Metabolic Responses to Injury

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1T.S. WALSH

The metabolic response toinjuryIntroduction 3

Features of the metabolic responsewhen not modified by medicalinterventions 3

Factors mediating the metabolicresponse to injury 3The acute inflammatory response 3The endothelium and blood vessels 4Afferent nerve impulses and sympatheticnervous system activation 4The endocrine response to surgery 5

Consequences of the metabolic responseto injur y 5

Hypovolaemia 5Increased energy metabolism andsubstrate cycling 7Catabolism and starvation 7Changes in red blood cell synthesis andblood coagulation 10

Factors modifying the metabolicresponse to injury 10

Control of blood glucose 11Manipulation of inflammation andcoagulation in severe infection 11

Anabolism 12

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THE METABOLIC RESPONSE TO INJURY

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 responseto 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 RESPONSEWHEN NOT MODIFIED BY MEDICALINTERVENTIONS

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 inflammatoryprocesses 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

occurred (positive nitrogen balance). The recovery phase

usually lasted 24 weeks.

This characteristic pattern probably occurs after all typesof injury, but the degree depends on the magnitude of tissue

injury and how the response is modified by interventions.

FACTORS MEDIATING THE METABOLICRESPONSE 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 inflammatorycells, 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 responseis 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

Table 1.1 SOME CYTOKINES INVOLVED IN THE ACUTEINFLAMMATORY RESPONSE

Cytokine Relevant actions

TNF-a Pro-inflammatory; release of leucocytes bybone marrow; activation of leucocytes andendothelial cells

IL-1 Fever; T-cell and macrophage activation

IL-6 Growth and differentiation of lymphocytes;activation of the acute-phase proteinresponse

IL-8 Chemotactic for neutrophils and T cells

IL-10 Inhibits immune function

(TNF = tumour necrosis factor; IL = interleukin)

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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, a2-macroglobulin) and

IL-10. The balance between pro- and anti-inflammatory

processes is extremely important but is not yet fully

understood.

THE ENDOTHELIUM AND BLOOD VESSELSLeucocyte 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 andnitric 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

into injured tissues, resulting in oedema formation. If

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 ANDSYMPATHETIC NERVOUS SYSTEMACTIVATION

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 metabolicresponse 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, fat4

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PRINCIPLES OF SURGICAL CARE

Macrophage activation Phagocytosis Cytokine release Prostanoid release Protease release

Plasma cascades activated

Coagulation/platelets Complement

Endothelial activation Vasodilatation Increased capillary

permeability

Fluid and protein leak Tissue oedema

Bacterial invasion

Haemorrhage intoinjured tissue

Stimulation of afferentnerve impulses

Neutrophil accumulation Phagocytosis Cytokine release Protease release

Neutrophilendothelialcell adherence andneutrophil migration

Fig. 1.1 Key events occurring at the site of tissue injury.

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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 SURGERYChanges 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 bodys fluid balance and in the changes

to substrate metabolism that occur following injury (see

below).

CONSEQUENCES OF THE METABOLICRESPONSE 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).

Fluid sequestration of plasma-like fluid in injuredtissues (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 2448 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 ischaemiareperfusion

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 ReninAdrenocorticotrophic hormone Cortisol Angiotensin(ACTH) AldosteroneProlactin

Antidiuretic hormone/argininevasopressin (ADH/AVP)

Unchanged secretion Thyroid-stimulating hormone (TSH)Luteinizing hormone (LH)Follicle-stimulatinghormone (FSH)

Decreased secretion Insulin TestosteroneOestrogenThyroidhormones

BOX 1.1 FACTORS MEDIATING THE METABOLIC RESPONSE TOINJURY

The acute inflammatory response

Inflammatory cells (macrophages, monocytes, neutrophils)Pro-inflammatory cytokines and other inflammatory mediators

Endothelial cell activation

Adhesion of inflammatory cellsVasodilatationIncreased permeability

Nervous system

Afferent nerve stimulation

Endocrine response

Increased secretion of stress hormonesDecreased secretion of anabolic hormones

Bacterial infection

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Fluid-conserving measuresOliguria, 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, emotionand 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.

