World J. Surg., 2, 203-214, 1978

Metabolic Changes Following Thermal Injury M. G6sta S. Arturson, M.D. Burn Center, University Hospital, Uppsala, Sweden

loss of energy as heat, and of water [ 1-4]. The 4 main environmental factors which determine the loss of water and heat from the body are the temperature, humidity and movement of the surrounding air, and the distribution of radiant energy over the body surface. It is possible to estimate the losses of water and heat, as well as to modify these losses by changes of the environment of the patient. Concomitantly with the transcutaneous loss of water and energy, there is an increased resting oxygen consumption and an excessive nitrogen loss (catabolism). These 2 changes are dependent on the nutritional status [4, 5] and can also be modified by environmental conditions such as temperature [6, 7]. The massive catabolic drive in patients with thermal injury is manifested by an early suppression of insulin secretion combined with a large increase in the concentrations of the catabolic hormones, catecholamines and glucagon, and probably also of cortisol. This stimulates lipolysis, ketogenesis, proteolysis, substrate flow to the liver, and gluconeogenesis [8, 9]. Thus, after injury, skeletal muscle protein is broken down not only to provide fuel but also to supply carbohydrate intermediates. This loss of "lean body tissue" decreases the patient's resistance to infection and intoxication, and is a great therapeutic problem.

Patients with extensive thermal injuries have a tremendous, long-lasting increase in transcutaneous heat loss by increased evaporation, radiation, and convection. Their ability to regulate skin temperature and heat loss is limited, and the core-skin insulation is inadequate. The corresponding posttraumatic metabolic response is a massive catabolic drive revealed as insulin insufficiency and increased release of catecholamines and glucagon. This stimulates lipolysis, proteolysis, substrate flow to the liver, and gluconeogenesis of amino acids. The increased heat production is related to an endogenous reset in metabolic activity and is further influenced by environmental conditions. Extensively burned patients cannot overcome the cold stress to which they are exposed by an increased functional heat insulation or by tolerating decreasing body temperature without reacting with a costly increase in heat production and without shivering. If the burn patients are permitted to control the heat supply from infrared heaters until they feel comfortable and all kinds of external environmental disturbances are eliminated, it is possible to reduce their metabolic rate to the normal value for the actual core temperature. The daily caloric requirements can be estimated and, in patients receiving a combined parenteral-enteral dietary program and infrared heat, weight loss can be entirely avoided. Infrared radiation is a practical and inexpensive way of distributing energy from the environment to the patient, suitable also in disaster situations. The ambient air temperature can be kept comfortable with respect to the patient's airways and to the nursing staff.

H o r m o n a l Effects on M e t a b o l i s m

An extensive skin burn causes a continuous loss of fluid from the blood circulation, and transcutaneous

The mechanisms by which the endocrine and metaboric response are activated, and the mode of action and physiological role of various hormones in maintaining homeostasis after thermal injury, have been studied extensively. Recent advances in this very

Supported by the Swedish Medical Research Council (Project Nos. 40X-676 and 40Y-2370). Reprint requests: Professor G6sta Arturson, M.D., Burn Center, University Hospital, S-750 14 Uppsala, Sweden.

0364-2313/78/0002-203 $02.40 9 1978 Soci6t6 Internationale de Chirurgie

203

204

broad field have clarified the posttraumatic pathways of metabolic fuel, especially gluconeogenesis of amino acids [10], the glucose flow, and etiology of the hypermetabolic response following injury [9], and hormone-metabolite interrelationships [8]. It is easy to understand how severe thermal injury with fright and pain, circulatory and pulmonary complications sometimes leading to shock and hypoxia, a chronic tremendous loss of water and heat, wound infection and sepsis activate the hormones of stress (catecholamines), the storage hormone (insulin), and the permissive hormones (glucagon, growth hormone, and glucocorticoids). Research workers agree that the sequence of metabolic events that occurs following thermal injury is related to hormonal control, but they differ in opinion concerning the causal relationship between hormonal and metabolic changes. In the very early or " e b b " phase of the burn syndrome, plasma cortisol and aldosterone are greatly increased concomitant with insulin insufficiency. Immediately postburn the adrenal cortex is stimulated to form glucocorticoids by corticotropin (ACTH) released from the anterior pituitary. The most active of the glucocorticoids in humans is cortisol, which the adrenal cortex makes from cholesterol. Plasma cholesterol rapidly decreases postburn. The measurement of free cortisol in the urine probably gives the most accurate picture of changes in adrenocortical activity. It has been shown that patients awaiting surgery excrete excessive amounts of free cortisol in the urine, demonstrating the effect of fear and apprehension on adrenocortical activity before surgery [ 11]. It is not surprising that the adrenal cortex in patients with thermal injury is rapidly stimulated to form cortisol. The adrenocortical response has been considered to be unnecessary for the metaboric response to occur. The general opinion is that adrenocorticai hormones do not initiate or maintain the protein catabolism, sodium retention, and potassium excretion which follows injury. However, Batstone et al. [8] have shown that the very high plasma cortisol concentration immediately following thermal injury correlated strongly over the first 5 days with the mobilization of gluconeogenic precursors (lactate, pyruvate, alanine, and glycerol) and of lipid metabolites. It was also correlated with protein catabolism as reflected by the very high plasma urea and blood alanine concentrations. This is no proof, but suggests that cortisol plays an important role in the first phase of the catabolic response. These results are in agreement with those of Ryan et al. [ 12] in hemorrhagic shock, which indicated that cortisol stimulates proteolysis, increases amino acid release, and inhibits amino acid incorporation into protein. These findings are contradictory to earlier results indicating that adrenocortical hormones have only a

