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1 T.S. WALSH

The metabolic response to

injury
Introduction 3 Consequences of the metabolic response Factors modifying the metabolic
to injury 5 response to injury 10
Features of the metabolic response
Hypovolaemia 5 Control of blood glucose 11
when not modified by medical
Increased energy metabolism and Manipulation of inflammation and
interventions 3
substrate cycling 7 coagulation in severe infection 11
Factors mediating the metabolic Catabolism and starvation 7
Anabolism 12
response to injury 3 Changes in red blood cell synthesis and
The acute inflammatory response 3 blood coagulation 10
The endothelium and blood vessels 4
Afferent nerve impulses and sympathetic
nervous system activation 4
The endocrine response to surgery 5

2
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INTRODUCTION
Following accidental or deliberate injury, a characteristic
series of changes occurs, both locally at the site of injury
and within the body generally; these changes are intended
to restore the body to its pre-injury condition. They are
mediated via many different systems, which interact in
a complex manner and may be modified by external factors,
such as drugs and other treatments administered to the
patient. The magnitude of the metabolic response is
generally proportional to the severity of tissue injury, but
can be modified by additional factors such as infection.
The response to injury has probably evolved to aid recovery,
by mobilizing substrates and mechanisms of preventing
infection, and by activating repair processes. However,
many of these physiological changes can now be modified
or corrected by treatments. Although the metabolic response
aims to return an individual to health, it can sometimes
have harmful effects. For example, a major response can
damage organs distant to the injured site itself. In modern
surgery, a major goal is to minimize the metabolic response
to surgery in order to shorten recovery times. This has
been achieved through surgical techniques that minimize
tissue damage. When a major metabolic response does
occur, the emphasis is on managing the patient in a way
that minimizes further tissue damage either at the original
site of injury or in other organs. This chapter describes the
principal physiological systems involved in the metabolic
response to injury, how they function and are controlled,
and at what stage they are important.
FEATURES OF THE METABOLIC RESPONSE
WHEN NOT MODIFIED BY MEDICAL
INTERVENTIONS
Early observations of the metabolic response to injury
were made in patients before the advent of medical
treatments such as intravenous fluids. This unmodified
response was divided into two phases: the ‘ebb’ and
the ‘flow’. During the ebb phase, which usually comprised
the first few hours after injury, the individual was cold
and hypotensive. In current medical practice this corre-
sponds to the period of traumatic shock before or during
resuscitation. When fluid therapies and blood transfusions
were introduced into medical practice, the shock that
occurred in this phase was sometimes found to be reversible
(‘reversible shock’) and in other cases irreversible
(‘irreversible shock’). Irreversible shock probably occurs
when the metabolic response has initiated inflammatory
processes that cause a downward spiral of further injury in
other organs.
The flow phase followed if the individual survived, and
was also described in two parts. The initial catabolic phase
was characterized by a high metabolic rate, breakdown of
proteins and fats, a net loss of body nitrogen (negative
nitrogen balance) and weight loss. This phase usually lasted
about a week and was followed by an anabolic phase, during
which protein and fat stores were restored and weight gain
THE METABOLIC RESPONSE TO INJURY
Table 1.1 SOME CYTOKINES INVOLVED IN THE ACUTE
INFLAMMATORY RESPONSE
Cytokine Relevant actions
TNF-a Pro-inflammatory; release of leucocytes by
bone marrow; activation of leucocytes and
endothelial cells
IL-1 Fever; T-cell and macrophage activation
IL-6 Growth and differentiation of lymphocytes;
activation of the acute-phase protein
response
IL-8 Chemotactic for neutrophils and T cells
IL-10 Inhibits immune function
1
(TNF = tumour necrosis factor; IL = interleukin)
occurred (positive nitrogen balance). The recovery phase
usually lasted 2–4 weeks.
This characteristic pattern probably occurs after all types
of injury, but the degree depends on the magnitude of tissue
injury and how the response is modified by interventions.
FACTORS MEDIATING THE METABOLIC
RESPONSE TO INJURY
The metabolic response is a complex interaction between
many body systems.
THE ACUTE INFLAMMATORY RESPONSE
Inflammatory cells (macrophages and neutrophils) and
cytokines (molecules with the capacity to act on a wide
range of cell types, both at the site of injury and at
distant sites in the body) are mediators of the acute
inflammatory response. Physical damage to tissues results
in local activation of cells such as tissue macrophages.
These cells release a variety of cytokines (Table 1.1). Some
of these, such as interleukin-8 (IL-8), attract large numbers
