mais d'autres recherches sont n6cessaires avant de pouvoir dire qu'une SUppl6mentation en acides amin6s branch6s peut 6tre utile. La recherche m0derne a d6montr6 l'importance de l'alimentation ent6rale qui emp6che la travers6e de la barri~re muqueuse par |es germes et les endotoxines. De m~me, il a 6t6 d6montr6 que beaucoup des perturbations mEtaboliques dans les suites de brt~lures et darts les 6tats septiques sont dues, du moins en Pat-tie, aux cytokines inflammatoires. L'analyse de leur pathogen~se et leur m6canisme d'action a la fois au niveau tissulaire et cellulaire offrent d'importantes perspectives pour am61iorer la COmpr6hension et ie contr61e thdrapeutique des d6sordres tn6taboliques du brfll6,

75 Resumen

La lesi6n t6rmica mayor est~i relacionada con grados extremos de hipermetabolismo y catabolismo como las manifestaciones metab61icas principales que ocurren una vez cumplida exitosamente la resucitaci6n de la fase de shock. Las determinaciones de sustratos y niveles hormonales, la calorimetrfa indirecta y el balance de nitr6geno son parilmetros metab61icos de carilcter bioqufmico que son titiles y filcilmente disponibles, los cuales merecen estudios seriados para el manejo metab61ico de los pacientes quemados. Sin embargo, la aplicaci6n de is6topos estables con cromatograffa de gas/espectrometrfa de masa y, mils recientemente, nuevas inmunodeterminaciones para factores de crecimiento y citocinas, ha incrementado nuestro conocimiento y comprensi6n de las manifestaciones metab61icas del trauma severo. La respuesta metab61ica en los pacientes quemados es bifisica, en tanto que la fase ebb inicial es seguida de una fase flow hipermetab61ica y catab61ica. E1 aumento en el consumo de oxigeno/tasa metab61ica se debe en parte a la p6rdida evaporativa de calor a partir de las heridas de las vfctimas de trauma, pero posib!emente tambi6n a un efecto central de la inflamaci6n sobre el hipotillamo. Aunque los carbohidratos en forma de glucosa parecen ser una fuente energ6tica importante, s61o hasta un milximo de 5-6 mg/kg/min son de beneficio. Los pacientes quemados exhiben aceleradas ratas de gtuconeog6nesis, oxidaci6n de glucosa y depuraci6n plasmiltica de glucosa. Adem~s, se presenta considerable ciclaje futil de intermediarios de carbohidratos, lo cual incluye metabolismo anaer6bico de lactato y actividad del ciclo de Cori originados en el metabolismo de la glucosa y de otros sustratos a nivel de la herida. Tambi6n se presenta lipolisis acelerada y ciclaje futil de ilcidos grasos. Sin embargo, evidencias recientes sugieren que los Ifpidos en la dieta de los pacientes con quemaduras y otras formas de trauma sirven no s61o como fuentes energ6ticas, sino tambi6n como un factor importante de modulaci6n del metabolismo de las prostaglandinas y de otras respuestas inmunitarias. E1 metabolismo de aminoilcidos en el paciente quemado se caracteriza por una oxidaci6n incrementada, sfntesis de urea y degradaci6n proteica prolongada y dif/cil de controlar mediante la terapia nutricional actual. Sin embargo, el prop6sito actual del soporte nutricional es optimizar la sintesis proteica. Pueden existir requerimientos especfficos de glutamina arginina suplementarias en las quemaduras, pero se requieren investigaciones adicionales antes de poder recomendar suplementos enriquecidos con aminoilcidos rac6micos en los pacientes quemados. Recientes investigaciones han revelado la importancia de la alimentaci6n enteral para estimular las defensas de la mucosa intestinal contra bacterias y endotoxinas. Tambi6n hay investigaciones que han demostrado que muchas de las alteraciones metab61icas de las quemaduras y las sepsis pueden ser debidas, por 1o menos en parte, alas citocinas inflamatorias. La investigaci6n de su patog6nesis y mecanismo de acci6n, tanto al nivel tisular como celular, ofrece perspectivas importantes de una mejor comprensi6n y de superior control terap6utico de las alteraciones metab61icas de los pacientes quemados.

76 Acknowledgments This work was supported by the University of Alberta Firefighters' Burn Trust, the Alberta Heritage Medical Research Fund, the National Institute of General Medical Sciences, and Grant-in-Aid from the Shriners' Burn Institute.