World J. Surg. Vol. 2, No. 2, March, 1978

permissive role to play in the metabolic response and do not initiate or control the alterations in metabolism [9, 11]. Aldosterone secretion by the adrenal follows closely that of cortisol. The most potent stimuli of aldosterone secretion are probably the sodium depletion and hypovolemia following thermal trauma. Insulin release is inhibited by the alpha adrenergic receptor stimulation which dominates the early phase of burn injury. In severe burns the low plasma insulin concentration is usually accompanied by higher glucose concentrations than would be expected, suggesting the presence of both insulin resistance and impaired insulin secretion. The high glucose concentrations might be due to increased gluconeogenesis. It has been suggested that increased cortisol concentration in the presence of relative insulin deficiency increases the activity of both the "lactate-glucose cycle" (Cori cycle) and the "alanine-glucose cycle" [8, 13]. Insulin enhances amino acid uptake and protein synthesis [ 14]. The net effect is a decreased amino acid release into the circulation. Following thermal injury, when the plasma insulin level is low, the plasma amino acids concentration increases. Increased sympathetic activity does not always cause inhibition of insulin release in response to a glucose load; sometimes a normal insulin response to glucose is observed [ 15]. With time after injury, the early response is followed by a "flow phase" characterized by increased oxygen consumption and heat production, negative nitrogen balance, and weight loss. This phase seems to be directed mainly by catecholamines and glucagon (Fig. 1). The early phase dominated by alpha adrenergic receptor effects is replaced by profound beta adrenergic receptor effects. The result is a greater mobilization of fatty acids and glucose. A close relationship exists between catecholamines and glucagon, although receptors for glucagon action are not identical with beta adrenergic receptors. The most dominating metabolic effect in the "flow phase" is the increased mobilization of glucose from the liver to the peripheral tissue [9]. The ratio of insulin to glucagon is considered to be important in determining the flow of substrates in the fiver [16, 17]. Glucagon was increased relative to insulin in the later phase postburn in the studies of Batstone et al., indicating increased glucogenolysis, gluconeogenesis, and ureagenesis at the expense of protein biosynthesis [ 18]. Glucagon exerts its effect primarily on the liver, and becomes important as cortisol levels fall. The glycogen synthetase activity is decreased (inhibited by catecholamines) which might be the cause of reduced glycogen storage after burn trauma [ 19]. The beta adrenergic receptor stimulation mainly exerted by epinephrine in the "flow phase" causes

M.G.S. Arturson: Metabolic Changes After Thermal Injury

205

ADIPOSE TISSUE

r

Fig. 1. Interrelationship between hormones and substrates in the "flow phase" after thermal injury characterized by enhanced !ip01ysis, protein breakdown, and gluconeogenesis from 3 carbon glucose intermediates and glycerol TG, triglyceride; FFA and FA, free or nonesterified fatty acids; C, cortisol; E, epinephrine; G, glucagon; I, insulin.

i

~

%\\

an increase in the intraceilular level of cyclic AMP. Consequently, as a response to a complex series of interactions, hyperglycemia occurs. Glycogen in liver and muscle cells is converted to glucose. Furthermore, epinephrine suppresses the release of insulin. Also, growth hormone is activated after thermal injury and stimulates free fatty acid release, thereby favoring fat utilization in the periphery [4]. Both glucose flow from the liver to the periphery and heat production increase with the extent of injury during the "flow phase" of injury. The glucose metabolism utilizes ATP, thereby generating ADP, which controls the rate of fuel oxidation. Hence. heat production and oxygen consumption can be related to glucose cycling through the ATP-ADP shuttle system, according to Wilmore [9]. Burn patients with sepsis have impaired gluconeogenesis during infection [20, 21]. The decreased glucose flow is correlated with a fall in oxygen consumption and in core temperature, indicating that glucose cycling may be necessary for the generation of heat [9]. Quantitatively the increase in metabolic rate is greater following severe thermal injury than after any other form of injury [ 10, 22. 23]. All main metabolic fuel pathways are utilized. The majority of the calorie deficit is met by oxidation of depot fat, representing a high energy fuel source of about 24% of the total body weight (17 kg in an adult man). But, "fat can only be burnt in the fire of carbohydrate." Total carbohydrate stores are small, however, providing less than 1.500 kcal. and amount to less than 1% of the body weight. The main significant Supply of carbohydrate intermediates, therefore, is from protein and amounts to about 16% of the body weight (11 kg in an adult man). Thus, after injury, protein is broken down. not simply by use as a fuel but to supply these carbohydrate intermediates (gluconeogenesis of amino acids, mainly alanine and glutamine).

LIVER

~ ,~ [K I

MUSCLE

al~f0s. ~ Urea J~

//7"

~/

I

I

1

cha,n / Jr

/ >' I / / !

No o= / Z z I / / The insulin insufficiency combined with the massive catabolic drive in patients following thermal injury results in enhanced lipolysis, protein breakdown, and gluconeogenesis from amino acids and glycerol. It has been questioned in the literature if this hormonal response can or should be modified, for instance by decreasing the secretion of the protein catabolic hormones or by inhibiting the protein catabolism or by using insulin to increase anabolism [8, 24]. On the other hand, therapeutic efforts to correct the posttraumatic hyperglycemia might be contraindicated since it may be important to maintain cerebral glucose delivery during a reduction in cerebral blood flow [25].

