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The metabolic response to injury: mechanisms and clinical implications

CB Michelsen and J Askanazi
J Bone Joint Surg Am. 1986;68:782-787.

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 Copyright 986 by The Journal of font’ cittcl Joint Surgery, Incorporated

Current Concepts Review

The Metabolic Response to Injury:

Mechanisms and Clinical Implications*t
BY C. B. MICHELSEN, M.D4, AND J. ASKANAZI, M.D4, NEW YORK, N.Y.

Ire)m the Department of Orthopedic Surgery and Anesthesiology, College of Physicians and Surgeons. Columbia University. Next York Cirs

The metabolic response to injury can be characterized The Metabolic Response to Stress

by an early (ebb) and late (flow) phase’7. The early phase

in the Non-Stressed State
refers to the first twenty-four to forty-eight hours, in which Cahill9 has calculated that during the first day of star-
circulatory hemostasis occurs. This early, or shock, phase vation, a normal seventy-kilogram man uses seventy-five
has received a great deal of attention, particularly in the grams of protein, 160 grams of adipose-tissue triglyceride,
period immediately following World War II. Over the past and most of his liver glycogen stores, as the liver produces
thirty years, and particularly in the last decade, increasing 180 grams of glucose. Continued fuel utilization (particu-
attention has been focused on the late, or flow, phase. Dur- larly oxidation of protein) at these rates would lead to death
ing this period, which extends for days or even weeks after in a matter of weeks2. This does not occur because the body
the early phase, a series of metabolic changes occurs, char- undergoes a wide variety of adaptations to reduce its de-
acterized by hypermetabolism and hypercatabolism. This pendence on glucose, which is synthesized primarily from
review examines the metabolic changes that occur in the muscle protein.
flow phase of injury. The advent of parenteral nutrition has The production of glucose from a variety of precursors
made it possible to provide metabolic support for the injured is an important adaptation during a brief fast. However,
patient. Thus, the implications ofthe metabolic changes that continued production of glucose from amino acids at these
occur after injury for the design of nutritional support reg- rates does not occur, and the fasting organism increases its
imens will be emphasized. oxidation of fat. Thus, the response to starvation can be
The
adaptations to starvation include the following se- divided into two stages23: an early phase, lasting approxi-
quence of events, which are reviewed in detail in the mately one week, and a later phase, lasting five to six weeks.
bibliography9’22t222425343539. (1) There is a progressive fall During the first days of a fast, when levels of insulin are
in the metabolic rate (the obvious teleological advantage of decreased and levels of glucagon are increased2-35-39, the
this is a reduction in the depletion of energy stores), and excretion of twelve to fourteen grams of nitrogen per day,
(2) the central nervous system progressively adapts to ke- the muscle release and splanchnic uptake of amino acids,
tones instead of glucose as a primary fuel (whole-body ke- and the continued release of glucose are evidence of glu-
tone oxidation). coneogenesis. Hepatic production and brain oxidation of
During periods of starvation in the normal human, a ketones increase, and gluconeogenesis from amino acids
sequence of responses develops that is aimed primarily at decreases. Muscular uptake of glucose also decreases during
over-all fuel conservation, with particular emphasis on the a fast38. As substrate availability is thought to limit hepatic
preservation of body protein9. These responses include a gluconeogenesist2333, the decreased release of muscle
progressive fall in the metabolic rate, decreasing glucose amino acids, especially alanine, is thought to be important
utilization by the central nervous system, decreasing hepatic in protein-sparing.
gluconeogenesis and protein catabolism, and increasing uti-
Effect of Nutrients on
lization of fat and ketone production’222224253539. In
the stressed patient, the responses appear to be aimed at the Reversing the Fasting State
provision of high circulating levels of substrates, particu- Gamble26, in life-raft studies designed to determine
larly glucose. The preservation of body-tissue stores does optimum rations for survival at sea, reported that 100 grams
not appear to be a primary consideration under these con- of glucose per day decreased urinary water loss by elimi-
ditions. nating the excretion of ketone bodies in fasting volunteers.
Further experiments on the effect of a six-day fast dem-
* Reprints are not available from the authors. The Current Concepts
Reviews for 1986 will be gathered as one reprint and offered for sale by
onstrated that while both 100 and 200 grams of glucose
The Journal in 1987. completely abolished the urinary excretion of ketones, max-
t Supported by United States Public Health Service Grant HL 23975.
College of Physicians and Surgeons. Columbia University, New
imum protein-sparing was obtained with 100 grams of glu-
York. N.Y. 10032. cose per day. The addition of egg powder did not signif-

