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

Factors modifying the metabolicresponse to injury 10Control of blood glucose 11Manipulation of inflammation andcoagulation in severe infection 11

Anabolism 12

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INTRODUCTION

Following accidental or deliberate injury, a characteristicseries of changes occurs, both locally at the site of injuryand within the body generally; these changes are intended to restore the body to its pre-injury condition. They aremediated 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 thepatient. The magnitude of the metabolic response isgenerally proportional to the severity of tissue injury, butcan be modified by additional factors such as infection. The response to injury has probably evolved to aid recovery,by mobilizing substrates and mechanisms of preventinginfection, and by activating repair processes. However,many of these physiological changes can now be modifiedor corrected by treatments. Although the metabolic responseaims to return an individual to health, it can sometimes have harmful effects. For example, a major response candamage organs distant to the injured site itself. In modernsurgery, 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 minimizetissue damage. When a major metabolic response doesoccur, the emphasis is on managing the patient in a way that minimizes further tissue damage either at the originalsite of injury or in other organs. This chapter describes theprincipal physiological systems involved in the metabolicresponse 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 medicaltreatments such as intravenous fluids. This unmodifiedresponse 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 duringresuscitation. When fluid therapies and blood transfusionswere introduced into medical practice, the shock thatoccurred in this phase was sometimes found to be reversible(‘reversible shock’) and in other cases irreversible(‘irreversible shock’). Irreversible shock probably occurswhen the metabolic response has initiated inflammatoryprocesses that cause a downward spiral of further injury inother organs.

The flow phase followed if the individual survived, andwas also described in two parts. The initial catabolic phasewas characterized by a high metabolic rate, breakdown ofproteins and fats, a net loss of body nitrogen (negativenitrogen balance) and weight loss. This phase usually lastedabout a week and was followed by an anabolic phase, duringwhich protein and fat stores were restored and weight gain

occurred (positive nitrogen balance). The recovery phaseusually lasted 2–4 weeks.

This characteristic pattern probably occurs after all typesof injury, but the degree depends on the magnitude of tissueinjury and how the response is modified by interventions.

FACTORS MEDIATING THE METABOLICRESPONSE TO INJURY

The metabolic response is a complex interaction betweenmany body systems.

THE ACUTE INFLAMMATORY RESPONSE

Inflammatory cells (macrophages and neutrophils) andcytokines (molecules with the capacity to act on a widerange of cell types, both at the site of injury and at distant sites in the body) are mediators of the acuteinflammatory response. Physical damage to tissues resultsin local activation of cells such as tissue macrophages.These cells release a variety of cytokines (Table 1.1). Someof these, such as interleukin-8 (IL-8), attract large numbersof circulating macrophages and neutrophils to the site ofinjury. 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 releaseinto the circulation initiates some of the systemic features of the metabolic response, such as fever (IL-1) and theacute-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 rapidamplification 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 inassociation 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 andcathepsin) and free radicals. Anti-inflammatory substancesand mechanisms also exist, such as antioxidants (forexample, glutathione, vitamin A and vitamin C), proteaseenzyme inhibitors (for example, a

2-macroglobulin) and

IL-10. The balance between pro- and anti-inflammatoryprocesses is extremely important but is not yet fullyunderstood.

THE ENDOTHELIUM AND BLOOD VESSELS

Leucocyte accumulation in injured tissues relies on astepwise process whereby cells initially adhere ‘lightly’ tothe endothelium, subsequently adhere ‘tightly’, and thenmigrate between endothelial cells into tissues (Fig. 1.1).These processes are controlled via specific moleculesreleased by endothelial cells and inflammatory cellsfollowing cell activation. ‘Light’ adhesion is mediated viathe selectins, and ‘tight’ adhesion via integrins and theintercellular adhesion molecule (ICAM) family.

