PART ONE

Principles in the Management of

Traumatic Injuries
CHAPTER

1 Metabolic Response to Trauma

Thomas A. Stark
| Harry L. Anderson, III

OUTLINE
Physiologic Response Clinical Implications
Mediators of the Response Modulation of the Response
Neuroendocrine Response Adult Respiratory Distress Syndrome
Lipid-Derived Mediators Nutrition As Therapy
Cytokines Deep Vein Thrombosis Prophylaxis
Polymorphonuclear Neutrophils Stress Gastritis

I
njury produces profound systemic effects. Hormones, or leukopenia, tachycardia, and tachypnea. When the
the autonomic nervous system, and cytokines all inflammatory response impairs function of organs or
produce a series of responses that are teleologically organ systems, the term multiple organ dysfunction syndrome
designed to help defend the body against the insult of (MODS) is used. As greater sophistication in the care of
trauma and promote healing. Classically, these responses the multiply injured patient has permitted careful obser-
have been described as the stress response, a term coined vation and analysis of the metabolic changes that accom-
by the Scottish chemist Cuthbertson in 1932.1 However, pany trauma; similar advances in the field of molecular
some of these responses may be counterproductive. The biology have allowed the identification and measure-
cascade of interactions is orchestrated in the severely ment of the precise hormones and inflammatory media-
traumatized patient to produce a host of responses that tors involved in the body’s response to trauma. This
follow a recognizable pattern, but the depth and dura- chapter reviews the mechanisms and consequences of
tion of these changes are variable, usually proportional the metabolic response to traumatic injury and some
to the extent of the injury and the presence of ongoing common approaches to the problems produced by these
stimulation. Stresses other than major trauma produce metabolic derangements.
alterations in the metabolic responses; examples are
burns, sepsis, and starvation. Each results in marked PHYSIOLOGIC RESPONSE
variations in the metabolic response, and this variability
persists during the later chronic and recovery phases of Tissue damage produces an inflammatory reaction that
the original injury (Fig. 1-1). causes local effects, such as tissue edema, vasoconstric-
The body’s initial response to insult (the acute phase) tion, and thrombosis. Other mediators released into the
is directed at maintaining adequate substrate delivery to systemic circulation act at sites removed from the injury.
the vital organs, in particular oxygen and energy. Cuth- For example, they stimulate the autonomic nervous
bertson’s pioneering work recognized the increases in system, with concomitant production of hormones, cyto-
basal temperature, energy expenditure, and oxygen con- kines, and arachidonic acid metabolites. The orches-
sumption, and also the loss of potassium and nitrogen.2,3 trated response seen with severe injury has been
The term systemic inflammatory response syndrome (SIRS) is described as having two phases that overlap, the ebb
used to describe the body’s response to infectious and phase, which occurs immediately and may last as long as
noninfectious causes and consists of two or more of the 24 hours after injury, and the flow phase, which may last
following—hyperthermia or hypothermia, leukocytosis for weeks.
1
2 PART I Principles in the Management of Traumatic Injuries

