World J. Surg. 16, 80--86, 1992
World Journal of Surgery © 1992 by the Soci~.t6 lnternational¢ de Chirurgie
Nutritional Support of the Burned Patient J. Paul W a y m a c k , M.D., Sc.D. and David N. Herndon, M.D. Shriners Burns Institute, Galveston Unit, and the Department of Surgery, University of Texas Medical Branch, Galveston, Texas, U.S.A. Burn patients develop a number of physiologic alterations among which is a markedly increased metabolic rate. Other metabolic changes include an increased rate of glucose production and utilization, a decreased rate of lipid metabolism, and an increased rate of both protein catabolism and anabolism. These alterations can effect other physiologic parameters, including immune function. They necessitate administration of large quantities of calories and protein to achieve positive nitrogen balance. The physiologic derangements leading to the hypermetabolism and the methotls for supplying the nutritional needs are discussed in this review.
It has been over a half century since Cuthbertson [I] demonstrated that traumatic injuries result in a prolonged period of negative nitrogen balance. In addition, the greater the extent of the injury, the more severe are the resulting metabolic alterations. These changes become maximal in major thermal injury patients. Patients suffering severe burn injuries initially experience an ebb phase where there is a decrease in their metabolic rate and cardiac output [2]. Following successful fluid resusitation, the cardiac output rapidly returns to normal and then achieves supranormal levels. Coincident with this, there is a marked increase in resting metabolic energy expenditure (RME) [3]. The degree of increase in metabolic rate appears to be directly proportional to the extent of burn injury. With more extensive burn injuries, the metabolic rate has been reported to approach 200% of normal [4J. Etiology of Hypermetabolism
Experimental studies by Aulick and coworkers [5] suggest that one of the major inciting events triggering the hypermetabolic response is contamination of the burn wound with bacteria. They have noted in multiple burned rat models that if the burn wounds are contaminated with Pseudomonas aeruginosa at the time of burn injury, the rats become hypermetabolic more rapidly than rats with uncontaminated burn wounds. They further noted that the degree of increase in the metabolic rate was directly proportional to the number of bacteria present in the burn wound [6]. Finally, they found that the use of topical antimicrobial agents, which delayed the onset of burn wound Reprint requests: J. Paul Waymack, M.D., Shriners Burns Institute, 610 Texas Avenue, Galveston, Texas 77550, U.S.A.
bacterial colonization and infection, also delayed the onset of the postburn hypermetabolic response. An alternative explanation for the postburn hypermetabolic response comes from Alexander and colleagues [7]. They have reported that the use of a continuous infusion of enteral tube feedings, beginning immediately following burn injury, prevented the postburn hypermetabolic response. This effect was not present if the initiation of tube feedings was delayed until 3 days following thermal injury. Those guinea pigs which were begun on immediate postburn enteral nutritional support, and thus did not become hypermetabolic, were also noted to avoid the gut mucosal atrophy seen in the animals which did not receive immediate enteral nutrition. Further, the animals receiving the immediate postburn enteral nutrition failed to develop the elevations of serum glucagon, cortisol, and catecholamines seen in the animals not receiving the immediate postburn enteral nutrition [8]. These findings were interpreted to indicate that the severe burn injury results in atrophy of the mucosa of the gastrointestinal tract, which may allow gut translocation of bacteria and endotoxin into the portal circulation. Such translocation has been demonstrated by Dietch and associates [9] in burned animal models. It has further been demonstrated that direct infusion of endotoxin into the portal vein of unburned healthy guinea pigs resulted in a hypermetabolic response similar to that seen in burned guinea pigs [10]. Thus the early enteral feedings may prevent postburn hypermetabolism by preventing portal vein endotoxemia. Confirmation of such an effect in clinical studies has not yet been obtained. During the initial week following burn injury, both core temperature and skin temperatures are markedly elevated [t 1]. As a result of this resetting of internal temperatures, burn patients prefer an ambient temperature which is significantly elevated compared to that which normal volunteers find comfortable. These findings have led some investigators to speculate that the hypermetabolic response seen in burn patients is a result of the requirement for an increased metabolic rate to maintain the desired body temperature in the face of excessive heat loss through the burned tissue. More recent studies have demonstrated that this is not the case. Burn patients placed in an environment where the temperature is set to their comfort zone continue to be hypermetabolic and to have an increased rate of oxygen consumption. This has led to the burn patient
J-P. Waymack and D.N. Herndon: Nutritional Support in Burns
being described as "internally warm, not just externally cold" [i2]. The hypermetabolic and hyperthermic responses seen following burn injury appear to be mediated, at least in part, by alterations in the metabolic set points of the hypothalamus [I 3]. The importance of the hypothalamus in regulating metabolic function has long been recognized. Hume and Egdahl [14] demonstrated that surgical denervation of an animal's limb prevented the normal adrenocortical response to mechanical trauma to that limb, Further support for this concept comes from Newsome and Rose [15] who found that the serum levels of both growth hormone and andrenocorticotropic hormone become elevated during the initial hour following inguinal herniorraphy in patients who received general but not spinal anesthesia. Several studies from Wilmore and coworkers [11] indicate that the reset hypothalamus triggers the increased metabolic rate by elevating the plasma levels of three hormones: catecholamines, g/ucagon, and cortisol. Evidence for this includes their ability to decrease the metabolic rate in burn patients through the use of alpha a n d beta adrenergic blocking agents. In addition, they were able to generate a hypermetabolic response tn normal volunteers, which mimicked that seen in burn patients, by a combined infusion of epinephrine, glucagon, and eortisol [16]. Carbohydrate Metabolism
bespite the fact that burn patients normally have elevated blood glucose levels, their insulin levels are not depressed but rather are elevated compared to nonburned controls [17]. Their hyperglycemia is due to the fact that the serum glucagon levels are elevated to a disproportionately greater degree than are the serum insulin levels. This concept is supported by a study of Jahoor and colleagues [18] in which they administered somatoStatin to severely burned patients. The somatostatin decreased the levels of both glucagon and insulin. This resulted in inCreased serum glucose concentrations because of decreased glucose uptake by peripheral tissues. When the somatostatin infusion was supplemented by a sufficient insulin infusion to achieve insulin levels equal to that seen in the burn patients prior to the somatostatin infusion, the patients developed Severe hypoglycemia, which necessitated a large glucose infusion to correct. Thus the elevated serum glucose concentrations reflect an increased rate of glucose synthesis (gluconeogenesis), not a decreased rate of glucose utilization, and the elevated glucagon levels seen following burn injury are critical for maintaining an adequate rate of glucose production to meet the !aatient's energy requirements. The combined elevation of both catabolic and anabolic hormones results in a number of other alterations in carbohydrate metabolism in burn patients. One of these is an increased rate of generation of glucose precursors. Aulick and Wilmore [19] demonstrated an increased rate of release of amino acids by Peripheral muscle tissue in burned patients. These amino acids are then extracted by the liver and utilized for gluconeogenesis. The accelerated rate of gluconeogenesis using amino acids as SUbstrate is partially responsible for the net decrease in the Serum levels of most amino acids in burn patients [20]. Of all the amino acids, only phenylalanine has been reported to be