782 THE JOURNAL OF BONE AND JOINT SURGERY

 THE METABOLIC RESPONSE TO INJURY 783

icantly alter protein balance, suggesting that when the Ca- phospholipids, and twenty-five grams offree glycerol. Bren-
loric intake is insufficient protein is used as an energy nan et al.M infused subjects. divided into two groups, with
source. either Intralipid (Kabivitrium; Almeda, California) or the
The effect of small doses of glucose to decrease protein amount of glycerol contained in that amount of Intralipid.
losses was replicated by Aoki et al.2, who showed that 150 In both groups, the blood glucose levels fell during the first
grams of glucose a day (37.5 grams consumed every six four days and then rose to control levels during the last four
hours) for seven days in three otherwise-fasting obese days. Levels of serum triglyceride were elevated during the
women rapidly reduced urinary excretion of urea. During Intralipid infusion, levels of free fatty acids were elevated
the seven days, the levels of plasma free fatty acids rose throughout the Intralipid study to more than fasting levels,
significantly. levels of 3-hydroxybutyrate rose slightly, and and levels of glycerol were higher during the glycerol in-
serum immunoreactive insulin levels decreased. Neither uri- fusion. Body levels of ketones were rapidly elevated by
nary ammonia nor urinary ketoacid levels changed from Intralipid infusion and were mildly elevated in the group
baseline levels. When glucose was no longer given, 3- that received glycerol. These levels were less than those
hydroxybutyrate levels increased dramatically, and excre- seen in starvation by the eighth day. Urinary excretion of
tion of ammonia and urinary ketoacid increased. Urinary nitrogen decreased from a mean of 13.3 grams to 6.5 grams
urea increased, and then decreased to levels seen when (Intralipid group) and from a mean of 12.6 grams to 4.5
glucose was given. Thus, small amounts of glucose appear grams (glycerol group) by the eighth day. The change in
to diminish hepatic production of glucose (as evidenced by urinary excretion of nitrogen was the same for both groups.
a decrease in urea production) and to suppress ammonia Thus, the levels of urinary excretion of nitrogen were com-
formation and the excretion of ketoacids, despite the gradual parable with those seen when glucose was infused (5.0
transition to a fasting state. The subjects were then starved grams when 568 kilocalories was infused) and lower than
for three weeks and again were fed the glucose meals for in the starved state (10.7 grams). On a short-term basis
seven days. During the seven days, blood glucose values (eight days), Intralipid reduced the negative nitrogen bal-
increased while the levels of plasma free fatty acids did not ance seen during fasting, hut appeared to do so as a function
change. Small amounts of glucose consumed late in star- of the glycerol component of the infusion. Wolfe et al.45
vation appear to conserve protein by decreasing the for- suggested that triglycerides are being mobilized or utilized
mation of ammonia. probably as a result of decreasing at a maximum rate during this time and that further addition
ketone levels in blood and excretion of the ketones. of fat does not improve the situation.
Extensive work was conducted by Moore et al. on the
effect of glucose, fat, and protein on nitrogen balance in The Stress Response
the fasting state5374245. Glucose given alone3745 was shown The metabolic response to stresses is characterized by
to decrease the negative nitrogen balance seen in starvation hypermetabolism, hyperglycemia , and hypercatabolism.
alone; however, in these studies glucose was given in two This sequence provides high circulating substrates at the
doses: 150 to 200 grams per day and 600 to 700 grams per expense of body-tissue stores. In injured patients. glucose
day. Glucose was given intravenously to otherwise fasting is required by the wound, by the central nervous system,
male subjects for eight days. Total urinary nitrogen de- and by red and white blood cells. Since glucose stores are
creased from I 2.4 grams on the first day to 5.0 grams (low limited, this glucose must be synthesized from the body’s
dose) and 3. 1 grams (high dose) by the seventh day; this protein stores. Increased mobilization and oxidation of fat
was less than the 10.5 grams excreted by starved controls occur to meet the increased energy demands of non-glucose-
on the seventh day’2. Plasma glucose levels were higher in dependent tissues. These tissues apparently preferentially
the subjects who received the high dose of glucose, but in utilize fat as an energy source, thereby preserving circulating
both cases the levels remained within normal limits during glucose for the wound and the central nervous system.
the infusion period. The rise in plasma ketone levels seen
in the starved state was completely inhibited by both doses Energy Metabolism in Stress
of glucose . Plasma concentrations of most amino acids were Cuthbertson6 and Cuthbertson and Tilstone8 divided
decreased in both conditions. However, while alanine levels the response after injury into the ebb and flow states. During
were decreased in the low-glucose group, they were in- the ebb, or shock, phase, the metabolic rate (measured by
creased in the high-glucose group, which may indicate de- oxygen consumption -- indirect calorimetry) is depressed,
creased gluconeogenesis from alanine. the body temperature is lowered, and the volume of cir-
The ability of fat to reduce a negative nitrogen balance culating blood is reduced. The flow phase, or period of
has also been studied. It is generally thought that carbo- increased metabolic activity, follows after a day or two.
hydrate in small quantities (less than 500 kilocalories per Cuthbertson6 and Cuthbertson and Tilstone5 noted an in-
day) has a nitrogen-sparing effect that is not shared by fat20. crease in urinary nitrogen, sulphur, phosphorus, potassium,
However, it is necessary to separate the effect of fatty acids magnesium, and creatinine paralleling the period of in-
from the gluconeogenic precursor glycerol. Intralipid is a creased oxygen consumption . Nitrogen excretion increased
fat source that is used in parenteral nutrition, each liter of to levels as high as twenty-three grams per day. The max-
which contains 100 grams of soybean oil, twelve grams of imum excretion generally occurred between the fourth and