of circulating macrophages and neutrophils to the site of
injury. Other cytokines, such as tumour necrosis factor
alpha (TNF-a), IL-1 and IL-6, activate these inflammatory
cells, enabling them to clear dead tissue and kill bacteria.
Although these cytokines are produced locally, their release
into the circulation initiates some of the systemic features
of the metabolic response, such as fever (IL-1) and the
acute-phase protein response (IL-6, see below). An impor-
tant determinant of the effects of the inflammatory response
is whether the effects of mediators remain localized
(paracrine effect) or become generalized in the body
(endocrine effect). This cascade of events results in rapid
amplification of the initial injurious stimulus so that,
within a few hours, large numbers of inflammatory cells
are present at the injured site, controlling and mediating
the inflammatory response via cytokines (Fig. 1.1).
Other pro-inflammatory substances are released in
association with tissue injury, leucocyte activation and 3
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PRINCIPLES OF SURGICAL CARE
Bacterial invasion
Macrophage activation
• Phagocytosis
• Cytokine release
• Prostanoid release
• Protease release Haemorrhage into
injured tissue
Neutrophil accumulation
• Phagocytosis
• Cytokine release
• Protease release
1
Neutrophil–endothelial
cell adherence and
neutrophil migration
Endothelial activation
• Vasodilatation
• Increased capillary
permeability
Fig. 1.1 Key events occurring at the site of tissue injury.
cytokine production. These include prostaglandins, kinins,
complement, various proteases (such as elastase and
cathepsin) and free radicals. Anti-inflammatory substances
and mechanisms also exist, such as antioxidants (for
example, glutathione, vitamin A and vitamin C), protease
enzyme inhibitors (for example, a -macroglobulin) and
2
IL-10. The balance between pro- and anti-inflammatory
processes is extremely important but is not yet fully
understood.
THE ENDOTHELIUM AND BLOOD VESSELS
Leucocyte accumulation in injured tissues relies on a
stepwise process whereby cells initially adhere ‘lightly’ to
the endothelium, subsequently adhere ‘tightly’, and then
migrate between endothelial cells into tissues (Fig. 1.1).
These processes are controlled via specific molecules
released by endothelial cells and inflammatory cells
following cell activation. ‘Light’ adhesion is mediated via
the selectins, and ‘tight’ adhesion via integrins and the
intercellular adhesion molecule (ICAM) family.
When tissues are injured, the local blood flow increases
because of vasodilatation. This steps up the local delivery
of inflammatory cells, oxygen and nutrient substrates that
are important in the healing process. Vasodilatation is
caused by substances such as kinins, prostaglandins and
nitric oxide, which are generated in response to injury
and inflammation. Nitric oxide, which is synthesized in
endothelial cells, is particularly important in controlling
blood flow to tissues, both in health and following injury.
In addition to vasodilatation, capillaries in injured tissues
become more permeable to plasma because endothelial
activation increases the size of intercellular pores. As a
result, fluid and colloid particles (principally albumin) leak
4 into injured tissues, resulting in oedema formation. If
Stimulation of afferent
nerve impulses
Plasma cascades activated
• Coagulation/platelets
• Complement
Fluid and protein leak
• Tissue oedema
tissue injury is severe and widespread (for example,
following severe burns), fluid loss into tissues can amount
to many litres.
At sites of injury, tissue factor is exposed which pro-
motes coagulation to decrease haemorrhage. This involves
a complex interaction between endothelial cells, platelets,
and circulating coagulation and inflammatory factors. A
situation of excess pro-coagulant activity can cause
impaired blood flow by occluding capillaries. This can
occur when inflammatory processes become generalized
in the circulation, commonly as a result of infection, and
cause disseminated intravascular coagulation.
AFFERENT NERVE IMPULSES AND
SYMPATHETIC NERVOUS SYSTEM
ACTIVATION
Impulses generated in afferent nerve endings at the site of
tissue injury have a role in mediating the metabolic response
to injury. The most important nerves are probably pain
fibres which comprise both unmyelinated C fibres and
myelinated A fibres. These are stimulated via direct trauma
or the release of nerve stimulants such as prostaglandins.
Nerve impulses reach the thalamus via the dorsal horn of
the spinal cord and the lateral spinothalamic tract. Afferent
impulses reaching the thalamus mediate the metabolic
response via several mechanisms:
1. Stimulation of the sympathetic nervous system.
Increased discharge of sympathetic nerves results in
tachycardia and increased cardiac output. Noradrenaline
(norepinephrine) release from sympathetic nerve endings
and adrenaline (epinephrine) release from the adrenal
gland increase circulating catecholamine concentrations.
This contributes to the changes in carbohydrate, fat
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THE METABOLIC RESPONSE TO INJURY

