Metabolism, the Stress Response to Surgery and Perioperative Thermoregulation

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Metabolism, the Stress Response to Surgery and Perioperative Thermoregulation

METABOLISM

Metabolism may be defined as the chemical processes which enable cells to function. Basal metabolic rate (BMR) is the minimum amount of energy required to maintain basic autonomic function and normal homeostasis. For example, energy is required by the myocardium to maintain heart rate and stroke volume and by nerve and muscle membranes to maintain membrane potentials. In a healthy resting adult, BMR is in the region of 2000 kcal day^–1 (equivalent to 40 kcal m^–2 h^–1). One calorie is the energy required in joules to raise the temperature of 1 g of water from 15 °C to 16 °C. Because this is a very small unit, a more practical measure in human physiology is the kcal or Calorie (C).

Adenosine triphosphate (ATP) is the ‘energy currency’ of the body. It contains two high-energy phosphate bonds and is present in all cells. Most physiological processes acquire energy from it. Oxidation of nutrients in cells releases energy, which is used to regenerate ATP. Conversion of one mole of ATP to adenosine diphosphate (ADP) releases 8 kcal of energy. Additional hydrolysis of the phosphate bond from ADP to AMP also releases 8 kcal (Fig. 11.1). Other high-energy compounds include creatine phosphate and acetyl CoA. The generation of energy through the oxidation of carbohydrate, protein and fat is termed catabolism, whereas the generation of stored energy as energy-rich phosphate bonds, carbohydrates, proteins or fats is termed anabolism (Fig. 11.2). The amount of energy released by carbohydrate, protein and fat metabolism is: carbohydrate 4.1 kcal g^–1, protein 4.1 kcal g^–1 and fat 9.3 kcal g^–1.

FIGURE 11.1 Hydrolysis of adenosine triphosphate (ATP). ADP, adenosine diphosphate; AMP, adenosine monophosphate.

FIGURE 11.2 Overview of metabolism.

CARBOHYDRATE METABOLISM

The final product of carbohydrate digestion is glucose, which is used to form ATP in cells. Because the cellular membrane is impermeable to glucose, it is transported by a carrier protein (GLUT4) across the membrane in a process termed facilitated diffusion. Activation of insulin receptors speeds translocation of GLUT4-containing endosomes into the cell membrane which then mediate glucose transport into the cell. Facilitated diffusion of glucose into cells is increased 10-fold in the presence of insulin, without which the rate of uptake would be inadequate. This is a passive process (i.e. it does not require energy expenditure by the cell). In contrast, glucose absorption in the gastrointestinal tract and reabsorption in the renal tubule are both active processes (i.e. are energy-consuming processes). They involve co-transport with sodium ions via sodium-dependent glucose transporters (SGLT).

PROTEIN METABOLISM

Proteins are composed of amino acids, of which there are more than 20 different types in humans. All amino acids have a weak acid group (-COOH) and an amine group (-NH₂). They are joined by peptide linkages to form peptide chains (primary structure), a reaction which releases a molecule of water in the process. The blood concentration of amino acids is approximately 1–2 mmol L^–1. Entry into cells requires facilitated or active transport using carrier mechanisms. They are then conjugated into proteins by the formation of peptide linkages. Formation of the peptide link requires 0.5–4.0 kcal derived from ATP. Large proteins may be composed of several peptide chains wrapped around each other (secondary structure) and bound by weaker links, e.g. hydrogen bonds, electrostatic forces and sulfhydryl bonds (tertiary structure).

Some amino acids present in the body are not present in proteins to any appreciable extent including, for example, ornithine, 5-hydroxytryptophan, L-dopa and thyroxine. Catecholamines, histamine and serotonin are formed from specific amino acids. Sulphur-containing amino acids are the source of urinary sulphate and provide sulphur for incorporation into various proteins, e.g. Coenzyme A.

There is equilibrium between the amino acids in plasma, plasma proteins and tissue proteins. Proteins may be synthesized from amino acids in all cells of the body, the type of protein depending on the genetic material in the DNA, which determines the sequence of amino acids formed and hence controls the nature of the synthesized proteins. Essential amino acids must be ingested as they cannot be synthesized in the body. Table 11.1 lists the eight essential amino acids. If there is dietary deficiency of any of these, the subject develops a negative nitrogen balance. Others are non-essential (i.e. may be synthesized in the cells). Synthesis is by the process of transamination, whereby an amine radical (-NH₂) is transferred to the corresponding α-keto acid. Breakdown of excess amino acids into glucose (gluconeogenesis) generates energy or storage as fat, both of which occur in the liver. The breakdown of amino acids occurs by the process of deamination, which takes place in the liver. It involves the removal of the amine group with the formation of the corresponding ketoacid. The amine radical may be recycled to other molecules or released as ammonia. In the liver, two molecules of ammonia are combined to form urea (Fig. 11.6). Amino acids may also take up ammonia to form the corresponding amide.