venous catheter, near-infrared spectroscopy (NIRS), and

continuous cardiac output monitoring by arterial wave-
Change from baseline

+ form analysis are as effective at guiding therapy.8-10

The measured serum lactate level may help guide
therapy and additional resuscitation. During shock states,
tissue perfusion is decreased and increasing numbers of
Time cells depend on anaerobic metabolism for energy. Nor-
malization of serum lactate levels can indicate a return
to global aerobic metabolic states and serve as an end
Death point for resuscitation. Partly because of the reversible
nature of hypoperfusion in the trauma setting, initial
serum lactate levels are not themselves independent pre-
Acute phase Chronic phase Recovery
dictors of morbidity and mortality.11
FIGURE 1-1 Phases of metabolism after critical illness and injury. Similar injuries to different body regions can produce
(Adapted from Mongardon N, Singer M: The evolutionary role of dramatic differences in metabolic requirement (Fig.
nutrition and metabolic support in critical illness. Crit Care Clin 1-2). Two injuries in particular are worth special mention
26:443–450, 2010.) because of their notable metabolic consequences. The
first is injury caused by head trauma. When brain injury
is superimposed on multisystem trauma, the risk of death
more than doubles.12 Increased mortality may not be
The first, or ebb, phase is characterized by the release directly caused by neurologic injury per se, but rather by
of catecholamines and vasoactive hormones. Cardiac the systemic consequences of deranged metabolism.13 In
output is elevated by increases in heart rate and cardiac addition, many methods whereby brain-injured patients
contractility. Peripheral and splanchnic vasoconstriction are managed after injury have themselves profound
occurs and extravascular fluids are mobilized to maintain effects on metabolism. Examples of these interventions
blood volume. These hemodynamic consequences act to include steroids, systemic dehydration, muscle paralysis,
preserve blood volume. The respiratory rate is also hyperventilation, hypothermia, hyperbaric oxygen
increased and this increase, in concert with the hemody- therapy, and barbiturate coma. The effectiveness of these
namic changes, drives maximal oxygen delivery. treatments has been challenged but they continue to
The blood glucose level is also elevated through a remain in use.14-16
complex and tissue-specific insulin resistance pathway.4 The second injury is the clinical entity of classic fat
The maintenance of blood glucose levels supports the embolism syndrome, seen particularly after long bone
obligate glucose-metabolizing tissues—brain, bone fractures. Fatty acid and triglyceride-rich fat globules
marrow, erythrocytes, granulation tissue, and the immune enter venous sinusoids at the fracture site. These fat
system. Free fatty acids are mobilized by the catabolic droplets migrate to the lung, where they are converted
hormones and become the main source of energy for by pulmonary lipase to free fatty acids, which can damage
peripheral tissue. Stored hepatic glycogen is limited and the pulmonary microvasculature. In addition, platelets
may be depleted within 1 day. are activated, aggregate, and attach to the fat droplet, a
As the catabolic or flow phase is established, the meta- process that may lead to a consumptive coagulopathy.
bolic emphasis is on the provision of substrate for healing.
The basal metabolic rate is elevated, and thereafter the
patient catabolizes muscle to make glucose. Birkhahn MEDIATORS OF THE RESPONSE
and colleagues found an almost 80% rise in catabolism
after skeletal trauma, and Kien and associates have NEUROENDOCRINE RESPONSE
reported elevations as high as 103% in burn patients.5,6 An early response of the neuroendocrine system is the
The total body nitrogen balance becomes negative. Some upregulation of the sympathoadrenal axis, which gener-
of the earlier changes of the ebb phase may be reversed; ates high plasma concentrations of epinephrine, norepi-
for example, a diuresis may occur, or the heart rate may nephrine, vasopressin, and dopamine. The peak and
slow. duration of the response parallel the severity of the
It may be difficult to separate the effects of the meta- trauma.17 These substances directly affect blood glucose
bolic response to trauma from the effects of shock or levels and also produce inhibition of glucose uptake by
incomplete resuscitation, but clearly such a distinction is tissue, which stimulates glucagon secretion. Sympathetic
necessary. The initial phase of the trauma response is activity promotes lipolysis within adipose tissue, which
complicated by an ongoing deficiency in tissue perfu- begins to provide an energy source for gluconeogene-
sion. The clinician must respond to dynamic changes in sis.18 Gluconeogenesis in the liver is stimulated by
physiology to make time-sensitive interventions. The pul- glucagon.
monary artery or Swan-Ganz catheter offers a continuous The hypothalamic-pituitary axis is stimulated at the
window into the minute to minute mechanics of the same time as the sympathetic nervous system after
severely injured patient. More recently, the safety and trauma.19 The pituitary releases adrenocorticotropic
usefulness of Swan-Ganz catheters in trauma resuscita- hormone (corticotropin, or ACTH), which stimulates
tion has been scrutinized and their routine use has the adrenal cortex to secrete glucocorticoid hormones
declined.7 Less invasive modalities such as the central such as cortisol and aldosterone. Epinephrine and
 Metabolic Response to Trauma CHAPTER 1 3

Burn size
115 70%
2800 6875 5500 110
2700 105 60%
6250 5000
2600 100 50%
2500 5625 4500 95
2400
2300 5000 4000 90
40%
2200 85
2100 4375 3500 90
2000