and protein metabolism that occur following injury

(see below). Interventions that reduce sympathetic
stimulation, such as epidural or spinal anaesthesia,
may attenuate these changes.
2. Stimulation of pituitary hormone release (see below).
THE ENDOCRINE RESPONSE TO SURGERY
Changes occur to circulating concentrations of many
hormones following injury (Table 1.2). These take place
as a result of direct stimulation of the various glands that
produce the hormones, and also because normal negative
feedback mechanisms are altered as part of the response
to injury. Hormonal changes are mainly involved in
maintaining the body’s fluid balance and in the changes
to substrate metabolism that occur following injury (see
below).
BOX 1.1 FACTORS MEDIATING THE METABOLIC RESPONSE TO
INJURY
The acute inflammatory response
Inflammatory cells (macrophages, monocytes, neutrophils)
Pro-inflammatory cytokines and other inflammatory mediators
Endothelial cell activation
Adhesion of inflammatory cells
Vasodilatation
Increased permeability
Nervous system
Afferent nerve stimulation
Endocrine response
Increased secretion of stress hormones
Decreased secretion of anabolic hormones
Bacterial infection
CONSEQUENCES OF THE METABOLIC
RESPONSE TO INJURY
HYPOVOLAEMIA
A reduced circulating volume is characteristic following
moderate to severe injury, and can occur for various reasons
(Table 1.3):
• Fluid loss may be in the form of blood (haemorrhage),
electrolyte-containing fluid (for example, nasogastric
suction, vomiting or sweating) or water (evaporation
from exposed organs during surgery). 1
• Fluid sequestration of plasma-like fluid in injured
tissues (sometimes termed third-space losses) occurs in
proportion to the severity and extent of injury. It results
from the increased ‘leakiness’ of the endothelium
described above, usually lasts 24–48 hours, and after
major surgery can amount to several litres. The extent
and duration of this leakiness may be prolonged if
the acute inflammatory response is exaggerated:
for example, by infection or the ischaemia–reperfusion
syndrome.
Decreased circulating volume is important because it
may reduce oxygen delivery to organs and tissues, lowering
rates of healing or even causing further damage. The
neuroendocrine response to hypovolaemia and a reduced
circulating volume attempts to restore normal fluid status
and maintain perfusion to vital organs. These interrelated
processes can be considered as fluid-conserving measures
and blood flow-conserving measures. With modern
management of patients, this response is less crucial to
survival because fluids and blood products can be
administered to correct hypovolaemia.