TABLE 11.1

Essential Amino Acids

Leucine

Isoleucine

Lysine

Methionine

Phenylalanine

Threonine

Tryptophan

Valine

FIGURE 11.6 Deamination is the process of metabolizing amino acids. Ammonia is the end product. Two molecules of ammonia combine as shown to form urea. This occurs in the liver.

During starvation or when no protein is ingested (e.g. after major surgery), 20–30 g day^–1 of protein is catabolized for energy purposes. This occurs despite the continuing availability of some stored carbohydrates and fats. When carbohydrate and fat stores are exhausted, the rate of protein catabolism is increased to > 100 g day^–1, resulting in a rapid decline in tissue function. During the systemic inflammatory response syndrome (SIRS) or after major surgery, there is functional catabolism also. Several hormones influence protein metabolism. Growth hormone, insulin and testosterone are anabolic, i.e. they increase the rate of cellular protein synthesis. Other hormones, e.g. glucocorticoids, are catabolic, i.e. they decrease the amount of protein in most tissues, except the liver. Glucagon promotes gluconeogenesis and protein breakdown. Thyroxine indirectly affects protein metabolism by affecting metabolic rate. If insufficient energy sources are available to cells, thyroxine may contribute to excess protein breakdown. Conversely, if adequate amino acid and energy sources are available, thyroxine may increase the rate of protein synthesis.

LIPID METABOLISM

Lipids are a diverse group of compounds characterized by their insolubility in water and solubility in non- polar solvents such as ether or benzene. They include fats, oils, steroids, waxes, etc. They serve as an immediate energy source but also provide storage energy. They include cholesterol, which is a precursor of steroids. They provide electrical insulation for nerve conduction and when combined with protein they are known as lipoproteins, an important component of cell membranes. Lipoproteins are also the predominant means for the transport of bloodstream lipids.

Lipids include triglycerides (TGs), phospholipids (PLs) and cholesterol. The basic structure of TGs and PLs is the fatty acid. Fatty acids are long-chain hydrocarbon organic acids. TGs are composed of three long-chain fatty acids bound with one molecule of glycerol (Fig. 11.7). Phospholipids have two long-chain fatty acids bound to glycerol with the third fatty acid replaced by attached compounds such as inositol, choline or ethanolamine. Although cholesterol does not contain fatty acid, its sterol nucleus is formed from fatty acid molecules.

FIGURE 11.7 Triglyceride structure. R represents a chain of carbon atoms.

Some polyunsaturated fatty acids are considered essential because they cannot be synthesized in humans and because they are precursors for eicosanoids. They must be acquired from plant sources. These essential fatty acids are linolenic acid and linoleic acid which together with their derivative arachidonic acid form prostaglandins, lipoxins and leukotrienes (collectively termed eicosanoids).

After absorption in the gastrointestinal tract, lipids are aggregated into droplets (diameter 90–1000 nm), termed chylomicrons, composed mainly of TGs. These molecules are too large to pass the endothelial cells of the portal system and so enter the circulation via the thoracic duct. Chylomicrons are metabolized by lipoprotein lipase adherent to the endothelium of many tissues throughout the body including adipose tissue but not adult liver. Chylomicrons carry cholesterol to the liver. The fatty acids and lipoproteins released from the liver into the circulation are derived from secondary products of chylomicron metabolism.

Transport of lipids from the liver or adipose cells to other tissues that need it as an energy source occurs by means of binding to plasma albumin. The fatty acids are then referred to as free fatty acids (FFAs), to distinguish them from other fatty acids in the plasma. After 12 h of fasting, all chylomicrons have been removed from the blood, and circulating lipids then occur in the form of lipoproteins. Lipoproteins are smaller particles than chylomicrons but are also composed of TGs, PLs and cholesterol. They may be classified as:

very low-density lipoproteins (VLDLs), consisting mainly of TGs

low-density lipoproteins (LDLs), consisting mainly of cholesterol

high-density lipoproteins (HDLs), consisting mainly of protein.

Cholesterol

Cholesterol is a lipid with a sterol nucleus and is formed from acetyl CoA. It may be absorbed from food (animal sources only) but is also synthesized in the liver and to a lesser extent other tissue. Its function is predominantly the formation of bile salts in the liver, which promote the digestion and absorption of lipids. The remainder is used in the formation of adrenocortical and sex hormones and it is deposited also in the skin, where it resists the absorption of water-soluble chemicals.

The serum cholesterol concentration is correlated with the incidences of atherosclerosis and coronary artery disease. Prolonged elevations of VLDL, LDL and chylomicron remnants are associated with atherosclerosis. Conversely, HDL is protective. Factors affecting blood cholesterol concentration are outlined in Figure 11.8.