Estimated caloric intake (MR + 25%) Kcal/day

75
1900 3750 3000 70 30%
1800 3500 2800

Estimated metabolic rate Kcal/day

Percent change in metabolic activity

3250 2600 65 Multiple trauma with
1700
Daily basal metabolic rate Kcal/day

3000 2400 60 patient on ventilator

1600
2750 2200 55
1500
2500 2000 50 20%
1400
2250 1800 45 Severe infection,
1300 40
2000 1600 multiple trauma
1200 35
1750 1400
1100 30
1500 1200 25 10%
1000 1100 Long bone fracture
20
900 1250 1000
1125 900 15
800 1000 800 10 Peritonitis
875 700 5
700 Postoperative
750 600 Normal 0

600 -5
625 500 Mild starvation
-10

500 500 400

-15

FIGURE 1-2 Changes in resting energy expenditure associated with trauma, burns, and other common clinical conditions. (Adapted From
Wilmore DW: The metabolic management of the critically ill, New York, 1977, Plenum Press.)

cortisol promote muscle breakdown, protein catabolism, platelet aggregation, altered pulmonary vascular reactiv-
and amino acid release. ity, and changes in endothelial permeability.
The effects of the flow phase of the metabolic response
to trauma are partly attributable to hormones such as CYTOKINES
glucagon and cortisol, but not entirely, because the cata- Protein mediators, collectively called cytokines, are pro-
bolic consequences extend beyond measurable elevated duced at the site of injury and by diverse circulating
levels of these hormones.20,21 This finding has implicated immune cells. Monocytes, lymphocytes, macrophages,
other factors such as cytokines or the suppression of and other cells release cytokines. They can act locally as
other hormonal axes such as those of somatostatin and paracrines by way of direct cell to cell communication or
growth hormone. systemically when produced in excess by way of endo-
crine mechanisms. The most important cytokines in
LIPID-DERIVED MEDIATORS trauma are tumor necrosis factor (TNF), the interleukins
Cyclooxygenase products of arachidonic acid metabo- (IL-1, IL-2, IL-6, and IL-8), the interferons, and various
lism are present in increased amounts in human studies growth factors such as granulocyte-macrophage colony-
of injury. Thromboxane A2 accentuates neutrophil stimulating factor (GM-CSF), and platelet-derived growth
aggregation and, with prostacyclin, has potent and oppos- factors (PDGFs). They enhance immune cell function
ing vascular effects that may have a role in pulmonary and are responsible for the systemic effects of inflamma-
hypoxic vasoconstriction and systemic vasodilation. tion and sepsis, such as fever, leukocytosis, hypotension,
Lipoxygenase products are also released in large quanti- delayed gastric emptying, and malaise.
ties and affect the permeability of the pulmonary vascu- Thought to be the most proximal mediator of the
lar bed. inflammatory response, TNF was originally described as
Platelet-activating factor (PAF) is a phospholipid the catabolic factor cachectin.22 At least two forms of TNF
metabolite released by a number of cells, including neu- exist.23,24 TNF influences cellular attraction as part of the
trophils. The response to PAF at the endothelial surface local inflammatory response, leukocyte migration, and
results in enhanced superoxide production, enhanced systemic hypotension.25,26 It also promotes muscle
4 PART I Principles in the Management of Traumatic Injuries