Etiology of the Increased Metabolic Rate Body temperature is normally maintained by a complex series of feedback reactions which control the production of body heat and the exchange of heat with the environment. At least 2 populations of thermosensors are known, one in the central nervous system and the other in the skin, each consisting of a dual set of elements sensitive to warming and to cooling. There is also some evidence for other thermosensors in the viscera and spinal cord [26]. It is usual to discriminate between autonomic (or physiological) and behavioral regulations, ascribing the former to the hypothalamus and the latter to the cerebral cortex. There is Still dispute about the relative importance and interrelationship of the peripheral and central mechanisms in determining the body's response to cold. Changes of the temperature of the blood perfusing the hypothalamus appear to be the most important factor in initiating heat loss or heat production. Coordinated responses of heat loss or

206

heat conservation, respectively, can be produced when the temperature of the blood pelf'using the hypothalamus is raised or lowered by as little as a fraction of a degree centigrade in man [27]. During fever, regulation of body temperature appears to take place normally, but at a higher baseline level. The body temperature in both febrile and nonfebrile subjects may be decreased or increased, respectively, by warming or cooling the hypothalamus. On the basis of this and other evidence, it has been postulated that the body's thermostatic "set-point" (function of various reference temperatures) is raised during fever [27]. The "set-point" is modified in fever by the influence of "pyrogens" [28]. The "pyrogens" are either exogenous "pyrogens" from the bacteria cell walls ("endotoxin") or endogenous "pyrogens" liberated from the tissues or the phagocytic cells of the host. The "pyrogens" can be detected in the circulation and appear to have a direct central action that mimics that of cold on the hypothalamic thermoregulatory centers. The biological system of thermoregulation following thermal injury is more complicated than any engineer's blueprint. It contains multiple sensors, multiple feedback loops, and multiple outputs. Furthermore, the thermal disturbances differ with time following the accident. The immediate signal to the brain that tissue injury has occurred is by sensory nerves. The afferent nervous signal to the hypothalamus following pain, hypoxia, and hypotension or hypovolemia is accompanied by immediate release of corticotropin and antidiuretic hormone. At the time of injury, the body's response to "stress," described as the "flight and fright mechanism," is a depression in the physiologic response to the hormonal discharge. This "ebb phase" is characterized by a redistribution of blood from the skin to the internal organs. Heat production is decreased. The early response is followed by the "flow phase" with increase in metabolic rate and flow of substrates. There is an apparent reset in the central temperature regulation. Both core and skin temperatures are elevated at any ambient temperature studied. when compared with normal man. If patients with burns are allowed to regulate the ambient temperature to achieve comfort, they select a mean ambient temperature for comfort which is significantly higher than normal. [7, 29-33] The ambient temperature selected is usually related to the extent of the injury. In the "flow phase", denervation of the wound or interruption of the sensory input to the brain does not appear to diminish the increased metabolic rate following thermal injury [9]. Only central nervous system narcosis has decreased sympathetic stimulation. resulting in a fall in metabolic rate [34]. From these studies it follows that changes in the tempera-

World J. Surg. Vol. 2, No. 2, March, 1978

ture of the blood perfusing the hypothalamus as well as of the concentration of circulating endogenous "pyrogens" in the region of the hypothalamus play a central role in the metabolic response. Injections of serotonin, epinephrine, norepinephrine, and prostaglandin E1 into the third ventricle of conscious animals produce high, prolonged fever in some species and hypothermia in others [28]. Administration of epinephrine and norepinephrine to normal man increases metabolic activity. In accordance with this finding, adrenergic blockade in patients with large surface area burns produced a consistent decrease in metabolic rate; this occurred with alpha and beta adrenergic blockade, or beta adrenergic blockade alone [35]. These results suggest that increased catecholamines (increased adrenergic activity) are important calorigenic mediators responsible for the increase in metabolic rate following injury. Infilsion of glucagon and growth hormone also increases calorigenesis [36]. If we accept a basic metabolic drive related to an endogenous reset in metabolic activity following thermal injury, we have to admit that little is known about the way in which this "set-point" is established and how it is modified in fever by the influence of "pyrogenic" agents and calorigenic hormones. It has been known since the fundamental work of Du Bois in 1948 [37] that in various fevers the heat production of the body increases about 13-16% for each degree C. This is about the average for most chemical reactions according to van't Hoff's law. The increase in metabolic rate for a given degree of fever is about the same for all kind of diseases investigated, as well as for fever produced by intravenous foreign protein. We would expect that the thermally injured patient with fever should also increase his metabolic rate not more than about 16% for each degree C due to an endogenous reset in metabolic activity. However, very often during the "flow phase" of the burn syndrome, the measured metabolic rate is much higher than could be calculated from sex, height, weight, age, and the actual rectal temperature of the patient. The patient is "hypermetabolic" or "hyperactive." The cause of this might be all kinds of influences by environmental conditions, especially heat loss. During the last 3 years influences by environmental conditions on patients with thermal injury have been investigated at our Burn Center. Based on the results, a new treatment of burns with infrared heaters has been developed [6, 31].

Material and M e t h o d s

The first problem was to measure the energy expenditure continuously without causing any discomfort

M.G.S. Arturson: Metabolic Changes After Thermal Injury

to the subject. A new, open-circuit, flow-through technique for frequently repeated m e a s u r e m e n t s of energy expenditure was designed [30]. The technique is based on the fact that energy expenditure can be determined with an error of less than 0.17% at 0.7 ~< RQ ~< 1, by measuring the expiratory air flow and its oxygen concentration according to the formula: l~ = 5.04 {[Vpu(F~o~- F)]/[1 + 0.082p]} where I~ = X?pu = F~o2 = F =

energy expenditure the flow of the pump the oxygen fraction of fresh air the measured oxygen fraction after the mixing system p = the energy fraction related to protein metabolism (protein fraction) The digitized signal from the oxygen analyzer is fed into a calculator, where a program computes the energy expenditure for the actual flow, temperature,

