METABOLIC RESPONSE TO

TRAUMA
Sudarsan Agarwal
sushiagarwal@gmail.com
Pinnamaneni Medical College
Vijayawada
 JOHN HUNTER
(1794)
• “Treatise on the
Blood, Inflammation and
gunshot wounds”

• “Impressions are
capable of producing or
increasing natural
actions and are then
called stimuli, but they
are capable of producing
too much action as well
as depraved, unnatural
or what we call diseased
action.”
 Basic Concepts in Homeostasis
1. Homeostasis is the foundation of normal
physiology.

2. Stress-free peri-operative care helps to restore

homeostasis following elective surgery.

3. Resuscitation, surgical intervention & critical care

can return the severely injured patient to a
situation in which homeostasis becomes
possible once again.
• As a consequence of modern understanding to
metabolic response to injury, elective surgery
practice seeks to reduce the need for a
homeostatic response by minimizing the
primary insult
(as for e.g – Minimal access surgery )
 Response Components
• Physiological Consequences
• Metabolic Manifestations
• Clinical Manifestations
• Laboratory Changes
 Response Components
PHYSIOLOGICAL METABOLIC
• Increased Cardiac Output • Hypermetabolism
• Increased Ventilation • Acclerated
• Increased Membrane Gluconeogenesis
Transport • Enhanced Protein
• Weight loss breakdown
• Wound Healing • Increased Fat oxidation
 Response Components
CLINICAL LABORATORY
• Fever • Leucocytosis/Leucopenia
• Tachycardia • Hyperglycemia
• Tachypnea • Elevated CRP/Altered acute
• Presence of wound or phase reactants
Inflammation • Hepatic/Renal dysfunction
• Anorexia
 Graded Nature of the injury response
• Metabolic response to injury is Graded and
evolves with time
 Mediators of injury response
• Neuro endocrine ( Hormonal )
• Metabolic and Cytokine axes
Hormonal
 Neuro-endocrine response to
injury/critical illness
The Neuro-endocrine response to severe
injury/critical illness is biphasic

1. Acute phase characterized by an actively secreting

pituitary & elevated counter regulatory hormones
(cortisol, glucagon, adrenaline).Changes are thought
to be beneficial for short-term survival.

2. Chronic phase associated with hypothalamic s

uppression & low serum levels of the respective
target organ hormones. Changes contribute
chronic wasting.
Purpose of Neuro- endocrine changes
following injury
The constellation of Neuro-endocrine changes
following injury acts to
1. Provide essential substrates for survival
2. Postpone anabolism
3. Optimise host defense

These changes may be helpful in the short

term, but may be harmful in the long-
term, especially to the severely injured patient who
would otherwise not have survived without medical
intervention
Proinflammatory cytokines
1. Il 1, Il 6, TNF alfa
2. NO
3. Endothelin 1

Cytokine antagonist
• Interleukin receptor antagonist, TNF soluble
receptors are released within hours of injury
 Physiological response to injury

The natural response to injury includes

1. Immobility
2. Anorexia
3. Catabolism
• In 1930, Sir David Cuthherstson derived the
metabolic response to injury in humans into
“ebb “ and “flow” phases
 Metabolic changes after major trauma
(Cuthbertson, Lancet, 1942)
EBB (Untreated shock) FLOW PHASE
• Dec body temp • Inc body temp
• Dec O2 consumption • Inc O2 consumption
• Lactic acidosis • Negative Nitrogen bal
• Inc stress hormones • Inc stress hormone
• Dec Insulin • Normal to Inc Insulin
• Hyperglycemia • Hyperglycemia
• Gluconeogenesis • Gluconeogenesis
• Inc substrate consumption • Proteinolysis (autocannabalism)
• Hepatic Acute phase response • Lipolysis
• Immune activation • Immunosuppression
 Ebb and Flow
Phase Duration Role Physiological Hormones