AldosteroneAldosterone secretion from the adrenal cortex is increased

by the following mechanisms (Fig. 1.2):

Secretion is raised via the reninangiotensin system atthe 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

according to electrolyte concentration) and activation

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 inresponse 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 stimulatesadrenal 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 4872 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 1020 mmol/24 hrs

(normal 5080 mmol/24 hrs). Urinary potassium excretion

increases, typically to > 100 mmol/24 hrs (normal 5080

mmol/24 hrs), but hypokalaemia is relatively rare in the

2448 hours following injury because a net efflux of

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Table 1.3 CAUSES OF FLUID LOSS FOLLOWING SURGERY AND TRAUMA

Nature of fluid Mechanism Contributing factors

Blood Haemorrhage Site and magnitude of tissue injuryPoor surgical haemostasis

Abnormal coagulation

Electrolyte-containing fluids Vomiting Anaesthesia/analgesia (e.g. opiates)Ileus

Nasogastric drainage IleusGastric surgery

Diarrhoea Antibiotic-related infectionEnteral feeding

Sweating PyrexiaWater Evaporation Prolonged exposure of viscera during surgeryPlasma-like fluid (third-space losses) Capillary leak/sequestration in tissues Acute inflammatory response

InfectionIschaemiareperfusion syndrome

BOX 1.2 URINARY CHANGES DURING THE METABOLICRESPONSE TO INJURY

Reduced urine volume in response to hypovolaemia and ADHreleaseLow urinary sodium and increased urinary potassium excretion dueto aldosterone releaseIncreased urinary nitrogen excretion due to the catabolic responseto injury

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potassium from cells occurs. This typical pattern may be

modified by fluid and electrolyte administration.

Blood flow-conserving measuresAn 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 ANDSUBSTRATE 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 workFollowing 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).

ThermogenesisPatients are frequently mildly pyrexial for 2448 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 610% for each

1C change in body temperature.

Basal metabolic rateFollowing 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, glucoselactate cycling

and triglyceride turnover involve simultaneous synthesis

and degradation. This general increase in substrate cyclingis 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

Angiotensin I

Angiotensin II

Anterior pituitary:Secretes ACTH

ACTH actions: Stimulation of aldosteronesecretion by adrenal cortex

Adrenal gland cortex:Secretes aldosterone

Aldosterone actions: Na+ and water retentionfrom distal renal tubules

Negative feedback onanterior pituitary

Angiotensin II actions: Stimulates aldosterone

secretion Stimulates thirst centres

in brain Potent vasoconstrictor

Kidney juxtaglomerularapparatus (JGA):Secretes renin

Reninangiotensin system

Angiotensinogen(plasma) Angiotensin-

converting enzyme(lung and other tissues)

Renin (JGA)

Fig. 1.2 The reninangiotensinaldosterone system.

(ACTH = adrenocorticotrophic hormone)

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of food to meet metabolic demand. Following severe injury

or major surgery, these two processes generally occur

simultaneously. The metabolic changes associated with

each process are different, and so the changes occurring in

any individual patient depend on which process predomi-

nates. Generally, uncomplicated surgery or moderate trauma

is followed by a period of starvation but little catabolism.

Major trauma or surgery complicated by sepsis may result

in marked catabolism, which outweighs any effect of

simultaneous starvation.

CatabolismCatabolism is mediated by catecholamines, cytokines and

other substances generated in response to injury and

released into the circulation. These bring about changesin carbohydrate, protein and fat metabolism.

Carbohydrate metabolismGlycogenolysis in the liver results in rapid depletion

of glycogen stores, which last for only 812 hours.