207

humidity, oxygen concentration, barometric pressure, and protein fraction. The equipment used for the measurement of energy expenditure is shown in Fig. 2. The m e a s u r e m e n t s do not cause any discomfort to the subject, who does not have to cooperate. The energy expenditure was assessed at _+ 2.6% when pulse technique was used with ambient air as the calibration gas. No systematic error (95% tolerance limits) c o m p a r e d with the conventional Douglas-bag method was found. Sixteen patients with the individual data given in Table 1 were studied on different occasions f r o m immediately after the burn trauma until complete healing of the wound. The results are based on about 1,400 m e a s u r e m e n t s of metabolic rate', covering most aspects of burn care. The patients were initially treated with lactated Ringer's solution (3 m l / k g b o d y weight per % area burned). F r o m the second day postburn, plasma and albumin were given. The intravenous nutrition was based on Intralipid| Intramin Forte | and 10 or 20% glucose [ 1, 38]. Vitamins and trace elements were given daily. No topical treat-

Fig. 2. The apparatus for measuring energy expenditure. To collect the expired air a plexiglass hood (1) is used. The expired air is drawn out through the hood and is mixed in a mixing container (2) with a volume of approximately 10 L. The pump (3) draws the mixture out of the container with a constant flow, which is measured by the flowmeter (4) calibrated by a spirometer. The mixing system consists of mixing container, pump, flowmeter, and connecting tubes. Its time constant is approximately 1 minute. From the flowmeter the mixed air flows to the open container (5), where temperature and humidity are measured (6). These parameters and the barometric pressure correct the flow to STPD. Fresh air and mixed air are connected to the two-way magnetic valve (7). With the valve in one position, the mixed air flows to the oxygen analyzer (8). In the other position of the valve, dried fresh air is analyzed. A switch (9) triggers the data collector (10), which transfers the analog output signal from the oxygen analyzer to the A/D converter (11). The digitized signal from the oxygen analyzer is fed into the calculator (12), where a program computes the energy expenditure for the actual flow, temperature, humidity, oxygen concentrations, barometric pressure, and protein fraction.

208

World J. Surg.

Table 1. The individual data of the patients investigated.

V o l . 2 , N o . 2, M a r c h ,

Wm

Metabolic rate

1978

-2

kcal m-2 h-I

Patient symbol

Calculated metabolic rate Age Sex kcal m-2h -1

Total body surface burned (%)

Fullthickness burn

44 18 39 15 55 61 27 29 34 56 47 64 29 33 21 13

52 55 39 65 23 24 42 66 47 58 62 26 45 26 42 13

33 55 0 57 23 24 40 5 20 58 62 12 25 26 42 13

o

O A A [] 9 , 9 @ 9 @

F F M F F F F M M M M M M M M M

33.4 38.5 39.5 35.4 32.4 32.5 35.7 39.6 38.9 36.3 35.6 33.0 39.5 37.6 39.9 39.8

ment was used. Four patients were treated with a respirator during the first 3 to 4 weeks postburn. The patients had separate quiet rooms with an air temperature varying between 25~ and 33~ and a relative humidity of about 40%. In the ceiling above each patient. 3 infrared heaters were placed parallel to the bed. Each heater was 1 m long and had an electric p o w e r of 860 kcal h -J (1 kW). In the plane o f the patient, the radiation effect from each heater was about 35 kcal m-Zh-1(40 W m-Z). The patients chose the amount of heat for comfort by operating a switch placed by the bed. The influences of environmental conditions on the metabolic rate were studied sometimes continuously for 24 hours. The patient's activities, as a result of the daily routine, were divided into groups and defined as falling asleep, lying at ease. routine tests, exercise, psychic disturbances, shivering, and pain. The exercise was physiotherapy and m o v e m e n t s when the bed was made. Psychic disturbances covered such things as anxiety, unpleasant dreams, the patient's waiting for a telephone call, and unknown persons coming into the patient's room.

Results The continuous intensive treatment of patients with severe burns involves different effects on the metabolic rate which can hardly be completely avoided. The ingestion of food increased the metabolic rate, the so-called specific dynamic effect. Carbohydrates and fats raised the metabolic rate above the B M R level 5 - 3 0 % for up to 9 hours after ingestion, and proteins produced an increase o f 30-70% for as long

80 -9O

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60

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-70

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40

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Fig. 3. The metabolic rates for some activities in the daily routine, showing increasing values of metabolic rate compared to those obtained when the patients were falling asleep. The patients were all treated with infrared heat.

as 12 hours. Intravenous infusion of amino acids raised the metabolic rate almost as much as the oral administration of amino acids. Careful observations of burn patients revealed that they very frequently have tonic or rhythmic muscle activities, sometimes invisible and only detectable by electromyography. With higher intensity the rhythmic activity is accompanied by shivering. It was usually possible to abolish these muscle activities by infrared heat. About 15-30 minutes before the onset of an increase in rectal temperature, the patient increased the heat supply to maximal value. About 15-30 minutes before the p e a k in b o d y temperature was reached, the metabolic rate decreased dramatically and the patient Switched off the infrared lamps. Ambient air temperature of 33~ was frequently not enough for patients with extensive burns to keep their body temperature at the " s e t - p o i n t " level, When they added infrared heat until comfort, the rectal temperature increased slightly and the metaboric rate decreased. Burn patients are extremely sensitive to various psychic disturbances [39]. The increased tension due to anxiety, fear of operations, and severe insomnia was found to increase the metabolic rate to the same extent as does shivering. The effect of different activities on the energy expenditure during treatment with infrared heat are summarized in Fig. 3. Figure 4 shows the relation between rectal temperature and measured values of metabolic rate observed during continuous treatment with infrared

M.G.S.