VOL. 68-A, NO. 5. JUNE 1986

784 C. B. MICHELSEN AND J. ASKANAZI

eighth day after both bone and non-bone injury. The nitro- loss that characterizes the catabolic state.
gen:sulphur and nitrogen:potassium ratios and the extent of
nitrogen loss indicated that the nitrogen was derived pri- Fat Metabolism during Stressed Starvation
manly from muscle breakdown. Those authors also noted Since fat serves as the primary energy substrate during
that the excretion of nitrogen was increased as a function stressed and non-stressed starvation, both states are char-
of the severity of the trauma unless the patient was already acterized by substantial increases in lipolysis. A hypertonic
depleted, in which case the response was attenuated. solution of glucose and amino acid given to a patient who
Kinney et al.29 designed a system to continuously mea- is nutritionally depleted as a result of uncomplicated star-
sure gas exchange in acutely ill patients. A rigid, transparent vation will suppress endogenous lipolytic activity; as the
head-canopy provides a closed system to measure oxygen availability of glucose to meet energy requirements in-
consumption and carbon dioxide production. Normal ranges creases, the mobilization of endogenous fat diminishest3.
of resting energy expenditure were found to be ± 10 per Administration of a similar solution to a patient who is
cent of predicted resting energy expenditure. The predicted metabolically stressed due to injury or infection will also
resting energy expenditure can be obtained from tables that reduce lipolysis, but to a lesser extent than in the non-
take into account height, weight. age, and sex. Resting stressed patient4. Thus, in the stressed patient the mobili-
energy expenditure is equal to the basal metabolic rate in- zation of endogenous fat seems to continue despite the avail-
creased by 10 per cent to account for the specific dynamic ability of exogenous glucose in quantities sufficient to meet
action of food, but does not include
expended in energy energy needs. Robin et al.4 ki-
examined free fatty-acid
activity. Uncomplicated elective operations did not increase netics in stressed patients using turnover of 4C..palmitate.
the level of resting energy expenditure. Multiple fractures In that study, suppression of oxidation of free fatty acid was
resulted in a 10 to 20 per cent increase for one to three greater in the unstressed than in the stressed fasting subjects.
weeks, while infection produced an increase of 15 to 50 per Gluconeogenesis and lipolysis are both increased in
cent. Extensive burn injury resulted in an increase from 40 fasting in the stressed as well as the non-stressed state. In
to 100 per cent that lasted for several weeks. the fasting unstressed state, compensatory mechanisms re-
Wilmore and Aulick43 and Wilmore et al. examined sult in a shift in fuel sources from gluconeogenesis to Ii-
whether the increase in oxygen consumption seen after a polysis. A major difference in these metabolic processes is
burn injury could be due to increased uptake of oxygen by observed when nutrients are infused. During unstressed star-
the wound. Twenty-one bum patients were studied between vation, both processes are significantly reduced, while in
the seventh and twenty-second day after injury, following the stressed state, there is a relative resistance to suppres-
an overnight fast. Cardiac output and total-body oxygen sion. Furthermore, endogenous and exogenous oxidation of
consumption were increased as a function of the severity of fat appear to persist even during infusions of hypertonic
the burn. Those authors concluded, therefore, that increased glucose solution.
whole-body oxygen consumption is not a function of in- These metabolic responses provide the precursors nec-
creased oxygen consumption by the wound, but rather is a essary to sustain critical physiological processes in the ab-
generalized systemic response. There is also, clearly, an sence of food. Glucose is released into the circulation in
increased requirement for glucose by the wound. large quantities to meet the requirements of the central ner-
vous system and the wound. Fat is released to meet the
Glucose Metabolism during Stress
metabolic needs of skeletal, cardiac, and respiratory mus-
The increase in blood glucose concentration that ac- des. There is resistance to utilization of glucose by these
companies injury was first reported in 1877 by Bernard6. A tissues. Metabolic changes develop such that muscle ap-
study of battle casualties in the 1950’s revealed that an parently continues to utilize fat even if sufficient glucose is
injured patient responds to oral glucose loads in a manner available. Finally, elevated levels of insulin suppress the
similar to that of a diabetic patient27. This response, now production of ketone bodies, which, during normal condi-
referred to as the diabetes of injury, has been noted even tions of nutrient deprivation, serve as an alternate energy
when blood glucose concentrations are only minimally el- source.
evated. Although insulin levels may be increased, they are Over the short term, these mechanisms serve the body
low for the prevailing glucose concentration9. well; however, when complications (such as sepsis) develop
The hyperglycemia of injury appears to be a result of and prolong the stress response, the drain on body reserves
increased production relative to normal, as uptake, clear- is so extensive that substrate and energy metabolism will
ance, and the rate of oxidation are all increased32. The el- eventually fail to meet organ and whole-body requirements.
evated rates of production, however, exceed the increased The result is a reduction in cellular energy levels3. map-
ability of the tissues to clear the glucose. When considered propriate administration of substrates can exacerbate this
together, the results of these studies suggest that healing phenomenon30. In the extreme case, this reduction can result
tissues require a high plasma concentration of glucoset5 and in multi-system organ failure7. Thus, although the substrate
that since the body’s glucose reserves are limited9, lean supply may be adequate early in stress, maximum recovery
tissue mass is sacrificed to meet this demand. The break- requires the supply of exogenous nutrients.
down of lean tissue explains the rate of urinary nitrogen In catabolic conditions such as injury or sepsis, there