References 1. Tredget, T.E., Shankowsky, H.A., Taerum, T., Moysa, G.L., Alton, J.D,M.: The role of inhalation injury in burn trauma: A Canadian experience. Ann. Surg. (in press) 2. Department of Health, Education, and Welfare: Reports of the Epidemiology and Surveillance of Injuries, Atlanta, Centers for Disease Control, 1982 (DHEW publication No. (HSM) 73-10001) 3. Feller, I., Tholen, D., Cornell, R.G.: Improvements in burn care 1965 to 1979. J.A.M.A. 244:2074, 1980 4. Deitch, E.D.: The management of burns. N. Engl. J. Med. 313:1389, 1985 5. Gump, G.E., Kinney, J.M.: Energy balance and weight loss in burned patients. Arch. Surg. 103:442, 1971 6. Long, C.L., Spencer, J.L., Kinney, J.M.: Carbohydrate metabolism in man: Effect of elective operations and major trauma. J. Appl. Physiol. 31:t 10, 1971 7. Soroff, H.S., Pearson, E., Artz, C.P.: An estimation of the nitrogen requirements for equilibrium in burned patients. Surg. Gynecol. Obstet. 112:159, 1961 8. Saffie, J.R., Medina, E., Raymond, J., Westenskow, D., Kravitz, M., Warden, G.D.: Use of indirect calorimetry in the nutritional management of burned patients. J. Trauma 25:32, 1985 9. Eccles, R.C,, Swinamer, D.L., Jones, R.L., King, E.E.: Validation of a compact system for measuring gas exchange. Crit. Care Med. •4:807, 1986 10. Phang, P.T., Rich, T., Ronco, J.: A validation and comparison study of two metabolic monitors. J.P.E.N.J. Parenter. Enteral. Nutr. •4:259, 1990 11. Matthews, D.E., Bier, D.M.: Stable isotope methods for nutritional investigation. Annu. Rev. Nutr. 3:309, 1983 12. Allsop, J.R., Wolfe, R.R., Burke, J.F.: Tracer priming the bicarbonate pool. J. Appl. Physiol. 45:137, 1978 13. Young, V.R.: Stable isotopes in nutrition research. Fed. Proc. 41:2677, 1982 14. Fong, Y., Moldawer, L.L., Shires, G.T., Lowry, S.F.: The biologic characteristics of cytokines and their implication in surgical injury. Surg. Gynecol. Obstet. f70:363, 1990 15. Cuthbertson, D.P.: The disturbance of metabolism produced by bony and non-bony injury, with notes on certain abnormal conditions of bone. Biochem. J. 24:1244, 1930 16. Cunningham, J.J., Hegarty, M.T., Meara, P.A., Burke, J.F.: Measured and predicted calorie requirements of adults during recovery from severe burn trauma. Am. J. Clin. Nutr. 49:404, 1989 17. lreton, C.S., Turner, W.W., Hunt, J.L., Baxter, C.: Evaluation of energy expenditures in burn patients. J. Am. Diet. Assoc. 86:331, 1986 18. Burke, J.F., Quinby, W,C., Bondoc, C.C., Sheehy, E.M., Moreno, H.C.: The contribution of a bacterially isolated environment to the prevention of infection in seriously burned patients. Ann. Surg. 186:377, 1987 19. Zawacki, B.E., Spitzer, K.W., Mason, A.D. Jr., Johns, L.A.: Does increased evaporative water loss cause hypermetabolism in burned patients? J. Appl. Physiol. 38:593, 1975 20, Kupper, T.S., Deitch, E.A., Baker, C.C., Wong, W.: The human burn wound as a primary source of interleukin-1 activity. Surgery 100:409, 1986 21, Ford, H,R,, Hoffman, R.A., Wing, E.J.: Characterization of wound cytokine in the sponge matrix model. Arch. Surg. 124: 1422, 1989 22. Walter, J.S., Meyers, P., Krueger, J.M.: Microinjection of interleukin-1 into brain: Separation of sleep and fever responses. Physiol. Behav. 44:555, 1988