81
elevated in burned and septic burn patients and this is felt to be due to a disproportionate rate of release by muscle tissue [20, 21]. Similar increases in the serum concentration of phenylalanine are seen in nonburn patients who are excessively catabolic due to an ongoing septic process [22]. Although the unburned extremities of burn patients utilize primarily lipids and minimal amounts of glucose as an energy source, the burned extremities in these patients metabolize a large amount of glucose to lactate and pyruvate [23]. This is consistant with the demonstration that the inflamatory cells in burn wounds (leukocytes and fibroblasts) primarily metabolize glucose in an anaerobic fashion for energy generation, whereas muscle tissue utilizes iipids [24]. It was further noted that the muscle tissue of the burned extremity primarily utilized fat as an energy source, as was true in the contralateral unburned extremity. Burn patients have a significant rate of hepatic uptake of lactate and pyruvate, which has been generated from anaerobic metabolism of glucose peripherally. The liver then synthesizes glucose from these substrates. This glucose is then reutilized as an energy source by the leukocytes and fibroblasts which are present in the burn wound [23]. This glucose-lactateglucose metabolic sequence is termed the Cori cycle. Further evidence for the importance of the Cori cycle in burn patients is provided by the demonstration that the rate of gluconeogenesis in burn patients is significantly elevated compared to that seen in nonburn patients and that the administration of glucose at a rate known to reduce hepatic gluconeogenesis in normal volunteers had only a minimal effect on the rate of gluconeogenesis in burned patients. Thus, burn patients have an accelerated Cori cycle in which glucose is synthesized by the liver a n d metabolized through anaerobic metabolism by the various cells present in the burn wound. The anaerobic metabolites of glucose (lactate and pyruvate) are then returned to the liver along with gluconeogenic amino acids released from muscle tissue for the synthesis of additional glucose. It is readily apparent that glucose is an important energy source in burn patients and that they require large amounts of glucose to avoid excessive protein catabolism. Unfortunately there are limits to the amount of glucose burn patients can handle. Studies by Wolfe and associates [2] have demonstrated that burn patients begin to develop difficulties in metabolizing glucose when the rate of infusion exceeds 4 mg/kg/min. This necessitates that lipid and protein be utilized to meet the remaining metabolic requirements of burn patients. Lipid Metabofism
Several aspects of lipid metabolism are significantly altered in burned patients. These alterations again appear to be due to the changes in serum concentrations of epinephrine, glucagon, cortisol, and insulin. Burn patients have been found to have a significantly increased rate of lipolysis compared to normal volunteers [25]. This increased rate of lipolysis can be partially blocked by the use of pharmacologic adrenergic blockade. It also has been shown that infusion of epinephrine can further accelerate the lipolytic response, except in those patients who have had most of their fat stores removed by prior deep tangential or fascial excisions of their burn wounds. This increased lipolytic response results in elevated serum levels of free fatty acids and glycerol [26]. While there is an increased
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serum concentration of free fatty acids, there is a decreased concentration of fatty acids bound to albumin. This is due to the decreased serum albumin levels seen in burned patients [26]. This finding may have some clinical significance since one of the major transport systems lbr non-esterified fatty acids into cells is by binding to serum albumin [27]. Another alteration of fat metabolism in burned patients is a decreased rate of ketone production (ketogenesis). Abbott and coworkers [28] found that severely burned patients who were fasted synthesized only half the amount of ketone bodies that nonburned fasted patients were able to synthesize. Since ketone bodies are one of the primary energy sources utilized to decrease protein catabolism, this would indicate that burn patients may require increased amounts of carbohydrate and protein in their diet in order to prevent protein catabolism and achieve positive nitrogen balance. The impaired ketogenesis may be the result of the elevated insulin levels seen in burn patients. Nonburned patients who are fasted have very low serum levels of insulin which thereby allows ketogenesis to occur. In contrast, burn patients have markedly elevated levels of insulin which is known to inhibit ketogenesis. The metabolism of fatty acids by the cyclooxygenase enzyme system is significantly increased in burn patients. This results in an increased rate of production of the physiologically active prostaglandins. These fatty acid metabolites include the reportedly immunosuppressive prostaglandin E (PGE), the vasoconstrictive thromboxanes, and the vasodilatory prostacyclin. Burn patients have been shown to have elevated blood and tissue concentrations of both thromboxane and PGE. Since these metabolites may result in immunosuppression and vasoconstriction and since burn patients are immunosuppressed and have decreased perfusion of the burn wound, it has been suggested that prevention of synthesis of these metabolites by dietary manipulations or pharmacologic agents might be beneficial to such patients [29, 30]. One method suggested to achieve this goal is through the use of Omega-3 fatty acids. The Omega-3 fatty acids, which are primarily obtained from fish oil, are metabolized by the cyclooxygenase enzyme system to yield PGE-3. The more common dietary fatty acids are of the Omega-6 group and are metabolized to yield PGE-I and PGE-2. PGE-1 and PGE-2 have been reported to have significant immunosuppressive properties while PGE-3 has been reported to be immunologically inert. It has therefore been hypothesized that by replacing the Omega-6 fatty acids obtained from standard vegetable and animal oils with the Omega-3 fatty acids, the postburn immunosuppression might be avoided or reversed. This has been reported to be the case in a burned guinea pig model [31]. However, PGE is an important down regulator of tumor necrosis factor production in response to endotoxin exposure [32]. Since severely elevated tumor necrosis factor levels can be lethal, failure to down regulate the rate of production of tumor necrosis factor could result in a significant mortality [33]. This possibility has been suggested by a study in which mice, administered a diet high in Omega-3 fatty acids and then infected, had a greater mortality rate than those fed a more standard diet containing Omega-6 fatty acids [34]. The ideal composition of fat in the diet of burn patients is thus not yet determined.