THE JOURNAL OF BONE AND JOINT SURGERY

 THE METABOLIC RESPONSE TO INJURY 785

is an increase in the plasma concentration of a number of needs of cardiac and skeletal muscle so that glucose may
proteins. termed acute-phase reactants; there be an may be spared for the tissues that specifically require it, such as
increased rate of synthesis of white blood cells to combat the central nervous system and the cellular immune system.
infection and promote wound-healing; and there is an in- This pattern, unlike that observed in the fasting normal
creased rate of cell proliferation at the wound site. All of human, does not readily yield to nutritional manipulation.
these require increased net synthesis of protein, which oc- Consequently, dosages of hypertonic glucose solution are
curs primarily in the liver and bone marrow. In the human, usually ineffective in these patients; more importantly, they
the major non-dietary source of amino acids for this visceral can pose an additional stress by precipitating increases in
protein synthesis is the breakdown ofmuscle protein. Major oxygen consumption, carbon dioxide production, and nor-
concerns of recent research in this area have been to deter- epinephrine excretion, and by inducing hepatic complica-
mine: ( 1 ) whether these net changes in the breakdown of tions. These findings should not be interpreted to indicate
muscle protein and visceral protein synthesis are due to that glucose infusion is contraindicated in stressed patients;
changes in unidirectional protein breakdown or synthesis, on the contrary, a certain level of carbohydrate intake is
or both together; (2) the nature of the metabolic and en- essential to meet obligatory glucose requirements. The im-
docrine factors mediating these changes; and (3) the effects portance of glucose has been underscored by data associ-
of nutrition on these processes. This area has been reviewed ating the administration of amino acids alone with a
in detail28. reduction in cellular energy levels in injured patients. It
Injury seems to be associated with increased protein seems that a nutritional regimen that is appropriate for a
synthesis and degradation, which occur regardless of nu- patient under metabolic stress should consist of a relatively
tritional status. The mechanisms by which these changes modest concentration of glucose administered with amino
are mediated are unclear. acids and other essential nutrients.
Although fat emulsions represent the logical alternative
Muscle and Plasma Amino-Acid Profiles
to glucose loading in patients with an exaggerated caloric
The loss of nitrogen after injury has been shown to requirement and a diminished ability to clear exogenous
occur primarily from muscle. The cumulative nitrogen loss glucose, there is some disagreement concerning the use of
after major elective orthopaedic surgery may be forty to fifty these products as an energy substrate. ln the United States,
grams of nitrogen36. With severe trauma, the loss may ex- fat emulsions are prescribed primarily for the prevention of
ceed 100 grams. These losses can be put in perspective by a deficiency of essential fatty acid.
remembering that one gram of nitrogen is the equivalent of
Nutritional Support in Severe, Late Stress
thirty grams of lean tissue. Thus, 200 grams of nitrogen is
the equivalent of 6,000 grams of lean tissue. The fuel patterns discussed in the preceding sections
A series of studies by Askanazi et al.35 has been aimed pertain to the flow phase of stress, which begins twenty-
at determining the mechanisms for the nitrogen loss that four to forty-eight hours after injury. As we learn more
occurs after surgery by examining the changes in plasma about stress metabolism, it is becoming increasingly clear
and muscle amino-acid patterns. that these patterns reverse in the latter stages of sepsis.
Injury causes characteristic changes from normal val- Advanced-stage sepsis is characterized by reduced utiliza-
ues of muscle and plasma amino-acid concentrations. These tion of fat and glucose and diminished tissue concentrations
are seen to varying extents in patients with operative trauma, of high-energy phosphates. As these effects become more
severe accidental injury, and sepsis. There are twofold to pronounced, nutritional support becomes progressively less
threefold increases in muscular concentrations of the large effective. Lipid clearance, in particular, is drastically im-