World J. Surg. Vol. 16, No. 1, Jan./Feb. 1992 23. Dinarello, C.A., Cannon, J.G., Wolff, S.M.: New concepts on the pathogenesis of fever. Rev. Infect. Dis. I0:168, 1988 24. Allard, J.P., Jeejheebhoy, K.N., Whitwell, J., Pashutiniski, L., Peters, W.J.: Factors influencing energy expenditure in patients with burns. J. Trauma 28:199, 1988 25. Goodwin, C.W.: Metabolism and nutrition in the thermally injured patient. Crit. Care Clin. 1:97, 1985 26. Aulick, L.H., Wilmore, D.W.: Increased peripheral amino acid release following thermal injury. Ann. Surg. 188:778, 1978 2% Perlmutter, D., Goldberger, G., Dinarello, C.A., Mizel, S.B., Colten, H.R.: Cachetin/tumor necrosis factor regulates hepatic acute phase gene expression. J. Clin. Invest. 78:1349, 1986 28. Newsholme, E.A., Leech, A.R.: Regulation of glucose and fatty acid oxidation in relation to energy demand in muscle. In Biochemistry for the Medical Sciences, E.A. Newsholme, A.R. Leech, editors, Chicester-New York-Brisbane-Toronto-Singapore, John Wiley and Sons, 1983, pp. 300-335 29. Leninger, A.L.: Electron transport, oxidative phosphorylation, and regulation of ATP production. In Principles of Biochemistry, 3rd edition, S. Anderson, J. Fox, editors, New York, Worth Publishers, 1982, pp. 467-510 30. Wilmore, D.W., Aulick, L.H. Mason A. Jr., Pruitt, B.A. Jr.: Influence of the burn wound on local and systemic responses to injury. Ann. Surg. 186:444, 1977 31. Wolfe, R.R., Herndon, D.N., Jahoor, F., Miyoshi, H., Wolfe, M.H.: Effect of severe burn injury of substrate cycling by glucose and fatty acids. N. Engl. J. Med. 317:403, 1987 32. Shulman, G.I., Ladenson, P.W., Wolfe, M.H., Ridgway, E.C., Wolfe, R.R.: Substrate cycling between gluconeogenesis and glycolysis in euthyroid, hypothyroid, and hyperthyroid man. J. Clin. Invest. 76:757, 1985 33. Burke, J.F., Wolfe, R.R., Mullany, D.J., Matthews, D.E., Bier, D.M.: Glucose requirements following burn injury. Ann. Surg. 190:274, 1979 34. Wolfe, R.R., Durkot, M.J., Allsopo, J.R., Burke, J.F.: Glucose metabolism in severely burned patients. Metabolism 28:1031, t979 35. Tredget, E.E., Burke, J.F.: Calorie and substrate requirements in trauma and sepsis. In Trauma, Sepsis, and Shock, the Physiologic Basis of Therapy, G.H.A. Clowes, Jr., editor, New York-Basel, Marcel Dekker, Inc., 1988, pp. 269-305 36. Aulick, L.H., Wilmore, D.W., Mason, A.D. Jr., Pruitt, B.A. Jr.: Peripheral blood flow in thermally injured patients. Fed. Proc. 36:417, 1977 37. Wolfe, R.R., Burke, J.F.: Effect of burn trauma on glucose turnover, oxidation, and recycling in guinea pigs. Am. J. Physiol. 233:E80, 1976 38. Cori, C.F.: Mammalian carbohydrate metabolism. Physio]. Rev. 1l:i43, 1931 39. Kreisbereg, R.A.: Pathogenesis and management of lactic acidosis. Ann. Rev. Med. 35:181, 1984 40. Laugness, U., Udenfriend, S.: Collagen proline hydroxylase activity and anaerobic metabolism. In Biology of the Fibroblast, E. Kulonen, J. Pikkaralnen, editors, New York, Academic Press, 1973, pp. 373 41. Hunt, T.K., Conolly, W.B,, Aronson, S.B.: Anaerobic metabolism and wound healing: An hypothesis for the initiation and cessation of collagen synthesis in wounds. Am. J. Surg. 135:328, 1978 42. Black, P.R., Brooks, D.C., Bessey, P.Q., Wolfe, R.R., Wilmore, D.W.: Mechanisms of insulin resistance following injury. Ann. Surg. 196:420, 1982 43. Jahoor, F., Wolfe, R.R.: Role of insulin and glucagon in the response of glucose and alanine kinetics in burn injured patients, J. Clin. Invest. 78:807, 1986 44. Czech, M.P.: New perspectives on the mechanism of insulin action. Recent Prog. Horm. Res. 40:346, 1985 45. Brooks, D.C., Bessey, P.Q., Black, P.R,, Wolfe, R.R., Wilmore, D.W.: Post-traumatic insulin resistance in uninjured forearm tissue. J. Surg. Res. 37:100, 1984 46. Shangraw, R.E., Jahoor, F., Miyoshi, H., Neff, W.A., Stuart, C.A., Herndon, D.N., Wolfe, R.R.: Differentiation between septic and postburn insulin resistance. Metabolism 38:983, 1989 47. Jahoor, F., Shangraw, R.E., Miyoshi, H., Wallfish, H., Herndon,


D.N., Wolfe, R.R.: Role of insulin and glucose oxidation in mediating the protein catabolism of burns and sepsis. Am. J. Physiol. 257:E323, 1989 48. Gottschlich, M.M., Alexander, J.W.: Fat kinetics and recommended dietary intake in burns. J . P . E . N . J . Parenter. Enteral. Nutr. ••:80, 1987 49. Galster, A.D., Bier, D.M., Cryer, P.E., Monafo, W.W.: Plasma palmitate turnover in subjects with thermal injury. J. Trauma 24:938, 1984 50. Wolfe, R.R., Herndon, D.N., Peters, E.J., Jahoor, F., Desai, M.H., Holland, O.B.: Regulation of lipolysis in severely burned children. Ann. Surg. 206:214, 1987 51. Wilmore, D.W., Moylan, J.A., Jelmkamp, G.M., Pruitt, B.A. Jr.: Clinical evaluation of a 10% intravenous fat emulsion for parenteral nutrition in thermally injured patients. Ann. Surg. 178:503, 1973 52. Kudsk, K.A., Stone, J.M., Sheldon, G.F.: Nutrition in trauma and burns. Surg. Clin. North Am. 62:183, 1982 53. Wan, J.M.F., Teo, T.C., Babayan, V.K., Blackburn, G.L.: Lipids and the development of immune dysfunction and infection. J.P.E.N.J. Parenter. Enteral. Nutr. 12:43S, 1988 54. Wolfe, B.M., Ney, D.M.: Lipid metabolism in parenteral nutrition. In Parenteral Nutrition, J.L. Rombeau, M.D. Caldwell, editors, Philadelphia, W.B. Saunders, 1986, pp. 72-99 55. Kinsella, J.E., Lokesh, B., Broughton, S.: Dietary polyunsaturated fatty acids and eicosanoids: Potential effects on the modulation of inflammatory and immune cells: An Overview. Nutrition 5:24, 1990 56. Hageman, J.R., McCulloch, K., Gora, P., Olsen, E.K., Pachman, L., Hunt, C.E.: Intralipid alterations in pulmonary prostaglandin metabolism and gas exchange. Crit. Care Med. ••:794, 1983 57. Abel, R.M., Fisch, D., Grossman, M.L.: Hemodynamic effects of intravenous 20% soy oil emulsion following coronary bypass surgery. J . P . E . N . J . Parenter. Enteral. Nutr. 7:534, 1983 58. Hamaway, K.J., Moldawer, L.L., Georgieff, M., Valicenti, A.J., Babyan, V.K., Bistrian, B.R., Blackburn, G.L.: The effect of lipid emulsions on reticuloendothelial system function in the injured animal. J . P . E . N . J . Parenter. Enteral. Nutr. 9:559, 1985 59. Freeman, J., Goldmann, D.A., Smith, N.E., Sidebottom, D.G., Epstein, M.F., Platt, R.: Association of intravenous lipid emulsion and coagulase-negative staphylococcal bacteremia in neonatal intensive care units. N. Engl. J. Med. 323:301, 1990 60. Griffin, E., Breckenridge, W.C., Kuksis, A., Bryan, M.H., Angel, A.: Appearance and characterization of lipoprotein X during continuous intralipid infusions in the neonate. J. Clin. Invest. 64:1703, 1979 61. Untraucht, S.: Alterations of serum lipoproteins resulting from -total parenteral nutrition with intralipid. Biochim. Biophys. Acta 711:176, 1982 62. Alexander, J.W., Saito, H., Ogle, C.K., Trocki, O.: The importance of lipid type in the diet after burn injury.Ann. Surg. 204:1, 1986 63. Endres, S., Ghobani, R., Kelley, V.E., Cannon, J., Dinarello, C.A.: The effect of dietary supplementation with N-3 polyunsaturated fatty acids on the synthesis of interleukin-I and tumor necrosis factor by mononuclear cells. N. Engl. J. Med. 320:252, 1989 64. Babayan, V.K.: Medium chain triglycerides and structured lipids. Lipids 22:417, 1987 65. Kinsella, J.E.: Lipids, membrane receptors, and enzymes: Effects of dietary fatty acids. J . P . E . N . J . Parenter. Enteral. Nutr. 14: 200S, 1990 66. Jensen, G.L., Mascioli, E.A., Seidner, D.L., Istafan, N.W., Donmitch, A.M., Selleck, K., Babayan, V.K., Blackburn, G.L., Bistrian, B.R.: Parenteral infusion of long- and medium-chain triglycerides and reticuloendothelial system function in man. J . P . E . N . J . Parenter. Enteral. Nutr. •4:467, 1990 67. DeMichele, S.J., Karlstad, M.D., Bistrian, B.R., Istafan, N., Babayan, V.K., Blackburn, G.L.: Enteral nutrition with structured lipid: Effect on protein metabolism in thermal injury. Am. J. Clin. Nutr. 50:1295, 1989 68. Mullen, J.L.: Consequences of malnutrition in the surgical patients. Surg. Clin. NOrth Am. 61:465, 1981

