• Following 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.
• The magnitude of the metabolic response is generally proportional to the severity of tissue injury and the presence of ongoing stimulation but can be modified by additional factors such as infection.
• The response to injury has evolved to aid recovery, by mobilising substrates and mechanisms of preventing infection, and by activating repair processes.

Table 1. Summary of the metabolic response to trauma

Figure 1. Summary of the metabolic response to trauma

• Bodily injury is accompanied by systemic as well as local effects. Any stress, which includes injury, surgery, anaesthesia, burns, vascular occlusion, dehydration, starvation, sepsis, acute medical illness, or even severe psychological stress will initiate the metabolic response to trauma.
• Following trauma, the body responds locally by inflammation and by a general response which is protective, and which conserves fluid and provides energy for repair. Proper resuscitation may attenuate the response, but will not abolish it.
• The response is characterised by an acute catabolic reaction, which precedes the metabolic process of recovery and repair. This metabolic response to trauma was divided into an ebb and flow phase by Cuthbertson.
• The ebb phase corresponds to the period of severe shock characterised by depression of enzymatic activity and oxygen consumption. Cardiac output is below normal, core temperature may be subnormal, and a lactic acidosis is present.
• The flow phase can be divided into:

• a catabolic phase with fat and protein mobilisation associated with increased urinary nitrogen excretion and weight loss; and
• an anabolic phase with restoration of fat and protein stores, and weight gain.

• In the flow phase, the body is hypermetabolic; cardiac output and oxygen consumption are increased, and there is increased glucose production. Lactic acid may be normal.

• The magnitude of the metabolic response depends on the degree of trauma and the concomitant contributory factors such as drugs, sepsis and underlying systematic disease. The response will also depend on the age and sex of the patient, the underlying nutritional state, the timing of treatment and its type and effectiveness. In general, the more severe the injury (i.e. the greater the degree of tissue damage), the greater the metabolic response.
• The metabolic response seems to be less aggressive in children and the elderly and in the premenopausal woman. Starvation and nutritional depletion also modify the response. Patients with poor nutritional status have a reduced metabolic response to trauma compared to well-nourished patients.
• Burns cause a relatively greater response than other injuries of comparable extent probably because of the propensity for greater continued volume depletion and heat loss.
• Whenever possible, it is critical to try to prevent or reduce the magnitude of the initial insult, because by doing so it may be possible to reduce the nature of the response, which while generally protective may be harmful. Thus aggressive resuscitation, control of pain and temperature, and adequate fluid and nutritional provision are critical.
• The precipitating factors can broadly be divided into:

Hypovolaemia

• Decrease in circulating volume of blood
• Increase in alimentary loss of fluid
• Loss of interstitial volume
• Extracellular fluid shift

Afferent impulses

• Somatic
• Autonomic

Wound factors: inflammatory and cellular

• Eicosanoids
• Prostanoids
• Leucotrienes
• Macrophages
• Interleukin-1 (IL-1)
• Proteolysis inducing factor (PIF)
• Platelet activating factor 

Toxins/sepsis

• Endotoxins
• Exotoxins

Oxygen free radicals

Hypovolaemia

• It is said that hypovolaemia, specifically involving tissue hypoperfusion is the most potent precipitator of the metabolic response. Hypovolaemia can also be due to external losses, internal shifts of extracellular fluids and changes in plasma osmolality. However, the most common cause is blood loss secondary to surgery or traumatic injury.

Table 2. ATLS classification of shock

• Class III or class IV shock is severe, and unless treated as a matter of urgency, will make the situation much worse. 
• The hypovolaemia will stimulate catecholamines which in turn trigger the neuroendocrine response. This plays an important role in volume and electrolyte conservation and protein, fat and carbohydrate catabolism. Early fluid and electrolyte replacement, and parenteral or enteral surgical nutrition administering amino acids to injured patients losing nitrogen at an accelerated rate; and fat and carbohydrates to counter caloric deficits may modify the response significantly. However, the availability of the methods should not distract the surgeon from his primary responsibility of adequate resuscitation.