Arturson: Metabolic Changes After Thermal Injury

Metabolic

209

Wm

-2

70

60

W m-2

Metabolic rate kcal m-2 h-I

rate

kcal m-2 h - I

70-

-80

60

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9

9

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9

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Fig. 4. Metabolic rate as a function of rectal temperature for burn patients just falling asleep and treated with infrared heat. The regression line is fitted by the method of least squares and has a slope of about 16%/~ The metabolic rate is given in kcal m-2h 1 as well as in W m 2.

heat when the patients fell asleep. All kinds of influences of environmental conditions on the metabolic rate were eliminated. The regression line has a slope of about 16%/~ The relation between rectal temperature and metabolic rate for the patients gives an average metabolic rate of 36 kcal m-2h - ' (42 W m -2) at a rectal temperature of 37~ The basal metabolism of the patients, calculated from sex, height, weight, and age with a supposed RQ of 0.85, is 35.9 _+ 3.0 kcal m 2h 1(41.5 _+ 3.5 W m-2). The relation between rectal temperature and energy expenditure, measured when the patients were lying at ease is shown in Fig. 5. The line has the same slope as when the patients fell asleep (Fig. 4) but is increased by a constant factor o f about 7 kcal m 2h l ( 8 W m ~). The combined treatment with infrared heaters, controlled by the patient, and provision of the predicted energy intake from the calculated basal metabolism, rectal temperature, and activity of the patient, controlled by the doctor, prevented any substantial weight loss of the patients (Fig. 6). The treatment with infrared heat has not been instituted in children or unconscious patients. Rectal temperature of 40.5~ has been the upper limit for heat supply. Preliminary results from studies of our patients with thermal injury treated with infrared radiation have shown decreased catecholamine secretion and lower urinary urea excretion than in burn patients treated in a conventional way. These observations, which must be confirmed, indicate a decreased catabolic drive due to treatment with infrared heat.

30-

I

I

I

I

36

37

38

39

Rectal temperature

; 0 ~

Fig. 5. Metabolic rate as a function of rectal temperature for burned patients lying at ease and treated with infrared heat. The broken line originates from Fig. 4. % of admission weight I00

o

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0-~9~

90 20-29% 30-39%

80 > 40%

i

I Weeks post burn

Fig. 6. Weight loss following thermal trauma. The curves were derived before techniques of combined enteral and parenteral feedings were available. They demonstrate the obligatory weight loss for different extents of burn that occurs if vigorous nutritional support is not instituted. Symbols refer to our study patients listed in Table 1, in whom weight loss was essentially prevented as energy support equaled energy demand.

Discussion Behavioral thermoregulation is associated with cerebral cortex activities involved in the conscious perception of thermal comfort and discomfort which can be related, subjectively, to changes in skin temperature. However, recent research has clearly shown the involvement also of deep body temperature in the

210

conscious sensation of thermal comfort [27]. This may be the reason why most patients with extensive bums, with large areas of damaged skin, are able to discriminate between thermal comfort and discomfort. Afferent impulses from peripheral thermoreceptors are not only a source of conscious information but also a very important input for the system of temperature regulation. They can signal thermal disturbances before the central temperature of the body has been influenced. That is the reason why the burn patients increased the heat supply 15-30 minutes before any detectable change in rectal temperature. The threshold and intensity of warm and cold sensations depend on the absolute temperature (T) of the skin, on the rate of change (dT/dt), and on the stimulus area. Thermal comfort and discomfort reflect an integrated state of the thermoregulatory system. It is also important that the methods of measuring the metabolic rate do not cause any discomfort to the patient, who does not have to cooperate [30]. Thereby, it is possible to measure the energy expenditure, for instance, when the patient has just fallen asleep and most of the disturbances are eliminated. Energy metabolism is related to environmental temperature, as is inferred in the definition of basal metabolic rate. At environmental temperatures within the thermonentral zone, thermal regulation is largely by redistribution of blood flow, thermoregulatory sweating has not begun, and metabolism is taking place at the minimal, basal rate [40]. In the thermoneutral zone, temperature regulation is achieved by nonevaporative physical processes alone. This is not the case following thermal injury. In patients with burns the thermoregulatory mechanisms are usually intact, but the ambient condition of thermal neutrality differs from that of normal subjects. Nonseptic patients with thermal injury respond to elevation of their ambient temperature above the zone of thermal neutrality with a decrease in rate of heat production and in dry heat loss, no change or slight increase in evaporative heat loss, and no significant or slight increase in body temperature. This response suggests that the zone of thermal neutrality after thermal injury is increased. Following severe thermal injury, metabolic heat production is substantially increased concomitant with a pronounced increase in evaporative heat loss and to some extent also in convective and radiative heat loss [ 2, 3, 41-44]. In a study of 8 burned patients, Wilmore and coworkers [ 33] showed that the average core temperature of patients with bums was elevated, and their mean skin temperatures were increased above normal. Heat transfer coefficients demonstrated a twofold increase in core-to-skin conductance of heat in patients with bums compared with control individuals. Patients with large burns were characterized by inadequate core-skin insula-