Gluconeogenesis is increased, particularly in the liver,

which converts substrates released from other tissues, such

as amino acids, into glucose. Insulin secretion is decreased

as a result of inhibition of pancreatic b-cells by cate-8

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Thalamus

Pyrexia

Heart and

cardiovascular system

Sympathetic activationTachycardia

PituitaryACTHAntidiuretic hormone

Suprarenal gland

AldosteroneCortisol

Adrenaline (ephinephrine)

Kidney

Reninangiotensin systemactivationNa+ reabsorptionK+ reabsorptionUrine volumes

Poor erythropoietin responseto anaemia

PancreasInsulin releaseGlucagon release

Skeletal muscle

Muscle breakdownRelease of amino acids intocirculation

Bone marrow

Impaired red cell production

Liver

GlycogenolysisGluconeogenesisLipolysisKetone body productionAcute-phase protein release

Site of injury/surgery

InflammationOedemaEndothelial activation

Blood flowAfferent nerve stimulation

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

BOX 1.3 PHYSIOLOGICAL CHANGES OCCURRING DURINGCATABOLISM

Carbohydrate metabolism

Glycogenolysis (stores last about 10 hours) Hepatic gluconeogenesis Insulin resistance of tissues Hyperglycaemia

Fat metabolism

Lipolysis Free fatty acids used as energy substrate by tissues (except

brain) Some conversion of free fatty acids to ketones in liver (used by

brain) Glycerol converted to glucose in the liver

Protein metabolism Skeletal muscle breakdown Amino acids converted to glucose in liver and used as substrate

for acute-phase protein production Negative nitrogen balance

Total energy expenditure increased in proportion to injury severityand other modifying factors.Progressive reduction in fat and muscle mass until stimulus forcatabolism ends.

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cholamines. In addition, a state of insulin resistance

occurs, meaning that cells become less sensitive to the

effects of insulin. This is caused by changes to the insulin

receptor/intracellular signal pathway. Together, these factors

result in hyperglycaemia, which provides glucose substrate

for the inflammatory and repair processes that follow injury.

However, the degree of control of glucose in the peri-

operative setting and during critical illness may have an

effect on recovery (see below).

Catecholamines and glucagon also increase gluconeo-

genesis. There is a correlation between the degree of hyper-

glycaemia that occurs and the severity of surgery or injury.

Fat metabolismAdipose tissue is a large triglyceride store that constitutes

the principal source of energy following trauma. The stress

hormones released as part of the metabolic response to

injury (catecholamines, glucagon, cortisol and growth

hormone) are all capable of activating the enzyme,

triglyceride lipase, within fat cells. This process is

exacerbated by the state of insulin resistance. Cortisolis a potent stimulus for lipolysis, and circulating cortisol

concentrations increase from normal baseline levels of 400 nmol/l to levels of > 1500 nmol/l within hours of

major surgery. Triglycerides are broken down into glycerol

and free fatty acids. Glycerol is a substrate for gluco-

neogenesis, and free fatty acids can be directly metabolized

by most tissues to generate energy. The brain is unable to

use free fatty acids for energy production, and in health

relies on glucose supply. Animals are unable to convert

free fatty acids into glucose, but the liver converts them

into ketone bodies that are water-soluble and can support

cerebral energy metabolism. Following severe trauma,

200500 g of fat may be broken down daily.

Protein metabolismSkeletal muscle is the major labile protein store in the

body. Following major injury, skeletal muscle is broken

down, releasing amino acids into the circulation. These

are metabolized principally in the liver, which converts a

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

response involves the liver increasing the production of

one group of proteins (positive acute-phase proteins) and

decreasing the production of others (negative acute-phase

proteins) (Table 1.4). The acute-phase response is mediated

in the liver by cytokines, especially IL-1, IL-6 and TNF.

Its function is not fully understood, but is probably con-

cerned with fighting infection and promoting healing.

The mechanism by which muscle catabolism occurs

is also incompletely understood. It is mediated by inflam-matory mediators and hormones, such as cortisol, released

as part of the metabolic response to injury. Trauma or

surgery associated with a minimal metabolic response

is usually accompanied by minimal muscle catabolism.

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.

In health, 80120 g/day dietary protein (1220 g

nitrogen) is ingested (1 g nitrogen = 6 g protein). Normally,

approximately 2 g/day nitrogen is lost in faeces and 1018

g/day in urine (mainly in the form of urea). During

catabolism, nitrogen intake is often reduced but urinary

losses can increase markedly, reaching 2030 g/day in

patients with severe trauma, sepsis or burns. Following

uncomplicated surgery, this negative nitrogen balance

usually lasts only 58 days, but in patients with prolonged

sepsis, burns or conditions associated with prolonged

inflammation (for example, acute pancreatitis) it may

persist for many weeks. Severe catabolism and negative

nitrogen balance cannot be reversed by feeding, but the

provision of protein and calories can attenuate the processes.

