HOMEOSTATIC RESPONSES TO SPECIFIC COMPONENTS OF INJURY

Critical illness creates a variety of complex interacting homeostatic responses.

The clinical features observed are the sum of changes known to occur after single
perturbations. In the following section, events frequently observed in surgical patients are
discussed as responses to one single change. These adjustments include volume loss,
underperfusion, starvation, tissue damage, and invasive infection.
Volume Loss. Acute volume reduction associated with accidental injury or an elective
surgical procedure is a nonlethal stimulus for the mechanisms that maintain circulation and
restore blood volume. Volume loss signifies the decrease of effective circulating blood
volume. The most frequent form of volume reduction in the surgical patient is simple
hemorrhage. With blood loss there is no initial change in plasma osmolality or tonicity, and
serum sodium and/or osmolality remains normal (this is referred to as isotonic volume
reduction). Various responses are initiated after simple volume reduction, including the
stimulation of pressor receptors in the arterial tree and volume receptors in the heart. These
and other signals lead to the elaboration of aldosterone and vasopressin, which augment
fluid retention.
In addition to the hormonal responses to a volume loss, there is a marked shift of fluid
across capillary beds into the bloodstream. 20 This refill phenomenon decreases
concentration of red cells (as measured by the hematocrit) and may slightly dilute the serum
protein concentration. Transcapillary refill is stimulated by as little as a 15% to 20% loss in
blood volume and, with other mechanisms, requires about 24 hours to restore blood
volume.
In addition to the hormonal responses to a volume loss, there is a marked shift of fluid
across capillary beds into the bloodstream. 20 This refill phenomenon decreases
concentration of red cells (as measured by the hematocrit) and may slightly dilute the serum
protein concentration. Transcapillary refill is stimulated by as little as a 15% to 20% loss in
blood volume and, with other mechanisms, requires about 24 hours to restore blood
volume.
In addition to hemorrhage, volume reduction occurs by other mechanisms. There may be
acute desalting water loss associated with vomiting, diarrhea, pancreatic fistula,
uncontrolled ileostomy loss, or intestinal obstruction. In these cases, there is minimal loss
of red cell mass but often a decrease in tonicity after mobilization of cell water, which is
relatively free of sodium. If osmotic changes in the plasma are marked because of loss of
sodium, the plasma electrolyte alterations become quite distinct from those of isotonic
volume reduction, as seen with mild to moderate hemorrhage.
Fluid losses may also cause the desiccation-dehydration syndrome, and excessive water is
lost from the skin or lungs without accompanying salt loss. Such marked dehydration is
characteristic of exposure to heat but can also occur with acute renal dysfunction, diarrhea
associated with tube feedings, diabetic ketoacidosis, and simple dehydration. A rise in
serum sodium, and thus in plasma tonicity, is characteristic of these states.
Underperfusion. Volume reduction is characterized by a set of compensatory responses that
attempt to maintain circulating volume and plasma tonicity. However, blood volume
reduction of any type, if severe enough, causes a prolonged low-flow state. During a low-