Afferent impulses

• Hormonal responses are initiated by pain and anxiety. The metabolic response may be modified by administration of adequate analgesia, which may be parenteral, enteral, regional or local. Somatic blockade may need to be accompanied by autonomic blockade, in order to minimise, or abolish the metabolic response. 

Wound factors

• Endogenous factors prolong or even exacerbate the surgical insult, despite the fact that the primary cause can be treated well. Tissue injury activates a specific response, along two pathways: 
• Inflammatory (humoral) pathway 
• Cellular pathway 
• Uncontrolled activation of endogenous inflammatory mediators and cells may contribute to this syndrome. 
• Both humoral and cell-derived activation products play a role in the pathophysiology of organ dysfunction. It is important, therefore, to monitor post-traumatic biochemical and immunological abnormalities whenever possible. 

Immune response: inflammatory pathway 

• The inflammatory mediators of injury have been implicated in the induction of membrane dysfunction.

Eicosanoids 

• These compounds, derived from eicosapolyenoic fatty acids, comprise the prostanoids and leucotrienes (LTs). Eicosanoids are synthesised from arachidonic acid which has been synthesised from phospholipids of damaged cell walls, white blood cells and platelets, by the action of phospholipase A2. The leucotrienes and prostanoids derived from the arachidonic acid cascade play an important role. 

Prostanoids 

• Cyclo-oxygenase converts arachidonic acid to prostanoids, the precursors of prostaglandin (PG), prostacyclins (PGI) and thromboxanes (TX). The term prostaglandins is used loosely to include all prostanoids. 
• The prostanoids (prostaglandins of the E and F series, prostacyclin (PGI2) and thromboxane synthesised from arachidonic acid by cyclo-oxygenase (in TXA2), endothelial cells, white cells and platelets, not only cause vasoconstriction (TXA2 and PGF1), but also vasodilatation (PGI2, PGE1 and PGE2). TXA2 activates and aggregates platelets and white cells, and PGI2 and PGE1 inhibit white cells and platelets. 

Leucotrienes 

• Lipoxygenase, derived from white cells and macrophages, converts arachidonic acid to leucotrienes (LTB4, LTC4 and LTD4). The leucotrienes (LTB4, LTC4 and LTD4) cause vasoconstriction, increased capillary permeability and bronchoconstriction.

Immune response: cellular pathway

• There are a number of phagocytic cells (neutrophils, eosinophils and macrophages), but the most important of these are the polymorphonuclear leucocytes and the macrophages. Normal phagocytosis commences with chemotaxis, which is the primary activation of the metabolic response, via the activation of complement. 
• The classic pathway of complement activation involves an interaction between the initial antibody and the initial trimer of complement components C1, C4 and C2. In the classic pathway, this interaction then cleaves the complement products C3 and C5 via proteolysis to produce the very powerful chemotactic factors C3a and C5a (anaphylotoxins). 
• The so-called alternative pathway seems to be the main route following trauma. It is activated by properdin, and proteins D or B, to activate C 3 convertase, which generates the anaphylotoxins C3a and C5a. Its activation appears to be the earliest trigger for activating the cellular system, and is responsible for aggregation of neutrophils and activation of basophils, mast cells and platelets to secrete histamine and serotonin, which alter vascular permeability and are vasoactive. In trauma patients, the serum C3 level is inversely correlated with the injury severity score (ISS). Measurement of C3a is superior because the other products are more rapidly cleared from the circulation. The C3a/C3 ratio has been shown to correlate positively with outcome in patients after septic shock. 
• The short-lived fragments of the complement cascade, C3a and C5a , stimulate macrophages to secrete interleukin-l (IL-1) and its active circulating cleavage product proteolysis-inducing factor (PIF). These cause proteolysis and lipolysis with fever. IL-1 activates T4 helper cells to produce IL-2, which enhances cell-mediated immunity. IL-1 and PIF are potent mediators stimulating cells of the liver, bone marrow, spleen and lymph nodes to produce acute-phase proteins which include complement, fibrinogen, a2-macroglobulin and other proteins required for defence mechanisms. 
• Monocytes can produce plasminogen activator, which can adsorb to fibrin to produce plasmin. Thrombin generation is important due to its stimulatory properties on endothelial cells. 
• Activation of factor XII (Hageman factor A) stimulates kallikrein to produce bradikinin from bradykininogen, which also affects capillary permeability and vaso-activity. A combination of these reactions causes the inflammatory response. 