77

69. Moore, F.D., Brennan, M.F.: Surgical injury. In Manual of Surgical Nutrition, F.D. Bellinger, editor, Philadelphia, Saunders, 1975, pp. 169-222 70. Kinney, J.M., Elwyn, D.H.: Protein metabolism and injury. Ann. Rev. Nutr. 3:433, 1983 71. Jahoor, F., Desai, M., Herdon, D.N., Wolfe, R.R.: Dynamics of the protein metabolic response to burn injury. Metabolism 4:330, 1988 72. Hedden, M.P., Mazuski, J.E., Chute, E.: General stimulation of muscle protein synthesis by branched-chain amino acids in vitro. Proc. Soc. Exp. Bio. Med. 160:410, 1979 73. Hagenfeldt, L., Eriksson, S., Wahren, J.: Influence of leucine on arterial concentrations and regional exchange of amino acids in healthy subjects. Clin. Sci. 59:173, 1980 74. Ella, M., Farrell, R., llie, V., Smith, R., Williamson, D.H.: The removal of infused leucine after injury, starvation and other conditions in man. Clin. Sci. 59:275, 1980 75. Desai, S.P., Bistrain, B.R., Moldawere, L.L., Miller, M.M., Blackburn, G.L.: Plasma amino acid concentrations during branched-chain amino acid infusion in stressed patients. J. Trauma 22:747; 1982 76. Wolfe, R.R., Goodenough, R.D., Burke. J.F., Wolfe, M.H.: Respons e of protein and urea kinetics in burn patients to different levels of protein intake. Ann. Surg. 197:163, 1983 77. Yu, Y.M., Wagner, D.A., Waleswski, J.C., Burke, J.F., Young, V.R.: A kinetic study of leucine metabolism in severely burned patients. Ann. Surg. 207:421, 1988 78. Milliken, W.J., Jr., Henderson, J.M., Galloweay, J.R.: In vivo measurement of leucine metabolism with stable isotopes in normal subjects and in those with cirrhosis fed conventional and branched-chain amino acid enriched diets. Surgery 98:405, 1986 79. Wolfson, A.M.I.: Amino acids-their role as an energy source. Proc. Nutr. Soc. 42:489, 1983 80. Brennan, M.F., Cerra, F., Daly, J.M., Fischer, J.E., Moldawer, L.L., Smith, R.J., Vinnars, E., Wannemacher, R., Young, V.R.: Report of a research workshop: Branched-chain amino acids in stress and injury. J.P.E.N.J. Parenter. Enteral. Nutr. •0:446, 1986 81. Garlick, P.J., Grant, I.: Amino acid infusion increases the sensitivity of muscle protein synthesis in vivo to insulin. Biochem. J. 254:579, 1988 82. Newsholme, E.A., Newsholme, D.P., Phil, D., Curt, R., Challoner, E., Ardawi, M.S.M.: A role for muscle in the immune system and its importance in surgery, trauma, sepsis and burns. Nutrition International 4:261, 1988 83. Bergstrom, L., Furst, P., Noree, L.O., Vinnars, E.: lntracellular free amino acid concentration in human muscle tissue. J. Appl. Physiol. 36:693, 1974 84. Smith, R.J.: Regulation of protein degradation in differentiated skeletal muscle cells in monolayer culture, in intracellular protein catabolism. Prog. Clin. Biol. Res. 180:633, 1984 85. Rennie, M.J., Hundal, H.S., Babil, P., MacLennan, P.A., Taylor, P.M., Watt, P.W.: Characteristics of a glutamine carrier in skeletal muscle have important consequence for nitrogen loss in injury, infection and chronic disease. Lancet 2:1008, 1986 86. Jepson, M.M., Bates, P.C., Broadbent, P., Pell, J.M., Millward, D.J.: Relationship between glutamine concentration and protein synthesis in rat skeletal muscle. Am. J. Physiol. 255:E166, 1988 87. Maclennan, P.A., Brown, R.A., Rennie, M.J.: A positive relationship between protein synthetic rate and intracellular glutamine concentration in perfused rat skeletal muscle. FEBS Lett. 215: 187, 1987 88. Vinnars, E., Bergstrom, J., Furst, P.: Influence of postoperative state on the intracellular free amino acids in human muscle tissue. Ann. Surg. 192:78, 1980 89. Askanazi, J., Carpentier, J.A., Michelsen, C.B., Elwyn, U.H., Furst, P., Kantrowitz, L.R., Gump, F.E., Kinney, J.M.: Muscle and plasma amino acids following injury: Influence of intercurrent infection. Ann. Surg. 192:78, 1980 90. Hundal, H.S., Rennie, M.J., Watt, P.W.: Characteristics of glutamine transport in perfused rat skeletal muscle. J. Physiol. (Lond) 393:283, 1987 91. Ahmed, A., Talor, P.M., Rennie, M.J.: Characteristics of glu-