flow state, oxygen delivery is inadequate for oxygen demands of the tissues despite
compensatory mechanisms, and cell deterioration occurs. Inadequate perfusion causes
accumulation of acid products, particularly lactic acid, within the body, and this is
associated with profound acidosis of both the intracellular and extracellular fluid
compartments. Compensatory adjustments are stimulated by the kidney and respiratory
tract. However, with underperfusion, minimal quantities of urine are excreted, and this,
accompanied by the presence of abnormal pigments in the plasma such as hemoglobin or
myoglobin, may cause acute renal failure. If a low-flow state persists, cellular damage
increases, disturbing membrane function. This effect is manifested by the need for large
volumes of fluid to resuscitate the patient, referred to in animal shock models as the
reuptake phenomenon. In addition, reperfusion may be associated with the generation of
free oxygen radicals, which cause tissue oxidative injury and cellular disruption. Thus,
recovery from low-flow states depends on the extent and duration of the insult. Brief
periods of underperfusion cause little sustained cellular damage, whereas more prolonged
episodes cause marked acidosis, renal failure, central nervous system (CNS) hypoxia, and
generalized disruption of cell function. Often, the patient does not recover if these
alterations are irreversible.
Starvation. In many surgical patients, fluid and nutrient intake is interrupted and
inadequate, or insufficient energy and protein are provided. When this occurs during simple
starvation, fat mobilization proceeds and ketosis results. Concentration of plasma substrate
generally reflects the decrease in glucose as a primary oxidizable fuel and the increase in
fatty acids as the body's major energy source. 5 Insulin appears to have a central role in
adaptation to fasting. As glucose and insulin levels fall, mobilization and utilization of fatty
acids are favored at high rates of oxidation. Increased concentrations of fatty acids compete
with glucose for entry into muscle cells and therefore are potent peripheral glucose
antagonists. After several days of starvation, fatty acids are primarily oxidized in the liver
to form acetoacetate, acetone, or beta-hydroxybutyrate, all referred to as ketone bodies.
During total starvation, concentrations of blood ketone rise markedly and serve as signals to
a variety of tissues to decrease glucose utilization or minimize protein breakdown. In
addition, ketone bodies serve as oxidizable fuel, since these compounds are a water-soluble
form of fat and can be used by the CNS during prolonged starvation. However, surgical
patients frequently receive some glucose in their intravenous solutions, which stimulates
insulin elaboration and limits ketosis.
Because carbohydrate stores are limited and because these glycogen stores are used rapidly
after stress, an ongoing supply of glucose must be provided. Skeletal muscle proteolysis
provides amino acids that serve as glucose precursors, although glycerol from triglyceride
breakdown may also be used as a carbon source for new glucose. 5 Gluconeogenesis results
and is generally proportional to the proteolysis and increased loss of urea in the urine.
Tissue Damage. Unlike the responses to simple starvation, which are characterized by a
generalized decrease in metabolism, injured patients demonstrate heightened metabolic
responses. These stem from the increased elaboration of catabolic hormones that stimulate
respiration, cardiac output, and mobilization and utilization of fuel. All the processes
contribute to the accelerated loss of body tissue. This response is characterized by increased
oxidation of fat and marked proteolysis, primarily in skeletal muscle. Volume loss,
underperfusion, and simple starvation may be additional components of this response, but
the specific presence of damaged tissue appears to be the initiator of this hypercatabolic
response. Tissue injury causes afferent nerve signals that increase elaboration of

adrenocorticotropic hormone (ACTH) and other pituitary hormones. However, other

substances, such as cell breakdown products or mediators released during inflammation,
may have additional metabolic effects. Many new inflammatory cells appear in the wound
soon after injury. Initially, leukocytes predominate, but later macrophages and fibroblasts
are the major cell types present. These cells release a variety of mediator substances,
including cytokines, soluble biochemical signals that influence the proliferation,
development, and function of surrounding cells to aid host resistance and wound repair.
Many of these substances have been identified and include the interleukins, tumor necrosis
factor (TNF)-alpha, the interferons, and various other growth factors (Table 42 Table 42).
These factors predominantly modify local cellular proliferation and regulate wound repair,
through their paracrine action, but they may also reach the bloodstream to exert systemic
effects, such as mediating fever, stimulating the elaboration of acute-phase proteins, and
causing redistribution of trace elements. These responses to inflammation are collectively
referred to as the acute-phase response. In addition, cytokines may stimulate the elaboration
of pituitary hormones and activate the cyclooxygenase pathway, causing prostaglandin
synthesis. Elaboration of prostaglandins, particularly PGE 2, may also contribute to some
of the systemic responses observed after tissue injury.
Invasive Infection. One major complication observed in surgical patients is infection. The
infective organisms are generally opportunistic bacteria that, under normal circumstances,
are ubiquitous, noninvasive, and therefore benign. However, the multiple sites of entry via
wounds and tubes that are present in the critically ill patient, coupled with alterations in
host defense mechanisms, cause increased susceptibility of injured patients to infection.
Infection alone initiates catabolic responses that are similar to (but not the same as) those
described after injury in noninfected patients. Both processes cause fever, hyperventilation,
tachycardia, accelerated gluconeogenesis, increased proteolysis, and lipolysis, with fat
utilized as the principal fuel. 10 If the infection is sudden and severe (such as would occur
with dehiscence of a colonic anastomosis), hypotension and septic shock may result. It is
now realized that the mediators for all these events are cytokines, products of the host's
own cells. In some cases the signal that initiates these alterations is bacterial endotoxin, a
lipopolysaccharide elaborated by gram-negative organisms. However, antigen-antibody
reactions may also trigger these events, and this mechanism is thought to be responsible for
the responses observed after gram-positive infections and antigenic stimulation, such as
blood transfusion reactions and responses following organ rejection.
After endotoxin, monocytes, macrophages, and lymphocytes are stimulated to produce
TNF, which mediates many of the systemic responses associated with infection (Fig. 44
Fig. 44). Many of the cellular events are mediated via the cyclooxygenase reaction and
can be markedly attenuated by administration of nonsteroidal anti-inflammatory agents,
which block the generation of prostaglandins. The systemic responses observed after
infection are related to the amount of cytokine elaborated; this has been demonstrated by
studies examining the response characteristics after infusion of increasing doses of TNF
into patients (Table 43 Table 43). In addition, other cytokines have been shown to
stimulate similar responses, and cytokines may interact and amplify the responses. Because
various cytokines serve as inflammatory signals, the response probably depends on the
specific disease process, the size of the initial inflammatory focus, and the type and extent
of bacterial colonization or infection. 17
RESPONSES TO ELECTIVE OPERATIVE PROCEDURES

