Metabolism, the stress response to surgery and perioperative thermoregulation

Metabolism

Metabolism may be defined as the chemical processes that enable cells to function. Basal metabolic rate (BMR) is the minimum amount of energy required to maintain basic autonomic function and normal homeostasis at rest. 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 to raise the temperature of 1 g of water from 15°C to 16°C. A more practical measure in human physiology is the kcal or calorie (Cal).

Cellular respiration pathway

The cellular respiration pathway describes how adenosine triphosphate (ATP) is produced from carbohydrates, fats and proteins. Amino acids, lipids, and other carbohydrates (see later for details of each) are converted to various intermediates, allowing them to enter the cellular respiration pathway through a variety of routes The main two intermediates are nicotinamide adenine dinucleotide (NAD ⁺ ) and flavin adenine dinucleotide (FAD ⁺ ). These molecules are present in high concentrations and can accept electrons to become negatively charged. They combine with a hydrogen atom to become their reduced forms, namely NADH and FADH ₂ . These reduced molecules act as shuttles for electrons in the process known as oxidative phosphorylation, in which they give up their electrons in the mitochondrial electron transport chain to create ATP, which the body can then use to drive energy-consuming processes (e.g. Na ⁺ transport or signalling).

Adenosine triphosphate is present in all cells and contains two high-energy phosphate bonds. It can be thought of as the energy currency of the body. Hydrolysis of 1 mole of ATP to adenosine diphosphate (ADP) releases 8 kcal of energy. Additional hydrolysis of the phosphate bond from ADP to adenosine monophosphate (AMP) also releases 8 kcal ( Fig. 13.1 ).

Once these molecules enter the pathways, it makes no difference where they came from; they simply go through the remaining steps, yielding NADH, FADH ₂ and ATP ( Fig. 13.2 ).

Let us consider the oxidation of 1 mole of glucose in the cellular respiration pathway in the presence of oxygen. Cellular respiration in the presence of oxygen consists of what can be considered as three distinct processes.

• 1.

  The glycolytic pathway ( g lycolysis) takes place in the cell cytoplasm and is not reliant on the presence of oxygen. Glycolysis results in the splitting of each 6-carbon glucose molecule into two 3-carbon molecules of pyruvate . This results in the net formation of two molecules of ATP anaerobically but also generates two pairs of NADH for entry into the electron transport chain (see Fig. 13.2 ).

• 2.

  Oxidation of each of the pyruvic acid (3-carbon) molecules to produce the 2-carbon acetyl–coenzyme A ( acetyl-CoA ) takes place in the mitochondria and results in the production of two pairs of NADH molecules for entry into the electron transport chain. Acetyl-CoA then combines with the 4-carbon molecule, oxaloacetic acid to form the 6-carbon molecule, citric acid . Citric acid enters the Krebs (or tricarboxylic acid; TCA) cycle. In this process, for each molecule of glucose that is metabolised, a further six pairs of NADH, two pairs of FADH ₂ and two molecules of ATP as well as six molecules CO ₂ are produced (see Fig. 13.2 ).

• 3.

  Oxidative phosphorylation also takes place in the mitochondrial matrix. This process is also known as the electron transport chain . Each molecule of NADH and FADH ₂ yields three and two molecules of ATP, respectively. Thus in perfect conditions, oxidative phosphorylation results in 38 molecules of ATP per molecule of glucose when the products of glycolysis are included. The total yield may be lower in certain circumstances.

The complete oxidation of 1 mole of glucose (180 g) in a calorimeter releases 686 kcal of heat energy (3.8 kcal g ^–1 ). However, because each of the 38 molecules of ATP releases 8 kcal, a maximum of 304 kcal of energy is synthesised from each mole of glucose. The efficiency of the glycolytic pathway is therefore 44%; the remainder of the energy is released as heat. Extra heat can be generated if required by uncoupling of oxidative phosphorylation. Protein and fat can potentially release 4.1 and 9.3 kcal g ^–1 of energy, respectively.

Carbohydrates

Cell membranes are impermeable to glucose, so it is transported by a carrier protein (GLUT4) across the membrane in a process termed facilitated diffusion, a passive process that does not require energy expenditure by the cell. Facilitated diffusion of glucose is increased tenfold by the action of insulin, which speeds the translocation of GLUT4-containing endosomes into the cell membrane. In contrast, glucose absorption in the GI tract and reabsorption in the renal tubule are both active (energy-consuming) processes involving cotransport with sodium ions via sodium-dependent glucose transporters (SGLT). The final product of carbohydrate digestion is glucose.