World J. Surg. Vol. 2, No. 2, March, 1978

tion when exposed to a cooler environment (25~C). This study also demonstrated that evaporative heat loss accounted for a greater percentage of the heat transfer in the thermally injured patients. Thus, patients with extensive bums are characterized by a tremendous long-lasting increase in transcutaneous heat loss by all rout es--by evaporation, radiation, and convection. When cutaneous cold receptors are activated by external cooling, cutaneous vasoconstriction ensues as a regulatory measure to achieve core insulation. In patients with thermal injury the core-skin insulation is inadequate, and the ability to regulate skin temperature and heat loss is limited. The reason for this might be that tissue injury results in increased cutaneous blood flow apparently to ensure oxygen and nutrient supply and promote wound healing [45]. Maximum vasodilation in thermally damaged tissue, mainly due to histamine release and increased biosynthesis of prostaglandins, creates a decreased peripheral resistance with a high flow state in the burned areas [46]. Another observation of importance in this context is that the inability to control skin blood flow and thereby to limit surface cooling may result in a reset in central or peripheral cold receptor function. The "set-point" for internal temperature regulation can be altered by changes in skin temperature. An imbalance between internal heating and surface cooling is found to give the same results [26, 27]. A similar mechanism may also operate in patients with extensive burns [32, 33]. Patients with extensive thermal injury lose a tremendous amount of heat for several weeks postburn, and they feel cold. They cannot overcome the cold stress to which they are exposed by an increased functional heat insulation through extremely reduced peripheral blood flow, or by tolerating some drop in body temperature, without reacting with a costly increase in heat production and without shivering. The tonic or rhythmic muscle activities so frequently observed in burn patients raises the metabolic rate above the basal level. Muscle contraction uses the terminal - P-bond of ATP, and thereby accelerates mitochondrial and cellular respiration markedly. As soon as muscle contractions start, the ADP formed stimulates mitochondrial electron transport and the oxygen consumed is about linear with the work performed. The increase in energy expenditure in burn patients measured when they are just falling asleep compared with when they are lying at ease is about 7 kcal m Zh 1 (8 W m -z) (Fig. 5). The difference between these two states is a slight tonic muscle activity. The patients are treated in exactly the same way with "equal kind of comfort." If the patients start shivering, the energy metabolism increases by a factor of 2 (Fig. 3). In a theoretical work by Stolwijk and Hardy [ 47],

M.G.S. Arturson: Metabolic Changes After Thermal Injury

thermoregulatory heat production in man (AM) has been described as the product of 2 temperature deviations from 2 reference values:

211

Table 2. Daily amounts of water, energy, amino acids, glucose and fat to be provided in intravenous feeding.

Amount per kg bodyweight per day High Basic requirements requirements

AM = 60 ( T H c - 36.6)('i~s - 34.1) kcal h -1 , where THc= head core temperature, and ~i's = mean skin temperature. If thermal injury causes the internal body temperature to fall, muscle activities induced by this fall disappear very quickly on exposure to infrared heat. The radiation causes skin temperature to rise rapidly, while the internal temperature goes up slowly. Since ATs goes to 0 in this process, the shivering threshold is exceeded even though the internal temperature is reduced. The muscles relax and the patient feels comfortable. If the burn patients themselves control the heat supply until they feel comfortable and all kinds of external environmental distm'bances are eliminated, it is possible at least for short periods to reduce the metabolic rate to normal value for the actual core temperature. Four main principles are of utmost importance in current nutritional management of patients with severe thermal injury, namely, early wound closure, prevention of septic complications, adequate nutrition, and control of the external environment. Successful therapy according to these principles avoids loss of "lean body tissue" and increases the patient's resistance to infection and intoxication. Rapid debridement of the burns eschar followed by immediate wound closure is not always possible. Because of the relatively high risks associated with immediate excision of the burn wound in patients with extensive burns, the surgeon is often forced to leave a large quantity of dead tissue attached to the body, sometimes for several weeks. During this period it is essential to feed the patient and, according to the results in the present investigation, to support him with a heat supply. The daily caloric requirements could be estimated and in patients receiving a combined parenteral-enteral dietary program and infrared heat, weight loss was entirely avoided (Fig. 6). Basic requirements according to Table 2 were provided in most of our burned patients, indicating that long-term supranormal caloric dietary programs can be modified. Patients with very extensive burns and high fever have high energy requirements (Table 2). In these patients the daily amounts of carbohydrate, fat, and amino acids were provided in intravenous nutrition according to Table 3. To this was added the daily requirements of vitamins (Vitalipid adult | and Soluvit | as well as trace elements (Addamel| Infrared radiation is a practical way of distributing energy from the environment to the patient. The method is inexpensive and the ambient air temperature can be kept comfortable with respect to the

Water Energy Amino acids Glucose Fat

50-60 ml 50-60 kcal 2 g (0,27 g N) 5g 3g

25-35 ml 25-30 kcal 1 g (0,13 g N)

2g 2g 11 g Nitrogen per 150 kcal I

Table 3. Daily amounts of carbohydrates, fat and amino

acids to be provided in intravenous nutrition in patients with high energy requirements. Amino Volume Energy acids Nitrogen % ml kcal g g Glucose 20 2,000 Intralipid | 20 1,000 IntraminForte | 11 1,800 (amino acids)

1,600 2,000 800

198

30.8

Total

4,400

198

30.8

4,800

This program gives -0.7 g nitrogen per 100 kcal (420 kJ) and 63 kcal per kg body weight. patient's airways and the nursing staff. Subsequent cfinical experience with several very extensive burns has now proven conclusively that such patients are usually able to control the heat supply from the infrared heaters.

Rrsum6

Les patients atteints de brfilures 6tendues ont, pendant longtemps, des pertes thermiques extr6mement importantes par 6vaporation accrue, radiation et convection. Ils ont perdu en pattie leur capacit6 de rrgulation de la temprrature cutanre et des pertes thermiques. L'isolation de l'organisme devient donc inadrquate. En m r m e temps, la rrponse m6tabolique posttraumatique est un hypercatabolisme considrrable qui se marque par un drficit en insuline et une librration accrue de catrcholamines et de glucagon. I1 y a donc augmentation de la lipolyse, de la protrolyse, de l'influx de substrats vers le foie et de la nroglycogenrse/t partir d'acides aminrs. La production accrue de calories est en rapport avec les perturbations mrtaboliques et est, de plus, influenc6e par l'environnement. Les malades atteints de brOlures 6tendues ne peuvent surmonter le stress par le froid auquel ils sont soumis: ils ne peuvent accroitre leur

212

isolation thermique fonctionnelle; ils rtagissent toute baisse de la t e m p t r a t u r e corporelle par une production accrue de chaleur et par des frissons. Si on laisse des brfilts contr61er eux-m~mes, selon leur degr6 de confort, la temp6rature d t g a g t e par des lampes/~ infrarourge, si de plus on 61imine toutes les perturbations de l'environnement, leur mdtabolisme basal peut 6tre ramen6 ~ des valeurs normales pour leur t e m p t r a t u r e centrale. Les besoins caloriques peuvent 6tre estimts et il est possible d ' t v i t e r comp l t t e m e n t les pertes de poids en alimentant les malades/~ la fois par voles enttrale et parenttrale et en les plaqant sous une lampe ~t rayons infrarouges. Celle-ci fournit de l'tnergie au patient, de fa~on pratique et economique, dans ces situations d6sastreuses. L a t e m p t r a t u r e ambiante peut rester dans des limites satisfaisantes p o u r les voies respiratoires du rnalade et pour l'tquipe soignante.