Endocrine Changes and Their Metabolic Consequences. Most patients requiring elective
operative procedures are adequately nourished. They fast overnight and receive intravenous
solution containing 5% glucose. They then receive a general anesthetic; the skin is prepared
and the operative site draped. An incision is then made.
One of the earliest consequences of the surgical incision is the rise in levels of circulating
cortisol that occurs when afferent nervous signals from the operative site reach the
hypothalamus to initiate the stress response, which then stimulates the elaboration of
cortisol. This hormone remains at two to five times normal levels for approximately 24
hours after a major operation. Cortisol has generalized effects on tissue catabolism and
mobilizes amino acids from skeletal muscle that provide substrates for wound healing and
serve as precursors for the hepatic synthesis of acute-phase proteins or new glucose. 26
Associated with the activation of the adrenal cortex is stimulation of the adrenal medulla
through the sympathetic nervous system, with elaboration of epinephrine. Urinary
catecholamines may be elevated for 24 to 48 hours after operation and may then return to
normal. This circulating neurotransmitter has an important role in circulatory adjustment,
but it may also stimulate hepatic glycogenolysis and gluconeogenesis in concert with
glucagon and glucocorticoids.
The neuroendocrine responses to operation also modify the various mechanisms in salt and
water excretion. Alterations in serum osmolarity and tonicity of body fluids secondary to
anesthesia and the operative stress stimulate the secretion of aldosterone and antidiuretic
hormone (ADH). The ability to excrete a water load after elective surgical procedures is
reduced. The usual postoperative patient concentrates urine to 1 to 2 ml. water per mOsm.
solute excreted, corresponding to a urine osmolarity of 500 to 1000 mOsm. per liter, even
in the presence of adequate hydration. Hence, weight gain secondary to salt and water
retention is usual after operation (Fig. 45 Fig. 45). Edema occurs to a varying extent in
all surgical wounds, and this accumulation is proportional to the extent of tissue dissection
and local trauma. Administration of sodium-containing solutions during operation replaces
this functional volume loss as extracellular fluid redistributes in the body. This third-space
fluid eventually returns to the circulation as the wound edema subsides, and diuresis begins
2 to 4 days after the operation.
Alterations occur in the response of the endocrine pancreas after elective operation. In
general, insulin elaboration is diminished and glucagon concentrations rise. This response
may be related to increased sympathetic activity or to the rise in levels of circulating
epinephrine, which is known to suppress insulin release. The increased elaboration of
glucagon may be related to increased stimulation of the sympathetic nervous system or to
alterations in circulating mediators. The rise in glucagon and the corresponding fall in
insulin are a potent signal to accelerate hepatic glucose production, and, with other
hormones (epinephrine and glucocorticoids), gluconeogenesis is maintained.
The postoperative hormonal responses are thought to orchestrate physiologic and
biochemical changes that benefit the host. Salt and water conservation support the
circulating blood volume. Augmented hepatic glucose production provides adequate
essential fuel for the nervous system, the red and white blood cells, and the healing wound.
Skeletal muscle proteolysis provides amino acid precursors for gluconeogenesis and hepatic
protein synthesis, although negative nitrogen balance occurs. Postoperative lipolysis
provides abundant quantities of free fatty acid, as an additional energy source. Current
techniques of postoperative care minimize, but do not reverse, these responses.