Toxins

• Endotoxin is a lipopolysaccaride component of bacterial cell walls. Endotoxin causes vascular margination and sequestration of leucocytes, particularly in the capillary bed. At high doses, granulocyte destruction is seen. A major effect of endotoxin, particularly at the level of the hepatocyte may be to liberate tumour necrosis factor (TNF) in the macrophages. 
• Toxins derived from necrotic tissue or bacteria, either directly or via activation of complement system, stimulate platelets, mast cells and basophils to secrete histamine serotonin. 

Oxygen free radicals

• Oxygen radical formation by white cells is a normal host defence mechanism. Changes after injury may lead to excessive production of oxygen free radicals, with deleterious effects on organ function.

• During trauma, several hormones are altered. 
• Adrenaline, noradrenaline, cortisol, and glucagon are increased, while certain others are decreased.
• The sympathetic–adrenal axis is probably the major system by which the body’s response to injury is activated. 
• Many of the changes are due to adrenergic and catecholamine effects, and catecholamines are increased after injury. 

Pituitary

• The hypothalamus is the highest level of integration of the stress response. The major efferent pathways of the hypothalamus are endocrine via the pituitary and the efferent sympathetic and parasympathetic systems. 
• The pituitary gland responds to trauma with two secretory patterns. Adrenocorticotrophic hormone (ACTH), prolactin, and growth hormone levels increase. The remainder are relatively unchanged.
• Pain receptors, osmoreceptors, baroreceptors and chemoreceptors stimulate or inhibit ganglia in the hypothalamus to induce sympathetic nerve activity. The neural endplates and adrenal medulla secrete catecholamines. Pain stimuli via the pain receptors also stimulate secretion of endogenous opiates, b-endorphin and pro-opiomelanocortin (precursor of the ACTH molecule), which modifies the response to pain and reinforces the catecholamine effects. The b-endorphin has little effect, but serves as a marker for anterior pituitary secretion. 
• Hypotension, hypovolaemia in the form of a decrease in left ventricular pressure and hyponatraemia stimulate secretion of vasopressin, antidiuretic hormone (ADH) from the supra-optic nuclei in the anterior hypothalamus, aldosterone from the adrenal cortex, and renin from the juxtaglomerular apparatus of the kidney. 
• As osmolality increases, the secretion of ADH increases, and more water is reabsorbed, thereby decreasing the osmolality – (negative feedback control system). Volume receptors are located in the atria and pulmonary arteries, and osmoreceptors are located near ADH neurones in the supra-optic nuclei of the hypohalamus. ADH acts mainly on the connecting tubules of the kidney but also on the distal tubules to promote reabsorption of water.
• Hypovolaemia stimulates receptors in the right atrium and hypotension stimulates receptors in the carotid artery. This results in activation of paraventricular hypothalamic nuclei which secrete releasing hormone from the median eminence into capillary blood which stimulates the anterior pituitary to secrete adrenocorticotrophin (ACTH). ACTH stimulates the adrenal cortex to secrete cortisol and aldosterone. The control of ACTH secretion is uncertain, but arginine vasopressin (AVP) may play a role. Changes in glucose concentration influence the release of insulin from the b cells of the pancreas, and high amino acid levels, the release of glucagon from the pancreatic a cells.
• Plasma levels of growth hormone are increased. However, the effects are transitory, and have little long term effect. Growth hormone reverses catabolism following injury. 