Table 1.2 HORMONAL CHANGES IN RESPONSE TO SURGERY AND TRAUMA

Hormonal change Pituitary Adrenal Pancreatic Others

Increased secretion Growth hormone (GH) Adrenaline Glucagon Renin
Adrenocorticotrophic hormone Cortisol Angiotensin
(ACTH) Aldosterone
Prolactin
Antidiuretic hormone/arginine
vasopressin (ADH/AVP)
Unchanged secretion Thyroid-stimulating – – –
hormone (TSH)
Luteinizing hormone (LH)
Follicle-stimulating
hormone (FSH)
Decreased secretion – – Insulin Testosterone
Oestrogen
Thyroid
hormones
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PRINCIPLES OF SURGICAL CARE
Table 1.3 CAUSES OF FLUID LOSS FOLLOWING SURGERY AND TRAUMA
Nature of fluid Mechanism
Blood Haemorrhage
Electrolyte-containing fluids Vomiting
Nasogastric drainage
Diarrhoea
Sweating
1 Water
Plasma-like fluid (third-space losses)
Evaporation
Capillary leak/sequestration in tissues
Fluid-conserving measures
Oliguria, together with sodium and water retention, is very
common after major surgery or injury. It may occur because
of decreased renal perfusion as a result of hypovolaemia,
but frequently arises even after normal circulating volume
is restored. Characteristic changes affect urine after major
surgery, which result from neuroendocrine responses.
Antidiuretic hormone (ADH)
Synthesis and secretion of ADH (sometimes called arginine
vasopressin or AVP) by the posterior pituitary are increased
in response to the following stimuli:
• direct afferent nerve impulses from the site of injury
• increased plasma osmolality (principally sodium ions)
detected by hypothalamic osmoreceptors
• afferent nerve impulses from atrial stretch receptors
(responding to reduced volume) and the aortic and
carotid baroreceptors (responding to reduced pressure)
• input from higher centres in the brain (pain, emotion
and anxiety).
ADH promotes the retention of free water (without
electrolytes) by cells of the distal renal tubule and collecting
duct. If excess water is administered during the period of
increased ADH secretion, plasma hypotonicity and hypo-
natraemia may occur.
Aldosterone
Aldosterone secretion from the adrenal cortex is increased
by the following mechanisms (Fig. 1.2):
• Secretion is raised via the renin–angiotensin system at
the juxtaglomerular apparatus within nephrons. Renin
is released from afferent arteriolar cells in response to
stimuli activated during hypovolaemia and reduced
renal blood flow. These include reduced afferent
arteriolar pressure, tubuloglomerular feedback
(signalling via the macula densa of the distal tubule
6 according to electrolyte concentration) and activation
Contributing factors
Site and magnitude of tissue injury
Poor surgical haemostasis
Abnormal coagulation
Anaesthesia/analgesia (e.g. opiates)
Ileus
Ileus
Gastric surgery
Antibiotic-related infection
Enteral feeding
Pyrexia
Prolonged exposure of viscera during surgery
Acute inflammatory response
Infection
Ischaemia–reperfusion syndrome
of the renal sympathetic nerves. Renin, a proteolytic
enzyme, converts circulating angiotensinogen to
angiotensin I. Angiotensin I is converted to angiotensin
II by angiotensin-converting enzyme (ACE), which is
found in plasma and in various tissues, particularly the
lung. Angiotensin II has several actions, which include
potent vasoconstriction of arterioles and stimulation
of aldosterone secretion by the adrenal cortex.
• ACTH secretion by the anterior pituitary is increased in
response to hypovolaemia and hypotension via afferent
nerve impulses from stretch receptors in the atria, aorta
and carotid arteries. It is also raised by ADH.
• Hyponatraemia or hyperkalaemia directly stimulates
adrenal cortex cells to increase secretion.
Aldosterone acts mainly via receptors on distal renal
tubular cells. The net effect is reabsorption of sodium ions
and simultaneous excretion of hydrogen and potassium
ions into urine. Aldosterone also effects ion transfer across
some other cell types: for example, cardiac muscle.
The duration of increased ADH and aldosterone
secretion is usually 48–72 hours. Urine volume is often
reduced during this period (about 0.5 ml/kg/hr), and urine
is concentrated as a result of water retention. Urinary
sodium excretion decreases, typically to 10–20 mmol/24 hrs
(normal 50–80 mmol/24 hrs). Urinary potassium excretion
increases, typically to > 100 mmol/24 hrs (normal 50–80
mmol/24 hrs), but hypokalaemia is relatively rare in the
24–48 hours following injury because a net efflux of
BOX 1.2 URINARY CHANGES DURING THE METABOLIC
RESPONSE TO INJURY
Reduced urine volume in response to hypovolaemia and ADH
release
Low urinary sodium and increased urinary potassium excretion due
to aldosterone release
Increased urinary nitrogen excretion due to the catabolic response
to injury
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Anterior pituitary:
Secretes ACTH

ACTH actions:
• Stimulation of aldosterone
secretion by adrenal cortex
Kidney juxtaglomerular
apparatus (JGA):
Secretes renin
Adrenal gland cortex:
Secretes aldosterone
Renin–angiotensin system

Renin (JGA) 1
Aldosterone actions:
• Na+ and water retention Angiotensinogen Angiotensin I
from distal renal tubules (plasma) Angiotensin-
• Negative feedback on
anterior pituitary converting enzyme
(lung and other tissues)

Angiotensin II

Angiotensin II actions:
• Stimulates aldosterone
secretion
• Stimulates thirst centres
in brain
• Potent vasoconstrictor

Fig. 1.2 The renin–angiotensin–aldosterone system.

(ACTH = adrenocorticotrophic hormone)