78

tamine transport in sarcolemmal vesicles from rat skeletal muscle. Am. J. Physiol, 259:E284, 1990 92. Newsholme, E.A., Leech, E.A.: Biochemistry for the Medical Sciences, Chichester, John Wiley & Sons, 1983, pp. 233-234 93. Newsholme, E.A., Crabtree, B., Ardawi, M.S.M.: The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells. Biosci. Rep. 4:393, 1985 94. Newsholme, E.A., Crabtree, B., Ardawi, M.S.M.: Glutamine metabolism in lymphocytes, its biochemical, physiological and clinical importance. Q. J. Exp. Physiol. 70:473, 1985 95. Newsbolme, E.A., Newsholme, P., Curl, R.: The role of citric acid cycle in cells of" the immune system and its importance in sepsis, trauma and burns. Biochem. Soc. Symp. 54:145, 1987 96. Newsholme, E.A., Parry-Billings, M., Phil, D.: Properties of glutamine release from muscle and its importance for the immune system. J.P.E.N.J. Parenter. Enteral. Nutr. 14:63s, 1990 97. Dimarchi, R.D., Tam, J.P., Kent, S.B., Merrifield, R.B.: Weak acid-catalyzed pyrrolidine carboxylic acid formation from glutamine during solid phase peptide synthesis. Int. J. Pept. Protein Res. •9:88, 1982 98. Stehle, P., Ratz, I., Furst, P.: In vivo utilization of intravenously supplied L-alanine-L-glutamine in various tissues of the rat. Nutrition 5:411, 1989 99. Adibi, S.A.: Experimental basis for use of peptides as substrate for parenteral nutrition: A review. Metabolism 36:1001, 1987 100. Furst, P., Albers, S., Stehle, P.: Glutamine-containingdipeptides in parenteral nutrition. J.P,E.N.J. Parenter. Enteral. Nutr. 14; 118s, 1990 101. Stehle, P., Ratz, I., Furst, P.: In vivo utilization of intravenously supplied L-alanine-L-glutamine in various tissues of the rat. Nutrition 5:411, 1989 102. Adibi, S.A.: Experimental basis of for use of peptides as substrate for parenteral nutrition: A review. Metabolism 36:1001, 1987 103. Hammarqvist, F., Wernerman, J., All, R., Von Der Decken, A., Vinnars, E.: Addition of glutamine to total parenterat nutrition after elective abdominal surgery spares free glutamine in muscle, counteracts the fall in muscle protein synthesis, and improves nitrogen balance. Ann. Surg. 209:455, 1989 104. Stehle, P., Zander, J., Mertes, N., Albers, S., Puchstein, C., Lawin, P., Furst, P.: Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet 1:231, 1989 105. Ziegler, T.R., Benfell, K., Smith, R.J., Young, L.S., Brown, E., Ferrari-Baliviera, E., Lowe, D,K., Wilmore, D.W.: Safety and metabolic effects of L-glutamine administration in humans. J.P.E.N.J. Parenter. Enteral. Nutr. 14:137s, 1990 106. Grant, J.P., Snyder, P.J.: Use of L-glutamine in total parenteral nutrition. J. Surg. Res. 44:506, 1988 107. Souba, W.W., Klimberg, V,S., Hautamaki, R.D., Mendenhall, W.H., Bova, F.C,, Howard, R.J., Bland, K.I., Copeland, E.M.: Oral glutamine reduces bacterial translocation following abdominal radiation. J. Surg. Res. 48:1, 1990 108. Souba, W.W., Klimberg, V.S., Plumley, D.A., Salloum, R.M., Flynn, T.C., Bland, K.I., Copeland, E.M.: The role of glutamine in maintaining gut structure and function and supporting the metabolic response to injury and infection. J. Surg. Res. 48:383, 1990 109. Seifter, E., Rettura, G., Barbul, A., Levenson, S.M.: Arginine: An essential amino acid for injured rats. Surgery 84:224, 1978 110. Barbul, A,: Arginine: Biochemistry, physiology and therapeutic implications. J.P.E.N.J. Parenter. Enterat. Nutr. •0:227, 1986 111. Saito, H., Trocki, O., Wang, S.L., Gonce, S.J., Joffe, S.N., Alexander, J.W.: Metabolic and immune effects of dietary arginine supplementation after burn. Arch. Surg. 122:784, 1987 112. Alexander, J.W., Gottschlich, M.M.: Nutritional immunomodulation in burn patients. Crit. Care Med. 18:S149, I990 113. Daly, J.M., Reynolds, J., Thorn, A., Kinsley, L., DietrickGallagher, M.: Metabolic effects of arginine in the surgical patients. Ann. Surg. 208:512, 1988 114. Barbul, A., Wasserkrug, H.L., Penberthy, L.T., Norman, N.Y., Tap, R.C., Efron, G.: Optimal levels of arginine in maintenance intravenous hyperalimentation. J.P.E.N.J. Parenter. Enteral. Nutr. 8:281, 1984