catabolism, free fatty acid release, and hepatic synthesis

of acute-phase reactants. TNF free receptor is a glycosyl-
ated protein found in membrane-bound and free-floating
forms. In contrast to IL-1, TNF appears to act peripher-
ally and has no direct effect on lymphocyte activation.27
The interleukins are polypeptides released from lym-
phocytes; each is numbered according to the amino acid
sequence that elicits its action.28 Circulating free recep- sTNFr
tors are known for IL-1 and IL-6. Free receptors may exist
for all cytokines. They appear to function in the regula- IL-1RA
tion of cytokine activity. IL-1, which can be detected in
the circulation within a few hours after injury, has mul-
sIL-2r
tiple biologic effects, including the activation of resting
T lymphocytes and macrophages, induction of hemato-
Control 1 2 4 12 1 3 7
poietic growth factors, stimulation of chemotaxis of neu- hour hour hour hour day day day
trophils, and synthesis of collagen and collagenases.
More profound systemic effects include fever and changes Time post-injury
in protein metabolism. Originally described as pyrexin,
IL-1 was shown in subsequent studies to act via the pro- FIGURE 1-3 The sequential release of cytokine receptors and
duction of prostaglandins in the hypothalamus and to receptor agonists after injury. IL-1RA, interleukin-1 receptor
alter the set point of the thermoregulator in the hypo- antagonist; sIL-2r, soluble interleukin-2 receptor; sTNFr, soluble
thalamus.29,30 It is in this way that antiprostaglandin TNF receptor. (Adapted from Cinat M, Waxman K, Vaziri ND,
agents, such as aspirin, can block the fever effect of et al: Soluble cytokine receptors and receptor antagonists are
IL-1.31 A byproduct of IL-1 metabolism can increase pro- sequentially released after trauma. J Trauma 39:112–118,1995.)
teolysis of human muscle and induce hepatic protein
synthesis.32,33 Identified as a B cell differentiation factor,
IL-6 is now recognized as the final common mediator in mediators of the stress response that multiplies the effect
a cascade of cytokine activity that alters hepatocyte of the already enhanced PMNs.42,43
protein synthesis.34,35
The interactions of cytokines with one another and CLINICAL IMPLICATIONS
the stress response hormones have been increasingly
studied. Cytokines are potent stimulators of the release The successful management of the metabolic changes
of other mediators (e.g., IL-1 acting on the hypothala- that accompany severe trauma influences and may
mus). Evidence exists for convoluted positive-feedback prevent some of the major complications of trauma—
relationships organized within the cytokine cascade. namely impaired immune function, multiple organ
Release of early mediators, for example TNF, triggers failure, and sepsis.44
release of the complete aggregate of cytokines, which
then combine to elicit the host response. MODULATION OF THE RESPONSE
The cytokine receptors and cytokine agonists may Researchers have tested novel therapeutic strategies and
have several roles in trauma patients. Both are released options aimed at selectively inhibiting the undesirable
in a sequential manner, paralleling the release of cyto- actions of cytokines while allowing the appropriate
kines, and they modulate the body’s response to trauma.36 responses to be expressed. Some effects of cytokines on
Figure 1-3 demonstrates the fluctuating levels of cytokine target tissue have been successfully blocked by the use of
receptors over time. Quantitative serum cytokine levels, anticytokine antibodies and specific cytokine receptor
particularly IL-6, correlate with injury severity and serve antagonists. Animal studies, in particular, have suggested
as a predictor of adverse outcomes and mortality.37,38 significant efficacy of these agents, but the results in
Although highly sensitive, lack of specificity has limited humans have been largely disappointing, particularly
their use in clinical settings. when they have been used in septic patients.45 Most of
the work, however, has focused on multicenter trials of
POLYMORPHONUCLEAR NEUTROPHILS patients who have sepsis from many causes, rather than
Catecholamines and glucocorticoids marginalize periph- solely the multiply injured. Caution must nonetheless be
eral polymorphonuclear neutrophils (PMNs) and recruit exercised because of the risk that these agents may neu-
them from the bone marrow.39,40 Lipids and cytokines tralize the beneficial, survival-enhancing effects of the
(e.g., IL-1, TNF, PAF) then prime these cells for enhanced cytokines and other elements of inflammation. Another
superoxide anion release and sequestration in end- problem with these therapies is that cytokines are rapidly
organs.41 Capillary endothelial integrity is disrupted, released after injury, and the administration of antibod-
leading to the formation of edema, defects in oxygen ies, by necessity, occurs later—after the initiation of the
delivery, hypoxic cellular injury, and other adverse con- cytokine cascade.
sequences for cellular homeostasis. This derangement Pharmacologic manipulation of the end-organ
leads to the clinical entity of multiple-organ failure. response to stress is also accomplished with some drug
Human studies have supported this sequence and also classes that act on specific mediators of the response. For
suggested that additional stress results in a rerelease of example, cyclooxygenase inhibitors such as ibuprofen
 Metabolic Response to Trauma CHAPTER 1 5

Critical illness

Catabolism Impaired GI motility Starvation for

medical reasons
Risk of aspiration
Unsuitable
nutrition protocols
Increased energy
requirements