potassium from cells occurs. This typical pattern may be
modified by fluid and electrolyte administration.
Blood flow-conserving measures
An important potential consequence of hypovolaemia is
reduced cardiac output, resulting in decreased blood flow
to organs. Cardiac output is determined by the cardiac
preload (the amount of blood returning to the heart), the
heart rate, the contractility of cardiac muscle (the rate
at which each contraction occurs) and the afterload
(a measure of the resistance against which the heart
pumps). Blood pressure is determined by the cardiac
output and the peripheral resistance of blood vessels
(mainly arterioles). Following injury, several mechanisms
act to maintain or increase cardiac output and blood
pressure despite hypovolaemia (Fig. 1.3).
INCREASED ENERGY METABOLISM AND
SUBSTRATE CYCLING
Metabolic rate (the energy expenditure of the body) can be
considered in three parts: energy required for physical work,
energy associated with heat production (thermogenesis) and
basal metabolic rate (BMR, comprising the energy needed
for enzyme reactions and ion pumps).
Physical work
Following injury physical work is usually decreased
because of inactivity, although heart and respiratory muscle
work may increase. Resting energy expenditure (the sum
of BMR and thermogenesis) is increased by up to 50%
following severe injury as a result of metabolic changes
(Fig. 1.4).
Thermogenesis
Patients are frequently mildly pyrexial for 24–48 hours
following injury. This occurs because cytokines, principally
IL-1, reset temperature-regulating centres in the hypo-
thalamus. Pyrexia may also complicate infection occurring
after injury. Metabolic rate increases by 6–10% for each
1°C change in body temperature.
Basal metabolic rate
Following injury, there is increased activity of protein,
carbohydrate and fat-related metabolic pathways (see
below) and of many ion pumps. The activity of some cycles
is apparently ‘futile’; for example, glucose–lactate cycling
and triglyceride turnover involve simultaneous synthesis
and degradation. This general increase in substrate cycling
is energy-dependent, but probably evolved to increase the
ability of the body to respond to altering demands.
CATABOLISM AND STARVATION
Catabolism is the breakdown of complex substances, such
as muscle proteins, to form simpler molecules (glucose,
amino acids and fatty acids) that are basic substrates for
metabolic pathways. Starvation is the inadequate intake 7
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PRINCIPLES OF SURGICAL CARE

Pituitary
Thalamus ACTH
Pyrexia Antidiuretic hormone

Suprarenal gland
Aldosterone
Heart and Cortisol
cardiovascular system Adrenaline (ephinephrine)
Sympathetic activation
Tachycardia
Kidney
Renin–angiotensin system
activation
1 Liver Na+ reabsorption
Glycogenolysis K+ reabsorption
Gluconeogenesis Urine volumes
Lipolysis Poor erythropoietin response
Ketone body production to anaemia
Acute-phase protein release
Pancreas
Insulin release
Site of injury/surgery Glucagon release
Inflammation
Oedema Skeletal muscle
Endothelial activation Muscle breakdown
Blood flow Release of amino acids into
Afferent nerve stimulation circulation

Bone marrow
Impaired red cell production

Fig. 1.3 Summary of metabolic responses to surgery and trauma.

of food to meet metabolic demand. Following severe injury

BOX 1.3 PHYSIOLOGICAL CHANGES OCCURRING DURING
or major surgery, these two processes generally occur
CATABOLISM
simultaneously. The metabolic changes associated with
Carbohydrate metabolism each process are different, and so the changes occurring in
● Ø Glycogenolysis (stores last about 10 hours) any individual patient depend on which process predomi-
● Ø Hepatic gluconeogenesis nates. Generally, uncomplicated surgery or moderate trauma
● Insulin resistance of tissues
is followed by a period of starvation but little catabolism.
● Hyperglycaemia
Major trauma or surgery complicated by sepsis may result
Fat metabolism in marked catabolism, which outweighs any effect of
● Ø Lipolysis
simultaneous starvation.
● Free fatty acids used as energy substrate by tissues (except
brain)
● Some conversion of free fatty acids to ketones in liver (used by Catabolism
brain) Catabolism is mediated by catecholamines, cytokines and
● Glycerol converted to glucose in the liver other substances generated in response to injury and
Protein metabolism released into the circulation. These bring about changes
● Ø Skeletal muscle breakdown in carbohydrate, protein and fat metabolism.
● Amino acids converted to glucose in liver and used as substrate
for acute-phase protein production Carbohydrate metabolism
● Negative nitrogen balance
Glycogenolysis in the liver results in rapid depletion
Total energy expenditure increased in proportion to injury severity of glycogen stores, which last for only 8–12 hours.
and other modifying factors.
Progressive reduction in fat and muscle mass until stimulus for Gluconeogenesis is increased, particularly in the liver,
catabolism ends. which converts substrates released from other tissues, such
as amino acids, into glucose. Insulin secretion is decreased
8 as a result of inhibition of pancreatic b-cells by cate-
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THE METABOLIC RESPONSE TO INJURY