States of Surgical Recovery. The period of catabolism initiated by operation, a combination

of inadequate nutrition and alteration of the hormonal environment, has been termed the
adrenergic-corticoid phase. 20 This period is followed by the onset of anabolism, which
occurs at a variable time in the patient's convalescence. In general, in the absence of
postoperative complications, this phase starts 3 to 6 days after open laparotomy of the
magnitude of a colectomy or gastrectomy, often concomitant with the start of oral feedings.
This turning point from catabolism to anabolism is referred to as the corticoid-withdrawal
phase because it is characterized by a spontaneous sodium and free-water diuresis, a
positive potassium balance, and a reduction in nitrogen excretion. This transitional phase
usually lasts only 1 to 2 days.
The patient then enters a prolonged period of early anabolism characterized by positive
nitrogen balance and weight gain. Protein synthesis is increased after sustained enteral
feedings, and this change is related to the return of lean body mass and muscular strength.
The fourth and final phase of surgical convalescence is late anabolism, the hallmark of
which is much slower weight gain. During this period, the patient is in nitrogen equilibrium
but in positive carbon balance, which follows deposition of body fat.
Modifying Postoperative Responses. Early investigators who studied the catabolic
responses after operation concluded that these responses were obligatory and irreversible.
However, Riegel and associates supplied adequate energy and nitrogen to postoperative
patients by feeding tube and greatly diminished the catabolic response to operation. 22
Holden and associates supported gastrectomy patients with intravenous nutrients and noted
that weight was maintained and near nitrogen balance achieved. 12 Thus, the catabolic
response to an elective operation is due in large part to inadequate food intake and is not an
obligatory consequence of operative stress.
Laparoscopic or thoracoscopic procedures have greatly reduced the postoperative impulses.
Such operations obviate the need for an open wound into the abdominal or thoracic
cavities. As a result, there is decreased postoperative pain, reduced postoperative
respiratory complications, decreased hospital stay, and an early return to normal activity,
such as food intake and exercise. Studies of patients undergoing open versus laparoscopic
cholecystectomy have shown that the minimally invasive approach is associated with a
reduced or comparable endocrine response 19 but a more normal immunologic response. 21
Such minimal access approaches will be more useful in the future and will be particularly
helpful in decreasing patient debility.
Various human studies have shown that many postoperative responses can be ablated after
denervation of the wound. Kehlet used epidural or spinal anesthesia in women undergoing
elective abdominal hysterectomy. 16 With epidural anesthesia extending from S5 to T4,
plasma concentrations of cortisol, aldosterone, glucose, and free fatty acids remained
normal, in contrast to increased concentrations in patients receiving general anesthesia
alone. Other workers have extended these observations and reported that low spinal
anesthesia blocks the elevation of catecholamines, hyperglycemia, and inhibition of insulin
release observed in patients undergoing surgical procedures on the lower half of the body.
These observations suggest that regional anesthetic techniques block afferent signals from
the wound and interrupt sympathetic nervous efferent signals to the adrenal gland and
possibly the liver. The effect of sympathetic blockade is a reduction in the apparent
magnitude of the stress response.
Growth hormone is an anabolic hormone that may improve the response to injury. Small
doses of growth hormone (approximately 3 to 4 mg. per day) and a hypocaloric diet were

administered to patients after elective gastrectomy or colectomy. 15 The subjects received