World J, Surg. Vol. 16, No, I. Jan./Feb. 1992 Protein Metabolism
Protein metabolism is also altered by severe burn injuries. The hormonal milieu which results from burn injury causes a significant increase in muscle protein catabolism [35, 36]. Aulick and Wilmore [19] measured amino acid concentrations in femoral arterial and venous blood samples obtained from burn patients. They demonstrated that there is a net release of amino acids from the extremities of burn patients. Kien and associates [37] showed that not only is there an increased rate of protein catabolism in burn patients, but there is also a significant increase in the rate of protein anabolism, Thus, the rate of protein breakdown into component amino acids and the subsequent reincorporation of these amino acids into other proteins is significantly elevated in burn patients. This protein synthesis, as well as the accelerated rate of hepatic gluconeogenesis utilizing amino acids as substrates, explains the fact previously mentioned in this review, that burn patients have decreased serum amino acid levels. The increased amino acid and protein recycling is obviously important in burn patients to allow for synthesis of collagen for wound healing, plus white blood cells and antibodies for resisting infections. It is therefore essential that negative nitrogen balance be avoided. McDougal and colleagues f38] demonstrated that intravenous infusion of increasing amounts of glucose or amino acids improved nitrogen balance in burn patients. Fat emulsions were also able to enhance nitrogen balance, but not to the same degree as an isocaloric amount of glucose or amino acid solution. They also noted that bacteremia further increased the amount of nitrogen or glucose required to achieve positive nitrogen balance. The ideal amount of protein which should be in the diet of burn patients has not yet been determined. Wolfe and coworkers [39] reported that increasing protein intake in burn patients from 1.4 g of protein/kg/day to 2.2 g protein/kg/day did not alter nitrogen balance. This finding may have been the result of the fact that the patients in this study were able to receive a very high non-nitrogenous caloric intake. This may have altered the protein kihetics in comparison to burn patients who failed to receive this quantity of carbohydrate and fat. Other investigators have found that successful administration of such caloric requirements in burn patients can be difficult. This is emphasized by a study of Alexander and colleagues [40] who demonstrated that increasing the percentage of protein in the diet of burn patients resulted in a number of immunologic benefits. They compared patients receiving 16.5% of their calories as protein to those receiving 23% of their calories as protein. Neither of the two groups were a~ble to successfully achieve the desired caloric intake. Nonetheless the group receiving the higher protein content was found to have significantly higher serum levels of IgG, transferrin, and complement factor 3. More importantly, they experienced fewer bacteremic days and had a significantly lower mortality rate. Caloric Requirements
One of the most important considerations when ordering nutritional support for the burn patient is the decision regarding the amount of calories the patient needs to receive each day. As has been mentioned, the metabolic rate of burn patients increases
J.P. Waymack and D,N. Herndon: Nutritional Support in Burns
proportionally with increasing burn size. This correlation holds true until the burn size exceeds approximately 50% to 60% of the total body surface area at which time there are minimal further changes [3]. There have been a number of formulas proposed for calculating the caloric requirements of burn patients. The most Widely used of these is the Curreri formula [41]. This formula calculates the daily caloric requirement in kilocalories to be equal to 25 times the body weight in kilograms plus 40 times the percentage of the total body surface area burned. This formula obviously tends to overestimate caloric requirements in small children with large burns. Molnar and coworkers [42] proposed that the initial calculation should be based on the Harris Benedict equation, multiplied by a factor of two [43]. A major Weakness with this formula is its lack of emphasis on burn size. The Galveston formula attempts to adjust for these deficiencies by utilizing absolute burn sizes. This formula estimates the caloric requirements of burned children to be equal to 1800 kcal/m 2 + 2200 kcal/m 2 of burn [44]. As is true for burn resuscitation formulas, it is important that each of these formulas should be recognized as merely rough estimates. Turner and colleagues [45] demonstrated, using indirect calorimetry, that the Curreri formula on average overestimated mean metabolic energy expenditure by 58% and the Harris Benedict underestimated it by 23%. Rutan and associates [46] found in patients with burns >45% of their total body surface area, resting energy expenditures exceeded predicted basal metabolic rates by approximately 50%. It is therefore recommended that severely burned patients have their resting metabolic energy expenditures (RME) measured at least once a Week and preferentially twice weekly using indirect calorimetry. This can readily be done at the bedside with portable COmputerized metabolic cai'ts which measure 02 uptake and CO2 production. Once the resting energy expenditure has been determined it is necessary to convert this to the total metabolic energy expenditure (TME). This compensates for the fact that the burn patient is frequently active and has a greater energy expenditure during the periods of activity. The factor necessary for converting RME to TME has been measured using both Stable isotope studies and caloric intake versus weight gain studies. The results of the stable isotope studies indicate that in burn patients the TME is equal to the RME multiplied by 1.2 [47]. In contrast, studies which compared caloric intake to Weight change indicate that caloric intake must be equal to RME multiplied by anywhere from 1.3 to 1.7 in order to prevent Weight loss [48, 49]. This discrepancy may be the result of burn l~atients converting muscle tissue which has fewer calories per Unit of weight, to fat which has more calories per unit of weight. Several investigators have attempted to decrease the metabolic rate, and thereby the nutritional requirements, of burn Patients by performing early excision of the burn wound. COmplete excision of the burn wound in animal models has been demonstrated to abolish the hypermetabolic response [50]. t'Iowever, less than total excision of the burn wound failed to decrease the hypermetabolic response in a burned sheep model [51]. Hildreth and colleagues [52] were unable to find any S~gnificant effect of early excision compared to delayed excision on metabolic rates of burn patients. This may have been due to the fact that they were not able to totally excise the entire burn wound, plus the fact that a significant donor site wound was