free fatty acids into glucose, but the liver converts them
Physical work 15% into ketone bodies that are water-soluble and can support
cerebral energy metabolism. Following severe trauma,
Thermogenesis 15%
200–500 g of fat may be broken down daily.
Physical work 25%
Protein metabolism
Thermogenesis 10% Skeletal muscle is the major labile protein store in the
body. Following major injury, skeletal muscle is broken
Basal metabolic down, releasing amino acids into the circulation. These
rate 70%
Basal metabolic are metabolized principally in the liver, which converts a
rate 65% major proportion into glucose for re-export to tissues for
energy metabolism. Amino acids are also used in the liver
as substrate for the ‘acute-phase protein response’. This 1
response involves the liver increasing the production of
Healthy sedentary 24 hours following major one group of proteins (positive acute-phase proteins) and
70 kg man surgery or moderate injury decreasing the production of others (negative acute-phase
• Total energy expenditure • Total energy expenditure proteins) (Table 1.4). The acute-phase response is mediated
about 1800 kcal/day increased 10–30% in the liver by cytokines, especially IL-1, IL-6 and TNF.
• Basal metabolic rate • Relative reduction in physical Its function is not fully understood, but is probably con-
comprises enzymes and work due to inactivity cerned with fighting infection and promoting healing.
ion pumps (85%) and the • Thermogenesis/heat energy
mechanical work of the increased by mild pyrexia
The mechanism by which muscle catabolism occurs
heart and respiratory • Basal metabolic rate increased is also incompletely understood. It is mediated by inflam-
system (15%) by raised enzyme and ion matory mediators and hormones, such as cortisol, released
pump activity and increased as part of the metabolic response to injury. Trauma or
cardiac work surgery associated with a minimal metabolic response
is usually accompanied by minimal muscle catabolism.
Fig. 1.4 Components of body energy expenditure in health and
following injury.
In patients with major tissue injury, marked catabolism
and loss of skeletal muscle can occur, especially when
factors that enhance the metabolic response, such as
sepsis, are present.
cholamines. In addition, a state of insulin resistance In health, 80–120 g/day dietary protein (12–20 g
occurs, meaning that cells become less sensitive to the nitrogen) is ingested (1 g nitrogen = 6 g protein). Normally,
effects of insulin. This is caused by changes to the insulin approximately 2 g/day nitrogen is lost in faeces and 10–18
receptor/intracellular signal pathway. Together, these factors g/day in urine (mainly in the form of urea). During
result in hyperglycaemia, which provides glucose substrate catabolism, nitrogen intake is often reduced but urinary
for the inflammatory and repair processes that follow injury. losses can increase markedly, reaching 20–30 g/day in
However, the degree of control of glucose in the peri- patients with severe trauma, sepsis or burns. Following
operative setting and during critical illness may have an uncomplicated surgery, this negative nitrogen balance
effect on recovery (see below). usually lasts only 5–8 days, but in patients with prolonged
Catecholamines and glucagon also increase gluconeo- sepsis, burns or conditions associated with prolonged
genesis. There is a correlation between the degree of hyper- inflammation (for example, acute pancreatitis) it may
glycaemia that occurs and the severity of surgery or injury. persist for many weeks. Severe catabolism and negative
nitrogen balance cannot be reversed by feeding, but the
Fat metabolism provision of protein and calories can attenuate the processes.
Adipose tissue is a large triglyceride store that constitutes Even patients undergoing uncomplicated abdominal surgery
the principal source of energy following trauma. The stress
hormones released as part of the metabolic response to
injury (catecholamines, glucagon, cortisol and growth Table 1.4 PROTEINS SYNTHESIZED BY THE LIVER WHICH ALTER
hormone) are all capable of activating the enzyme, AS PART OF THE ACUTE-PHASE PROTEIN RESPONSE
triglyceride lipase, within fat cells. This process is Positive acute-phase proteins (Ø after injury)
exacerbated by the state of insulin resistance. Cortisol ● C-reactive protein

is a potent stimulus for lipolysis, and circulating cortisol ● Haptoglobins

● Ferritin
concentrations increase from normal baseline levels of ª
● Fibrinogen
400 nmol/l to levels of > 1500 nmol/l within hours of ● a -Antitrypsin
1
major surgery. Triglycerides are broken down into glycerol ● a -Macroglobulin
2
and free fatty acids. Glycerol is a substrate for gluco- ● Plasminogen

neogenesis, and free fatty acids can be directly metabolized Negative acute-phase proteins (Ø after injury)
by most tissues to generate energy. The brain is unable to ● Albumin
use free fatty acids for energy production, and in health ● Transferrin