115. Barbul, A.: Arginine: Biochemistry, physiology and therapeutic implications. J.P.E.N. J, Parenter. Enteral. Nutr. •0:227, 1986 116. Barbul, A., Lazarou, S.A., Efron, D.T., Wasserkrug, H.L., Effron, G.: Arginine enhances wound healing and lymphocyte immune responses in humans. Surgery 108:331, 1990 117. Hibbs, J.B., Taintor, R.R., Vavrin, Z.: Macrophage cytotoxicity: Role for L-arginine deaminase and imino nitrogen oxidation to nitrite. Science 235:473, 1987 118. Granger, D.L., Hibbs, J.B., Jr., Perfect, J.R., Durack, D.T.: Specific amino acid (L-arginine) requirement for the microbiostatic activity of murine macrophages. J. Clin. Invest. 81:1129, 1988 119. Granger, D.L., Hibbs, J.B., Jr., Perfect, J.R., Durack, D.T.: Metabolic fats of L-arginine in relation to microstatic capability of murine macrophages. J. Clin. Invest. 85:264, 1990 120. Randomski, M.W., Palmer, R.M.J., Moncada, S.: An L-arginine/ nitric oxide pathway present in human platelets regulates aggregation. Proc. Natl. Acad. Sci. 87:5193, 1990 121. Leaf, C.D., Wishnock, J.S., Tennenbaum, S.R.: L-arginine is a precursor for nitrate biosynthesis in humans. Biochem. Biophys. Res. Commun. 163:1032, 1989 122. Albina, .I.E., Mills, C.D., Barbul, A., Thirkill, C.E., Henry, W.L., Jr., Mastrofrancesco, B., Caldwell, M.D.: Arginine metabolism in wounds, Am. J. Physiol. 254:E459, 1988 123. Albina, J.E., Mills, C.D., Henry, W.L., Jr., Caldwell, M.D.: Temporal expression of different pathways of L-arginine metabolism in healing wounds. J. Immunol. 144:3877, 1990 124. Barbul, A., Rettura, G., Prior, E., Levenson, S.M., Seifter, E.: Supplemental arginine, wound healing and thymus: Argininepituitary interactions. Surg. Forum 29:93, 1978 125. Barbul, A., Lazarou, S.A., Efron, D.T,, Wasserkrug, H.L., Efron, G.: Arginine enhances wound healing and lymphocyte immune response in humans. Surgery 108:331, 1990 126. Manson, J.M., Wilmore, D.W.: Positive nitrogen balance with human growth hormone and hypocaloric intravenous feeding. Surgery 100:188, 1986 127. Windmueller, H.G., Spaeth, A.E.: Respiratory fuel and nitrogen metabolism in vivo in small intestine of fed rats. J. Biol. Chem. 255:107, 1980 128. Windmueller, H.G., Spaeth, A.E.: Intestinal metabolism of glutamine and glutamate from the lumen as compared to glutamine from blood. Arch. Biophys. Biochem. 171:662, 1975 129. Wilmore, D.W., Smith, R.J., O'Dwyer, S.T., Jacobs, D.O., Ziegler, T.R,, Wang, X.D.: The gut: A central organ after surgical stress. Surgery 104:917, 1988 130. Muhlbacher, F., Kapadia, C.R., Colpoys, M.F., Smith, R.J., Wilmore, D.W.: Effects of glucocorticoids on glutamine metabolism in skeletal muscle. Am. J. Physiol. 247:E75, 1984 131. Brooks, D., Bessey, P.Q., Black, P.R., Aoki, T.T., Wilmore, D,W.: Insulin stimulated branched-chain amino acid uptake diminishes nitrogen efflux from skeletal muscle of injured patients. J. Surg. Res. 40:395, 1986 132. Souba, W.W., Herskowitz, K., Salloum, R.M., Chen, M.K., Austgen, T.R.: Gut glutamine metabolism, J.P.E.N.J. Parenter. Enteral. Nutr. 14:45s, 1990 133. Barry, G.: Structure, biochemistry, and assembly of epithelial tight junctions. Am. J. Physiol. 253:c749, 1987 134. Madara, J.L.: Loosening tight junctions: Lessons from the intestine. J. Clin. Invest. 83:1089, 1989 135. Dobbins, W.O., 3rd.: Gut immunophysiology: A gastroenterologist's view with emphasis on pathophysiology. Am. J. Physiol. 242:G1, 1982 136. Wells, C.L., Maddaus, M.A., Simons, R.L.: Proposed mechanisms for the translocation of intestinal bacteria. Rev. Infect. Dis. 10:958, 1988 137. Deitch, E.A.: The management of burns. N. Eng|. J. Med. 323:1249, 1990 138. Levine, G.M., Deren, J.J., Steiger, E.: Role of oral intake in maintenance of gut mass and disaccharidase activity. Gastroenterology 67:975, 1974 139. Dworkin, L.D., Levine, G.M., Farber, N.J.: Small intestinal mass of the rat is partially determined by indirect effects of intraluminal nutrition. Gastroenterology 7•:626, 1976