parenteral nutrition containing 20 calories per kg. per day and 1 gm. protein per kg. per day.
The nine control subjects lost 3.3 kg. (5.9% of preoperative weight) and had a cumulative
nitrogen loss of 32.64.2 gm. per 8 days. The patients receiving growth hormone lost
significantly less weight (1.3 kg.) and nitrogen loss was 7.13.1 gm. per 8 days (p <.001)
(Fig. 46 Fig. 46). Body compositional analysis of other patients receiving growth
hormone demonstrated significant gain in lean body mass compared with controls (Fig. 47
Fig. 47). 4
RESPONSES TO ACCIDENTAL INJURY
General Features and Time Course. Events that occur after injury are generally graded
responses: the more severe the injury, the greater is the response (Fig. 48 Fig. 48). The
response generally increases until a maximal level is reached; severity of injury over and
above this level simply causes a maximal response.
Responses to injury change with time, and events occurring at various points in time were
initially described as periods of ebb and flow. The early phase (ebb or low-flow phase)
occurred immediately after injury and was characterized by a fall in metabolic functions
and a decrease in core temperature but increased levels of stress hormones. 27 Blood
glucose might fall to hypoglycemic levels if the patient could not be resuscitated, and
measurements were made in the terminal state. With restoration of blood flow and with
time, the patient's responses changed (Table 44 Table 44). The metabolic rate rose, body
temperature became elevated, and blood insulin levels were normal or even increased, as
were catecholamines, glucose, and blood lactate. Levels of free fatty acids were generally
normal or decreased. These changes occurred during the flow phase, which is also referred
to as the chronic or hyperdynamic phase of injury. It was later realized that many of the
early changes were related to hypovolemia and organ perfusion; with resuscitation of the
patient and restoration of circulating blood volume, flow-phase responses occurred rapidly.
Aside from research directed toward improved shock resuscitation, most investigative work
has now been focused on the later or hyperdynamic phase of injury when wound closure,
nutritional support, prevention of infection, and respiratory support are central to patient
care.
Several other characteristics of the metabolic responses to injury may confound
interpretation of the patient's response. Complications occur in injured patients, particularly
the complication of infection, and these effects appear additive to injury responses.
Treatment variables alter injury responses, and repeated operative procedures, use of
glucocorticoids, patient paralysis during mechanical ventilation, use of positive endexpiratory pressure ventilation, and administration of pressor drugs are therapies that alter
hemodynamics and metabolism and thus may influence usual responses.
Other factors unique to each individual patient influence the metabolic responses to injury.
These include nutritional state, body composition, and other disease processes.
Signals That Initiate the Injury Responses
1. Afferent sensory nerve fibers provide the most direct and the quickest route for signals
to arrive at the CNS after stress. It has frequently been suggested that pain may serve as the
initial afferent signal after injury, and many studies suggest that the afferent nerve signals
from the injured area are essential to stimulate the pituitary-adrenal axis. 13 The
adrenocortical response to injury was not observed in animals after section of the peripheral
nerves to the area of injury, transection of the spinal cord above the injury, or section
through the medulla oblongata. A similar pattern of response to denervation before injury