Adrenal hormones

• Plasma cortisol and glucagon levels rise following trauma. The degree is related to the severity of injury. The function of glucocorticoid secretion in the initial metabolic response is uncertain, because the hormones have little direct action, and they seem primarily to augment the effects of other hormones such as the catecholamines. 
• With passage into the later phases after injury, a number of metabolic effects take place. Glucocorticoids exert catabolic effects such as gluconeogenesis, lipolysis and amino acid breakdown from muscle. Catecholamines also participate in these effects by mediating insulin and glucose release and the mobilisation of fat.
• There is an increase in aldosterone secretion, and this results in a conservation of sodium and thereby water. 
• Catecholamines are released in copious quantities following injury, primarily stimulated by pain, fea, and baroreceptor stimulation. 

Pancreatic hormones

• There is a rise in the blood sugar following trauma. The insulin response to glucose in normal individuals is reduced substantially with alpha adrenergic stimulation, and enhanced with beta adrenergic stimulation.

Renal hormones

• Aldosterone secretion is increased by several mechanisms. The renin–angiotensin mechanism is the most important. When the glomerular arteriolar inflow pressure falls, the juxtaglomerular apparatus of the kidney secretes renin, which acts with angiotensinogen to form angiotensin I. This is converted to angiotensin II, a substance which stimulates production of aldosterone by the adrenal cortex. Reduction in sodium concentration stimulates the macula densa, a specialised area in the tubular epithelium adjacent to the juxtaglomerular apparatus, to activate renin release. An increase in plasma potassium concentration also stimulates aldosterone release. Volume decrease and a fall in arterial pressure stimulates the release of ACTH via receptors in the right atrium and the carotid artery. 

Other hormones

• Atrial natriuretic factor (ANF) or atriopeptin is a hormone produced by the atria, predominantly the right atrium of the heart, in response to an increase in vascular volume. ANF produces an increase in glomerular filtration and pronounced natriuresis and diuresis. It also produces inhibition of aldosterone secretion which minimises kaliuresis and causes suppression of ADH release. 
• ANF has highlighted the heart's function as an endocrine organ. ANF has great therapeutic potential in the treatment of intensive care patients who are undergoing parenteral therapy. 

Hyperdynamic state

• Following illness or injury, the systemic inflammatory response occurs, in which there is an increase in activity of the cardiovascular system, reflected as tachycardia, widened pulse pressure and a greater cardiac output. 
• There is an increase in the metabolic rate, with an increase in oxygen consumption, increased protein catabolism and hyperglycaemia. 
• The cardiac index may exceed 4.5 litres/minute/m²after severe trauma or infection in those patients who are able to respond adequately. Decreases in vascular resistance accompany this increased cardiac output. This hyperdynamic state elevates the resting energy expenditure to more than 20% above normal. In an inadequate response, with a cardiac index of less than 2.5 litres/minute/m², oxygen consumption may fall to values of less than 100 ml/minute/m²(normal 120–160 ml/minute/m²). Endotoxins and anoxia may injure cells and limit their ability to utilise oxygen for oxidative phosphorylation. 
• The amount of ATP synthesised by an adult is considerable. However, there is no reservoir of ATP or creatinine phosphate, and therefore cellular injury and lack of oxygen results in rapid deterioration of processes requiring energy, and lactate is produced. Because of anaerobic glycolysis only two ATP equivalents instead of 34 are produced from one mole of glucose in the Krebs cycle.
• Lactate is formed from pyruvate, which is the end product of glycolysis. It is normally reconverted to glucose in the Cori cycle in the liver. However, in shock, the oxidation reduction (redox) potential declines and conversion of pyruvate to acetyl co-enzyme A for entry into the Krebs cycle is inhibited. Lactate therefore accumulates because of impaired hepatic gluconeogenesis, causing a severe metabolic acidosis. 
• A persistent lactic acidosis in the first 3 days after injury not only correlates well with the injury severity score (ISS), but also confirms the predictive value of lactic acidosis towards subsequent adult respiratory distress syndrome. 
• Accompanying the above changes is an increase in oxygen delivery to the microcirculation. Total body oxygen consumption (VO₂) is increased. These reactions produce heat, which is also a reflection of the hyperdynamic state. 