When tissues are injured, the local blood flow increasesbecause of vasodilatation. This steps up the local delivery of inflammatory cells, oxygen and nutrient substrates thatare important in the healing process. Vasodilatation iscaused by substances such as kinins, prostaglandins andnitric oxide, which are generated in response to injury and inflammation. Nitric oxide, which is synthesized inendothelial cells, is particularly important in controllingblood flow to tissues, both in health and following injury. In addition to vasodilatation, capillaries in injured tissuesbecome more permeable to plasma because endothelialactivation increases the size of intercellular pores. As aresult, fluid and colloid particles (principally albumin) leakinto 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. Asituation of excess pro-coagulant activity can causeimpaired blood flow by occluding capillaries. This canoccur when inflammatory processes become generalized in the circulation, commonly as a result of infection, andcause disseminated intravascular coagulation.

AFFERENT NERVE IMPULSES ANDSYMPATHETIC NERVOUS SYSTEMACTIVATION

Impulses generated in afferent nerve endings at the site oftissue injury have a role in mediating the metabolic responseto injury. The most important nerves are probably pain fibres which comprise both unmyelinated C fibres andmyelinated A fibres. These are stimulated via direct traumaor 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. Afferentimpulses 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 endingsand adrenaline (epinephrine) release from the adrenalgland increase circulating catecholamine concentrations.This contributes to the changes in carbohydrate, fat 4

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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 afferent nerve impulses

Neutrophil accumulation• Phagocytosis• Cytokine release• Protease release

Neutrophil–endothelialcell 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 sympatheticstimulation, 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 manyhormones following injury (Table 1.2). These take place as a result of direct stimulation of the various glands thatproduce the hormones, and also because normal negativefeedback mechanisms are altered as part of the response to injury. Hormonal changes are mainly involved inmaintaining the body’s fluid balance and in the changes to substrate metabolism that occur following injury (seebelow).

CONSEQUENCES OF THE METABOLICRESPONSE TO INJURY

HYPOVOLAEMIA

A reduced circulating volume is characteristic followingmoderate 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, nasogastricsuction, vomiting or sweating) or water (evaporationfrom exposed organs during surgery).

• Fluid sequestration of plasma-like fluid in injuredtissues (sometimes termed third-space losses) occurs inproportion to the severity and extent of injury. It resultsfrom the increased ‘leakiness’ of the endotheliumdescribed above, usually lasts 24–48 hours, and aftermajor surgery can amount to several litres. The extentand duration of this leakiness may be prolonged if the acute inflammatory response is exaggerated: for example, by infection or the ischaemia–reperfusionsyndrome.

Decreased circulating volume is important because itmay reduce oxygen delivery to organs and tissues, loweringrates of healing or even causing further damage. Theneuroendocrine response to hypovolaemia and a reducedcirculating volume attempts to restore normal fluid statusand maintain perfusion to vital organs. These interrelatedprocesses can be considered as fluid-conserving measuresand blood flow-conserving measures. With modernmanagement of patients, this response is less crucial tosurvival because fluids and blood products can beadministered 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) AldosteroneProlactinAntidiuretic hormone/arginine vasopressin (ADH/AVP)

Unchanged secretion Thyroid-stimulating – – –hormone (TSH)Luteinizing hormone (LH)Follicle-stimulating hormone (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 verycommon after major surgery or injury. It may occur becauseof decreased renal perfusion as a result of hypovolaemia, but frequently arises even after normal circulating volume is restored. Characteristic changes affect urine after majorsurgery, which result from neuroendocrine responses.

Antidiuretic hormone (ADH)Synthesis and secretion of ADH (sometimes called argininevasopressin or AVP) by the posterior pituitary are increasedin 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 andcarotid baroreceptors (responding to reduced pressure)

• input from higher centres in the brain (pain, emotionand anxiety).

ADH promotes the retention of free water (withoutelectrolytes) by cells of the distal renal tubule and collectingduct. If excess water is administered during the period ofincreased ADH secretion, plasma hypotonicity and hypo-natraemia may occur.