has been described in humans. Both growth hormone and ACTH levels in the serum rise
within 1 hour after incision in patients receiving general anesthesia and undergoing
cholecystectomy or inguinal herniorrhaphy. However, this hormonal response did not occur
in patients undergoing abdominal procedures when epidural blockade was employed in
conjunction with the general anesthetic. 16 Nerve afferents also appear to stimulate the
elaboration of ADH after trauma. In addition, several factors that accompany the stress of
critical illnessrestraint, immobilization, environmental disturbancesmost likely alter
afferent nerve impulses and affect the response to injury.
2. Fluid loss from the vascular compartment stimulates volume and pressure receptors,
initiating a series of CNS-mediated cardiovascular adjustments. Cardiac output falls,
peripheral resistance increases, and blood is redistributed to vital organs to maintain
function. With progressive volume loss into the area of injury, the resulting hypoperfusion
reduces tissue oxygenation and disturbs the acid-base equilibrium. Chemoreceptor
stimulation thus serves as additional afferent input to both vasomotor and respiratory
centers during hypovolemia. Because loss of fluid volume after injury is closely related to
the extent of tissue damage, these specific mechanisms allow a quantitative response to
occur after trauma (i.e., the response is directly proportional to the size of the injury).
3. Circulating substances may directly or indirectly stimulate the CNS and set in motion
the injury response. Alterations in serum electrolytes, release of cell breakdown products,
changes in the amino acid pattern, and elaboration of endotoxin and the release of
cytokines, all originating from or a direct result of the wound, may initiate homeostatic
adjustments that develop after injury.
Signal Integration and Effector Mechanisms: Role of the CNS. The brain receives a variety
of signals that stress has occurred and integrates this afferent input. Although the
sympathetic nervous system is not essential to the adaptation to simple starvation, the CNS
is essential to the hypermetabolic response to injury; patients with brain death and
associated soft tissue injury failed to mount a flow-phase response. Similarly, in severely
burned patients, morphine anesthesia, which markedly reduced hypothalamic function,
caused a prompt decrease in hypermetabolism, rectal temperature, and cardiac output. 27 In
patients with an intact CNS, various adjustments are observed within the hypothalamus and
pituitary gland; these alterations in neurohormonal control appear to be specific
compensatory adjustments to stress. These alterations in CNS control have an impact on
thermoregulation, substrate mobilization, and intraorgan energy transfer.
Cytokines produced in the wound may signal the brain to initiate these changes.
Conversely, it has been demonstrated that cytokines are produced within the brain and have
been found in the cerebrospinal fluid of patients after head injury and meningitis. 18 There
is an extensive network of interleukin-1 (IL-1) nerve fibers innervating the hypothalamus,
and this cytokine may be central in initiating and directing the metabolic response to stress.
For example, chronic CNS exposure to IL-1 produced catabolism in the rat. 11 Significant
loss of weight, negative nitrogen balance, and hyperpyrexia were demonstrated in the
animals infused with IL-1 into the cerebral ventricle compared with saline-infused controls.
This stress response was also associated with activation of the hypothalamic-pituitary axis.
Hormonal Environment. Hypothalamic stimulation creates a variety of hormonal alterations
in patients after injury: in all phases of injury there is a marked rise in the counterregulatory
hormones glucagon, glucocorticoids, and catecholamines. In contrast, plasma
concentrations of the patient's anabolic hormone insulin may be low, normal, or elevated
(Fig. 49 Fig. 49). During the flow or hypermetabolic phase of injury, insulin

concentrations are normal or increased. However, the effects of these elevated insulin
concentrations on peripheral tissues (skeletal muscle and fat) are blunted. The cause of the
marked insulin resistance is related to diminished food intake and an altered hormonal
environment that exerts anti-insulin activity. 3 The counterregulatory hormones glucagon,
cortisol, and catecholamines oppose the storage or anabolic functions of insulin. In the
short term, they maintain blood glucose levels and prevent hypoglycemia. More chronic
hormonal elaboration accelerates body catabolism.
Glucocorticoids are also released after stress, and steroids have potent effects on substrate
and mineral metabolism. Cortisol is elaborated in response to increasing concentrations of
ACTH released from the anterior pituitary gland. Cortisol mobilizes amino acids from
skeletal muscle and increases hepatic gluconeogenesis; it also causes marked insulin
resistance, and these effects cause the marked hyperglycemia associated with acute illness.
3
Catecholamines. Elaboration of catecholaminesepinephrine and norepinephrinemay be
the most basic of the hormonal responses to stress. 27 These hormones exert regulatory
effects on cardiac output, regional circulation, blood glucose, and oxidative metabolism.
Epinephrine stimulates glycogenolysis, which, in skeletal muscle, promotes lactate
production. In addition, epinephrine at higher concentrations markedly inhibits insulin
elaboration, thus facilitating amino acid and fat mobilization.
The infusion of any one of these catabolic hormones alone in normal individuals causes
minimal alterations in metabolism and circulation. However, when the three hormones are
infused together, the effects are synergistic and sustained. Negative nitrogen balance,
gluconeogenesis, and hypermetabolism are observed, associated with salt and water
retention, all major components of the injury response (Table 45 Table 45). Thus, it
appears that the simultaneous elaboration of the counterregulatory hormones glucagon,
cortisol, and epinephrine is responsible in part for the posttraumatic changes.
Role of Cytokines. Another regulatory component appears to mediate other changes that
occur after injury. Inflammation associated with wound repair generates a variety of signals
such as substance P, bradykinin, and prostaglandins. Whereas most of these signals direct
local inflammatory events, some may reach the bloodstream and alter systemic metabolism.
Such a molecule is IL-1, which stimulates a variety of responses commonly observed in the
critically ill host, including the mobilization of leukocytes, the stimulation of fever, the
redistribution of circulating iron and other trace minerals, and the hepatic stimulation of
acute-phase protein synthesis. Other substances that participate in the stress response and
may be viewed as systemic mediators include TNF, IL-2, IL-6, and interferon-gamma. The
cytokines may amplify a variety of immunologic and hormonal signals, and thus act
synergistically to mediate inflammatory responses. 9 Thus, besides hormonal regulation,
the presence of a wound elicits other signals that stimulate additional responses or augment
hormone-directed changes in metabolism.
Characteristics of Flow Phase of Injury Response
Hypermetabolism. After injury, oxygen consumption rises above basal levels predicted on
the basis of age, sex, and body size. The metabolic rate is usually determined by measuring
the exchange of respiratory gases and calculating heat production from oxygen
consumption and carbon dioxide production. The degree of hypermetabolism (i.e.,
increased oxygen production) is generally related to the severity of the injury. Patients with
long bone fractures exhibit a 15% to 25% increase in metabolic rate, whereas those with
multiple injuries increase metabolic needs by 50%. Patients with severe burn injuries