FIGURE 11.8 Factors affecting blood cholesterol concentration.

There is a feedback mechanism whereby increased cholesterol absorption from the diet results in inhibition of the enzyme HMG-CoA reductase, which regulates synthesis of cholesterol. There are many hormonal influences in cholesterol metabolism also, including increased plasma concentrations in response to abnormally low concentrations of thyroid hormone, insulin and androgens. Oestrogen reduces cholesterol concentration by an unknown mechanism. The family of cholesterol-lowering drugs termed statins are inhibitors of the enzyme HMG-CoA reductase.

Lipids are ingested in similar proportions to carbohydrates and may be used as an energy source immediately or stored in the liver or adipose cells for later use as an energy source. The stages in the use of TGs as an energy source are as follows. TG is hydrolysed to its constituent glycerol and three fatty acids; glycerol is then conjugated to glycerol 3-phosphate and enters the glycolytic pathway, which generates ATP as described above. Fatty acids need carnitine as a carrier agent to enter mitochondria, where they undergo beta oxidation. The precise number of ATP molecules formed from a molecule of TG depends on the length of the fatty acid chain, longer chains providing more acetyl CoA and hence more molecules of ATP. Newborns have a special type of fat, termed brown fat, which on exposure to a cold stressor is stimulated to break down into free fatty acids and glycerol. In brown adipose tissue, oxidation and phosphorylation are not coupled and therefore the metabolism of brown fat is especially thermogenic.

Ketones

Initial degradation of fatty acids occurs in the liver, but the acetyl-CoA may not be used either immediately or completely. Ketones, or keto acids, are either acetoacetic acid, formed from two molecules of acetyl CoA, β-hydroxybutyric acid, formed from the reduction of acetoacetic acid, or acetone, formed when a smaller quantity of acetoacetic acid is decarboxylated (Fig. 11.9). These three substances are collectively termed ketones. They are organic acids formed in the liver, from which they diffuse into the circulation and are transported to the peripheral tissues where they may be used for energy. Their importance is that they accumulate in diabetes and starvation, such as may occur in the perioperative period. In both circumstances, no carbohydrates are being metabolized. In diabetes, decreased insulin results in a reduction in intracellular glucose, and in starvation, carbohydrates are lacking simply because they are not being ingested. The ensuing breakdown of fat as described above results in large quantities of ketones being released from the liver to the peripheral tissues. There is a limit to the rate at which ketones are used by the tissues, because depletion of essential carbohydrate intermediate metabolites slows the rate at which acetyl CoA can enter the Krebs cycle (see Fig. 11.5). Hence, blood ketone concentration may increase rapidly, causing metabolic acidosis and ketonuria. Acetone may be discharged on the breath to give a characteristic sweet odour.

FIGURE 11.9 Ketone formation.

Measuring Metabolic Rate

Basal metabolic rate (BMR) is determined at complete mental and physical rest 12–14 h after food ingestion, if body temperature is within the normal range. Metabolic rate increases by approximately 8% for every 1 °C rise of body temperature. BMR may be measured by indirect calorimetry which involves the measurement of water, CO₂ or protein breakdown products produced to enable the metabolic rate to be quantified. Alternatively, the O₂ consumption can be measured. A total of 4.82 kcal of energy is produced per litre of O₂ consumed although accurate assessment depends on information about the type of food ingested. Factors influencing BMR are listed in Table 11.2.

TABLE 11.2

Factors Influencing Metabolic Rate

Malnutrition (20%)

Sleep (15%)

Exercise (up to 2000 × BMR)

Protein ingestion

Age: < 5 years has × 2 BMR of > 70

Thyroid hormone imbalance (increase or decrease by 50%)

Sympathetic stimulation

Testosterone (by 15%)

Temperature

Anaesthesia (20% reduction) (regional anaesthesia – no effect)

THE STRESS RESPONSE TO SURGERY

The stress response is a physiological response which has evolved to protect the body from injury and to enhance chances of survival. It involves cardiovascular, thermoregulatory and metabolic mechanisms and was first described by Cuthbertson in 1929.

Surgery or trauma consistently elicits a characteristic neuroendocrine and cytokine response in proportion to the extent of injury or metabolic insult. Minor surgery on a limb has a negligible stress response, in contrast to major surgery such as a laparotomy or thoracotomy. The characteristics of the stress response to surgery are summarized in Table 11.3. There are two principal components to the stress response to surgery: the neuroendocrine response and the cytokine response. The neuroendocrine response is stimulated by painful afferent neural stimuli reaching the CNS. It may be diminished and sometimes eliminated altogether by dense neural blockade from a regional anaesthetic technique.