neutral amino acids, including leucine, isoleucine, valine, paired in the final stages of critical illness.
methionine, phenylalanine, and tyrosine, with much smaller We now know that there are specific patients for whom
or no change in plasma concentrations. As a result, ratios the side effects of excessive infusion of glucose may offset
of muscle:plasma concentration rise as much as threefold. the physiological benefits of total parenteral nutrition. This
There is an increase in net protein breakdown in muscle and category consists of patients who are under significant met-
increased net transport of amino acids from muscle to the abolic stress as a result of injury or infection. For these
liver. people, delivery of the maximum possible glucose dosage
may not be an acceptable therapeutic goal. It is essential,
Recommendation for a Nutritional Regimen in Stress
in such circumstances, to recognize the cost at which lean
In a teleological sense, the response to injury and in- body mass is being preserved. Recent findings indicate that,
fection can be viewed as a mobilization of body protein, during metabolic stress, matching glucose dosage to glucose
fat, and carbohydrate stores to ensure normal or above- need may be preferable to supplying an overabundance of
normal circulating levels of substrate (glucose, free fatty glucose. Fat emulsions, previously prescribed solely for
acids, and amino acids) in the absence of dietary intake. their ability to prevent deficiency of essential fatty acids,
The persistence of gluconeogenesis despite high serum con- have gained acceptance as auxiliary caloric substrates and
centrations of glucose reflects the urgent nature of the re- may provide the answer to satisfying increased energy re-
quirement for glucose. Fat is mobilized to meet the energy quirements in the presence of impaired utilization of glu-

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786 C. B. MICHELSEN AND J. ASKANAZI

cose. As the usage of these products increases, some of the non-protein caloric load as fat, the composition of the reg-
metabolic complications that are associated with glucose imen of total parenteral nutrition is ultimately governed by
loading may be avoided. the patient’s clinical condition and responses to nutritional
When determining the dosage of glucose, several fac- support.
tors should be considered. Tissues that prefer glucose, such Putting aside the discussion of caloric substrate, we
as the central nervous system and the blood corpuscles, arrive at the issue that is probably the most crucial to the
require approximately 400 to 500 kilocalories of carbohy- success of nutritional support - that of timing. It is now
drate per day. In the absence of this dosage, the body resorts clear that nutritional support in any form becomes progres-
to proteolysis to meet the precursor requirements of glu- sively less effective as the severity of the stress response
coneogenesis, so that supplying the minimum glucose dos- increases. Consequently, if such supportive therapy is to
age seems essential if protein is to be spared. This quantity benefit the patient, it must be instituted early in the course
of glucose is also necessary to maintain a normal or near- of illness. If a patient is previously well nourished, the goal
normal concentration of high-energy phosphates in muscle should be prevention of major loss of protein while mini-
and to minimize the increase in excretion of norepinephrine mizing complications. Under these conditions, nutritional
that is typical of the postoperative state. support may be given via a peripheral vein as a combination
While there is clearly a need for some glucose during of nutrients that
approximate metabolic expenditure. If the
stress, the question of whether to supply the balance of stress is expected
to continue for longer than five to seven
required non-protein calories as glucose or fat remains to days, a full regimen of central venous support should be
be answered. What is certain is that the prevention of es- instituted that aims for, as a minimum, nitrogen equilibrium.
sential fatty-acid deficiency necessitates the administration In the nutritionally depleted patient, an attempt to achieve
of at least 5 per cent of the total energy requirement in the positive nitrogen balance should be made as early as is
form of fat. Although we usually supply one-half of the practical.

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