(greater than 50% of body surface area) demonstrate resting metabolic rates that may reach
twice basal levels. These rates of heat production in trauma patients are contrasted with
those that occur in postoperative patients, who rarely increase their basal metabolic rate by
more than 10% to 15% after operation.
Concomitant with the development of hypermetabolism, the trauma patient usually
develops a 1 to 2 C. elevation in body temperature. This posttraumatic fever is a wellrecognized component of the injury response, represents an upward shift in the
thermoregulatory set point of the brain, 1 and is probably the consequence of increased
levels of IL-1. In general, if this febrile response is not marked (less than 38.5 C.) and the
patient is asymptomatic, the fever is rarely treated.
Alterations in Protein Metabolism. Extensive urinary nitrogen loss occurs after major
injury. Because of the magnitude of these losses and the progressive wasting of skeletal
muscle mass and associated muscle weakness, it was originally hypothesized that the
nitrogen loss was a generalized and accelerated breakdown of muscle protein. 8 Like other
responses, the loss of nitrogen after injury is related to the extent of the trauma but also
depends on the age, sex, and previous nutritional status of the patient, since these factors
help determine the size of the muscle mass.
Nitrogen balance studies demonstrate marked negative nitrogen balance after injury, but
these studies reflect only net nitrogen catabolism and not the absolute rate of nitrogen
breakdown. In normal individuals, nitrogen equilibrium is maintained by a careful balance
between rates of protein synthesis and degradation. Negative nitrogen balance occurs if the
breakdown rate increases and protein synthesis remains the same, or if the breakdown rate
remains the same and the rate of synthesis decreases (Table 46 Table 46).
Muscle is the origin of the nitrogen loss in the urine after extensive injury. However, it has
been recognized that the composition of amino acid efflux from skeletal muscle does not
reflect the composition of muscle protein. Alanine and glutamine constitute the majority of
amino acids released, whereas each makes up only about 6% of muscle protein. Glutamine
is extracted by the kidneys, where it contributes ammonium groups for ammonia
generation, a process that produces the net loss of acid, and this effect can be augmented by
administration of glucocorticoids. 23 Glutamine is also taken up by the gastrointestinal
tract, where it serves as an oxidative fuel. The gut enterocytes convert glutamine primarily
to ammonia and alanine, and these two substances are released into the portal venous blood.
The ammonia is then removed by the liver and converted to urea; the alanine may also be
removed by the liver and serve as a gluconeogenic precursor. After the stress of a standard
laparotomy, glutamine consumption by the bowel and the kidneys is accelerated, 24 and the
reaction appears to be regulated by increased elaboration of the glucocorticoids. 23
Although skeletal muscle releases alanine at an accelerated rate, the gastrointestinal tract
and kidneys also accelerate alanine production. This amino acid is extracted by the liver
and used in the synthesis of glucose, glutathione, and acute-phase proteins. Therefore,
glutamine and alanine are important compounds that participate in the transfer of nitrogen
from skeletal muscle to visceral organs. However, their metabolic pathways favor the
production of urea and ammonia, which are lost from the body (Fig. 410 Fig. 410).
Alterations in Glucose Metabolism. Hyperglycemia commonly occurs after injury. Hepatic
glucose production is increased, and the accelerated gluconeogenesis generally tends to be
related to the extent of the injury. 29 Much of the new glucose generated by the liver in
injured patients arises from 3-carbon precursors (lactate, pyruvate, amino acids, and
glycerol) released from peripheral tissues.