140. Johnson, L.R., Copeland, E.M., Dudrick, J.J.: Structural and hormonal alterations in the gastrointestinal tract of parenterally fed rats. Gastroenterology 68: t 17, 1975 141. Alverdy, J.A., Chi, H.S., Sheldon, G.S.: The effect of parenteral nutrition on gastrointestinal immunity: The importance of intestinal stimulation. Ann. Surg. 202:681, 1985 142. Moore, F.A., Moore, E.E., Jones, T.N., McCroskey, B.L., Peterson, V.M.: TEN vs TPN following major abdominal trauma: Reduced septic morbidity. J. Trauma 29:916, 1989 143. Border, J.R., Massett, J,, LaDuca, J., Seibel, R., Steinberg, S., Mills, B., Lost, P., Border, D.: The gut origin septic states in blunt multiple trauma (ISS-40) in the ICU. Ann. Surg. 206:427, 1987 144. Wilmore, D.W.: Nutrition and metabolism following thermal injury. Clin. Plast. Surg. •:603, 1979 145. Bessey, P.Q., Watters, J.M., Aoki, T.T., Wilmore, D.W.: Combined hormonal infusion stimulates the metabolic response to injury. Ann. Surg. 200:264, 1984 146. Shamoon, H.M., Hendler, R., Sherwin, R.S.: Synergistic interactions among anti-insulin hormones in the pathogenesis of stress hyperglycemia in humans. J. Clin. Endocrinol. Metab. 52:1235, 1985 147. Watters, J.M., Bessey, P.Q., Dinarello, C.A,, Wolff, S.M., Wilmore, D.W.: Both inflammatory and endocrine mediators stimulate host responses to sepsis. Arch. Surg. 12l:179, 1986 148. Kupper, T.S., Deitch, E. A., Baker, C.C., Wong, W.: The human burn wound as a primary source of interleukin-1 activity. Surgery 100:409, 1986 149. Sauder, D.N., Monick, M.M., Hunninghake, G.W.: Epidermal cell derived thymocyte activating factor (ETAF) is a potent T cell chemoattractant. J. Invest. Dermatol. 85:431, 1985 150. Heideman, M.: Complement activation by thermal injury and its possible consequences for immune defense. In The Immune Consequences of Thermal Injury, J.L. Ninneman, editor, Baltimore, Williams and Wilkins, 1981, pp. 127-131 151. Okusawa, S., Dinarello, C.A., Yancey, K.B., Endres, S., Lawley, J-J., Frank, M.M., Burke, J.F., Gelfand, J.A.: C5a induction of human interleukin-l. J. Immunol. 139:2635, 1985 152. Marano, M.A., Fong, Y., Moldawer, L.L., Tracey, K.J., Lowry, S.F., Beutler, B., Shires, T.S.: Serum cachectin/TNF in critically ill burn patients correlates with infection and mortality. Surg. Gynecol. Obstet. 170:32, 1990 153. Guo, J., Dickerson, C., Chrest, F.J., Adler, W.H., Munster, A.M., Winchurch, R.A.: Increased levels of circulating interleukin.6 in burn patients. Clin. lmmunol. Immunopathol. 54:361, 1990 154. Tredget, E.E., Yu, Y,M., Zhong, S., Burini, R., Okusawa, S., Gelfand, J.A., Dinarello, C.A., Young, V.R., Burke, J.F.: Role of Interleukin I and tumor necrosis factor on energy metabolism in rabbits. Am. J. Physiol. 255:E760, 1988 155. Feingold, K.R., Grunfeld, C.: Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo. J. Clin. Invest. 80:184, t987 156. Perlmutter, D.H., Dinarello, C.A., Punsal, P.K., Colten, H.R.: Cachectin tumor necrosis factor regulates hepatic acute phase gene expression. J. Clin. Invest. 78:1349, 1986 157. Warren, R.S., Starnes, H.F., Gabrilove, J.L.: The acute metabolic effects of tumor necrosis factor administration. Arch. Surg. 122:1396, 1987 158. Dinarello, C.A., Mier, J.W.: Current concepts: Lymphokines. N. Engl. J. Med. 317:940, 1987 159. Tracey, K.J., Lowry, S.F., Fahey, T.J., Ill, Albert, J.D., Fong, Y., Hesse, D., Beutler, B., Manogue, K.R., Calvano, S., Wet, H., Cerami, A., Shires, G.R.: Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg. Gynecol. Obstet. 164:415, 1987