References

1. Arturson, G.: Burn shock. Triangle 13:105, 1974 2. Gump, F.E., Kinney, J.M.: Caloric and fluid losses through the burn wound. Surg. Clin. North Am. 50:1235, 1970 3. Lamke, L.-O.: Evaporative water loss from normal and burnt skin. Linkrping, Sweden, 1971 4. Wilmore, D.W.: Nutrition and metabolism following thermal injury. Clin. Plast. Surg. 1:603, 1974 5. Liljedahl, S.O., Birke, G.: The nutrition of patients with extensive burns. Nutr. Metab. 14 [Suppl.]:ll0, 1972 6. Danielsson, U., Arturson, G., Wennberg, L.: The elimination of hypermetabolism in burned patients. A method suitable for clinical use. Burns 2:110, 1976 7. Barr, P.O., Birke, G., Liljedahl, S.O., Plantin, L.-O.: Oxygen consumption and water loss during treatment of burns with warm dry air. Lancet 1:164, 1968 8. Batstone, G.F., Alberti, K.G.M.M., Hinks, L., Smythe, P., Laing, J.E., Ward, C.M., Ely, D.W., Bloom, S.R.: Metabolic studies in subjects following thermal injury. Burns 2:207, 1976 9. Wilmore, D.W.: Hormonal responses and their effect on metabolism. Surg. Clin. North Am. 56:999, 1976 10. Kinney, J.M., Long, C.L., Duke, J.H.: Carbohydrate and nitrogen metabolism after injury. In Energy Metabolism in Trauma, Porter, R., Knight, J., editors London, Churchill, 1970, p. 103 11. Johnston, I.D.A.: The endocrine response to trauma. In Parenteral Nutrition in Acute Metabolic Illness, Lee, H.A., editor. London, New York, Academic Press, 1974, p. 211 12. Ryan, N.T., George, B.C., Odessey, R., Egdahl, R.H.: Effect of hemorrhagic shock, fasting and corticosterone administration on leucine oxidation and incorporation into protein by skeletal muscle. Metabolism 23:901, 1974 13. Cahill, G.F., Jr., Herrera, M.G., Morgan, A.P., Soeldner, J.S., Steinke, J., Levy, P.L., Reichard, G.A., Jr., Kipnis, D.M.: Hormonal-fuel interrelationships during fasting. J.Clin. Invest. 45:1751, 1966

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14. Fulks, R.M., Li, J.B., Goldberg, A.L.: Effects ofinsufin, glucose, and amino acids on protein turnover in rat diaphragm. J. Biol. Chem. 250:290, 1975 15. Wilmore, D.W., Mason, A.D., Jr., Pruitt, B.A., Jr.,: Insulin response to glucose in hypermetabolic burn patients. Ann. Surg. 183:314, 1976 16. Unger, R.H.: Glucagon and the insulin: glucagon ratio in diabetes and other catabolic illnesses. Diabetes 20:834, 1971 17. Parifla, R., Goodman, M.N., Toews, C.J.: Effect of glucagon: insulin ratios on hepatic metabolism. Diabetes 23:725, 1974 18. Marliss, E.B., Aoki, T.T., Unger, R.H., Soeldner, J.S., Cahill, G.F., Jr.: Glucagon levels and metabolic effects in fasting man. J.Clin. Invest. 49:2256, 1970 19. Hessman, Y.: Glycogen storage in thermal trauma. Acta Univ. Upps. [Suppl.] 185:1, 1974 20. Wilmore, D.W., Mason, A.D., Jr., Pruitt, B.A., Jr.,: Impaired glucose flow in burned patients with gramnegative sepsis. Surg. Gynecol. Obstet. 143:720, 1976 2l. Gump, F.E., Long, C., Killian, P., Kinney, J.M.: Studies of glucose intolerance in septic injured patients. J. Trauma /4:378, 1974 22. Kinney, J.M.: Calories-nitrogen-disease and injury relationships. In Symposium on Total Parenteral Nutrition. AMA Food Sci. Com. 1972, p. 35 23. Kinney, J.M., Duke, J.H., Long, C.L., Gump, F.E.: Tissue fuel and weight loss after injury. J. Clin. Pathol. 23[ Suppl. 4] :65, 1970 24. Hinton, P., Allison, S.P., Littlejohn, S., Lloyd, J.: Insulin and glucose to reduce catabolic response to injury in burned patients. Lancet ! :767, 1971 25. Lindsey, A., Santeusanio, F., Braaten, J., Faloona, G.R., Unger, R.H.: Pancreatic alpha-cell function in trauma. J.A.M.A. 227:757, 1974 26. Thauer, R.: In Physiological and Behavioral Temperature Regulation. Hardy, J.D., Gagge, A.P., Stolwijk, J.A.J., editors. Springfield, Illinois, Charles C. Thomas, 1970, p. 472 27. Precht, H., Christophersen, J., Hensel, H., Larcher, W.: Temperature and Life. Berlin-Heidelberg-New York, Springer-Verlag, 1973, p. 524 28. Zweifach, B.W., Grant, L., Mc Cluskey, R.T.: The Inflammatory Process Vol. IiI. New York, London, Academic Press, 1974 29. Davies, J.W.L., Liljedahl, S.O.: The effect of environmental temperature on the metabolism and nutrition of burned patients. Proc. Nutr. Soc. 30:165, 1971 30. Danielsson, U., Arturson, G., Wennberg, L.: A new technique for the long-term stable measurement of energy expenditure. Burns 2:107, 1976 31. Arturson, G.: Transport and demand of oxygen in severe burns. J. Trauma 17:179, 1977 32. Wilmore, D.W., Orcutt, T.W., Mason, A.D., Jr., Pruitt, B.A., Jr.: Alterations in hypothalamic function following thermal injury. J. Trauma 15:697, 1975 33. Wilmore, D.W., Mason, A.D., Jr., Johnson, D.W., Pruitt, B.A., Jr.: Effect of ambient temperature on heat production and heat loss in burn patients. J. Appl. Physiol. 38:593, 1975 34. Taylor, J.W., Hander, E.W., Skreen, R. W., Wilmore, D.W.: Effect of CNS narcosis on the sympathetic response to stress. J. Surg. Res. 20:313, 1976 35. Wilmore, D.W., Long, J.M., Mason, A.D., Jr., Skreen, R.W., Pruitt, B.A., Jr.: Catecholamines: me-