Ebb <24 hrs Maintenance of blood Dec BMR, Dec temp, Catechol,
volume, Dec O2 consump, Cortisol,
catecholamines vasoconst, Inc CO, Inc aldosterone
heart rate, acute
phase proteins
Flow
Catabolic 3 – 10 Maintenance of Inc BMR, inc Temp, Inc. Insulin,
days energy inc O2 consump, -ve Glucagon,
N2 balance Cortisol, Catechol
but insulin
resistance
Anabolic 10 – 60 Replacement of lost +ve Nitrogen balance Growth hormone,
(MOORE) days tissue IGF
 Ebb
• Starts at the time of injury and lasts for
approximately 24-48 hours
• Main hormones in ebb phase are
catecholamines, cortisol, and aldosterone
• It may be attenuated by proper resuscitation
but not completely abolished
• The main physiological role of this phase is to
conserve both circulating volume and energy
stores for recovery and repair
 Flow
• It lasts for several wks
• This phase involves mobilization of body
energy stores for repair and recovery
• Following resuscitation , Ebb phase evolves
into hypermetabolic flow phase, which
corresponds to SIRS
 Key catabolic elements of flow phase
• Hypermetabolism
• Alterations in skeletal muscle protein
• Alterations in Liver protein
• Insulin resistance
 Hypermetabolism
Majority of trauma patients demonstrate energy
expenditure approximately 15-25% above
predicted healthy resting values

Factors which increases this metabolism are

centreal thermodysregulation, increased
sympathetic activity, increased protein turnover,
wound circulation abnormalities etc..
 Hypermetabolism
Hyper metabolism following injury:

1. Is mainly caused by an acceleration of futile

metabolic cycles
2. Is limited in modern practice on account of
elements of routine critical care.
 Skeletal muscle wasting
1. Provides amino acids for protein synthesis in
central organ/tissues
2. Is mediated at a molecular level mainly by
activation of the ubiquitin-protease pathway
3. Can result in immobility & contribute to
hypostatic pneumonia & death if prolonged and
excessive
 Hepatic acute phase response

• The Hepatic acute phase response represents a

reprioritization of body protein metabolism towards
the liver & is characterized by:
• 1. Positive reactants (CRP) : plasma concentration
increases
• 2. Negative reactants (albumin) : : plasma
concentration decreases
 Insulin resistance
• The degree of insulin resistance is directly
proportional to magnitude of the injurious
process.
• Following routine upper abdominal
surgery, insulin resistance may persist foe appr 2
wks
• Postop patients with insulin resistance behave in
a similar manner to individuals with type 2
diabetes
• The mainstay of treatment is i.v insulin
• Intensive insulin infusions are better over
conservative approach.
• Main labile energy reserve in the body is fat
• Main labile protein reserve in the body is
skeletal muscle

• While fat mass can be reduced without major

detriment to function, loss of protein mass
results not only in skeletal muscle wasting, but
also depletion of visceral protein mass
• With lean issue, each 1 g of nitrogen is
contained within 6.25 g of protein, which is
contained in approximately 36 g of wet weight
tissue.
• Thus the loss of 1 g of nitrogen in urine is
equivalent to the breakdown of 36 g of wet
weight lean tissue.
• Protein turnover in the whole body is of the
order of 150-200 g per day.
• A normal human ingests 70-100 g of protein
per day, which is metabolized and excreted in
urine as ammonia and urea(14 g N/day)
• During total starvation, urinary loss of
nitrogen is rapidly attenuated by a series of
adaptive changes
• Loss of body weight follows a similar course
, thus accounting for the survival of hunger
strikers for a period of 50-60 days
• Following major injury, and particularly in the
presence of ongoing septic complications , this
adaptive change fails to occur, and there is a
state of auto cannibalism , resulting in
continuing urinary nitrogen losses of 10-20
g/day(500 g lean tissue/day)
• As with total starvation, once loss of body
protein mass has reached 30-40 % of the
total, survival is unlikely
 In critically ill patients with
resuscitation,
• <24 hrs – Body weight increases due to extracellular water
expansion by 6-10 litres.

– This can be overcome by careful intra operative management of

fluid balance

• 1-10 days – Total body protein will diminish by 15% and

body weight will reach negative balance as the expansion
of extra cellular space resolves

