Inflammatory cells and cytokines are the principal mediators of the acute inflammatory response. Physical damage to tissues results in local activation of cells such as tissue macrophages which 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. Others, such as tumour necrosis factor alpha (TNF-α), IL-1 and IL-6, activate these inflammatory cells, enabling them to clear dead tissue and kill bacteria. Although these cytokines are produced and act locally (paracrine action), 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) (endocrine action). Other pro-inflammatory (prostaglandins, kinins, complement, proteases and free radicals) and anti-inflammatory substances such as antioxidants (e.g. glutathione, vitamins A and C), protease inhibitors (e.g. α₂-macroglobulin) and IL-10 are also released (Fig. 1.1). The clinical condition of the patient depends on the extent to which the inflammation remains localized and the balance between these pro- and anti-inflammatory processes.

Table 1.1 Cytokines involved in the acute inflammatory response

Cytokine	Relevant actions
TNF-α	Proinflammatory; release of leucocytes by bone marrow; activation of leucocytes and endothelial cells
IL-1	Fever; T-cell and macrophage activation
IL-6	Growth and differentiation of lymphocytes; activation of the acute-phase protein response
IL-8	Chemotactic for neutrophils and T cells
IL-10	Inhibits immune function

(TNF = tumour necrosis factor; IL = interleukin)

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

The endothelium and blood vessels

The expression of adhesion molecules upon the endo-thelium leads to leucocyte adhesion and transmigration (Fig. 1.1). Increased local blood flow due to vasodilatation, secondary to the release of kinins, prostaglandins and nitric oxide, as well as increased capillary permeability increases the delivery of inflammatory cells, oxygen and nutrient substrates important for healing. Colloid particles (principally albumin) leak into injured tissues, resulting in oedema.

The exposure of tissue factor promotes coagulation which, together with platelet activation, decreases haemorrhage but at the risk of causing tissue ischaemia. If the inflammatory process becomes generalized, widespread microcirculatory thrombosis can result in disseminated intravascular coagulation (DIC).

Afferent nerve impulses and sympathetic activation

Tissue injury and inflammation leads to impulses in afferent pain fibres that reach the thalamus via the dorsal horn of the spinal cord and the lateral spinothalamic tract and further mediate the metabolic response in two important ways:

1. Activation of the sympathetic nervous system leads to the release of noradrenaline from sympathetic nerve fibre endings and adrenaline from the adrenal medulla resulting in tachycardia, increased cardiac output, and changes in carbohydrate, fat and protein metabolism (see below). Interventions that reduce sympathetic stimulation, such as epidural or spinal anaesthesia, may attenuate these changes.

2. Stimulation of pituitary hormone release (see below).

The endocrine response to surgery

Surgery leads to complex changes in the endocrine mechanisms that maintain the body’s fluid balance and substrate metabolism, with changes occurring to the circulating concentrations of many hormones following injury (Table 1.2). This occurs either as a result of direct gland stimulation or because of changes in feedback mechanisms.

Table 1.2 Hormonal changes in response to surgery and trauma

Consequences of the metabolic response to injury

Hypovolaemia

Reduced circulating volume often characterizes moderate to severe injury, and can occur for a number of reasons (Table 1.3):

• Loss of blood, electrolyte-containing fluid or water.

• Sequestration of protein-rich fluid into the interstitial space, traditionally termed “third space loss”, due to increased vascular permeability. This typically lasts 24–48 hours, with the extent (many litres) and duration (weeks or even months) of this loss greater following burns, infection, or ischaemia–reperfusion injury.

Table 1.3 Causes of fluid loss following surgery and trauma

Nature of fluid	Mechanism	Contributing factors
Blood	Haemorrhage	Site and magnitude of tissue injury Poor surgical haemostasis Abnormal coagulation
Electrolyte-containing fluids	Vomiting	Anaesthesia/analgesia (e.g. opiates) Ileus
	Nasogastric drainage	Ileus Gastric surgery
	Diarrhoea	Antibiotic-related infection Enteral feeding
	Sweating	Pyrexia
Water	Evaporation	Prolonged exposure of viscera during surgery
Plasma-like fluid	Capillary leak/sequestration in tissues	Acute inflammatory response Infection Ischaemia–reperfusionsyndrome

Decreased circulating volume will reduce oxygen and nutrient delivery and so increase healing and recovery times. The neuroendocrine responses to hypovolaemia attempt to restore normovolaemia and maintain perfusion to vital organs.

Positive acute-phase proteins (↑ after injury)

Negative acute-phase proteins (↓ after injury)

• Albumin

• Transferrin

The mechanisms mediating muscle catabolism are incompletely understood, but inflammatory mediators and hormones (e.g. cortisol) released as part of the metabolic response to injury appear to play a central role. Minor surgery, with minimal metabolic response, is usually accompanied by little muscle catabolism. Major tissue injury is often associated with marked catabolism and loss of skeletal muscle, especially when factors enhancing the metabolic response (e.g. sepsis) are also present.