AldosteroneAldosterone secretion from the adrenal cortex is increasedby the following mechanisms (Fig. 1.2):

• Secretion is raised via the renin–angiotensin system atthe juxtaglomerular apparatus within nephrons. Renin is released from afferent arteriolar cells in response tostimuli activated during hypovolaemia and reducedrenal blood flow. These include reduced afferentarteriolar pressure, tubuloglomerular feedback(signalling via the macula densa of the distal tubuleaccording to electrolyte concentration) and activation

of the renal sympathetic nerves. Renin, a proteolyticenzyme, converts circulating angiotensinogen toangiotensin I. Angiotensin I is converted to angiotensinII by angiotensin-converting enzyme (ACE), which isfound in plasma and in various tissues, particularly thelung. Angiotensin II has several actions, which includepotent 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 afferentnerve impulses from stretch receptors in the atria, aortaand 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 renaltubular cells. The net effect is reabsorption of sodium ionsand simultaneous excretion of hydrogen and potassium ions into urine. Aldosterone also effects ion transfer acrosssome other cell types: for example, cardiac muscle.

The duration of increased ADH and aldosteronesecretion is usually 48–72 hours. Urine volume is oftenreduced during this period (about 0.5 ml/kg/hr), and urine is concentrated as a result of water retention. Urinarysodium excretion decreases, typically to 10–20 mmol/24 hrs(normal 50–80 mmol/24 hrs). Urinary potassium excretionincreases, typically to > 100 mmol/24 hrs (normal 50–80mmol/24 hrs), but hypokalaemia is relatively rare in the24–48 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 haemostasisAbnormal 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

InfectionIschaemia–reperfusion 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 bemodified by fluid and electrolyte administration.

Blood flow-conserving measuresAn important potential consequence of hypovolaemia isreduced cardiac output, resulting in decreased blood flow to organs. Cardiac output is determined by the cardiacpreload (the amount of blood returning to the heart), theheart 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 mechanismsact 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 beconsidered in three parts: energy required for physical work,energy associated with heat production (thermogenesis) andbasal metabolic rate (BMR, comprising the energy neededfor 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 24–48 hoursfollowing injury. This occurs because cytokines, principallyIL-1, reset temperature-regulating centres in the hypo-thalamus. Pyrexia may also complicate infection occurringafter injury. Metabolic rate increases by 6–10% for each 1°C change in body temperature.

Basal metabolic rateFollowing injury, there is increased activity of protein,carbohydrate and fat-related metabolic pathways (seebelow) and of many ion pumps. The activity of some cyclesis apparently ‘futile’; for example, glucose–lactate cyclingand triglyceride turnover involve simultaneous synthesis and degradation. This general increase in substrate cyclingis energy-dependent, but probably evolved to increase theability of the body to respond to altering demands.

CATABOLISM AND STARVATION

Catabolism is the breakdown of complex substances, suchas muscle proteins, to form simpler molecules (glucose,amino acids and fatty acids) that are basic substrates formetabolic pathways. Starvation is the inadequate intake

Angiotensin I

Angiotensin II

Anterior pituitary:Secretes ACTH

ACTH actions:• Stimulation of aldosterone secretion by adrenal cortex

Adrenal gland cortex:Secretes aldosterone

Aldosterone actions:• Na+ and water retention from distal renal tubules• Negative feedback on anterior pituitary

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

Kidney juxtaglomerularapparatus (JGA):Secretes renin

Renin–angiotensin system

Angiotensinogen(plasma) Angiotensin-

converting enzyme(lung and other tissues)

Renin (JGA)

Fig. 1.2 The renin–angiotensin–aldosterone system.(ACTH = adrenocorticotrophic hormone)

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of food to meet metabolic demand. Following severe injury or major surgery, these two processes generally occursimultaneously. The metabolic changes associated with each process are different, and so the changes occurring inany individual patient depend on which process predomi-nates. Generally, uncomplicated surgery or moderate traumais 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 ofsimultaneous starvation.

CatabolismCatabolism is mediated by catecholamines, cytokines andother substances generated in response to injury andreleased into the circulation. These bring about changes in carbohydrate, protein and fat metabolism.