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created at the time of burn wound excision. It therefore appears that the caloric requirements of burn patients are not altered by surgical intervention. One possible future avenue for simplifying metabolic support of burn patients may be through the use of recombinant DNA technology products. One such product, recombinant insulinlike growth factor I, has been demonstrated to blunt the postburn hypermetabolic response [53]. It should be mentioned that whether or not pharmacologic blunting of the hypermetabolic response will have a beneficial effect on burn patient survival remains an area of controversy [54]. Administration of recombinant human growth hormone to burn patients has been demonstrated to improve their nitrogen balance [55]. The resulting increased protein anabolism has also been shown to decrease significantly the time required for donor site healing [56]. Enteral versus Parenteral Nutrition
There are two methods by which nutrition can be supplied to the burn patient. These are parenterally through a central venous catheter and enterally by mouth or through a feeding tube. The use of central venous catheters in burned patients entails a number of risks [57]. These complications include a significant incidence of sepsis and a lesser risk of thrombosis. Additionally, it has been shown that the use of total parenteral nutrition (TPN), in lieu of enteral nutrition, results in an atrophy of the intestinal mucosa and an increased plasma concentration of hormones associated with inflammatory responses [58]. It has also been demonstrated that TPN results in elevations of serum insulin levels to a greater degree than that seen with enteral nutrition. This elevation decreases fat mobilization (lipolysis) and thereby reduces the concentration of free fatty acids in the blood to miniscule levels [59]. As was mentioned earlier in this paper, such elevations in insulin levels also decrease the rate of ketone body synthesis. Such reductions necessitate that the body utilize more protein for energy generation and can thereby increase protein catabolism and impair positive nitrogen balance. TPN is also associated with the development of fatty liver changes due to the inability of patients on TPN to generate a lipolytic response because of the elevated insulin levels. Another complication of TPN is its ability to alter endotoxin tumor necrosis factor metabolism. Fong and colleagues [60] have reported that administration of TPN to normal healthy volunteers increases their production of tumor necrosis factor in response to endotoxin exposure. This hyperactive response could be interpreted as being deleterious to patients since elevated tumor necrosis factor levels are considered to be one of the contributing factor in death from endotoxin shock [61]. Herndon and coworkers [62] have compared TPN to enteral nutrition in a randomized series of burn patients. They noted a significantly lower helper/suppressor T lymphocyte ratio in the TPN group. In a later, larger series they found a higher mortality rate in the TPN group compared to the enterally fed group [63]. These findings emphasize the fact that TPN should rarely be utilized in burn patients. It has long been recognized that major burn injuries result in alterations in gastrointestinal function in the immediate postburn period. This postburn ileus was initially thought to con-
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traindicate the use of enteral feedings for the first several days following burn injury. More recent studies have indicated that the ileus is confined to the stomach and colon and that the small intestine continues to function normally [64]. As such, immediate postburn enteral nutrition is possible through the use of feeding tubes placed through the nose past the stomach into the small bowel. McArdle and associates [65] demonstrated this to be a safe and efficacious way to begin achieving positive nitrogen balance immediately following burn injury. This technique also allows for continuing the enteral feedings in patients who later develop gastric ileus due to sepsis. Larkin and Moylan [66] have shown that enteral feedings can provide complete nutritional support and achieve positive nitrogen balance in burn patients without the use of parenteral nutrition. As such, the use of parenteral nutrition in burn patients rarely if ever should become necessary. One of the more common complications of enteral tube feedings in burn patients is a significant incidence of diarrhea. A number of studies have evaluated this troublesome problem. Diarrhea has been found to be correlated with the use of cimetidine, antibiotics, excessive dietary lipid content, and diminished dietary vitamin A content [67, 68]. The incidence of diarrhea has been demonstrated to be decreased in patients who began receiving tube feedings within 48 hours of burn injury and who receive continuous rather than intermittant tube feedings [68, 69]. As such it is important for this as well as previously listed reasons, to initiate enterai feedings as early as possible in the postburn period. Limiting the fat content of the diet to
World Journal of Surgery © 1992 by the Soci~.t6 lnternational¢ de Chirurgie
Nutritional Support of the Burned Patient J. Paul W a y m a c k , M.D., Sc.D. and David N. Herndon, M.D. Shriners Burns Institute, Galveston Unit, and the Department of Surgery, University of Texas Medical Branch, Galveston, Texas, U.S.A. Burn patients develop a number of physiologic alterations among which is a markedly increased metabolic rate. Other metabolic changes include an increased rate of glucose production and utilization, a decreased rate of lipid metabolism, and an increased rate of both protein catabolism and anabolism. These alterations can effect other physiologic parameters, including immune function. They necessitate administration of large quantities of calories and protein to achieve positive nitrogen balance. The physiologic derangements leading to the hypermetabolism and the methotls for supplying the nutritional needs are discussed in this review.