relies on glucose supply. Animals are unable to convert 9

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PRINCIPLES OF SURGICAL CARE
Table 1.5 A COMPARISON OF NITROGEN AND ENERGY LOSSES IN A MODERATE TO SEVERE CATABOLIC STATE AND DURING THE
DIFFERENT PHASES OF STARVATION*
Catabolic state
Nitrogen loss (g/day) 20–25
Energy expenditure (kcal/day) 2200–2500
* Values are approximate and relate to a 70 kg man.
can lose about 600 g muscle protein (1 g protein = 5 g wet
1 muscle mass), amounting to 6% of total body protein. This
is usually regained within 3 months.
Starvation
Starvation occurs in relation to trauma and surgery for
several reasons:
• the illness requiring treatment (for example, gastric
carcinoma), which may have reduced nutritional intake
for weeks/months prior to surgery
• fasting prior to surgery
• fasting after surgery, especially to the gastrointestinal
tract
• loss of appetite associated with illness.
The response of the body to starvation can be described
in two phases (Table 1.5).
Acute starvation
This is accompanied by metabolic changes that preserve
the glucose supply to the brain. Glycogenolysis and gluco-
neogenesis occur in the liver, releasing glucose for cerebral
energy metabolism. Lipolysis in fat stores releases free
fatty acids for use by other tissues, and glycerol which
is converted to glucose in the liver. These processes can
sustain the normal energy requirements of the body
(about 1800 kcal/day for a 70 kg adult) for approximately
10 hours.
Chronic starvation
This is initially accompanied by muscle breakdown to
release amino acids, which are converted to glucose by
hepatic gluconeogenesis. In addition, fatty acids released
from adipose tissue are converted by the liver to ketones.
Tissue energy supply is in the form of glucose, fatty acids
and ketones. The brain is unable to utilize free fatty acids
and uses about 70% of the glucose generated by hepatic
gluconeogenesis. With prolonged starvation, the brain
adapts to utilize ketones as the primary energy substrate,
rather than glucose. This adaptation reduces muscle protein
loss and switches metabolism to increase fat consumption,
so that net body nitrogen loss is reduced. Hepatic gluco-
neogenesis from amino acids decreases to about 25% of
its previous rate, and overall metabolic rate and energy
requirements fall, the latter from 1800 kcal/day to about
1500 kcal/ day (Table 1.5). This state is termed compensated
starvation, which continues until body fat stores are
10 depleted. At this stage, when an individual is often close
Acute starvation Compensated starvation
14 3
1800 1500
to death, muscle protein breakdown again increases to
provide glucose for cerebral metabolism.
CHANGES IN RED BLOOD CELL SYNTHESIS
AND BLOOD COAGULATION
Anaemia is common after major surgery or trauma because
of bleeding and the haemodilution that occurs when blood
losses are replaced with crystalloid or colloid fluids (Ch. 2).
In addition, the bone marrow production of new red cells
is impaired. The reasons for this are unclear, but include
an inappropriately low release of erythropoietin by the
kidney and impaired maturation of red blood cell precursors.
In addition, changes to iron metabolism occur that increase
storage iron (bound to ferritin) and decrease the available
iron (bound to transferrin). These changes are probably
due to the effects of inflammation, but how this may be of
benefit is unclear. Recent evidence suggests that actively
correcting anaemia in patients after surgery or during
critical illness when they are not bleeding is not beneficial
(Ch. 4).
Following tissue injury, the blood may become hyper-
coagulable. This is usually a transient feature lasting
1–2 days, but it increases the risk of thromboembolism
after surgery or trauma. Contributing factors include:
• endothelial injury and activation, which in turn activates
the coagulation pathways
• increased activation of platelets in response to
circulating mediators such as adrenaline (epinephrine)
and cytokines
• dehydration and/or reduced venous blood flow due
to immobility
• an increase in circulating concentrations of pro-
coagulant factors, such as fibrinogen, and a decrease in
circulating natural anticoagulants, such as protein C.
Rarely, patients develop hypocoagulable states. These
are usually found in association with shock, massive blood
transfusion or sepsis. The most extreme form of coagu-
lopathy is disseminated intravascular coagulation.
FACTORS MODIFYING THE METABOLIC
RESPONSE TO INJURY
The magnitude and duration of the metabolic response
to injury are influenced by many factors. Some of these
are summarized in Table 1.6. There has been considerable
research into ways of decreasing the metabolic response and
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THE METABOLIC RESPONSE TO INJURY