TABLE 11.3

Components of the Stress Response to Surgery

The cytokine component of the stress response is stimulated by local tissue damage at the site of the surgery itself and is not inhibited by regional anaesthesia. It is diminished by minimally invasive surgery, especially laparoscopic techniques. Triggers are listed in Table 11.4.

TABLE 11.4

Triggers of the Neuroendocrine and Cytokine Response in Patients After Surgery

Noxious afferent stimuli (especially pain)

Local inflammatory tissue factors, especially cytokines

Pain and anxiety

Starvation

Hypothermia and shivering

Haemorrhage

Acidosis

Hypoxaemia

Infection

There is growing evidence that the stress response is detrimental and is associated with postoperative morbidity. It has adverse effects on several key physiological systems, including the cardiovascular, respiratory and gastroenterological systems.

Consequences of the Neuroendocrine Element of the Stress Response

Protein Catabolism

Major surgery results in a net excretion of nitrogen-containing compounds, referred to as negative nitrogen balance, reflecting catabolism of protein into amino acids for gluconeogenesis. This is partly because of perioperative starvation, but mainly because of the stress response, which causes decreased total protein synthesis, in addition to protein breakdown. Peripheral skeletal muscle is predominantly affected, but visceral protein may also be catabolized. Catecholamines, cortisol, glucagon and interleukins (IL-1 and IL-6) are involved in proteolysis and gluconeogenesis. Protein catabolism contributes to weight loss and impaired wound healing, and may delay overall postoperative recovery. Up to 0.5 kg day^–1 of lean muscle mass may be lost postoperatively because of this aspect of the stress response.

Carbohydrate Mobilization

Hyperglycaemia and insulin intolerance are major features of the stress response and may persist for several days postoperatively. They result from increased blood concentrations of catecholamines, cortisol and glucagon and also from sympathetic nervous system stimulation (by further increasing catecholamine release from the adrenal medulla). These hormones also inhibit insulin and therefore glucose uptake into muscle, fat and liver. Moreover, there is decreased sensitivity of muscle and liver to circulating insulin during the stress response. Blood glucose concentrations may increase to over 11 mmol L^–1, leading to glycosuria and osmotic diuresis.

Fat Metabolism

The net effect of the hormonal alterations listed in Table 11.3 is lipolysis, stimulated by catecholamines acting at α₁-adrenoreceptors, with resultant increased concentrations of FFAs in the circulation. FFAs may be oxidized in the liver to form ketones (e.g. acetoacetate), which may be used as a source of energy by peripheral tissues.

Cardiovascular Effects

The stress response to surgery and postoperative pain activates the sympathetic nervous system (SNS), which may increase myocardial oxygen demand by increasing heart rate and arterial pressure. Activation of the SNS may also cause coronary artery vasoconstriction, reducing the supply of oxygen to the myocardium, which in turn can predispose to myocardial ischaemia. This effect may be aggravated by the fact that there is a hypercoagulable state postoperatively and the stress response is an important factor in causing this. The concentration of antidiuretic hormone (ADH) increases during the stress response, and this is known to contribute to increased platelet adhesiveness (Fig. 11.10).

FIGURE 11.10 Potential effect of the surgical stress response on coronary arterial blood flow. ADH, antidiuretic hormone; SVR, systemic vascular resistance; SNS, sympathetic nervous system.

Respiratory Effects

Postoperative pulmonary dysfunction may also result from pain and the stress response to major surgery. The most important alteration in respiratory function caused by the stress response is a reduction in functional residual capacity (FRC). This is the amount of air remaining in the lungs at the end of a normal expiration. The main cause of reduction in FRC is postoperative pain, which reduces the depth and rate of breathing. When FRC is reduced, it may become less than the closing capacity, the volume of air in the lungs required to prevent alveolar collapse. When FRC is less than closing capacity, airway closure occurs, with resultant ventilation-perfusion mismatch, shunting of blood and hypoxaemia.

Gastrointestinal Effects

The stress response to surgery stimulates both afferent nociceptive input and efferent SNS output, resulting in ileus and excessive SNS stimulation relative to parasympathetic nervous system (PNS) stimulation. Postoperative ileus is a temporary impairment of gastrointestinal motility after major surgery. It delays resumption of an enteral diet, and this starvation itself prolongs the stress response to surgery.

Immunological System Effects

Many mediators of the stress response (cortisol, interleukins, prostaglandins, etc.) are cellular and humoral immunosuppressants. It is not known if stress response-mediated immunosuppression, which occurs for several days after surgery, influences patient outcome.

Afferent Neural Stimuli

Afferent noxious stimuli (such as pain, pressure, burning, distension) are transmitted by Aα and C nerve fibres. They enter the spinal cord via the dorsal root and synapse in the dorsal horn.