It has been over a half century since Cuthbertson [I] demonstrated that traumatic injuries result in a prolonged period of negative nitrogen balance. In addition, the greater the extent of the injury, the more severe are the resulting metabolic alterations. These changes become maximal in major thermal injury patients. Patients suffering severe burn injuries initially experience an ebb phase where there is a decrease in their metabolic rate and cardiac output [2]. Following successful fluid resusitation, the cardiac output rapidly returns to normal and then achieves supranormal levels. Coincident with this, there is a marked increase in resting metabolic energy expenditure (RME) [3]. The degree of increase in metabolic rate appears to be directly proportional to the extent of burn injury. With more extensive burn injuries, the metabolic rate has been reported to approach 200% of normal [4J. Etiology of Hypermetabolism
Experimental studies by Aulick and coworkers [5] suggest that one of the major inciting events triggering the hypermetabolic response is contamination of the burn wound with bacteria. They have noted in multiple burned rat models that if the burn wounds are contaminated with Pseudomonas aeruginosa at the time of burn injury, the rats become hypermetabolic more rapidly than rats with uncontaminated burn wounds. They further noted that the degree of increase in the metabolic rate was directly proportional to the number of bacteria present in the burn wound [6]. Finally, they found that the use of topical antimicrobial agents, which delayed the onset of burn wound Reprint requests: J. Paul Waymack, M.D., Shriners Burns Institute, 610 Texas Avenue, Galveston, Texas 77550, U.S.A.
bacterial colonization and infection, also delayed the onset of the postburn hypermetabolic response. An alternative explanation for the postburn hypermetabolic response comes from Alexander and colleagues [7]. They have reported that the use of a continuous infusion of enteral tube feedings, beginning immediately following burn injury, prevented the postburn hypermetabolic response. This effect was not present if the initiation of tube feedings was delayed until 3 days following thermal injury. Those guinea pigs which were begun on immediate postburn enteral nutritional support, and thus did not become hypermetabolic, were also noted to avoid the gut mucosal atrophy seen in the animals which did not receive immediate enteral nutrition. Further, the animals receiving the immediate postburn enteral nutrition failed to develop the elevations of serum glucagon, cortisol, and catecholamines seen in the animals not receiving the immediate postburn enteral nutrition [8]. These findings were interpreted to indicate that the severe burn injury results in atrophy of the mucosa of the gastrointestinal tract, which may allow gut translocation of bacteria and endotoxin into the portal circulation. Such translocation has been demonstrated by Dietch and associates [9] in burned animal models. It has further been demonstrated that direct infusion of endotoxin into the portal vein of unburned healthy guinea pigs resulted in a hypermetabolic response similar to that seen in burned guinea pigs [10]. Thus the early enteral feedings may prevent postburn hypermetabolism by preventing portal vein endotoxemia. Confirmation of such an effect in clinical studies has not yet been obtained. During the initial week following burn injury, both core temperature and skin temperatures are markedly elevated [t 1]. As a result of this resetting of internal temperatures, burn patients prefer an ambient temperature which is significantly elevated compared to that which normal volunteers find comfortable. These findings have led some investigators to speculate that the hypermetabolic response seen in burn patients is a result of the requirement for an increased metabolic rate to maintain the desired body temperature in the face of excessive heat loss through the burned tissue. More recent studies have demonstrated that this is not the case. Burn patients placed in an environment where the temperature is set to their comfort zone continue to be hypermetabolic and to have an increased rate of oxygen consumption. This has led to the burn patient
J-P. Waymack and D.N. Herndon: Nutritional Support in Burns
being described as "internally warm, not just externally cold" [i2]. The hypermetabolic and hyperthermic responses seen following burn injury appear to be mediated, at least in part, by alterations in the metabolic set points of the hypothalamus [I 3]. The importance of the hypothalamus in regulating metabolic function has long been recognized. Hume and Egdahl [14] demonstrated that surgical denervation of an animal's limb prevented the normal adrenocortical response to mechanical trauma to that limb, Further support for this concept comes from Newsome and Rose [15] who found that the serum levels of both growth hormone and andrenocorticotropic hormone become elevated during the initial hour following inguinal herniorraphy in patients who received general but not spinal anesthesia. Several studies from Wilmore and coworkers [11] indicate that the reset hypothalamus triggers the increased metabolic rate by elevating the plasma levels of three hormones: catecholamines, g/ucagon, and cortisol. Evidence for this includes their ability to decrease the metabolic rate in burn patients through the use of alpha a n d beta adrenergic blocking agents. In addition, they were able to generate a hypermetabolic response tn normal volunteers, which mimicked that seen in burn patients, by a combined infusion of epinephrine, glucagon, and eortisol [16]. Carbohydrate Metabolism
bespite the fact that burn patients normally have elevated blood glucose levels, their insulin levels are not depressed but rather are elevated compared to nonburned controls [17]. Their hyperglycemia is due to the fact that the serum glucagon levels are elevated to a disproportionately greater degree than are the serum insulin levels. This concept is supported by a study of Jahoor and colleagues [18] in which they administered somatoStatin to severely burned patients. The somatostatin decreased the levels of both glucagon and insulin. This resulted in inCreased serum glucose concentrations because of decreased glucose uptake by peripheral tissues. When the somatostatin infusion was supplemented by a sufficient insulin infusion to achieve insulin levels equal to that seen in the burn patients prior to the somatostatin infusion, the patients developed Severe hypoglycemia, which necessitated a large glucose infusion to correct. Thus the elevated serum glucose concentrations reflect an increased rate of glucose synthesis (gluconeogenesis), not a decreased rate of glucose utilization, and the elevated glucagon levels seen following burn injury are critical for maintaining an adequate rate of glucose production to meet the !aatient's energy requirements. The combined elevation of both catabolic and anabolic hormones results in a number of other alterations in carbohydrate metabolism in burn patients. One of these is an increased rate of generation of glucose precursors. Aulick and Wilmore [19] demonstrated an increased rate of release of amino acids by Peripheral muscle tissue in burned patients. These amino acids are then extracted by the liver and utilized for gluconeogenesis. The accelerated rate of gluconeogenesis using amino acids as SUbstrate is partially responsible for the net decrease in the Serum levels of most amino acids in burn patients [20]. Of all the amino acids, only phenylalanine has been reported to be