Even patients undergoing uncomplicated abdominal surgery

Table 1.4 PROTEINS SYNTHESIZED BY THE LIVER WHICH ALTERAS PART OF THE ACUTE-PHASE PROTEIN RESPONSE

Positive acute-phase proteins ( after injury) C-reactive protein Haptoglobins Ferritin Fibrinogen a

1-Antitrypsin

a2-Macroglobulin

Plasminogen

Negative acute-phase proteins ( after injury) Albumin Transferrin

Physical work 25%

Physical work 15%

Thermogenesis 15%

Basal metabolicrate 70%

Thermogenesis 10%

Basal metabolicrate 65%

Healthy sedentary70 kg man

Total energy expenditureabout 1800 kcal/day

Basal metabolic ratecomprises enzymes andion pumps (85%) and themechanical work of the

heart and respiratorysystem (15%)

24 hours following majorsurgery or moderate injury

Total energy expenditureincreased 1030%

Relative reduction in physicalwork due to inactivity

Thermogenesis/heat energyincreased by mild pyrexia

Basal metabolic rate increasedby raised enzyme and ionpump activity and increasedcardiac work

Fig. 1.4 Components of body energy expenditure in health and

following injury.

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can lose about 600 g muscle protein (1 g protein = 5 g wet

muscle mass), amounting to 6% of total body protein. This

is usually regained within 3 months.

StarvationStarvation occurs in relation to trauma and surgery for

several reasons:

the illness requiring treatment (for example, gastriccarcinoma), 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 starvationThis 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 starvationThis 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

depleted. At this stage, when an individual is often close

to death, muscle protein breakdown again increases to

provide glucose for cerebral metabolism.

CHANGES IN RED BLOOD CELL SYNTHESISAND 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 includean 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

12 days, but it increases the risk of thromboembolism

after surgery or trauma. Contributing factors include:

endothelial injury and activation, which in turn activatesthe coagulation pathways

increased activation of platelets in response tocirculating mediators such as adrenaline (epinephrine)

and cytokines

dehydration and/or reduced venous blood flow dueto 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 METABOLICRESPONSE 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 and10

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Table 1.5 A COMPARISON OF NITROGEN AND ENERGY LOSSES IN A MODERATE TO SEVERE CATABOLIC STATE AND DURING THEDIFFERENT PHASES OF STARVATION*

Catabolic state Acute starvation Compensated starvation

Nitrogen loss (g/day) 2025 14 3

Energy expenditure (kcal/day) 22002500 1800 1500

* Values are approximate and relate to a 70 kg man.

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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).

MANIPULATION OF INFLAMMATION ANDCOAGULATION 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 surgeryor with critical illness (most of whom had undergone cardiacsurgery) found that tight blood glucose control in the post-operative period using insulin infusions decreased operativemortality and complication rates.

Van den Berghe G, et al. New Engl J Med 2001;345:13591367.

EBM 1.2 MANAGEMENT OF SEVERE SEPSIS

Recombinant human activated protein C reduces 28-daymortality in severe sepsis, even if multiple organ failure hasalready developed.

Taylor FB, et al. J Clin Invest 1987; 79:918925.Bernard GR, et al. N Engl J Med 2001; 344:699709.

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 withGenetic predisposition how an individual responds to injury and infectionCoexisting disease The presence of disease, such as cancer and chronic inflammatory disease, may influence

the metabolic responseDrug treatments Pre-existing anti-inflammatory or immunosuppressive therapy, such as steroids, may alter

responsesNutritional 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 FACTORSSeverity of injury Greater tissue damage is associated with a greater metabolic responseNature of injury Some types of tissue injury cause a proportionate metabolic response. An example is major

burn injury, which is associated with a major responseIschaemiareperfusion 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 calledischaemiareperfusion injury

Temperature Extreme hypothermia and hyperthermia are both detrimental to the metabolic responseInfection 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, whichare 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

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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

associated with an obvious clinical improvement in the

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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Metabolic Responses to Injury