Insufficient coverage of energy target by EN alone

Negative protein-energy balance Supplemental

Undernutrition parenteral
nutrition

Increased morbidity
?
Increased mortality
Longer length of stay
Longer recovery

FIGURE 1-4 Factors whereby enteral nutrition may result in undernutrition of critically ill and injured patients—the potential role of
supplemental parenteral nutrition. (Adapted from Thibault R, Pichard C: Parenteral nutrition in critical illness: Can it safely improve
outcomes? Crit Care Clin 26:467–480, 2010.)

inhibit the production of eicosanoids and may thus blunt hydrocortisone therapy attenuates the stress response
the physiologic response to cytokines, such as fever, asso- and decreases the likelihood of hospital-acquired pneu-
ciated with TNF, IL-1, and IL-6. In patients with sepsis, monia.54 Further research is needed to establish practical
ibuprofen has shown some improvement in clinical therapeutic strategies, particularly in traumatic brain
parameters, but has not been proven to decrease the injury, in which high-dose steroids have been associated
duration of shock or improve mortality.46 with an increase in mortality.55
Control of hyperglycemia in critically ill surgical Human activated protein C (drotrecogin alfa [acti-
patients has been shown in a large, prospective, random- vated]) was one of the first approved recombinant agents
ized trial to decrease morbidity and mortality. Intensive targeting the procoagulant and generalized inflamma-
insulin therapy (IIT) requires maintenance of blood tory response that occurs during sepsis. It had been ini-
glucose levels below 110 mg/dL.47 Subsequent analysis tially found to reduce death rates in patients with severe
found that increased mortality from hypoglycemic events sepsis.56 Ongoing surveillance proved that there was no
negates the benefits of IIT in clinical practice. Trauma survival benefit in patients with severe sepsis when com-
patients, however, were a subset found to having bene- pared with placebo, and the drug has since been with-
fited the most from IIT.48 Further investigation is neces- drawn from the market.57
sary to determine safe and effective mechanisms for Pharmacologic manipulation of the response to trau-
glycemic control in trauma patients. matic injury has been met with limited success. Research
The role of glucocorticoids in modulating the stress continues to attempt to identify agents that protect the
response remains unclear. In severe cases of injury, sepsis, patient from the deleterious effects of the host response.
and critical illness, the adrenal system is unable to supply Knowing which patient may benefit from a particular
the overwhelming demand for glucocorticoids, and a medication may be a function of that individual’s unique
relative adrenal insufficiency ensues.49 Pharmacologic DNA. Current studies have identified specific genetic
factors such as even a single dose of etomidate have also polymorphisms that are predictors of adverse outcomes
proven to increase rates of adrenal insufficiency and in severe trauma and sepsis.58 Future investigation may
mortality in the critically ill.50 Multiple trials have failed help develop individually tailored treatments.
to identify a definite improvement in mortality, although
low-dose corticosteroid therapy may decrease the dura- ADULT RESPIRATORY DISTRESS SYNDROME
tion of shock states and improve short-term survival.51-53 The adult respiratory distress syndrome (ARDS) is an
In trauma patients, there is some evidence that acute illness characterized by noncardiogenic pulmonary
6 PART I Principles in the Management of Traumatic Injuries