Water and salt retention

• The oliguria which follows injury is a consequence of the release of antidiuretic hormone (ADH) and aldosterone. 
• Secretion of ADH from the supra-optic nuclei in the anterior hypothalamus is stimulated by volume reduction and increased osmolality. The latter is mainly due to an increased sodium content of the extracellular fluid. Volume receptors are located in the atria and pulmonary arteries, and osmoreceptors are located near ADH neurones in the hypothalamus. ADH acts mainly on the connecting tubules of the kidney but also on the distal tubules to promote reabsorption of water.
• Aldosterone acts mainly on the distal renal tubules to promote reabsorption of sodium and bicarbonate and increased excretion of potassium and hydrogen ions. Aldosterone also modifies the effects of catecholamines on cells, thus affecting the exchange of sodium and potassium across all cell membranes. The release of large quantities of intracellular potassium into the extracellular fluid may cause a significant rise in serum potassium especially if renal function is impaired. Retention of sodium and bicarbonate may produce metabolic alkalosis with impairment of the delivery of oxygen to the tissues. After injury urinary sodium excretion may fall to 10–25 mmol/24 hours and potassium excretion may rise to 100–200 mmol/24 hours.

Carbohydrates

• Critically ill patients develop a glucose intolerance which resembles that found in pregnancy and in diabetic patients. This is as a result of both increased mobilisation, and decreased uptake of glucose by the tissues. The turnover of glucose is increased, and the serum glucose is higher than normal. 
• Glucose is mobilised from stored glycogen in the liver by catecholamines, glucocorticoids and glucagon. Glycogen reserves are limited, and glucose can be derived from glycogen for 12–18 hours only. Early on, the insulin blood levels are suppressed (usually lower by 8 units/ml) by the effect of adrenergic activity of shock on degranulation of the b cells of the pancreas. Thereafter gluconeogenesis is stimulated by corticosteroids and glucagon. The suppressed insulin favours the release of amino acids from muscle, which are then available for gluconeogenesis. Growth hormone inhibits the effect of insulin on glucose metabolism. 
• Thyroxine also accelerates gluconeogenesis, but T3 and T4 levels are usually low or normal in severely injured patients. 
• As blood glucose rises during the phase of hepatic gluconeogenesis, blood insulin concentration rises, sometimes to very high levels. Provided that the liver circulation is maintained, gluconeogenesis will not be suppressed by hyperinsulinaemia or hyperglycaemia, because the accelerated rate of glucose production in the liver is required for clearance of lactate and amino acids which are not used for protein synthesis. This period of breakdown of muscle protein for gluconeogenesis and the resultant hyperglycaemia characterises the catabolic phase of the metabolic response to trauma. 
• The glucose level following trauma should be carefully monitored. Hyperglycaemia may exacerbate ventilatory insufficiency, and may provoke an osmotic diuresis, and hyperosmolality. The optimum blood glucose level is between 4 and 10 mmol/L. Control of the blood glucose is best achieved by titration with intravenous insulin, based on a sliding scale. However, because of the degree of insulin resistance associated with trauma, the quantities required may be considerably higher than normal. 
• Parenteral nutrition may be required, and this may exacerbate the problem. However, glucose remains the best energy substrate following major trauma. 60–75% of the caloric requirements should be supplied by glucose, with the remainder being supplied using a fat emulsion.