79

160. Uehara, A., Gottschall, P.E., Dahl, R.R., Arimura, A.: Interleukin-I stimulates ACTH release by an indirect action which requires endogenous corticotropin releasing factor. Endocrinology 121:1580, 1987 161. Sandier, S., Bentzen, K., Borg, L.A.H.: Studies on the mechanisms causing inhibition of insulin secretion in rat pancreatic islets exposed to human interleukin-I beta indicate a perturbation in the mitochondrial function. Endocrinology 124:i492, 1989 162. Woloski, M.M.R.N.J., Smith, E.M., Meyer, W.J., 111, Fuller, G.M., Blalock, J.E.: Corticotropin-releasing activity of monokines. Science 230:1035, 1985 163. Bernton, E.W., Beach, J.E., Holady, J.W., Smallridge, R.C., Fein, H.G.: Release of multiple hormones by a direct action of interleukin-1 on pituitary cells. Science 238:521, 1987 164. Baracos, V., Rodemann, P., Dinarello, C.A., Goldberg, A.L.: Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-I). N. Engl. J. Med. 303:553, 1983 165. Libby, P., Ordovas, J.M., Auger, K.R., Robbins, A.H., Birinyi, L.K., Dinarello, C.A.: Endotoxin and tumor necrosis factor induce interleukin-I gene expression in adult human vascular endothelial cells. Am. J. Pathol. 124:179, 1986 166. Dayer, J.M., DeRochemonteix, B., Burrus, B.: Human recombinant interleukin-1 stimulates collagenase and prostaglandin E 2 production by human synovial cells. J. Clin. Invest. 77:645, 1986 167. Lee, M.D., Zentella, A., Pekala, P.H., Cerami, A.: Effect of endotoxin-induced monokines on glucose metabolism in the muscle cell line L6. Biochemistry 84:2590, 1987 168. Vary, T.C., Siegel, J.H., Nakatani, T., Sato, T., Aoyama, H.: Effect of sepsis on activity of pyruvate dehydrogeanse complex in skeletal muscle and liver. Am. J. Physiol. 250:E634, 1986 169. Sayeed, M.M.: Ion transport in circulatory and/or septic shock. Am. J. Physiol. 252:R809, 1987 170. Spitzer, J.A., Deaciuc, I.V.: IP3-independent Ca2+ release in permeabilized hepatocytes of endotoxemic and septic rats. Am. J. Physiol. 16:E130, 1987 171. Dinaretlo, C.A., Savage, N.: Interleukin-I and its receptor. Crit. Rev. immun. 9:1, 1989 172. Kunkel, S.L., Remick, D.G., Stricter, R.M., Larrick, J.W.: Mechanisms that regulate the production and effects of tumor necrosis factor-alpha. Crit. Rev. Immunol. 9:93, 1989 173. Granger, D.L., Lehninger, A.L.: Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells. J. Celt. Biol. 95:527, 1982 174. Kilbourn, R.G., Klostergaard, J., Lopez-Berestein, G.: Activated macrophages secrete a soluble factor that inhibits mitochondrial respiration of tumor ceils. J. Immunol. 133:2577, 1984 175. Rosenstreitch, D.L., Yost, S.L., Brown, K.M.: Human urinederived inhibitors of interleukin-1. Rev. Infect. Dis. 9(suppl 5): 594, 1987 176. Jiang, J., He, G., Zhang, S., Wang, X., Yang, N., Zhu, Y., Wilmore, D.W.: Low-dose growth hormone and hypocaloric nutrition attenuate the protein-catabolic response after major operation. Ann. Surg. 210:513, 1989 177. Tracey, K.J., Yuman, F., Hesse, D.G,: Anti-cachetin/TNFmonoclonal antibodies prevent septic shock during lethal bacteremia. Nature 33:662, 1987 178. Strock, L.L., Singh, H., Abdullah, A., Miller, J.A., Herndon, D.N.: The effect of insulin-like growth factor I on postburn hypermetabolism. Surgery 108:161, 1990 179. Herndon, D.N., Barrow, R.E., Kunkel, K.R., Broemeling, L., Rutan, R.L.: Effects of recombinant human growth hormone on donor-site healing in severely burned children. Ann. Surg. 212: 424, 1990

Metabolic changes following thermal injury.

Metabolic profiles of thermal trauma.

The immunologic response to thermal injury.

Neurohumoral responses to thermal injury.

Thermal injury in TAPIA breast reconstruction-thermal injury to thoracodorsal artery perforator flap.

The role of mediators in the response to thermal injury.

Hypertonic saline dextran resuscitation of thermal injury.

Evaluation of erythropoietin levels in the anemia of thermal injury.

Propolis modulates fibronectin expression in the matrix of thermal injury.

The effect of thermal injury on plasma carnitine in rats.

Thermal injury patterns associated with electronic cigarettes.

Posterior interosseous nerve syndrome from thermal injury.

Acute gastric disease after cutaneous thermal injury.

Thermal effects of hooding incubators.

Tracheobronchial polyps following thermal inhalation injury.

Heparin cofactor activity following thermal injury.

Myocardial depression in acute thermal injury.

Does the thermal plasticity of metabolic enzymes underlie thermal compensation of locomotor performance in the eastern newt (Notophthalmus viridescens)?

Muscle blood flow following thermal injury.

Alterations in hypothalamic function following thermal injury.

Alterations in intestinal permeability after thermal injury.

Rhabdomyolysis, compartment syndrome and thermal injury.

Acute liver disease after cutaneous thermal injury.

Thermal injury to the sigmoideum following hysteroscopic hydrothermal ablation.