edema. This refractory hypoxemia arises in part as a A recent study comparing a special enteral formula-
consequence of lung inflammation secondary to the tion of eicosapentaenoic acid, gamma-linolenic acid, and
mediators of the acute response to trauma. Damage to antioxidants versus a standard formulation to patients
the alveolar-capillary interface results in intrapulmonary during the early stages of sepsis (without organ failure)
shunting of blood, raised pulmonary vascular pressures, yielded different results.69 The study, funded in part by
and surfactant depletion. the product manufacturer, revealed no significant differ-
The syndrome is primarily treated by mechanical ven- ence in mortality between the two groups. A significant
tilation, and the National Institutes of Health Acute reduction in the appearance of cardiac and respiratory
Respiratory Distress Syndrome Network has identified failure occurred in the study population given the special
that low tidal volume ventilation (6 mL/kg predicted enteral formulation versus those given the standard
body weight) was superior to using traditional tidal formula control. Subjects in the test arm also experienced
volumes (12 mL/kg of predicted body weight) in treat- a benefit of fewer days on mechanical ventilation, fewer
ing hypoxemia.59 When therapy fails to keep pace with days in the intensive care unit, and shorter length of hos-
progressive lung dysfunction, alternative therapies— pital stay. The concept of immunonutrition continues to
such as high-frequency oscillatory ventilation, prone evolve and, particularly within the last 5 years, the approach
positioning, and extracorporeal life support (ECLS) or to the modulation of nutrition by timing to feed, amounts,
extracorporeal membrane oxygenation (ECMO)—may route of administration,and composition of the nutri-
be indicated.60-63 tional product have yielded new information regarding
how to optimally feed injured and critically ill patients.
NUTRITION AS THERAPY
The advantages of enteral nutrition over parenteral DEEP VEIN THROMBOSIS PROPHYLAXIS
nutrition have been clearly demonstrated, and the gas- The hypercoagulable state exists immediately following
trointestinal tract should be used whenever possible. severe traumatic injury, and an even more severe injury
Recently, a role for supplemental parenteral nutrition may be followed by increases in the hypercoagulable
has been advocated (Fig. 1-4). The traditional prefer- state.70 When this condition exists in combination with
ence is to feed patients by the enteral route for reasons patient immobility and direct venous injury, Virchow’s
that include a reduction of the number of enteric organ- triad for venous thrombosis is complete. Tissue injury
isms that may be responsible for bacterial translocation. may be responsible for the release of tissue thromboplas-
Stimulation of the enterocyte brush border and gut- tin, which initiates the conversion of factor VII to enzyme
associated lymphoid tissue is an important protective factor VIIa. Therefore, it is important to provide deep
mechanism against the proliferation of the offending venous thrombosis (DVT) prophylaxis with subcutane-
organisms.64 The route of feeding may also have an ous mixed or low-molecular-weight heparins when pos-
impact on the production of cytokines after injury; sible, except in cases in which specific contraindications
thus, use of the enteral route may confer an additional exist, such as intracranial hemorrhage, known peptic
advantage.65 ulcer, solid organ laceration, and hematoma. An alterna-
Considerable attention has focused on nutrients that tive is the placement of a sequential compression device
attenuate the metabolic response to injury. Nutrients on the limbs. The overall efficacy of DVT prophylaxis is
that appear to enhance the immune system include argi- well established; it is important that prophylaxis be main-
nine, glutamine, and nucleic acids. The immune system tained for the duration of the hospital stay or at least
may be enhanced by altering the relative amounts of until the patient is fully mobile.71
omega-6 versus omega-3 unsaturated fatty acids.66,67 Traumatic brain injury with intracranial hemorrhage
Other nutrients may act as oxidants, preventing damage prohibits the use of chemoprophylaxis. Recent data have
by free radicals, such as the common antioxidants vita- demonstrated a three- to fourfold increased risk of DVT
mins A, C, E, and the trace element selenium. in brain-injured patients. This patient population
There has been lukewarm interest in the concept of requires early application of appropriate nonpharmaco-
“immunonutrition”to ameliorate the end-organ damage logic measures and an early decision on the placement
from critical illness and sepsis, which may later result in of inferior vena cava filters (removable, if possible) for
acute renal failure and ARDS. A study of supplementa- pulmonary embolism prophylaxis.72
tion with an enteral diet of omega-3 fatty acid, gamma-
linolenic acid, and antioxidants versus an isocaloric STRESS GASTRITIS
enteral formulation was reported in 2011. These nutri- Stress gastritis is common to the multiply injured inten-
ents are typically thought to modulate the systemic sive care unit population, and patients left untreated may
inflammatory response.68 The study randomized 272 have clinically significant gastrointestinal bleeding. The
adults who had developed acute lung injury and required principal risk factors for stress gastritis are head injury,
mechanical ventilation. Enteral nutrition was provided to mechanical ventilation, and abnormal coagulation pro-
both patient groups using a standard protocol, and the files. Prophylaxis using histamine-2 receptor antagonists
study supplement was provided twice daily to the study or proton pump inhibitors is very effective.73
cohort of patients. The study was halted early because of
futility. The ventilator-free and intensive care unit-free SUMMARY
days were lower in the omega-3 group and, although not
significant, hospital and 60-day mortality were higher in Injury produces a series of physiologic changes mediated
the omega-3 group. by local and systemic agents and systemic effects, mainly