In health, the normal dietary intake of protein is 80–120 g per day (equivalent to 12–20 g nitrogen). Approximately 2 g of nitrogen are lost in faeces and 10–18 g in urine each day, mainly in the form of urea. During catabolism, nitrogen intake is often reduced but urinary losses increase markedly, reaching 20–30 g/day in patients with severe trauma, sepsis or burns. Following uncomplicated surgery, this negative nitrogen balance usually lasts 5–8 days, but in patients with sepsis, burns or conditions associated with prolonged inflammation (e.g. acute pancreatitis) it may persist for many weeks. Feeding cannot reverse severe catabolism and negative nitrogen balance, but the provision of protein and calories can attenuate the process. Even patients undergoing uncomplicated abdominal surgery can lose ~600 g muscle protein (1 g of protein is equivalent to ~5 g muscle), amounting to 6% of total body protein. This is usually regained within 3 months.

Starvation

This occurs following trauma and surgery for several reasons:

• Reduced nutritional intake because of the illness requiring treatment

• 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).

Table 1.5 A comparison of nitrogen and energy losses in a catabolic state and starvation*

Acute starvation is characterized by glycogenolysis and gluconeogenesis in the liver, releasing glucose for cerebral energy metabolism. Lipolysis releases FFAs for oxidation by other tissues and glycerol, a substrate for gluconeogenesis. These processes can sustain the normal energy requirements of the body (~1800 kcal/day for a 70 kg adult) for approximately 10 hours.

Chronic starvation is initially associated with muscle catabolism and the release of amino acids, which are converted to glucose in the liver, which also converts FFAs to ketone bodies. As described above, the brain adapts to utilize ketones rather than glucose and this allows greater dependency on fat metabolism, so reducing muscle protein and nitrogen loss by about 25%. Energy requirements fall to about 1500 kcal/day and this ‘compensated starvation’ continues until fat stores are depleted when the individual, often close to death, begins to break down muscle again.

Changes in red blood cell synthesis and coagulation

Anaemia is common after major surgery or trauma because of bleeding, haemodilution following treatment with crystalloid or colloid and impaired red cell production in bone marrow (because of low erythropoietin production by the kidney and reduced iron availability due to increased ferritin and reduced transferrin binding). Whether moderate anaemia confers a survival benefit following injury remains unclear, but actively correcting anaemia in non-bleeding patients after surgery or during critical illness does not improve outcomes.

Following tissue injury, the blood typically becomes hypercoagulable and this can significantly increase the risk of thromboembolism; reasons include:

• endothelial cell injury and activation with subsequent activation of coagulation cascades

• platelet activation in response to circulating mediators (e.g. adrenaline and cytokines)

• venous stasis secondary to dehydration and/or immobility

• increased concentrations of circulating procoagulant factors (e.g. fibrinogen)

• decreased concentrations of circulating anticoagulants (e.g. protein C).

Factors modifying the metabolic response to injury

The magnitude of the metabolic response to injury depends on a number of different factors (Table 1.6) and can be reduced through the use of minimally invasive techniques, prevention of bleeding and hypothermia, prevention and treatment of infection and the use of locoregional anaesthesia. Factors that may influence the magnitude of the metabolic response to surgery and injury are summarised in table 1.6.

Table 1.6 Factors associated with the magnitude of the metabolic response to injury

Factor	Comment
Patient-related factors
Genetic predisposition	Gene subtype for inflammatory mediators determines individual response to injury and/or infection
Coexisting disease	Cancer and/or pre-existing inflammatory disease may influence the metabolic response
Drug treatments	Anti-inflammatory or immunosuppressive therapy (e.g. steroids) may alter response
Nutritional status	Malnourished patients have impaired immune function and/or important substrate deficiencies. Malnutrition prior to surgery is associated with poor outcomes
Acute surgical/trauma-related factors
Severity of injury	Greater tissue damage is associated with a greater metabolic response
Nature of injury	Some types of tissue injury cause a disproportionate metabolic response (e.g. major burns),
Ischaemia–reperfusion injury	Reperfusion of ischaemic tissues can trigger an injurious inflammatory cascade that further injures organs.
Temperature	Extreme hypo- and hyperthermia modulate the metabolic response
Infection	Infection is associated with an exaggerated response to injury. It can result in systemic inflammatory response syndrome (SIRS), sepsis or septic shock.
Anaesthetic techniques	The use of certain drugs, such as opioids, can reduce the release of stress hormones. Regional anaesthetic techniques (epidural or spinal anaesthesia) can reduce the release of cortisol, adrenaline and other hormones, but has little effect on cytokine responses

Anabolism

Anabolism involves regaining weight, restoring skeletal muscle mass and replenishing fat stores. Anabolism is unlikely to occur until the processes associated with catabolism, such as the release of pro-inflammatory mediators, have subsided. This point is often temporally associated with obvious clinical improvement in patients, who feel subjectively better and regain their appetite. Hormones contributing to this process include insulin, growth hormone, insulin-like growth factors, androgens and the 17-ketosteroids. Adequate nutritional support and early mobilization also appear to be important in promoting enhanced recovery after surgery (ERAS).