After absorption into cells, glucose may be used immediately or stored in the form of glycogen, particularly in the liver and muscles. The process of releasing glucose molecules from the glycogen molecule in times of high metabolic demand is termed glycogenolysis . This process is initiated by the enzyme phosphorylase , which is activated in the presence of adrenaline and glucagon (released from the α cells of the pancreas in response to hypoglycaemia).

Proteins

Proteins may be synthesised from the 22 amino acids found in all cells of the body. The type of protein depends on the genetic material in the DNA, which determines the sequence of amino acids formed and the nature of the synthesised proteins.

There is equilibrium between the amino acids in plasma, plasma proteins and tissue proteins. The nine essential amino acids ( Box 13.1 ) must be ingested as they cannot be synthesised in the body. Others are non-essential (i.e. may be synthesised in the cells). Synthesis occurs by transamination, whereby an amine radical ( ^– NH ₂ ) is transferred to the corresponding α-keto acid. Amino acids have a weak carboxylic acidic group ( ^– COOH) and an amine group ( ^– NH ₂ ). Their entry into cells requires facilitated or active transport using carrier mechanisms. They are conjugated into proteins by the formation of peptide linkages using energy derived from ATP. Large proteins may be composed of several peptide chains wrapped around each other (secondary structure) and bound by weaker links, such as hydrogen bonds, electrostatic forces and sulfhydryl bonds (tertiary structure).

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 keto acid. 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. 13.3 ). Amino acids may also take up ammonia to form the corresponding amide.

Several hormones influence protein metabolism. Growth hormone, insulin and testosterone are anabolic (i.e. they increase the rate of cellular protein synthesis). Other hormones, such as 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.

Lipids

Lipids are a diverse group of compounds characterised by their insolubility in water and solubility in non-polar solvents. The three main lipid groups are the TGs, phospholipids (PLs) and cholesterol. Functions of lipids include the following:

• Storage of energy for long-term use (e.g. TGs)

• Hormonal roles (e.g. steroids such as oestrogen)

• Insulation – thermal (TGs) and electrical (sphingolipids)

• Protection of internal organs (e.g. TGs and waxes)

• Structural components of cells (e.g. PL membranes and cholesterol)

The basic structure of both TGs and PLs is the fatty acid, which is a carboxylic acid with a long aliphatic chain. This chain can be either saturated (with no C-C double bonds) or unsaturated (one or more double bonds). Triglycerides are composed of three long-chain fatty acids bound with one molecule of glycerol. Phospholipids differ in that the third fatty acid is replaced by a compound such as inositol, choline or ethanolamine. Cholesterol has a sterol nucleus that is formed from fatty acid molecules.

After absorption in the GI tract, lipids are aggregated into chylomicrons (diameter 90–1000 nm). These molecules are too large to pass the endothelial cells of the portal system and so enter the circulation via the thoracic duct. Chylomicrons transport lipids to adipose, cardiac, and skeletal muscle tissue, where their TG components are hydrolysed by the activity of the lipoprotein lipase, allowing the released free fatty acids (FFAs) to be absorbed by the tissues. The remnants (e.g. cholesterol) are taken up by the liver.

Alpha-linolenic (omega-3) and linoleic (omega-6) acids are the essential polyunsaturated fatty acids that cannot be synthesised in humans and must be acquired from plant and fish sources. Together with their derivative arachidonic acid, they form prostaglandins, lipoxins and leukotrienes (collectively termed eicosanoids).

Transport of lipids from the liver or adipose cells to other tissues as an energy source occurs by binding to plasma albumin. The fatty acids are then referred to as 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; or

• 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 synthesised in the liver and, to a lesser extent, other tissue ( Fig. 13.4 ). Its primary function is in the formation of bile salts in the liver, which promote the digestion and absorption of lipids. Other functions include the formation of adrenocortical and sex hormones and as part of the water-resisting properties of skin.