Fat

• The principal source of energy following trauma is adipose tissue. Lipids stored as triglycerides in adipose tissue are mobilised when insulin falls below 25 units/mL. Because of the suppression of insulin release by the catecholamine response after trauma, as much as 200–500 g of fat may be broken down daily after severe trauma. Tumour necrosis factor (TNF) and possibly IL-1 play a role in the mobilisation of fat stores. 
• Catecholamines and glucagon activate adenylcyclase in the fat cells to produce cyclic adenosine monophosphate (cyclic AMP). This activates lipase which promptly hydrolyses triglycerides to release glycerol and fatty acids. Growth hormone and cortisol play a minor role in this process as well. Glycerol provides substrate for gluconeogenesis in the liver which derives energy by b-oxidation of fatty acids, a process inhibited by hyperinsulinaemia.
• Ketones are released into the circulation and are oxidised by all tissue except the blood cells and the central nervous system. Ketones are water soluble and will pass the blood–brain barrier freely permitting rapid central nervous system adaptation to ketone oxidation. 
• Free fatty acids provide energy for all tissues and for hepatic gluconeogenesis. Canitine, synthesised in the liver, is required for the transport of fatty acids into the cells. 
• There is a limit to the ability of traumatised patients to metabolise glucose, but a high glucose load makes management of the patient much more difficult. For this reason, nutritional support of traumatised patients requires a mixture of fat and carbohydrate. 

Amino acids

• The intake of protein by a healthy adult is between 80 and 120 g of protein – 1–2 g protein/kg/day. This is equivalent to 13–20 g of nitrogen per day. In the absence of an exogenous source of protein, amino acids are principally derived from the breakdown of skeletal muscle protein. Following trauma or sepsis the release rate of amino acids increases by three to four times. This process appears to be induced by proteolysis inducing factor (PIF), which has been shown to increase by as much as eight times in these patients. The process manifests of marked muscle wasting. 
• Cortisol, glucagon and catacholamines also play a role in this reaction. The mobilised amino acids are utilised for gluconeogenesis or oxidation in the liver and other tissues, but also for synthesis of acute-phase proteins required for immunocompetence, clotting, wound healing and maintenance of cellular function. 
• Certain amino acids such as glutamic acid, asparagine and aspartate can be oxidised to pyruvate, producing alanine or to a-ketogluterate, producing glutamine. The others must first be deaminated before they can be utilised. In the muscle, deamination is accomplished by transamination from branched chain amino acids. In the liver amino acids are deaminated by urea production, which is excreted in the urine. After severe trauma or sepsis as much as 20 g/day of urea nitrogen is excreted in the urine. As 1 g urea nitrogen is derived from 6.25 g degraded amino acids, this protein wastage is 125 g/day.
• One gram of muscle protein represents 5 g wet muscle mass. Such a patient would be losing 625 g of muscle mass per day. A loss of 40% of body protein is usually fatal, because failing immunocompetence leads to overwhelming infection. Cuthbertson1# showed that nitrogen excretion and hypermetabolism peaked several days after injury, returning to normal after several weeks. This is a characteristic feature of the metabolic response to illness. The most profound alterations in metabolic rate and nitrogen loss occur after burns. 
• To measure the rates of transfer and utilisation of amino acids mobilised from muscle or infused into the circulation, the measurement of the central plasma clearance rate of amino acids (CPCR-AA) has been developed. Using this method a large increase in peripheral production and central uptake of amino acids into the liver has been demonstrated in injured patients, especially if sepsis is also present. The protein-depleted patient can be improved dramatically by parenteral or enteral alimentation provided adequate liver function is present. Amino acid infusions in patients who ultimately die cause plasma amino acid concentration to rise to high levels with only a modest increase in CPCR-AA. This may be due to hepatic dysfunction caused by anoxia or toxins liberated by bacteria responsible for sepsis. Possibly, inhibitors, which limit responses to IL-l and PIF, may be another explanation.