81
elevated in burned and septic burn patients and this is felt to be due to a disproportionate rate of release by muscle tissue [20, 21]. Similar increases in the serum concentration of phenylalanine are seen in nonburn patients who are excessively catabolic due to an ongoing septic process [22]. Although the unburned extremities of burn patients utilize primarily lipids and minimal amounts of glucose as an energy source, the burned extremities in these patients metabolize a large amount of glucose to lactate and pyruvate [23]. This is consistant with the demonstration that the inflamatory cells in burn wounds (leukocytes and fibroblasts) primarily metabolize glucose in an anaerobic fashion for energy generation, whereas muscle tissue utilizes iipids [24]. It was further noted that the muscle tissue of the burned extremity primarily utilized fat as an energy source, as was true in the contralateral unburned extremity. Burn patients have a significant rate of hepatic uptake of lactate and pyruvate, which has been generated from anaerobic metabolism of glucose peripherally. The liver then synthesizes glucose from these substrates. This glucose is then reutilized as an energy source by the leukocytes and fibroblasts which are present in the burn wound [23]. This glucose-lactateglucose metabolic sequence is termed the Cori cycle. Further evidence for the importance of the Cori cycle in burn patients is provided by the demonstration that the rate of gluconeogenesis in burn patients is significantly elevated compared to that seen in nonburn patients and that the administration of glucose at a rate known to reduce hepatic gluconeogenesis in normal volunteers had only a minimal effect on the rate of gluconeogenesis in burned patients. Thus, burn patients have an accelerated Cori cycle in which glucose is synthesized by the liver a n d metabolized through anaerobic metabolism by the various cells present in the burn wound. The anaerobic metabolites of glucose (lactate and pyruvate) are then returned to the liver along with gluconeogenic amino acids released from muscle tissue for the synthesis of additional glucose. It is readily apparent that glucose is an important energy source in burn patients and that they require large amounts of glucose to avoid excessive protein catabolism. Unfortunately there are limits to the amount of glucose burn patients can handle. Studies by Wolfe and associates [2] have demonstrated that burn patients begin to develop difficulties in metabolizing glucose when the rate of infusion exceeds 4 mg/kg/min. This necessitates that lipid and protein be utilized to meet the remaining metabolic requirements of burn patients. Lipid Metabofism
Several aspects of lipid metabolism are significantly altered in burned patients. These alterations again appear to be due to the changes in serum concentrations of epinephrine, glucagon, cortisol, and insulin. Burn patients have been found to have a significantly increased rate of lipolysis compared to normal volunteers [25]. This increased rate of lipolysis can be partially blocked by the use of pharmacologic adrenergic blockade. It also has been shown that infusion of epinephrine can further accelerate the lipolytic response, except in those patients who have had most of their fat stores removed by prior deep tangential or fascial excisions of their burn wounds. This increased lipolytic response results in elevated serum levels of free fatty acids and glycerol [26]. While there is an increased
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serum concentration of free fatty acids, there is a decreased concentration of fatty acids bound to albumin. This is due to the decreased serum albumin levels seen in burned patients [26]. This finding may have some clinical significance since one of the major transport systems lbr non-esterified fatty acids into cells is by binding to serum albumin [27]. Another alteration of fat metabolism in burned patients is a decreased rate of ketone production (ketogenesis). Abbott and coworkers [28] found that severely burned patients who were fasted synthesized only half the amount of ketone bodies that nonburned fasted patients were able to synthesize. Since ketone bodies are one of the primary energy sources utilized to decrease protein catabolism, this would indicate that burn patients may require increased amounts of carbohydrate and protein in their diet in order to prevent protein catabolism and achieve positive nitrogen balance. The impaired ketogenesis may be the result of the elevated insulin levels seen in burn patients. Nonburned patients who are fasted have very low serum levels of insulin which thereby allows ketogenesis to occur. In contrast, burn patients have markedly elevated levels of insulin which is known to inhibit ketogenesis. The metabolism of fatty acids by the cyclooxygenase enzyme system is significantly increased in burn patients. This results in an increased rate of production of the physiologically active prostaglandins. These fatty acid metabolites include the reportedly immunosuppressive prostaglandin E (PGE), the vasoconstrictive thromboxanes, and the vasodilatory prostacyclin. Burn patients have been shown to have elevated blood and tissue concentrations of both thromboxane and PGE. Since these metabolites may result in immunosuppression and vasoconstriction and since burn patients are immunosuppressed and have decreased perfusion of the burn wound, it has been suggested that prevention of synthesis of these metabolites by dietary manipulations or pharmacologic agents might be beneficial to such patients [29, 30]. One method suggested to achieve this goal is through the use of Omega-3 fatty acids. The Omega-3 fatty acids, which are primarily obtained from fish oil, are metabolized by the cyclooxygenase enzyme system to yield PGE-3. The more common dietary fatty acids are of the Omega-6 group and are metabolized to yield PGE-I and PGE-2. PGE-1 and PGE-2 have been reported to have significant immunosuppressive properties while PGE-3 has been reported to be immunologically inert. It has therefore been hypothesized that by replacing the Omega-6 fatty acids obtained from standard vegetable and animal oils with the Omega-3 fatty acids, the postburn immunosuppression might be avoided or reversed. This has been reported to be the case in a burned guinea pig model [31]. However, PGE is an important down regulator of tumor necrosis factor production in response to endotoxin exposure [32]. Since severely elevated tumor necrosis factor levels can be lethal, failure to down regulate the rate of production of tumor necrosis factor could result in a significant mortality [33]. This possibility has been suggested by a study in which mice, administered a diet high in Omega-3 fatty acids and then infected, had a greater mortality rate than those fed a more standard diet containing Omega-6 fatty acids [34]. The ideal composition of fat in the diet of burn patients is thus not yet determined.
World J, Surg. Vol. 16, No, I. Jan./Feb. 1992 Protein Metabolism
Protein metabolism is also altered by severe burn injuries. The hormonal milieu which results from burn injury causes a significant increase in muscle protein catabolism [35, 36]. Aulick and Wilmore [19] measured amino acid concentrations in femoral arterial and venous blood samples obtained from burn patients. They demonstrated that there is a net release of amino acids from the extremities of burn patients. Kien and associates [37] showed that not only is there an increased rate of protein catabolism in burn patients, but there is also a significant increase in the rate of protein anabolism, Thus, the rate of protein breakdown into component amino acids and the subsequent reincorporation of these amino acids into other proteins is significantly elevated in burn patients. This protein synthesis, as well as the accelerated rate of hepatic gluconeogenesis utilizing amino acids as substrates, explains the fact previously mentioned in this review, that burn patients have decreased serum amino acid levels. The increased amino acid and protein recycling is obviously important in burn patients to allow for synthesis of collagen for wound healing, plus white blood cells and antibodies for resisting infections. It is therefore essential that negative nitrogen balance be avoided. McDougal and colleagues f38] demonstrated that intravenous infusion of increasing amounts of glucose or amino acids improved nitrogen balance in burn patients. Fat emulsions were also able to enhance nitrogen balance, but not to the same degree as an isocaloric amount of glucose or amino acid solution. They also noted that bacteremia further increased the amount of nitrogen or glucose required to achieve positive nitrogen balance. The ideal amount of protein which should be in the diet of burn patients has not yet been determined. Wolfe and coworkers [39] reported that increasing protein intake in burn patients from 1.4 g of protein/kg/day to 2.2 g protein/kg/day did not alter nitrogen balance. This finding may have been the result of the fact that the patients in this study were able to receive a very high non-nitrogenous caloric intake. This may have altered the protein kihetics in comparison to burn patients who failed to receive this quantity of carbohydrate and fat. Other investigators have found that successful administration of such caloric requirements in burn patients can be difficult. This is emphasized by a study of Alexander and colleagues [40] who demonstrated that increasing the percentage of protein in the diet of burn patients resulted in a number of immunologic benefits. They compared patients receiving 16.5% of their calories as protein to those receiving 23% of their calories as protein. Neither of the two groups were a~ble to successfully achieve the desired caloric intake. Nonetheless the group receiving the higher protein content was found to have significantly higher serum levels of IgG, transferrin, and complement factor 3. More importantly, they experienced fewer bacteremic days and had a significantly lower mortality rate. Caloric Requirements
One of the most important considerations when ordering nutritional support for the burn patient is the decision regarding the amount of calories the patient needs to receive each day. As has been mentioned, the metabolic rate of burn patients increases
J.P. Waymack and D,N. Herndon: Nutritional Support in Burns
proportionally with increasing burn size. This correlation holds true until the burn size exceeds approximately 50% to 60% of the total body surface area at which time there are minimal further changes [3]. There have been a number of formulas proposed for calculating the caloric requirements of burn patients. The most Widely used of these is the Curreri formula [41]. This formula calculates the daily caloric requirement in kilocalories to be equal to 25 times the body weight in kilograms plus 40 times the percentage of the total body surface area burned. This formula obviously tends to overestimate caloric requirements in small children with large burns. Molnar and coworkers [42] proposed that the initial calculation should be based on the Harris Benedict equation, multiplied by a factor of two [43]. A major Weakness with this formula is its lack of emphasis on burn size. The Galveston formula attempts to adjust for these deficiencies by utilizing absolute burn sizes. This formula estimates the caloric requirements of burned children to be equal to 1800 kcal/m 2 + 2200 kcal/m 2 of burn [44]. As is true for burn resuscitation formulas, it is important that each of these formulas should be recognized as merely rough estimates. Turner and colleagues [45] demonstrated, using indirect calorimetry, that the Curreri formula on average overestimated mean metabolic energy expenditure by 58% and the Harris Benedict underestimated it by 23%. Rutan and associates [46] found in patients with burns >45% of their total body surface area, resting energy expenditures exceeded predicted basal metabolic rates by approximately 50%. It is therefore recommended that severely burned patients have their resting metabolic energy expenditures (RME) measured at least once a Week and preferentially twice weekly using indirect calorimetry. This can readily be done at the bedside with portable COmputerized metabolic cai'ts which measure 02 uptake and CO2 production. Once the resting energy expenditure has been determined it is necessary to convert this to the total metabolic energy expenditure (TME). This compensates for the fact that the burn patient is frequently active and has a greater energy expenditure during the periods of activity. The factor necessary for converting RME to TME has been measured using both Stable isotope studies and caloric intake versus weight gain studies. The results of the stable isotope studies indicate that in burn patients the TME is equal to the RME multiplied by 1.2 [47]. In contrast, studies which compared caloric intake to Weight change indicate that caloric intake must be equal to RME multiplied by anywhere from 1.3 to 1.7 in order to prevent Weight loss [48, 49]. This discrepancy may be the result of burn l~atients converting muscle tissue which has fewer calories per Unit of weight, to fat which has more calories per unit of weight. Several investigators have attempted to decrease the metabolic rate, and thereby the nutritional requirements, of burn Patients by performing early excision of the burn wound. COmplete excision of the burn wound in animal models has been demonstrated to abolish the hypermetabolic response [50]. t'Iowever, less than total excision of the burn wound failed to decrease the hypermetabolic response in a burned sheep model [51]. Hildreth and colleagues [52] were unable to find any S~gnificant effect of early excision compared to delayed excision on metabolic rates of burn patients. This may have been due to the fact that they were not able to totally excise the entire burn wound, plus the fact that a significant donor site wound was
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created at the time of burn wound excision. It therefore appears that the caloric requirements of burn patients are not altered by surgical intervention. One possible future avenue for simplifying metabolic support of burn patients may be through the use of recombinant DNA technology products. One such product, recombinant insulinlike growth factor I, has been demonstrated to blunt the postburn hypermetabolic response [53]. It should be mentioned that whether or not pharmacologic blunting of the hypermetabolic response will have a beneficial effect on burn patient survival remains an area of controversy [54]. Administration of recombinant human growth hormone to burn patients has been demonstrated to improve their nitrogen balance [55]. The resulting increased protein anabolism has also been shown to decrease significantly the time required for donor site healing [56]. Enteral versus Parenteral Nutrition
There are two methods by which nutrition can be supplied to the burn patient. These are parenterally through a central venous catheter and enterally by mouth or through a feeding tube. The use of central venous catheters in burned patients entails a number of risks [57]. These complications include a significant incidence of sepsis and a lesser risk of thrombosis. Additionally, it has been shown that the use of total parenteral nutrition (TPN), in lieu of enteral nutrition, results in an atrophy of the intestinal mucosa and an increased plasma concentration of hormones associated with inflammatory responses [58]. It has also been demonstrated that TPN results in elevations of serum insulin levels to a greater degree than that seen with enteral nutrition. This elevation decreases fat mobilization (lipolysis) and thereby reduces the concentration of free fatty acids in the blood to miniscule levels [59]. As was mentioned earlier in this paper, such elevations in insulin levels also decrease the rate of ketone body synthesis. Such reductions necessitate that the body utilize more protein for energy generation and can thereby increase protein catabolism and impair positive nitrogen balance. TPN is also associated with the development of fatty liver changes due to the inability of patients on TPN to generate a lipolytic response because of the elevated insulin levels. Another complication of TPN is its ability to alter endotoxin tumor necrosis factor metabolism. Fong and colleagues [60] have reported that administration of TPN to normal healthy volunteers increases their production of tumor necrosis factor in response to endotoxin exposure. This hyperactive response could be interpreted as being deleterious to patients since elevated tumor necrosis factor levels are considered to be one of the contributing factor in death from endotoxin shock [61]. Herndon and coworkers [62] have compared TPN to enteral nutrition in a randomized series of burn patients. They noted a significantly lower helper/suppressor T lymphocyte ratio in the TPN group. In a later, larger series they found a higher mortality rate in the TPN group compared to the enterally fed group [63]. These findings emphasize the fact that TPN should rarely be utilized in burn patients. It has long been recognized that major burn injuries result in alterations in gastrointestinal function in the immediate postburn period. This postburn ileus was initially thought to con-
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traindicate the use of enteral feedings for the first several days following burn injury. More recent studies have indicated that the ileus is confined to the stomach and colon and that the small intestine continues to function normally [64]. As such, immediate postburn enteral nutrition is possible through the use of feeding tubes placed through the nose past the stomach into the small bowel. McArdle and associates [65] demonstrated this to be a safe and efficacious way to begin achieving positive nitrogen balance immediately following burn injury. This technique also allows for continuing the enteral feedings in patients who later develop gastric ileus due to sepsis. Larkin and Moylan [66] have shown that enteral feedings can provide complete nutritional support and achieve positive nitrogen balance in burn patients without the use of parenteral nutrition. As such, the use of parenteral nutrition in burn patients rarely if ever should become necessary. One of the more common complications of enteral tube feedings in burn patients is a significant incidence of diarrhea. A number of studies have evaluated this troublesome problem. Diarrhea has been found to be correlated with the use of cimetidine, antibiotics, excessive dietary lipid content, and diminished dietary vitamin A content [67, 68]. The incidence of diarrhea has been demonstrated to be decreased in patients who began receiving tube feedings within 48 hours of burn injury and who receive continuous rather than intermittant tube feedings [68, 69]. As such it is important for this as well as previously listed reasons, to initiate enterai feedings as early as possible in the postburn period. Limiting the fat content of the diet to