Carbohydrate metabolismGlycogenolysis in the liver results in rapid depletion of glycogen stores, which last for only 8–12 hours.Gluconeogenesis is increased, particularly in the liver,which converts substrates released from other tissues, suchas amino acids, into glucose. Insulin secretion is decreasedas a result of inhibition of pancreatic b-cells by cate-8

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ThalamusPyrexia

Heart and cardiovascular system Sympathetic activationTachycardia

Pituitary ACTH Antidiuretic hormone

Suprarenal gland Aldosterone Cortisol Adrenaline (ephinephrine)

Kidney Renin–angiotensin system activation Na+ reabsorption K+ reabsorption Urine volumesPoor erythropoietin response to anaemia

Pancreas Insulin release Glucagon release

Skeletal muscle Muscle breakdownRelease of amino acids into circulation

Bone marrowImpaired red cell production

Liver Glycogenolysis Gluconeogenesis Lipolysis Ketone body production Acute-phase protein release

Site of injury/surgeryInflammationOedemaEndothelial 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● Ø Glycogenolysis (stores last about 10 hours)● Ø Hepatic gluconeogenesis● Insulin resistance of tissues● Hyperglycaemia

Fat metabolism● Ø 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● Ø 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 theeffects of insulin. This is caused by changes to the insulinreceptor/intracellular signal pathway. Together, these factorsresult in hyperglycaemia, which provides glucose substratefor 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 aneffect 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 constitutesthe principal source of energy following trauma. The stresshormones released as part of the metabolic response toinjury (catecholamines, glucagon, cortisol and growthhormone) are all capable of activating the enzyme,triglyceride lipase, within fat cells. This process isexacerbated by the state of insulin resistance. Cortisol is a potent stimulus for lipolysis, and circulating cortisolconcentrations increase from normal baseline levels of ª400 nmol/l to levels of > 1500 nmol/l within hours of major surgery. Triglycerides are broken down into glyceroland free fatty acids. Glycerol is a substrate for gluco-neogenesis, and free fatty acids can be directly metabolizedby most tissues to generate energy. The brain is unable touse free fatty acids for energy production, and in healthrelies 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 supportcerebral energy metabolism. Following severe trauma,200–500 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 brokendown, 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 forenergy metabolism. Amino acids are also used in the liver as substrate for the ‘acute-phase protein response’. Thisresponse involves the liver increasing the production of one group of proteins (positive acute-phase proteins) anddecreasing the production of others (negative acute-phaseproteins) (Table 1.4). The acute-phase response is mediatedin 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, releasedas part of the metabolic response to injury. Trauma orsurgery 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 whenfactors that enhance the metabolic response, such as sepsis, are present.

In health, 80–120 g/day dietary protein (12–20 gnitrogen) is ingested (1 g nitrogen = 6 g protein). Normally,approximately 2 g/day nitrogen is lost in faeces and 10–18g/day in urine (mainly in the form of urea). Duringcatabolism, nitrogen intake is often reduced but urinarylosses can increase markedly, reaching 20–30 g/day inpatients with severe trauma, sepsis or burns. Followinguncomplicated surgery, this negative nitrogen balanceusually lasts only 5–8 days, but in patients with prolongedsepsis, burns or conditions associated with prolongedinflammation (for example, acute pancreatitis) it may persist for many weeks. Severe catabolism and negativenitrogen balance cannot be reversed by feeding, but theprovision 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 (Ø after injury)● C-reactive protein● Haptoglobins● Ferritin● Fibrinogen● a1-Antitrypsin● a2-Macroglobulin● Plasminogen

Negative acute-phase proteins (Ø after injury)● Albumin● Transferrin

Physical work 25%

Physical work 15%

Thermogenesis 15%

Basal metabolicrate 70%

Thermogenesis 10%

Basal metabolicrate 65%

Healthy sedentary 70 kg man• Total energy expenditure about 1800 kcal/day• Basal metabolic rate comprises enzymes and ion pumps (85%) and the mechanical work of the heart and respiratory system (15%)

24 hours following major surgery or moderate injury• Total energy expenditure increased 10–30%• Relative reduction in physical work due to inactivity• Thermogenesis/heat energy increased by mild pyrexia• Basal metabolic rate increased by raised enzyme and ion pump activity and increased cardiac work

Fig. 1.4 Components of body energy expenditure in health andfollowing injury.

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can lose about 600 g muscle protein (1 g protein = 5 g wetmuscle mass), amounting to 6% of total body protein. Thisis usually regained within 3 months.