Local Factors and the Immunological (Cytokine) Response

Afferent neural stimuli are not the sole means of eliciting the stress response to surgery. Severe injury in a denervated limb also elicits the response, suggesting a non-neural stimulus. Cytokines and mediators of inflammation are released in response to local tissue destruction or trauma, increasing peripheral nociceptive activity. The magnitude of this response is proportional to the extent of tissue damage.

Effect of General Anaesthesia on the Stress Response

Intravenous (with the exception of etomidate) and inhalational anaesthetic agents have no appreciable effect on either the neuroendocrine or the cytokine elements of the stress response, irrespective of dose. Etomidate inhibits the 11β-hydoxylase enzyme involved in adrenal cortisol synthesis leading to reduced cortisol concentrations and is associated with increased mortality in the critically ill when infusions of etomidate are used for sedation. At much higher doses, adrenal 18β-hydroxylase and cholesterol side chain cleavage enzymes are inhibited, thus reducing aldosterone and other steroid hormone synthesis. There is some evidence that inhibition of 11β-hydoxylase occurs after a single induction dose of etomidate, reducing plasma cortisol concentrations for several hours, but the clinical significance of this is unclear. High-dose opioid analgesia (e.g. morphine 4 mg kg^–1 or fentanyl 50–100 μg kg^–1) may completely inhibit the neuroendocrine element (with the exception of that triggered by cardiopulmonary bypass). If the opioid is given after the surgical incision, it does not prevent the emergence of the stress response. These high doses of opioids are impractical for most operations.

Effect of Epidural Anaesthesia and Analgesia on the Stress Response

Neuroendocrine Element

While only very high-dose, opioid-based general anaesthesia completely inhibits the stress response to upper abdominal surgery epidural anaesthesia, commenced before the surgical incision and continued postoperatively, significantly reduces it. Epidural anaesthesia and analgesia for lower limb or pelvic surgery completely suppresses the response. Administration of local anaesthetic drugs into the epidural space is more effective in this respect than administration of opioids alone.

Cytokine Element

The systemic release of cytokines in response to local tissue damage is not influenced by any anaesthetic technique, including epidural anaesthesia and analgesia. However, the cytokine element of the stress response is reduced by limiting the extent of the surgical incision, in particular, by use of laparoscopic techniques.

Benefits of Modifying the Stress Response

It is generally agreed that it is beneficial to decrease the stress response in patients with cardiovascular disease. Neonates undergoing cardiac surgery show a decreased stress response when anaesthesia is supplemented with sufentanil and may suffer fewer postoperative complications.

There is actually no evidence that limiting the endocrine and metabolic responses to surgery is beneficial in all patients. However, regional anaesthesia may reduce complications in elderly high-risk patients (decreased cardiovascular and respiratory complications, reduced hospital stay) but further studies are needed to confirm this.

THERMOREGULATION AND ANAESTHESIA

Mammals are homeothermic, requiring a nearly constant internal body temperature; core temperature is one of the most closely guarded physiological parameters. Although core temperature varies daily with circadian rhythm and monthly in women, body temperature does not deviate more than a few tenths of a degree either side of normal. Anaesthesia and surgery have dramatic effects on temperature regulation, such that post-operative hypothermia is the rule rather than the exception. Hypothermia results in significant morbidity, including shivering, coagulopathy, prolonged duration of drug action and increased risk of surgical wound infection.

Physiology

It is useful to consider thermoregulatory physiology in terms of a two-compartment model. A central core compartment, comprising the major trunk organs and the brain (the main sources of heat production), accounts for two-thirds of body heat content. Core body temperature is maintained within a narrow range (36.8–37.2 °C), which facilitates optimal cellular enzyme function. This range is known as the ‘interthreshold range’, temperatures within this range result in little homeostatic regulation. The peripheral compartment consists of skin and subcutaneous tissues over the body surface, and the limbs. It amounts to about one-third of total body heat content. In contrast with the core, peripheral tissues have wide variation in temperature, ranging from 2–3 °C below to more than 20 °C below core temperature in extreme conditions. Peripheral tissue acts as a heat sink to absorb or give up heat in an attempt to maintain core temperature within its narrow range.

Heat Balance

Thermogenesis

Maintaining core temperature within a narrow range requires balancing heat production and loss. It is achieved by a control system consisting of afferent thermal receptors, central integrating systems and efferent control mechanisms (Fig. 11.11). It was formerly believed that the spinal cord and brainstem were passive conductors of afferent signals to the preoptic area of the hypothalamus, but it is now accepted that thermoregulation is a ‘multi-level, multiple-input’ system with the spinal cord, nucleus raphe magnus and locus subcoeruleus involved both in generating afferent thermal signals and modulating efferent thermoregulatory responses.