Fluid and Electrolyte Balance

In addition to reduced oral fluid intake in the perioperative period, fluid and electrolyte balance may be altered in the surgical patient for several reasons:

• ADH and aldosterone secretion as described above

• Loss from the gastrointestinal tract (e.g. bowel preparation, ileus, stomas, fistulas)

• Insensible losses (e.g. sweating secondary to fever)

• Third space losses as described above

• Surgical drains

• Medications (e.g. diuretics)

• Underlying chronic illness (e.g. cardiac failure, portal hypertension).

Careful monitoring of fluid balance and thoughtful replacement of net fluid and electrolyte losses is therefore imperative in the perioperative period.

Normal water and electrolyte balance

Water forms about 60% of total body weight in men and 55% in women. Approximately two-thirds is intracellular, one-third extracellular. Extracellular water is distributed between the plasma and the interstitial space (Fig. 1.5A).

Fig. 1.5 Distribution of fluid and electrolytes between the intracellular and extracellular fluid compartments.

A Approximate volumes of water distribution in a 70 kg man. B Cations and anions.

The differential distribution of ions across cell membranes is essential for normal cellular function. The principal extracellular ions are sodium, chloride and bicarbonate, with the osmolality of extracellular fluid (normally 275–295 mOsmol/kg) determined primarily by sodium and chloride ion concentrations. The major intracellular ions are potassium, magnesium, phosphate and sulphate (Fig. 1.5B).

The distribution of fluid between the intra- and extravascular compartments is dependent upon the oncotic pressure of plasma and the permeability of the endothelium, both of which may alter following surgery as described above. Plasma oncotic pressure is primarily determined by albumin.

The control of body water and electrolytes has been described above. Aldosterone and ADH facilitate sodium and water retention while atrial natriuretic peptide (ANP), released in response to hypervolaemia and atrial distension, stimulates sodium and water excretion.

In health (Table 1.7):

• 2500 to 3000 ml of fluid is lost via the kidneys, gastrointestinal tract and through evaporation from the skin and respiratory tract

• fluid losses are largely replaced through eating and drinking

• a further 200–300 ml of water is provided endogenously every 24 hours by the oxidation of carbohydrate and fat.

Table 1.7 Normal daily losses and requirements for fluids and electrolytes

In the absence of sweating, almost all sodium loss is via the urine and, under the influence of aldosterone, this can fall to 10–20 mmol/24 hrs. Potassium is also excreted mainly via the kidney with a small amount (10 mmol/day) lost via the gastrointestinal tract. In severe potassium deficiency, losses can be reduced to about 20 mmol/day, but increased aldosterone secretion, high urine flow rates and metabolic alkalosis all limit the ability of the kidneys to conserve potassium and predispose to hypokalaemia.

In adults, the normal daily fluid requirement is ~30–35 ml/kg (~2500 ml/day). Newborn babies and children contain proportionately more water than adults. The daily maintenance fluid requirement at birth is about 75 ml/kg, increasing to 150 ml/kg during the first weeks of life. After the first month of life, fluid requirements decrease and the ‘4/2/1’ formula can be used to estimate maintenance fluid requirements: the first 10 kg of body weight requires 4 ml/kg/h; the next 10 kg 2ml/kg/h; thereafter each kg of body requires 1ml/kg/h. The estimated maintenance fluid requirements of a 35 kg child would therefore be:

The daily requirement for both sodium and potassium in children is about 2–3 mmol/kg.

Assessing losses in the surgical patient

Only by accurately estimating (Table 1.8) and, where possible, directly measuring fluid and electrolyte losses can appropriate therapy be administered.

Table 1.8 Sources of fluid loss in surgical patients

	Typical losses per 24 hrs	Factors modifying volume
Insensible losses	700–2000 ml	↑ Losses associated with pyrexia, sweating and use of non-humidified oxygen
Urine	1000–2500 ml	↓ With aldosterone and ADH secretion; ↑ With diuretic therapy
Gut	300–1000 ml	↑ Losses with obstruction, ileus, fistulae and diarrhoea (may increase substantially)
Third-space losses	0–4000 ml	↑ Losses with greater extent of surgery and tissue trauma