StarvationStarvation occurs in relation to trauma and surgery forseveral reasons:

• the illness requiring treatment (for example, gastriccarcinoma), which may have reduced nutritional intakefor 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 describedin 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 cerebralenergy 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 cansustain 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 torelease amino acids, which are converted to glucose byhepatic gluconeogenesis. In addition, fatty acids releasedfrom adipose tissue are converted by the liver to ketones.Tissue energy supply is in the form of glucose, fatty acidsand ketones. The brain is unable to utilize free fatty acidsand uses about 70% of the glucose generated by hepaticgluconeogenesis. With prolonged starvation, the brainadapts to utilize ketones as the primary energy substrate,rather than glucose. This adaptation reduces muscle proteinloss 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 energyrequirements fall, the latter from 1800 kcal/day to about1500 kcal/ day (Table 1.5). This state is termed compensatedstarvation, which continues until body fat stores aredepleted. At this stage, when an individual is often close

to death, muscle protein breakdown again increases toprovide glucose for cerebral metabolism.

CHANGES IN RED BLOOD CELL SYNTHESISAND BLOOD COAGULATION

Anaemia is common after major surgery or trauma becauseof bleeding and the haemodilution that occurs when bloodlosses 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 thekidney and impaired maturation of red blood cell precursors.In addition, changes to iron metabolism occur that increasestorage iron (bound to ferritin) and decrease the availableiron (bound to transferrin). These changes are probably due to the effects of inflammation, but how this may be ofbenefit is unclear. Recent evidence suggests that activelycorrecting anaemia in patients after surgery or duringcritical 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 activatesthe coagulation pathways

• increased activation of platelets in response tocirculating 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 incirculating natural anticoagulants, such as protein C.

Rarely, patients develop hypocoagulable states. These are usually found in association with shock, massive bloodtransfusion 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 considerableresearch 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) 20–25 14 3

Energy expenditure (kcal/day) 2200–2500 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 oftissue injury through improvements in surgical techniques.In situations of exaggerated metabolic response, where thepatient either has undergone major surgery or is critically ill, several recent trials have suggested that interventions to alter aspects of the metabolic response can improvepatient survival.

CONTROL OF BLOOD GLUCOSE

Hyperglycaemia is a major component of the stressresponse, and is usually more severe following major trauma or surgery. Recent evidence suggests that, aftermajor (particularly cardiac) surgery and during criticalillness, tighter control of blood glucose using insulin isassociated with lower mortality and complication rates(EBM 1.1).

MANIPULATION OF INFLAMMATION ANDCOAGULATION IN SEVERE INFECTION

When severe infection complicates an illness, the metabolicresponse becomes exaggerated and is thought to contributeto further tissue injury and organ failure. This is calledsepsis syndrome and is a major cause of morbidity andmortality in hospitals. The concentrations of many cytokinesand other inflammatory factors in the circulation aremarkedly increased. Many large RCTs have tested whetherusing therapeutic interventions such as monoclonal anti-bodies to neutralize certain factors (for example, TNF-a, IL-6 or endotoxin) could improve survival of patients inthese situations. The majority of these studies have shownno benefit from such interventions and indeed sometimesshow harm. However, a recent large RCT in which activatedhuman protein C was administered to patients with severesepsis demonstrated a clear improvement in survival (EBM 1.2). This factor, which has anti-inflammatory andanticoagulant actions, is normally present in the circulationbut is deficient in patients with severe sepsis. The drug isrecommended for use in many countries under the guidanceof 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;345:1359–1367.

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; 79:918–925.Bernard GR, et al. N Engl J Med 2001; 344:699–709.

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 responseIschaemia–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 calledischaemia–reperfusion 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, restoringskeletal muscle mass and strength, and replenishing fatstores. 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 thepatient, who feels better and regains his or her appetite.Hormones contributing to the process of anabolism include insulin, growth hormone, insulin-like growthfactors, androgens and the 17-ketosteroids. The factorscontrolling the rate of anabolism are complex, but nutri-tional support and the activity level of the patient areimportant contributing factors.

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PRINCIPLES OF SURGICAL CARE

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