FIGURE 11.11 Control of thermoregulation.

Body heat is produced by metabolism, shivering and exercise. Basal metabolic rate cannot be manipulated by thermoregulatory mechanisms. Vasoconstriction and shivering are the principal autonomic mechanisms of preserving body heat and increasing heat production.

Adjacent to the centre in the posterior hypothalamus on which the impulses from cold receptors impinge, there is a motor centre for shivering. It is normally inhibited by impulses from the heat-sensitive area in the anterior hypothalamus, but when cold impulses exceed a certain rate, the motor centre for shivering becomes activated by ‘spillover’ of signals and it sends impulses bilaterally into the spinal cord. Initially, this increases the tone of skeletal muscles throughout the body, but when this muscle tone increases above a specific level, shivering is observed. Shivering may increase heat production six-fold.

Non-shivering thermogenesis is also an important mechanism in increasing heat production, but is probably limited in its effectiveness to neonates. Its role in adult thermogenesis is thought to be minimal, increasing the rate of heat production by < 10–15%, compared to the doubling seen in neonates. Non-shivering thermogenesis occurs mainly in brown adipose tissue (BAT). This subtype of adipose tissue contains large numbers of mitochondria in its cells, which are supplied by extensive SNS innervation. When sympathetic stimulation occurs, oxidative metabolism of the mitochondria is stimulated. However, it is uncoupled from phosphorylation, so that heat is produced instead of generating ATP. Exercise may increase heat production by as much as 20-fold for a short time at maximal intensity.

Heat Loss

Perioperative heat loss occurs predominantly by radiation (50–60%), convection (25–30%) evaporation (10–20%) and conduction (5%). Radiation is the major route of heat loss and is proportional to the difference in temperature between the patient and environment to the power of four. Conductive and convective heat losses are proportional to the difference between skin temperature and ambient temperature. Air flow accelerates cooling at a rate proportional to the square root of the air velocity. Evaporative heat loss from skin is usually minimal (< 5% of overall heat loss) as is evaporation from the respiratory tract in a warm operating theatre, particularly when using a heat and moisture filter in the breathing system. Evaporative losses may become significant in surgery in which warm moist viscera are exposed to the air, e.g. laparotomy, and following the application of cleaning fluids (particularly alcoholic), when the latent heat of vaporization draws heat from the body to lower core temperature by as much as 0.2–0.4 °C m^− 2.

Thermoregulation

Thermoregulation is achieved by a physiological control system consisting of peripheral and central thermoreceptors, an integrating control centre and efferent response systems (see Fig. 11.11).

Thermoreceptors: Afferent thermal input comes from anatomically distinct cold and heat receptors, located predominantly in the skin, but also centrally. The afferent thermal input comes from both core (80%) and peripheral (20%) compartments. The peripheral input is by thermally sensitive receptors located in the skin and mucous membranes, while core input occurs from thermoreceptors located in the hypothalamus itself (20%), brain (20%), spinal cord (20%), and thoracic and abdominal tissue (20%). Cold-specific receptors are innervated by Aδ fibres. Heat receptors are innervated by C fibres. Cold receptors in the skin outnumber heat receptors 10-fold and are the major mechanism by which the body protects itself against cold temperatures. Afferent input from these cold receptors in the skin is transmitted ultimately to the posterior hypothalamus.

Afferent thermal signals provide feedback to temperature-regulating centres in the hypothalamus. The preoptic area of the hypothalamus contains temperature-sensitive and temperature-insensitive neurones. The temperature-sensitive neurones, which predominate by 4:1, increase their discharge rate in response to increased local heat and this activates heat loss mechanisms. Conversely, cold-sensitive neurones increase their rate of discharge in response to cooling. Detection of cold differs from detection of heat, in that the principal mechanism of detection of cold is input from cutaneous cold receptors. At normothermia, most afferent input comes from cold receptors. Blockade of this afferent input by regional anaesthesia explains why the lower limbs are often perceived by the patient as feeling warm when epidural or spinal anaesthesia is established.

Central Control: The central control mechanism, situated in the hypothalamus, determines mean body temperature by integrating thermal signals from peripheral and core structures and comparing mean body temperature with a predetermined ‘set point’ temperature. The set point or physiological ‘thermostat’ of the thermoregulatory system is the temperature at which the system requires zero action to maintain that temperature (36.8–37.2 °C). The limits of this range represent the thresholds at which cold or heat responses are instigated, and hence it has been termed the ‘interthreshold range’. Normally it is < 1 °C, but this increases to 4 °C during general anaesthesia.

Effector Mechanisms: The most effective mechanisms for controlling body temperature are behavioural. In extreme cold conditions, vasoconstriction and shivering are of limited effect compared to behavioural measures such as taking shelter and wearing protective clothing.

Physiological responses to heat result in vasodilatation and sweating which are the major autonomic mechanisms of increasing heat loss. Maximal sweating rates may reach over 1 L h^–1 for a short time, resulting in heat loss of up to 15 times BMR.

Physiological responses to cold are generally of more relevance to anaesthesia because hypothermia is common during most procedures. In normal adults, the first response to a decrease in core temperature below the normal range (36.5–37.5 °C) is peripheral vasoconstriction. If core temperature continues to decrease, shivering commences. Vasoconstriction and shivering are characterized by threshold onset, gain and maximal response intensity. Threshold is the temperature at which the effector is activated. Gain is the rate of response to a given decrease in core temperature. Normally, the threshold core temperature for thermoregulatory vasoconstriction is 36.5 °C, with shivering commencing at 36.0–36.2 °C.

Measurement of Temperature

Core temperature may be evaluated reliably by an infrared thermometer at the tympanic membrane (provided that the external auditory meatus is free of ear wax) or by thermocouples positioned in the distal oesophagus, nasopharynx or pulmonary artery. Skin surface temperature varies with ambient temperature and induction of anaesthesia, and is usually also measured with a thermocouple. Rectal and bladder temperature may lag behind changes in core temperature because these organs are not perfused well enough to reflect rapid changes in body heat content.

Effect of General Anaesthesia on Thermoregulation

General anaesthesia has a number of effects on homeostatic mechanisms controlling thermoregulation which combine to cause hypothermia and impair the mechanisms which would normally limit the associated heat loss.

Widening of the Interthreshold Range

As discussed above, the interthreshold range is a narrow range of core temperature within which thermoregulatory mechanisms are relatively quiescent. General anaesthesia causes a dose-dependent widening of this interthreshold range, with an increase in the temperature at which thermoregulatory responses to heat are activated and an even greater reduction in the temperature at which thermoregulatory responses to cold are activated. Typically, the interthreshold range widens by about 4 °C, with the body becoming poikilothermic within this temperature range (Fig. 11.12). However, once core temperature falls outside this range, the gain (the rate of response to a given decrease in core temperature) and maximal response intensity of homeostatic mechanisms are unaffected. All general anaesthetic agents, both volatile and intravenous, impair thermoregulatory responses to a similar, but not identical, extent.

FIGURE 11.12 Thresholds for thermoregulatory effectors. (A) Under normal conditions, the range of core temperatures within which no effector is active, i.e. normal temperature, is approximately 0.5 °C. (B) During general anaesthesia, the range of core temperatures within which no effector is active is increased to approximately 4.0 °C.

Stages of Hypothermia

Mild hypothermia during general anaesthesia follows a distinctive pattern and occurs in three phases (Fig. 11.13):

FIGURE 11.13 Characteristic patterns of hypothermia during general anaesthesia (GA) alone, epidural or spinal anaesthesia alone and combined general and epidural anaesthesia. Patients in this last category are more likely to develop profound hypothermia than others (see text).

Phase 1 (Redistribution Stage): Under normal conditions, the temperature gradient between core and peripheral compartments is maintained by tonic vasoconstriction. On induction of anaesthesia, normal vasoconstrictor tone is reduced, and vasodilatation occurs, allowing heat to flow down its concentration gradient from the warm core to the cooler periphery, resulting in a mild core hypothermia (core temperature about 35.5–36.0 °C). This core hypothermia occurs because of redistribution of body heat on induction of anaesthesia, and overall heat loss from the body is minimal. Redistribution hypothermia results in an initial rapid decrease in core temperature of approximately 1 °C over the first 30 min, but mean body temperature and body heat content remain constant during this 30 min (Fig. 11.14).

FIGURE 11.14 Typical perioperative changes in core and peripheral compartment sizes.

There are a number of factors which affect the magnitude of this initial phase 1 hypothermia.

The greater the temperature gradient between the core and periphery, the greater is the decrease in core temperature. Patients who have been left in a cold reception room, for example, will have a relatively cold peripheral compartment and will suffer a greater degree of redistribution hypothermia.

Patients who are obese tend to be chronically vasodilated and have a warm peripheral compartment. Consequently, they suffer less vasodilatation on induction of anaesthesia and the reduced core–peripheral gradient also limits the magnitude of the redistribution hypothermia.

Neonates, and to a lesser extent children, have a much smaller peripheral compartment than adults and any decrease in core temperature on induction of anaesthesia is likely to be true heat loss rather than redistribution hypothermia.

Phase 2 (Heat Loss > Heat Production): Phase 2 is a slower linear decrease in core temperature to 34–35 °C over the next 2 h and occurs as a result of heat loss exceeding heat production. General anaesthesia reduces metabolic heat production by 15–40%, particularly through decreased brain metabolism and reduced respiratory muscle activity. Increased heat loss occurs through peripheral vasodilatation, evaporative heat loss from the body surface, and evaporative losses from exposed body cavities (some animal studies have shown that as much as 50% of total heat loss can come from exposed bowel).