M.G.S. Arturson: Metabolic Changes After Thermal Injury

36. 37. 38.

39. 40.

41.

diator of the hypermetabolic response to thermal injury. Ann. Surg. 180:653, 1974 Aulick, L.H., Wilmore, D.W., Mason, A.D., Jr.: Mechanism of glucagon calorigenesis. Fed. Proc. 35:401, 1976 Du Bois, E.F.: Fever and the Regulation of Body Temperature. Springfield, Illinois, Charles C. Thomas, Publisher, 1948 Wretling, A.: Amino acids and fat emulsions. In Parenteral Nutrition in Acute Metabolic Illness. Lee, H.A., editor. London, New York, Academic Press, 1974, pp. 53 and 77 Bernstein, N.R.: Emotional Care of the Facially Burned and Disfigured. Boston, Little, Brown and Company, 1976 Tilstone, W.J.: The effects of environmental conditions on the metabolic requirements after injury. In Parenteral Nutrition in Acute Metabolic Illness. Lee, H.A., editor. London, New York, Academic Press, 1974 Zawacki, B.E., Spitzer, K.W., Mason, A.D., Jr., Johns, L.A.: Does increased evaporative water loss

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42. 43.

44. 45. 46. 47.

cause hypermetabolism in burn patients? Arm. Surg. 171:236, 1970 Gump, F.E., Kinney, J.M.: Energy balance and weight loss in burned patients. Arch. Surg. 103:442, 1971 Neely, W.A., Petro, A.B., Holloman, G.A., Rushton, F.W., Don Turner, M., Hardy, J.D.: Researches on the cause of burn hypermetabolism. Ann. Surg. 179:291, 1974 Warden, G.D., Wilmore, D.W., Rogers, D.W., Mason, A.D., Jr., Pruitt, B.A., Jr.: Hypernatremic state in hypermetabolic burn. Arch. Surg. 106:420, 1973 Gump, F.E., Price, J.B., Jr., Kinney, J.M.: Blood flow and oxygen consumption in patients with severe burns. Surg. Gynecol. Obstet. 130:23, 1970 Arturson, G.: Prostaglandins in human burn-wound secretion. Burns 3:112, 1977 Stolwijk, J.A., Hardy, J.D.: In Physiological and Behavioral Temperature Regulation. Hardy, J.D., Gagge, A.P., Stolwijk, J.A.J., editors. Springfield, Ill., Charles C. Thomas, Publisher, 1970

Invited Commentary Douglas W. Wilmore, M.D. USA Institute of Surgical Research, Brooke Army Medical Center, Fort Sam Houston, Texas, U.S.A.

Arturson has presented an excellent overview of the major metabolic alterations which occur following human burn injury. Although all investigators in the field of post-traumatic metabolism agree on the methods of treatment of burn patients (keep them in warm ambient environments, feed high calorie diets, minimize infection, and close the burn wound), there still remains controversy concerning the etiology of the hypermetabolic response to burn injury. There is little doubt that the large quantity of oxygen utilized by the body results from a systemic or generalized increase in aerobic metabolism. Oxygen consumption is elevated in both the viscera and extremities of burn patients [ 1]. This large quantity of heat is then transferred to the surface and lost to the environment. Indirect evidence suggests that cutaneous perfnsion is elevated, and direct measurements of extremity blood flow demonstrate that the increased surface blood flow is directed predominantly to the burn wound [2]. In spite of the fact that the wound is cooled by the rapid evaporation of water, the wound surface of a burned leg is actually

hotter than the skin of the contralateral uninjured limb. This marked increase in wound perfusion and wound temperature which occurs in the burn patient presumably facilitates wound healing and surface repair. Moreover, the neovasculature of the wound appears sympathectomized and is not under reflex control; the burned wound fails to vasoregulate in response to central thermal regulatory drives like the innervated normal cutaneous vasculature. These factors then account for the insulative defect which occurs following burn injury and the large obligatory transfer of heat from the central core (viscera) to the surface of the body. But, is the hypermetabolic response to burn injury a result of environmental cooling? Arturson presents clinical studies suggesting that burn patients are cold and can " t u r n d o w n " their hypermetabolic response by warming themselves with self-regulated radiant heaters. We have repeated this study and are unable to confirm his findings. A summary of our data on the interrelationship between ambient temperature and hypermetabolism is as follows: