Metabolic Changes in Burned Patients

Symposium on Burns

Metabolic Changes in Burned Patients Douglas W. Wilmore, M.D.,* and L. Howard Aulick, Ph.D., Major, M.S.C.t

Extensive thennal injury initiates the most marked alterations in body metabolism associated with any illness observed in contemporary society. The persistent tachycardia, hyperpnea, hyperpyrexia, and marked body wasting of the burned patient reflect the heightened metabolic activity and accelerated body catabolism which characterize this stress response to injury. These systemic alterations in metabolism occur as a result ofthe cutaneous inflammatory process and are thought to facilitate wound repair. Although these systemic metabolic changes following major injury have been extensively studied and catalogued, it has been difficult to relate the alterations in total body metabolism and physiologic function to the events that occur in the healing wound. This article reviews the local and systemic metabolic alterations that occur following thermal injury and integrates these events in an effort to detennine the systemic priorities and homeostatic strategy of the body following extensive damage to the cutaneous surface.

METABOLIC PRIORITIES OF THE HEALING BURN WOUND Thennal injury results in coagulation necrosis of the cellular elements of the epidermis and dennis; the depth of injury is determined by the intensity and duration of heat exposure. With tissue injury vessels are disrupted or thrombosed and cells destroyed; interstitial fluid, cellular elements, and connective tissue interact. Adjacent intact vessels soon dilate and platelets and leukocytes begin to adhere to the vascular endothelium as an early event in the inflammatory response. Increased capillary penneability is then observed as plasma leaks from the microvasculature 'Clinical Associate Professor of Surgery, University of Texas School of Medicine at San Antonio; Staff Surgeon, United States Institute of Surgical Research, Brooke Army Medical Center, Fort Sam Houston, Texas tUnited States Army Institute of Surgical Research, Brooke Army Medical Center, Fort Sam Houston, Texas The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Surgical Clinics of North America-Vol. 58, No.6, December 1978

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DOUGLAS W. WILMORE AND

L. HOWARD AULICK

Table 1. Characteristics of Wound Cellular Components UNIQUE METABOLIC CELL TYPE

ORIGIN

FUNCTION

CHARACTERISTICS

High rate of anaerobic glycolysis;5 low O 2 consumption even in an O 2 rich environment, respiratory burst occurs with phagocytosis 4 Consumes glucose as an energy source and produces lactate IO

Polymorphonuclear neu trophilic leukocyte

Myeloid tissue

Inhibit and kill bacteria; elaborate pyrogens

Macrophage

Arise from local tissue;15 transformed from monocytes in blood I5

Vascular endothelium

Arise as vascular sprouts from existing vessels

Fibroblast

Thought to arise from perivascular cells in the wound lO

Debrides injured tissue;lO processes macromolecules to amino acids and simple sugars; attracts other macrophages; possibly signals fibroblasts; 15 and possibly signals for microvascularization Forms the neovasculature which: provides nutrients; possibly clears metabolic end products Synthesize collagen, proteoglycans, and elastin

Epithelium

Other epithelium

Surface

Best environment for collagen synthesis is in an acidic environment with O 2 tension >10-20 torr; needs reducing environment (ascorbic acid); collagen synthesis increased by lactate;' oxygen and glucose both essential for collagen synthesisI4 Increased glucolysis in the presence of oxygen;ll increased pentose phosphate pathway

into the area of damage. Wound edema is followed by an influx ofnumerous polymorphonuclear neutrophilic leukocytes and monocytes that accumulate at the site of injury. Following these initial inflammatory events, new capillaries, immature fibroblasts, and newly formed collagen fibrils appear within the wound. The neovasculature and other com-

1175

METABOLIC CHANGES

150

WOUND BLOOD FLOW

- ...... -

100 50 0 200 100 0

900l 600

WOUND GLUCOSE CONSUMPTION

300 LLI (!)

0

Z

«

I U

:::e 0

500

WOUND LACTATE PRODUCTION

400 300 200 100 0 2500

COLLAGEN BIOSYNTHESIS

2000 1500 SKIN GRAFT

1000

-1

500 04-~~~~~-'~r-r-~~~~

-I

0

I

2

3 4

5

6

7

8

9

10 "

12 13 14 15 16 17 18 19 20 21

TIME IN DAYS Figure 1. Alterations in metabolic events which occur with time following a full thickness injury. Note that oxygen and glucose consumption increases with wound blood flow and that lactate production increases in parallel with wound oxygen consumption. Adapted from dataof the authors and others. 11. 12. 14

ponents of wound repair support the rapidly regenerating epithelium that resurfaces a partial thickness injury. With full thickness burns, these elements form a luxuriant bed of granulation tissue that readily accepts a split-thickness skin graft. The heterogeneity of cellular components making up granulation tissue (Table 1) complicate analysis of wound metabolism. However, it is apparent that glucose is the major metabolic fuel for all cellular components of the healing wound, although complete oxidation of this sugar may not occur. 5. 10. H. 14 Even with exposure to 100 per cent oxygen, granulation

1176

DOUGLAS W. WILMORE AND

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HOWARD AULICK

tissue produces lactate, which is similar to the metabolic handling of glucose by normal epithelial structures. 12 Thus, intense glycolysis in the presence of oxygen is a special feature of cutaneous reparative tissue. This is not to imply that oxygen and oxidative energy production are not necessary for wound repair. For example, polymorphonuclear neutrophilic leukocytes consume very little oxygen at rest (even in an oxygen rich environment) but rapidly increase oxygen uptake with phagocytosis. 4 This respiratory burst was initially thought to provide energy forphagocytosis but subsequent studies demonstrated that the extra oxygen was converted to hydrogen peroxide and utilized by the leukocyte as a bacteriostatic agent. While oxygen is utilized by leukocytes for host defense, fibroblasts require oxygen for synthetic purposes. Atmospheric oxygen is essential for the hydroxylation of proline to hydroxyproline, a key step in collagen synthesis. 10, 14 In spite of these and other known oxygen requirements, studies that determine the metabolic characteristics of granulation tissue demonstrate that this tissue relies predominantly on anaerobic glycolysis (increased glucose consumption and accelerated lactate production) as the major energy source. 12 The rate of high energy bond formation in granulation tissue is increased 1.5 to 2 times above levels of uninjured skin; approximately 70 per cent of the ATP being derived from the Embden-Meyerhof pathway and the remaining energy (30 per cent) produced by oxidation of glucose. The increased metabolic demands of the healing wound can only be met by accelerated glucose uptake, particularly when considering the relative inefficiency of ATP formation by anaerobic glycolysis. The basis of this metabolic strategy is unclear but the high lactate concentration may inhibit bacterial growth, increase wound blood flow, and stimulate collagen synthesis by the fibroblast. 8 Amino acids, lipid precursors, and micronutrients are also essential for cellular and collagen synthesis. Increased pentose shunt activity occurs in regenerating epithelium and this pathway is responsible for the synthesis of DNA and lipidY,14 Collagen synthesis by the fibroblast requires energy, oxygen, and essential and nonessential amino acids (collagen is composed of approximately one-third glycine, one-third proline and hydroxyproline, and one-third other amino acids). Ascorbic acid and trace minerals are necessary co-factors in collagen synthesis. Amino acids are also required for the fibroblast to synthesize proteoglycans (mucopolysaccharides) and elastin. Because the burn wound represents a highly active, rapidly replicating tissue, delivery of nutrients to the cells is essential for replication and wound repair. Studies in tumor systems demonstrate that the probability of a cell undergoing mitosis is directly proportional to its distance from a capillary: cell necrosis occurs when the cell-capillary distance exceeds 3 mm. Adequate nutrient delivery and "waste" removal are assured by the development of a dense plexus of capillaries. Although the original cutaneous vasculature may be disrupted or destroyed by the burn injury, new capillaries are rapidly formed from existing vessels. Blood flow to the wound is markedly enhanced within a week following full thickness injury or even earlier following partial thickness injury. The cause of the rapid proliferation of vascular endothelium is unknown, although hypoxia, increased tissue lactate concentrations, substances elaborated by

1177

METABOLIC CHANGES

Table 2. Effects of Local Heating and Induced Hyperthermia on Leg Blood Flow (Mean ± SE) LEG BLOOD FLOW

(ml per 100 mlleg volume per min)

Local heating Controls Uninjured extremities in burned patients Injured extremities in burned patients Reflex heating Controls Small leg burns in burned patients Large leg burns in burned patients

N

Before

After

4

2.86 ±0.29 3.50 ±0.25 6.08 ±0.67

5.95 ±0.48 6.09 ±0.61 8.70 ±0.70

2.93 ±0.29 3.64 ±0.52 7.11 ±0.78

4.56 ±0.25 5.94 ±0.91 7.79* ±0.76

5 8

5 5 9

*No change in limb blood flow; all other studies demonstrate significant blood flow changes with direct or indirect heating

leukocytes or macrophages, and an angiogenic peptide have all been suggested as possible mediators of vascular growth. Anatomically and physiologically it is difficult to argue that cells in the well vascularized granulating wound produce lactate because of limited oxygen availability. The dense capillary network in mature granulation tissue occupies 30 to 50 per cent of the microscopic field. From a physiologic standpoint, blood flow to other hypoxic tissues is increased, but this high level of flow will return to normal with reestablishment of adequate oxygenation. This is not the case in the granulating wound, in which marked variations in arterial oxygen tension have little or no effect on blood flow. Because of the importance of the neovasculature to wound healing and the known interrelationship between tissue metabolism and blood flow, a series of experiments was conducted in patients to determine the local and systemic factors which affect the wound circulation. Total limb blood flow was measured in injured and uninjured legs of burned patients by venous occlusion plethysmography. 1 Limb blood flow was essentially normal in the uninjured legs of burned patients but rose in a curvilinear fashion with the size of the leg surface burn. This suggested that most of the extra peripheral blood flow was directed to the superficial wound: a conclusion that was later supported by muscle blood flow studies demonstrating that skeletal muscle perfusion was the same in burned and unburned legs as it was in the limbs of normal controls. 3 The selected elevation in wound blood flow could not be explained by a complete loss of vascular smooth muscle tone. This was demonstrated by studies of severely burned legs with high basal flows; increasing limb surface temperature caused further vasodilation to occur. The burn wound appeared to be "functionally" denervated, however, since it failed

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DOUGLAS W. WILMORE AND

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to vasodilate when its temperature was held constant and the patient's core temperature was elevated 0.4 to 0.5° C by external heating (Table 2). This loss ofneurogenic vasomotor control of the burn wound is most likely the combined result of actual physical disruption of sympathetic efferent nerves at the time of injury and the presence of local inflammatory and metabolic factors that interfere with neuromuscular transmission in other vessels that retain their innervation. Chemical vasodilators identified in the burn wound include such inflammatory products as histamine, kinins, and various prostaglandins. Increased rates of obligatory lactate production may also contribute to local vasodilation. Actual physical denervation of wound microvasculature is most apparent after inflammation subsides and the wound is completely healed. While local chemistry should approach that of normal skin with wound closure, reflex vasomotor control to the healed wound is still markedly reduced. The most likely explanation for this faulty or limited vascular innervation of the burn wound is the evidence that regeneration of sympathetic nerves in granulation tissue is slow and vascular reinnervation often incomplete, particularly if split thickness skin grafts are utilized. 6 The high obligatory levels of wound blood flow serve to increase wound temperature and thus accelerate wound healing. It is well known that the rates of chemical reactions increase with heating and all biological systems demonstrate an optimal temperature for maximal function. Gimbel and associates varied surface temperatures over the bed of split thickness donor sites and examined the influence of temperature on the rate of epithelization. 7 They found that epithelial growth rate increased to a peak at a surface temperature around 40° C but was sharply reduced at temperatures above this point or below 26° C. High rates of superficial blood flow bring heat from visceral tissues of these febrile patients to the wound, elevating wound temperatures above that of unburned skin. 1 Considering the evaporating cooling that occurs from the burn wound, the impact of increased superficial blood flow on maintaining an elevated wound temperature is even more impressive. This increase in wound temperature supports cell proliferation and accelerates wound healing.

WOUND COMMUNICATION WITH THE HOST: HOW DO WE KNOW WHEN WE'RE INJURED? Following injury or infection, afferent stimuli signal the brain that tissue damage and/or microbiologic invasion have occurred. These signals set into motion an integrated neurohormonal response programmed to aid host defense and facilitate tissue repair. To determine the role of afferent nervous signals from the area of injury during burn hypermetabolism, a variety of studies were conducted in thermally injured patients which interrupted nervous afferent signals from the wound to the brain. Neural afferent activity from the wound apparently is not the primary signal since complete denervation of the injured area has no significant effect on the patient's hypermetabolism or febrile state. 20 At one time, it was thought that the increased evaporative water loss

METABOLIC CHANGES

1179

from the damaged surface stimulated peripheral cold receptors and provided afferent nervous signals to the brain; burned patients became hypermetabolic because they felt cold. Although a variety of early studies suggested a thermoregulatory basis for postburn hypermetabolism, additional work questioned the significance of such environmental factors in a thermal neutral environment, since covering the wound with a water impermeable membrane and blocking evaporative water loss in this environment failed to reduce the metabolic rate of burned patients. 22 In another study, oxygen consumption was determined in burned patients in a variety of ambient temperatures (19 to 33° C). is Metabolic rate decreased as ambient temperature increased and this effect was related to burn size. However, metabolic rate remained markedly elevated even when ambient temperature was increased up to or above thermal neutrality, suggesting that environmental factors in this warm environment were not the dominant stimulant of burn hypermetabolism, but the increased heat production was the consequence of an elevated metabolic state. Hypermetabolism following thermal injury is temperature sensitive but is not temperature dependent. Although heat production can be reduced by treating burned patients in a warm environment, the marked elevation in metabolic rate does not return to normal with external heating. As will be discussed later, the additional metabolic demands placed on the burned patient presumably reflect the energy costs of healing alarge surface area wound. It is, however, important to minimize thermal drives by treating patients in a warm environment. Because of the inability to identify specific nervous afferent stimuli as the initiators and propagators of the hypermetabolic response, a search for possible circulating factors has begun. In one study, serum collected from burned patients and normal controls was injected into the preoptic area of the hypothalamus of rabbits. Injection of normal serum resulted in no more than a 0.1 ° C rise in rectal temperature, but serum from nine of the 13 patients elicited a febrile response (0.63 to 0.93° C over two hours). Limulus lysate assay for endotoxin was negative in all samples. Mter heat treatment of the serum, the febrile response was attenuated, suggesting that endogenous pyrogens (the product of the body's cells participating in the inflammatory reaction) mediated this febrile response. These studies, taken together, suggest that circulating (rather than neurogenic) signals arising from the wound notify higher centers in the nervous system that an injury has occurred. The endogenous pyrogen is but one product of phagocytic cells which may initiate the systemic response to inflammation. Other mediator substances liberated from leukocytes are known to have specific and direct metabolic effects on the liver and pancreas, altering organ substrate flux, intracellular trace element distribution, and plasma hormonal concentrations. Moreover, this basic metabolic response to injury (presumably determined by circulating factors) is amplified by painful stimuli (afferent nervous signals) that freq uen tly accompany tre atm en t of cri tic ally ill pa tien ts. E very effort should be made to minimize this stimulation since pain, like other nocuous stimuli, will further exaggerate the basic hypermetabolic response to injury.

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DOUGLAS W. WILMORE AND

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HOWARD AULICK

CENTRAL NERVOUS SYSTEM READJUSTMENTS IN RESPONSE TO THE WOUND Afferent signals, originating in the burn wound, must ultimately excite efferent neural and/or hormonal mechanisms before any response to injury can occur. The essential role of the central nervous system in the hypermetabolic response to injury is apparent by the failure of patients with "brain death" to mount a hypermetabolic response to injury.20 Similarly, morphine anesthesia, which markedly reduces hypothalamic function, results in a prompt decrease in hypermetabolism, rectal temperature, and cardiac output in severely burned patie~ts. Evidence to date suggests that hypothalamic and pituitary function is modified by stress and that the resultant alterations in neurohumoral efferent activity appear to mediate the response to injury. These adjustments in the central nervous system affect both thermoregulation and metabolism of burned patients. Burned patients appear to thermoregulate around an elevated central reference temperature. They maintain, for example, increased body temperature over a wide range ofthermal environments.!. 18.21 The apparent increase in the body's "thermostat" also causes these febrile patients to seek above normal environmental temperatures for their thermal comfort.19 Further evidence of a hypothalamic temperature reset in these patients is the relative vasoconstriction of unburned skin as compared with normal skin when related to comparable central body temperatures. To examine the effect of major cutaneous injury on pituitary gland function, human growth hormone response to insulin hypoglycemia and arginine infusion was measured in nine patients and five normal men. 19 Fasting human growth hormone was significantly elevated in the burned patients both during the acute and recovery phases of injury; the elevated human growth hormone during the period of hypermetabolism occurred despite the associated fasting hyperglycemia. The human growth hormone response to hypoglycemia was more rapid, but the peak response diminished in the burned patient when compared with recovered patients and controls; this attenuated response was also observed following arginine infusion. In other studies, the hypothalamic and/or pituitary control of the calorigenic mediators, thyroid hormone and catecholamines, was assessed. Consistent with previous reports, burned patients were not hyperthyroid; serum T4 and T3 concentrations were significantly reduced following injury and reversed-T3 was elevated. Basal levels of thyroid stimulating hormone (TSH) were normal as was the TSH response following TRH stimulation, in spite of the low levels of active thyroid hormone which are associated with an exaggerated TSH response in hypothyroidism. This suggests that the hypothalamic and pituitary control of the thyroid gland is altered in response to the low level of circulating thyroid hormone. In contrast, catecholamines (epinephrine and norepinephrine), the other major calorigenic mediators, are markedly elevated even when patients are sleeping comfortably in a warm room. Adrenergic activity has been related to the extent of burn and to the oxygen consumption of

METABOLIC CHANGES

1181

the patient. Carefully controlled adrenergic blockade in patients with large surface burns demonstrated a consistent decrease in metabolic rate with alpha and beta or beta adrenergic blockade alone. These studies suggest that specific adjustments occur within the hypothalamus and pituitary of burned patients. Alterations in hypothalamic activity could have pronounced effects on the entire body since this small area of the central nervous system contains centers for thermoregulation, satiety, glucose control, as well as areas that affect hypophyseal and autonomic nervous function. Readjustments in temperature and metabolic control within the brain are expressed by alterations in function of the autonomic nervous system. All the associated changes in pituitary and adrenal hormonal elaboration further contribute to the sympathetic response to injury to facilitate mobilization and utilization of body fuels.

SYSTEMIC RESPONSES TO INJURY: THE BODY'S SUPPORT OF THE HEALING WOUND Supply of Substrate As previously noted, the cellular components of inflammation and wound repair rely on glucose as the primary metabolic fuel. Because total body glucose stores are limited and liver and muscle glycogen is exhausted within the first several days after injury, a mechanism for the ongoing synthesis of new glucose is provided, presumably to ensure adequate supply of this essential fuel. Through an elaborate set of interacting hormonal signals, hepatic glucose synthesis increases following major injury.20 Gluconeogenesis reaches its maximum rate during the second and third weeks following injury and then returns to normal with closure of the wound. This rate of glucose production is related to the size of the total body surface injury and may reach levels twice normal in the more severely injured patients. To determine if all peripheral tissues utilize glucose, substrate flux was measured across injured and uninjured extremities of severely burned patients matched for age, weight, and extent of the total body surface burn. 21 Both groups of patients demonstrated similar systemic responses to injury, as reflected by cardiac index, oxygen consumption, and body temperature (Table 3). Net glucose uptake across the uninjured extremities was low, suggesting that fat, not glucose, was the primary fuel for skeletal muscle, a finding similar to that observed in normal man. However, increased glucose uptake occurred in the extensively injured extremities. While the quantity of oxygen utilized by the burned limbs was sufficient to account for oxidation of all glucose consumed, a large quantity of lactate was produced. Calculated on a weight basis, the lactate produced accounted for most, ifnot all, of the glucose consumed by the extensively injured limbs, suggesting that little or no oxygen was utilized for glucose metabolism in the burned legs. The oxygen consumed by these extremities must be used, therefore, for the oxidation of fat.

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DOUGLAS W. WILMORE AND

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Table 3. Comparison of Patients with Small and Large Leg Burns (Mean and Range or S.E.M.)

Patient Characteristics Number of subjects Number of studies Age (years) Weight (kg) Body surface area (m') Per cent total body surface burn Per cent total leg burn Postburn day studied Systemic Responses Cardiac index (liters per m' per min) Oxygen consumption (ml per m' per min) Rectal temperature (OC) Mean skin temperature (OC) Peripheral Responses Mean leg skin temperature eC) Leg blood flow (ml per 100 mlleg per min) Leg oxygen consumption (ml per 100 mlleg per min) Leg glucose uptake (mg per 100 mlleg per min) Leg lactate production (mg per 100 mlleg per min)

SMALL LEG

LARGE LEG

BURNS

BURNS

8 9 28 (17-50) 73.2 (57.5-89.4) l.89 (l.63-2.1O) 40.5 (12-57.5) 9.5 (0-17.5) 12 (8-19)

7

7.82 204 38.5 36.1

± ± ± ±

0.70 12 0.3 0.2

7 27 (18-50) 70.1 (58.6-83.7) l.88 (l. 70-2. 07) 42 (12-6l.5) 58.0 (37.5-82.5) 14 (7-22) 7.46 241 38.3 36.1

± ± ± ±

0.81 22 0.3 0.2

35.2 ± 0.3 4.22 ± 0.43 0.187 ± 0.037

35.5 ± 0.3 8.02 ± 0.51* 0.240 ± 0.010

0.037 ± 0.033

0.336 ± O.077t

0.060 ± 0.055

0.299 ± 0.075!

"'P < 0.001. tP < 0.01. !P < 0.05.

These in vivo studies confirm the in vitro observations of a disproportionate increase in glycolysis in the presence of oxygen in the healing wound. The lactate produced by the wound is extracted by the liver and recycled to glucose (an energy utilizing process). What glucose is completely oxidized to CO 2 and water is replaced by the liver which converts gluconeogenic amino acids to new glucose. The energy utilized by the liver is primarily derived from body fat. That fat is the major oxidized fuel of the body is confirmed by the respiratory exchange ratio (RQ) which ranges from 0.70 to 0.76 in these and other injured patients. From this gas exchange data the quantity of glucose oxidized by the body can be estimated and ranges from 15 to 35 per cent of the total quantity of glucose produced (Table 4). Thus, increased carbon flow through the Cori cycle (glucose-tolactate-to-glucose) occurs; maintenance of this process requires energy. Amino acids are released from structural and functional protein (primarily skeletal muscle) and are transported to the liver to serve as glucose precursors and building blocks for acute phase and other plasma

1183

METABOLIC CHANGES

Table 4. Approximate Glucose Turnover by Various Tissues (Gram per 24 Hours)

Brain Renal cortex Renal medulla Muscle RBC, WBC, platelets Wound Total Per cent oxidized

NORMAL* (12-HOUR FAST)

NORMAL" (8-DAY FAST)

50% TOTAL BODY SURFACE BURN (12-HOUR FAST)

120 34 2 30 34

45 Very low 2 Very low 34

120 ? Low 2
220 66t

90 =50t

200 to 225t 360 to 400§ =25t

':'From the data of Cahill. tCalculated from measurements. !Increased red cell turnover. §Compatible with total body measurements which demonstrate a two-fold increase in total body glucose turnover.

proteins. The gluconeogenic amino acids are de aminated by the liver and their nitrogen residue transferred to urea which is excreted in the urine. Alanine is the major gluconeogenic amino acid. Measurement of alanine release from lower extremities demonstrated that burned patients increased the rate of peripheral alanine release approximately three times normal. 2 The magnitude of the peripheral alanine release is related to burn size and is consistent with the increased rates of gluconeogenesis and ureagenesis observed in these patients. Generation of Extra Heat: The Hypermetabolic Response to Thermal Injury Increased oxygen consumption is a characteristic systemic metabolic response to thermal injury, and the extent of the hypermetabolism is related to the size of the total body surface burn. In normal man, approximately two-thirds of resting metabolic heat production takes place in the head and trunk. Splanchnic oxygen consumption in a limited number of burned patients has been reported to increase 50 to 60 per cent above normal resting levels. Peripheral oxygen consumption has been determined in burned and unburned legs of patients by measuring limb blood flow and femoral arteriovenous oxygen differences. 21 Leg oxygen consumption was unaffected by the local presence of a burn wound, but remained a relatively constant proportion of total body oxygen consumption (5 to 6 per cent) of both hypermetabolic burned patients and normal controls. This relationship between limb and total body aerobic metabolism is in good agreement with the estimates of 5.9 per cent in normals. 17 Since splanchnic oxygen consumption increases following thermal injury9 and peripheral oxygen uptake remains a fixed portion of total aerobic metabolism, burn hypermetabolism appears to be a generalized or systemic response involving the entire body. Consequently, the general increase in body heat production appears to be distributed in a relatively normal fashion-two thirds of the heat being produced in the visceral tissues and the other one-third in the extremities (Fig. 2).

1184

DOUGLAS W. WILMORE AND

ORGAN OXYGEN CONSUMPTION

L.

DISTRIBUTION OF

HOWARD AULICK

ETIOLOGY OF HEAT PRODUCED 50~ TBSBURN

KIDNEYS 7"4

BIOCHEMICAL INEFFICIENCY AND

SPECIFIC DYNAMIC ACTION 55"4

LIVER LIVER

18"4

25"4 O~-----L--

Figure 2.

____

~

______L -____- L______

Partition of the hypermetabolism following thermal injury.