Phase 3 (Plateau Phase): Phase 3 is a core temperature plateau (or thermal equilibrium), where heat loss equals heat production (either metabolic or warming devices) (Fig. 11.14). This core temperature plateau results largely from thermoregulatory vasoconstriction, triggered by a core temperature of 33–35 °C. Patients with impaired autonomic responses (e.g. elderly, diabetics, Parkinson’s disease, Shy-Drager syndrome, etc.) are less able to establish effective vasoconstriction and in these patients, establishment of a plateau phase may be delayed or even absent.

Effect of Regional Anaesthesia on Thermoregulation

Regional anaesthesia has a similar effect to general anaesthesia on thermoregulation and hypothermia. Regional anaesthesia widens the interthreshold range. The reasons for this are not clear, but are probably related to a blockade of afferent input to the hypothalamus. As with general anaesthesia, redistribution of body heat during spinal or epidural anaesthesia is the main cause of hypothermia. Because redistribution during spinal or epidural anaesthesia is confined usually to the lower half of the body, the initial core hypothermia is not as pronounced as in general anaesthesia (approximately 0.5 °C). Otherwise, the pattern of hypothermia during spinal or epidural anaesthesia is similar to that seen during general anaesthesia for the first two phases. The major difference for spinal or epidural anaesthesia is that the plateau phase does not emerge because vasoconstriction is blocked (see Fig. 11.13). Heat loss continues unabated during epidural anaesthesia despite the activation of effector mechanisms above the level of the block. Therefore, patients undergoing long procedures with combined general and epidural anaesthesia are at risk of a greater degree of hypothermia.

Consequences of Perioperative Hypothermia

In specific circumstances, hypothermia may have a protective effect in terms of reducing basal metabolic rate. The use of moderate hypothermia is routine practice in many centres during cardiopulmonary bypass. It is generally agreed, however, that, in most situations, the deleterious consequences of mild hypothermia outweigh the potential benefits, with evidence emerging that hypothermia per se is responsible for adverse postoperative outcomes. In particular, hypothermic patients are more likely than normothermic patients to have postoperative wound infections. The initial 3–4 h after bacterial contamination are thought to be crucial in determining whether clinical infection ensues. In vitro studies suggest that platelet function and coagulation are impaired by hypothermia, and mildly hypothermic patients lose > 25% more blood in the perioperative period than do normothermic patients. In addition, perioperative thermal discomfort is often remembered by patients as the worst aspect of their perioperative experience (Table 11.5).

TABLE 11.5

Consequences of Perioperative Hypothermia

Physical, Active and Passive Strategies for Avoiding Perioperative Hypothermia

Preventing redistribution-induced hypothermia may be achieved by physical and pharmacological means (Table 11.6). Redistribution of heat results when anaesthetic-induced vasodilatation allows heat to flow from the core to the periphery down its concentration gradient. Pre-emptive skin surface warming does not increase core temperature but increases body heat content, particularly in the legs, and removes the gradient for heat loss via the skin. However, this approach is rarely used in clinical practice because it requires 1 h of prewarming. This is unfortunate because it is a far more effective method of minimizing peri-operative hypothermia than trying to rewarm patients who have become hypothermic.

TABLE 11.6

Strategies for Prevention of Perioperative Hypothermia

Intraoperative use of forced air convective warming device

Reflective space blankets

Heating and humidifying inspired gases

Increased ambient temperature to 23 °C

Warmed i.v. fluids

Passive insulation with a single layer of any insulating material reduces cutaneous heat loss by 30–50%. Because only 10% of metabolic heat production is lost in heating and humidifying inspired gases, this method is relatively ineffective. Heat and moisture exchange filters retain significant amounts of moisture and heat within the respiratory system, but are only 50% as effective as active mechanisms. Ambient temperature determines the rate of heat loss by radiation and convection and maintains normothermia if close to initial, preinduction, core temperature (36 °C). However, this is usually impractical, as operating room staff find this temperature uncomfortable. Water mattresses are demonstrably ineffective at preventing heat loss, possibly because relatively little heat is lost from the back. Moreover, decreased local tissue perfusion associated with local temperatures of 40 °C may lead to skin necrosis. Heat loss may be reduced if intravenous fluids are warmed before or during administration.

Forced air warming systems are undoubtedly the best way to maintain normothermia during long procedures and are particularly effective when used intra-operatively for vasodilated patients, allowing heat applied peripherally to be transferred rapidly to the core. Their use increases core temperature and reduces the incidence of postanaesthetic shivering (Table 11.6).