Studies have been performed to determine the sites of glucose utilization produced by the
liver. First, glucose uptake was measured across injured and uninjured extremities. Net
glucose flux across uninjured extremities was low, suggesting that fat, not glucose, was the
primary fuel for resting skeletal muscle in the postabsorptive state. However, increased
glucose uptake occurred across the injured extremity. 28 In addition, the injured extremity
released large quantities of lactate, which represented as much as 80% of the glucose
consumed. Specialized cells of the wound and inflammatory tissue (fibroblasts,
macrophages, leukocytes) undergo anaerobic metabolism and demonstrate a large capacity
for lactate production. Additional measurements have further characterized the glucose
disposal in resting patients after injury (Fig. 411 Fig. 411).
In addition to the accelerated glucose flow that occurs after injury, there is profound insulin
insensitivity. These effects do not occur because of inadequate quantities of insulin released
from the endocrine pancreas, for in most cases hyperinsulinemia exists. However, similar
effects are observed after alterations in the hormonal environment. For example, insulinmediated forearm glucose uptake is markedly diminished in normal subjects after 2 hours
of epinephrine infusion. Similarly, 3 days of glucocorticoid administration decreases
insulin-stimulated forearm glucose uptake. 3
Alterations in Fat Metabolism. To support hypermetabolism, increased gluconeogenesis,
and interorgan substrate flux, stored triglyceride is mobilized and oxidized at an accelerated
rate. This may be the result of continuous sympathetic nervous system stimulation.
Although there is accelerated mobilization and utilization of free fatty acids in injured
subjects, ketosis during brief starvation is blunted, and the accelerated protein catabolism
remains uncontrolled. If severely injured patients are unfed, their fat and protein stores are
rapidly depleted. Such malnutrition increases susceptibility to added stresses of
hemorrhage, operation, and infection and may contribute to organ system failure, sepsis,
and death.
Circulatory Adjustments. In the initial phase of injury, blood volume is reduced, peripheral
resistance increases, and cardiac output falls. With resuscitation and restoration of blood
volume, cardiac output returns to normal and then increases, a characteristic of the flow of
hyperdynamic phase of injury. This augmented blood flow is necessary to maintain wound
perfusion and the increased demands of visceral organs. Marked vasodilation occurs in
vessels that perfuse injured areas, and this is accompanied by the ingrowth of new
capillaries.
The neurovasculature of a large wound appears to be released from central neurogenic
regulation, although it is not known whether this effect is the result of actual physical
disruption of vasomotor efferent nerves or of interference with neuromuscular transmission
in innervated vessels due to the local inflammatory factors. This loss of neural control
allows local environmental factors to exert a major influence on wound blood flow. Control
of wound circulation is similar to other critical tissues (heart, brain, working skeletal
muscle), in which blood flow varies as a function of local metabolic conditions rather than
being part of integrated central vasoregulatory reflexes. This implies that as long as blood
pressure is maintained, wound perfusion is ensured.
SUMMARY
Homeostatic adjustments constantly occur in surgical patients in an effort to maintain the
milieu intrieur and ensure wound healing. Multiple factors, including diminished blood
volume, tissue underperfusion, reduced food intake, extensive tissue damage, and invasive
infection, initiate these responses via the neuroendocrine system. As a result of these

physiologic adjustments, tissue perfusion is maintained, which supports the increased

metabolic demands accompanying critical illness. Increased skeletal muscle proteolysis and
accelerated gluconeogenesis are coupled responses that also occur; these biochemical
alterations provide essential nutrients to support vital organ function and wound repair.
An elective or semielective operative procedure in the previously healthy patient stimulates
minor catabolic changes when present-day anesthetic and operative techniques are
successfully employed. However, multiple injuries, large burns, invasive infections, and
major operative procedures in patients with minimal physiologic reserve, such as the
elderly, require constant intervention on the part of the surgeon to help maintain the internal
environment and aid recovery. As a result, patients with catabolic illnesses can sustain nearmaximal stresses and yet heal their wounds and resolve their infections. With appropriate
support of bodily changes, body composition and function are restored, and the patients
return to a useful and normal life.