Following injury, the heat produced in the fasted patient is primarily a result of fat oxidation. Because the patients are febrile some of the increase in oxygen consumption is related to the elevated body temperature (Ql0 effect). However, this effect of temperature on metabolism is small and only accounts for 10 to 20 per cent of the extra oxygen consumed. The major portion of the heat produced is the result of biochemical inefficiency. Once high energy phosphate bonds are synthesized, they are utilized for mechanical, transport, or synthetic work. Some increase in mechanical work occurs in injured patients because of increased respiratory and cadiac activity, but this accounts for a minor portion of the total heat produced. Similarly, transport work may be increased slightly (probably a result of the initial sodium load administered during resuscitation and/or the large solute load handled by the kidneys during catabolism). However, synthetic work is the most clearly identifiable requirement for extra energy; the thermally injured patient produces new glucose, acute phase proteins, albumin, and leukocytes and heals a large surface wound. The increased energy requirement for protein synthesis may account for the major quantity of energy utilized for synthetic purposes. The energy yield from the conversion of glucose to lactate in the wound is inefficient when compared with the complete glucose oxidation. The relative contribution of all these synthetic processes to the production of body heat is unknown at this time.

METABOLIC CHANGES

1185

The extra heat given off by these relatively inefficient metabolic processes in the febrile patient is sufficient to raise body temperatures despite accelerated rates of heat loss across the surface wound. Increased rates of wound blood flow channel body heat to the injured surface where it raises local temperatures above that of uninjured skin. Not only will this increase in wound temperature accelerate healing, as mentioned earlier, but the generalized febrile response to injury is thought to be beneficial to the host, especially following exposure to infectious organism. 13 Resistance to infection in experimental animals is favorably influenced by raising body temperature, either by elevating ambient temperature or by supporting the organisms' fever mechanisms. However, the increased heat production imposes a metabolic cost to the patient which results in accelerated tissue catabolism and disruption of body mass. The increased energy demands must be met by a vigorous feeding program if the complications of catabolism and weight loss are to be averted and the accelerated thermogenic mechanisms supported.

The Controlled Hyperdynamic Circulation: Balancing Local Metabolic Demands Against Central Influences Perfusion must be of sufficient magnitude to maintain essential organ function yet support wound metabolic requirements and maintain adequate defense against microbiologic invasion. In response to those increased circulating demands, cardiac output rises above normal resting levels as soon as plasma volume is restored following injury. This increase in cardiac output is generally related to the extent of injury, and may reach levels three to four times normal in the more severely injured patient with adequate cardiovascular reserve. Much of this extra blood flow is directed to peripheral tissues, since splanchnic perfusion in burned patients increases slightly but represents a smaller portion of the cardiac output (14 to 17 per cent) than it does in normals (23 per cent) or patients with postoperative infection (22 per cent). The relationship between burn size and cardiac output suggests that the wound has some influence on these hemodynamic changes and direct measurements of wound blood flow confirm these high rates of wound perfusion. The estimated cardiac index of a "typical" patient with burns of 50 per cent of total body surface would exceed 7.0 liters per m 2 per Inin. Based on actual measurements of splanchnic, 9 limb, 1 muscle, 3 and renal blood flow (unpublished data), assuming no change in brain circulation but arise in coronary perfusion proportional to changes in total blood flow, one may partition the cardiac index of this hyperdynamic patient during the flow phase of injury (Fig. 3). This illustrates the general shift in the distribution of total body circulation toward the periphery with the major portion of the extra flow going to the wound. This increase in superficial flow is, however, well within maximum levels of cutaneous flow observed in resting men under heat stress. These studies demonstrate that blood flow in several regional vascular beds has not increased in proportion to oxygen consumption, and this is particularly true of the splanchnic bed and skeletal muscle. Moreover, flow to uninjured skin appears normal, below the levels which would be

1186

DOUGLAS W. WILMORE AND

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8.0

7.0 OTHER OTHER

7-16%

21-27% ~

6.0

l'

BRAIN

~

6-7%

SPLANCIINIC

12-14%

HEART

>< 5.0

5%

UJ

RENAL

"" :z::

12-14% SPLANCHNIC

14-17% w

4.0


"" ""
RENAL

3.0

15%

OTHER

2-23%

B~iN

~T'4%

SKIN

51-57% 2.0

SPLANCHNIC

20-25%

SKIN

25-27% RENAL

20-25% 1.0 SKIN

4-10% MUSCLE

MUSCLE

81:

15-20% RESTING NORMAL

BURN PATIENT

MUSCLE

7-81: SEVERE HEAT STRESS-NORMAL

Figure 3. Distribution of the cardiac index in a patient with a 50 per cent total body surface burn compared with resting normal and a severely heat stressed normaL

expected with the elevated rectal temperature observed in burned patients. These changes in regional blood flow reflect a balance between central regulatory drives (for example, systemic blood temperature and body temperature) and local metabolic demands: such adjustments in blood flow ensure adequate perfusion of the highly vascularized wound.

SUMMARY The systemic metabolic and circulatory alterations following thermal injury are directed to support the healing wound. The open wound is an immediate priority of the body; structural and functional components of uninjured tissue undergo breakdown to provide energy, substrate, and micronutrients for the healing wound. Glucose is synthesized by the liver and utilized by granulation tissue. Wound blood flow is elevated and the injured surface is heated to enhance repair. These changes in systemic metabolism and directed by alterations in neurohumoral control; the exact mechanisms utilized by the wound to initiate these changes are presently not known.

1187

METABOLIC CHANGES

REFERENCES 1. Aulick, L. H., Wilmore, D. W., Mason, A. D., Jr., et al.: Influence of the burn wound on peripheral circulation in thermallyinjuredpatients. Am. J. PhysioI.,237:901-906, 1977. 2. Aulick, L. H., and Wilmore, D. W.: Leg amino acid turnover in burn patients. Fed. Proc., 37:536, 1978. 3. Aulick, L. H., Wilmore, D. W., Mason, A. D., Jr., et al.: Muscle blood flow following thermal injury. Ann. Surg., in press. 4. Babior, B. M.: Oxygen-dependent microbial killing by phagocytes. New EngI. J. Med., 298: 659-668, 1978. 5. Cline, M. J.: Metabolism of the circulating leukocyte. Physiol. Rev., 45:674-720, 1965. 6. Fitzgerald, M. J., Martin, F., and Paletta, F. X.: Innervation of skin grafts. Surg. GynecoI. Obstet., 124:808-812, 1967. 7. Gimbel, N. S., and Farris, W.: Skin grafting. The influence of surface temperature on the epithelization rate of split thickness skin donor sites. Arch. Surg., 92:544-547,1966. 8. Grant, M. E., and Prockop, D. J.: The biosynthesis of collagen. New EngI. J. Med., 286: 291-300, 1972. 9. Gump, F. E., Price, J. B., Jr., and Kinney, J. M.: Blood flow and oxygen consumption in patients with severe burns. Surg. GynecoI. Obstet., 130:23-28, 1970. 10. Hunt, T. K, and Van Winkle, W., Jr.: Fundamentals of Wound Management in Surgery. New Jersey, Chirurgecom, Inc., 1976. 11. 1m, M. J., and Hoopes, J. E.: Enzyme activities in the repairing epithelium during wound healing. J. Surg. Res., 10:173-179,1970. 12. 1m, M. J., and Hoopes, J. E.: Energy metabolism in healing skin wounds. J. Surg. Res., 10: 459-464, 1970. 13. Kluger, M. J.: The evolution and adaptive value of fever. Am. Sci., 66:38-43,1978. 14. Lampiaho, K, and Kulonen, E.: Metabolic phases during the development of granulation tissue. Biochem. J., 105:333-341, 1967. 15. Leibovich, S. J., and Ross, R.: The role of the macrophage in wound repair. Am. J. PathoI., 78:71-100, 1975. 16. Remensynder, J. P., and Majno, G.: Oxygen gradients in healing wounds. Am. J. PathoI., 52:301-323, 1968. 17. Stolwijk, J. A. J.: Mathematical model of thermoregulation. In Hardy, J. D., Gagge, A. P., and Stolwijk, J. A. J. (eds.): Physiological and Behavioral Temperature Regulation. Springfield, Charles C Thomas, 1970, p. 703. 18. Wilmore, D. W., Long, J. A., Skreen, R., et aI.: Catecholamines: Mediator of the hypermetabolic response to thermal injury. Ann. Surg., 180:653-668,1974. 19. Wilmore, D. W., Orcutt, T. W., Mason, A. D., Jr., et al.: Alterations in hypothalamic function following thermal injury. J. Trauma, 15:697-703,1975. 20. Wilmore, D. W.: Hormonal responses and their effects on metabolism. SURG. CLIN. NORTH AM., 56:999-1018, 1976. 21. Wilmore, D. W., Aulick, L. H., Mason, A. D., Jr., et aI.: The influences of the burn wound on local and systemic response to injury. Ann. Surg., 186:444-458, 1977. 22. Zawacki, B. E., Spitzer, K W., Mason, A. D., Jr., et aI.: Does increased evaporative water loss cause hypermetabolism in burn patients? Ann. Surg., 171 :236-240, 1970. United States Army Institute of Surgical Research Brooke Army Medical Center Fort Sam Houston, Texas 78234