The gut

• The intestinal mucosa has a rapid synthesis of amino acids. Depletion of amino acids results in atrophy of the mucosa causing failure of the mucosal antibacterial barrier. This may lead to bacterial translocation from the gut to the portal system and is probably one of the causes of liver injury, overwhelming infection and multisystem failure after severe trauma. The extent of bacterial translocation in trauma has not been defined. The presence of food in the gut lumen is a major stimulus for mucosal cell growth. Food intake is invariably interrupted after major trauma. The supply of glutamine may be insufficient for mucosal cell growth, and there may be an increase in endotoxin release, bacterial translocation and hypermetabolism. Early nutrition (within 24–48 hours) and early enteral rather than parenteral feeding may prevent or reduce these events. 

• During this phase the patient is in positive nitrogen balance, regains his weight and restores his fat deposits. The hormones which contribute to anabolism are growth hormones, androgens and 17-ketosteroids. The utility of growth hormone, and also more recently, of insulin-like growth factor (IGF-1) in reversing catabolism following injury, is critically dependent on adequate caloric intake.

• Survival after injury depends on a balance between the extent of cellular damage, the efficacy of the metabolic response and the effectiveness of treatment. 
• Hypovolaemia due to both external losses and internal shifts of extracellular fluid seems to be the major initiating trigger for the metabolic sequence. Fear and pain, tissue injury, hypoxia and toxins from invasive infection add to the initiating factor of hypovolaemia. The degree to which the body is able to compensate for injury is astonishing, although sometimes the compensatory mechanisms may work to the patient’s disadvantage. Adequate resuscitation to shut off the hypovolaemic stimulus is important. Once hormonal changes have been initiated, the effects of the hormones will not cease merely because hormonal secretion has been turned off by replacement of blood volume. 
• Thus once the metabolic effects of injury have begun, therapeutic or endogenous restitution of blood volume may lessen the severity of the metabolic consequences but cannot prevent them. 
• Mobilisation and storage of the energy fuel substrates, carbohydrate, fats and protein is regulated by insulin, balanced against catecholamines, cortisol and glucagon. However, infusion of hormones has failed to cause more than a modest response. 
• Rapid resuscitation, maintenance of oxygen delivery to the tissues, removal of devitalised tissue or pus, and control of infection, are the cornerstones. The best metabolic therapy is excellent surgical care. 
• Therapy should be aimed at removal of the factors triggering the response. Thorough resuscitation, elimination of pain, surgical debridement and when necessary drainage of abscesses and appropriate antibiotic administration, coupled with respiratory and nutritional support to aid defence mechanisms, are of fundamental importance. 

Ebb phase

• This develops within the first hours after injury (24–48 hours).
• The main physiological role of the ebb phase is to conserve both circulating volume and energy stores for recovery and repair.
• The predominant hormones regulating the ebb phase are catecholamines, cortisol and aldosterone (following activation of the renin–angiotensin system).
• The magnitude of this neuroendocrine response depends on the degree of blood loss and the stimulation of somatic afferent nerves at the site of injury.

Flow phase

• Following resuscitation, the ebb phase evolves into a hypermetabolic flow phase.
• This phase involves the mobilisation of body energy stores for recovery and repair.
• It is characterised by:
• Tissue oedema (from vasodilatation and increased capillary leakage)
• Increased basal metabolic rate (hypermetabolism)
• Increased cardiac output
• Raised body temperature
• Leukocytosis
• Increased oxygen consumption
• Increased gluconeogenesis
• The flow phase may be subdivided into an initial catabolic phase, lasting approximately 3–10 days, followed by an anabolic phase, which may last for weeks if extensive recovery and repair are required following serious injury.
• During the catabolic phase, the increased production of counterregulatory hormones (including catecholamines, cortisol, insulin and glucagon) and inflammatory cytokines (e.g. IL-1, IL-6 and TNFa) results in significant fat and protein mobilisation, leading to significant weight loss and increased urinary nitrogen excretion. 
• The increased production of insulin at this time is associated with significant insulin resistance and, therefore, injured patients often exhibit poor glycaemic control. The combination of pronounced or prolonged catabolism in association with insulin resistance places patients within this phase at increased risk of complications, particularly infectious and cardiovascular.