Table 1.6 FACTORS ASSOCIATED WITH THE MAGNITUDE OF THE METABOLIC RESPONSE TO INJURY

Factor Comment
PATIENT-RELATED FACTORS Recent evidence shows that gene subtype for inflammatory mediators is associated with
Genetic predisposition how an individual responds to injury and infection
Coexisting disease The presence of disease, such as cancer and chronic inflammatory disease, may influence
the metabolic response
Drug treatments Pre-existing anti-inflammatory or immunosuppressive therapy, such as steroids, may alter
responses
Nutritional status Malnourished patients may have decreased immune function or deficiency in important
substrates. Malnutrition prior to surgery or trauma is associated with poor outcomes
ACUTE SURGICAL/TRAUMA-RELATED FACTORS
Severity of injury
Nature of injury
Greater tissue damage is associated with a greater metabolic response
Some types of tissue injury cause a proportionate metabolic response. An example is major 1
burn injury, which is associated with a major response
Ischaemia–reperfusion injury If resuscitation is not quick and/or effective, the reperfusion of previously ischaemic tissues
can set off a cascade of inflammation that further injures organs. This is called
ischaemia–reperfusion injury
Temperature Extreme hypothermia and hyperthermia are both detrimental to the metabolic response
Infection The occurrence of infection is often associated with an exaggerated response to injury. If
infection spreads to the systemic circulation, it can result in sepsis or septic shock, which
are associated with a massive inflammatory response
Anaesthetic techniques The use of certain drugs, such as opioids, can reduce the release of stress hormones.
Regional anaesthetic techniques for major surgery can reduce the release of cortisol,
adrenaline (epinephrine) and other hormones, but has little effect on cytokine responses

MANIPULATION OF INFLAMMATION AND

how this might affect patient outcome. In surgical practice,
the major advances have been in reducing the extent of
tissue injury through improvements in surgical techniques.
In situations of exaggerated metabolic response, where the
patient either has undergone major surgery or is critically
ill, several recent trials have suggested that interventions
to alter aspects of the metabolic response can improve
patient survival.
CONTROL OF BLOOD GLUCOSE
Hyperglycaemia is a major component of the stress
response, and is usually more severe following major
trauma or surgery. Recent evidence suggests that, after
major (particularly cardiac) surgery and during critical
illness, tighter control of blood glucose using insulin is
associated with lower mortality and complication rates
(EBM 1.1).
COAGULATION IN SEVERE INFECTION
When severe infection complicates an illness, the metabolic
response becomes exaggerated and is thought to contribute
to further tissue injury and organ failure. This is called
sepsis syndrome and is a major cause of morbidity and
mortality in hospitals. The concentrations of many cytokines
and other inflammatory factors in the circulation are
markedly increased. Many large RCTs have tested whether
using therapeutic interventions such as monoclonal anti-
bodies to neutralize certain factors (for example, TNF-a,
IL-6 or endotoxin) could improve survival of patients in
these situations. The majority of these studies have shown
no benefit from such interventions and indeed sometimes
show harm. However, a recent large RCT in which activated
human protein C was administered to patients with severe
sepsis demonstrated a clear improvement in survival
(EBM 1.2). This factor, which has anti-inflammatory and
anticoagulant actions, is normally present in the circulation
but is deficient in patients with severe sepsis. The drug is
recommended for use in many countries under the guidance
of intensive care specialists.

EBM 1.1 BLOOD GLUCOSE CONTROL

‘A large single-centre RCT in patients who had had major surgery
or with critical illness (most of whom had undergone cardiac
surgery) found that tight blood glucose control in the post-
operative period using insulin infusions decreased operative
mortality and complication rates.’
Van den Berghe G, et al. New Engl J Med 2001;
345:1359–1367.
EBM 1.2 MANAGEMENT OF SEVERE SEPSIS
‘Recombinant human activated protein C reduces 28-day
mortality in severe sepsis, even if multiple organ failure has
already developed.’
Taylor FB, et al. J Clin Invest 1987; 79:918–925.
Bernard GR, et al. N Engl J Med 2001; 344:699–709.
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PRINCIPLES OF SURGICAL CARE

associated with an obvious clinical improvement in the

ANABOLISM
Anabolism is the process of regaining weight, restoring
skeletal muscle mass and strength, and replenishing fat
stores. It is unlikely to occur until the processes
associated with catabolism, such as the release of inflam-
matory mediators, have subsided. This point is often
patient, who feels better and regains his or her appetite.
Hormones contributing to the process of anabolism
include insulin, growth hormone, insulin-like growth
factors, androgens and the 17-ketosteroids. The factors
controlling the rate of anabolism are complex, but nutri-
tional support and the activity level of the patient are
important contributing factors.

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