– This can be overcome by blocking Neuro endocrine response

with epidural analgesia and early enteral feeds
 Avoidable factors that compound the
response to injury
1. Continuing hemorrhage
2. Hypothermia
3. Tissue edema
4. Tissue under perfusion
5. Starvation
6. Immobility
• Volume loss: Careful limitation of intra
operative administration of colloids and
crystalloids so that there is no net weight gain
• Hypothermia : RCT have shown that
normothermia by an upper body forced air
heating cover reduces wound
infection, cardiac complications and bleeding
and transfusion requirements
• Tissue edema : During systemic
inflammation, fluid, plasma
proteins, leucocytes, macrophages and
electrolytes leave the vascular space and
accumulate in the tissues.
• This can diminish the alveolar diffusion of
oxygen and may lead to reduced renal
function
• Systemic inflammation and tissue under perfusion: the
vascular endothelium controls vasomotor tone and micro
vascular flow and regulates trafficking of nutrients and
biologically active molecules.
• Administration of activated protein C to critically ill patients
has been shown to reduce organ failure and death and is
thought to act, in part, via preservation of the micro
circulation in vital organs
• Maintaining the normoglycemia with insulin infusion during
critical illness has been proposed to protect the
endothelium, probably in part, via inhibition of excessive
iNOS- induced NO release , and thereby contribute to the
prevention of organ failure and death
• Starvation : During starvation, the body is faced with
an obligate need to generate glucose to sustain
cerebral energy metabolism(100g of glucose per day)
• This is achieved in the first 24 hours by mobilizing
glycogen stores and thereafter by hepatic
gluconeogenesis from amino acids, glycerol and
lactate.
• The energy metabolism of other tissues is sustained by
mobilizing fat from adipose tissue
• Such fat metabolisation is mainly dependent on a fall in
circulating insulin levels.
• Eventually , accelerated loss of lean tissue is reduced as
a result of the liver converting free fatty acids into
ketone bodies, which can serve as a substitute for
glucose for cerebral energy metabolism.
• Provision of 2 litres of iv 5% D as iv fluids for surgical
patients who are fasted provides 100g of glucose per
day and has a significant protein sparing effect.
• Modern guidelines on fasting prior to anesthesia allow
intake of clear fluids upto 2 hours before surgery.
• Administration of carbohydrate drink at this time
reduces perioperative anxiety and thirst and decreases
post operative insulin resistance
• Immobility : Has been recognized as a potent
stimulus for inducing muscle wasting. Early
mobilization is an essential measure to avoid
muscle wasting
A prospective approach to prevent unnecessary
aspects of the surgical stress response
1. Minimal access techniques
2. Blockade of afferent painful stimuli (epidural
anesthesia)
3. Minimal periods of starvation
4. Early mobilization
 Therapeutic implications
The catabolic response to injury is always a
major concern in postoperative care. Three
types of interventions were tried to reduce this.
These are:
–Nutritional
–Hormonal
–Biologic
 Nutritional :
Three important aspects of nutrition have to be
considered
• Route of administration (enteral/parenteral): enteral
nutrition is preferred. It improves the protein balance
& clinical outcome
• Timing (early versus late feeding):
– enteral nutrition is started as early as possible. Early is
superior in its effects on catabolic & hyper metabolic
response to injury.
– A slower rate of fluid resuscitation after trauma
hemorrhage leads to a faster restoration of the depressed
cell-mediated immunity. Whereas rapid fluid resuscitation
produces a prolonged depression of immune responses.
Composition of feeding(nutritional
supplements): commonly tried are
• Glutamine (both for enteral & parenteral
nutrition)
• Branched chain amino acids –
leucine, isoleucine & valine
• Arginine can stimulate GH & IGF-1 release and
is a substrate for NO production. At high doses
it promotes wound healing
• Unsaturated fatty acids: They can modulate
cytokine biology. Anti inflammatory effect of fish
oil is due to n-3 polyunsaturated fatty acids.
• Fats rich in n-6 polyunsaturated fatty acids
enhance IL-1 production & tissue response to
cytokines.
• Fats rich in n-3 polyunsaturated fatty acids have
the opposite effect.
• Monounsaturated fatty acids decrease tissue
responsiveness to cytokine. IL-6 production is
enhanced by total unsaturated fatty acid intake.
• Dietary nucleotides: may improve cell-
mediated immunity. A combination of
arginine, n-3 polyunsaturated fatty acids &
nucleotides has been used as “immune
enhancing “diet.
 Hormonal treatment:
• Anabolic hormones –GH, IGF-1 & insulin promote
positive nitrogen balance.
• GH supplementation improves wound healing &
decreases postoperative wound infection rate.
• IGF-1 mediates most of the metabolic effects of
GH. Exogenous IGF-1 reduces gut mucosal
atrophy in trauma.
• Both GH & IGF-1 are powerful modulators of the
effector function of phagocytic cells.
 Biologic treatment:
• Various strategies have been tried, which include
antibodies to endotoxin, TNF or IL-6.
• But most patients with sepsis have elevated levels
of cytokines & other mediators.
• So this can be given as “prophylaxis” for patients
with high risk, for example, those undergoing
major surgical procedures.
• Genetic alterations can occur during injury &
infection. Hence in the future, gene therapy will
have a role in the management of trauma
patients who are critically ill.