HMG-CoA reductase is the rate-controlling enzyme in the production of cholesterol. It is inhibited by LDL and cholesterol. This enzyme is the target for statins used in the prevention of hypercholesterolaemia and atherosclerosis. High thyroid-stimulating hormone (TSH) (e.g. hypothyroidism) and low insulin levels result in higher cholesterol levels. Oestrogen reduces cholesterol concentrations.

High serum cholesterol concentrations are correlated with increased incidences of atherosclerosis and coronary artery disease. Prolonged increases in VLDL, LDL and chylomicron remnants are associated with atherosclerosis. Conversely, HDL is protective.

Lipids may be stored in the liver or adipose cells for later use or used immediately as an energy source. Triglyceride 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 earlier. Fatty acids need carnitine as a carrier agent to enter mitochondria, where they undergo β oxidation. The precise number of ATP molecules formed from a molecule of TG depends on the length of the fatty acid chain; longer chains provide 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 FFAs 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 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. 13.5 ). Ketones are organic acids that diffuse from their site of production in the liver into the circulation for transport to peripheral tissues, where they are available for oxidisation to acetyl-CoA to produce energy as ATP. Ketones are produced in response to prolonged fasting, starvation, intense exercise and diabetes. In these conditions, carbohydrate metabolism is absent or minimal, leading to intense gluconeogenesis. 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 fat breakdown results in large quantities of ketone release from the liver. Ketones can cross the blood–brain barrier and are an important energy source when glucose is lacking. There is a limit to the rate of tissue ketone utilisation because depletion of essential carbohydrate intermediate metabolites slows the rate at which acetyl-CoA can enter the Krebs cycle. Hence blood ketone concentration may increase rapidly, causing metabolic acidosis and ketonuria. Acetone may be discharged on the breath, giving a characteristic sweet odour.

Basic nutritional requirements

Exercise, metabolic stress or illness will require additional calories above basal metabolic requirements. When prescribing nutrition in critical care, catabolism, muscle wasting and nitrogen loss are inevitable regardless of caloric input, and trying to match the calorie requirement can lead to very large amounts of energy being prescribed. This could lead to overfeeding, which is associated with poor outcomes. The European Society for Clinical Nutrition and Metabolism (ESPEN) recommends starting at 25–30 kcal kg ^–1 day ^–1 with a protein intake of 1 g kg ^–1 day ^–1 . Protein gives approximately 4 kcal g ^–1 ; the remaining calorie requirement should be provided by carbohydrates and lipids in a ratio of 1:1. Carbohydrates also provide approximately 4 kcal g ^–1 and lipids 9 kcal g ^–1 .

The lipid content of total parenteral nutrition (TPN) is increasingly in the form of olive oil–based preparations, which are well tolerated in the critically ill. The protein requirement includes nitrogen 0.15–0.2 g kg ^–1 day ^–1 with the addition of 0.35 g kg ^–1 day ^–1 glutamine in critically ill patients. The electrolyte content of TPN should be guided by serum concentrations and ongoing losses. Typical daily requirements are shown in Table 13.1 (see also Chapter 12 ). A typical TPN prescription is shown in Table 13.2 .

Starvation

Starvation is defined as a severe deficiency in calorie intake to less than that required for maintenance of metabolic requirements. Initially glycogenolysis provides the brain with its primary energy substrate, glucose, until depletion of glycogen occurs after approximately 24 h. Blood glucose concentrations are then maintained by gluconeogenesis, with a peak effect at around 2 days. Gluconeogenesis uses products from lipolysis and muscle breakdown to produce glucose and acetyl-CoA; this increases the formation of ketone bodies. The clinical consequence of starvation is the progressive loss of tissue fat and protein. The average adult has sufficient stores to sustain life for about 3 months.

During starvation or when no protein is ingested (e.g. after major surgery), 20–30 g day ^–1 of protein is catabolised 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 marked systemic inflammation or after major surgery, functional catabolism also occurs.

Nutritional status can be assessed by history (weight loss, recent dietary intake, relevant gastrointestinal (GI) disease and comorbidities such as neoplasia). Examination reveals consequences of vitamin and mineral deficiencies (e.g. bruising, gum disease, osteomalacia) and evidence of soft tissue wasting and dehydration. Body mass index (BMI, kg m ^–2 ) is a crude measurement and does not account for body composition (e.g. fat vs. muscle). Body mass index categories are as follows:

• Underweight (<18.5)

• Ideal (18.5–24.9)

• Overweight (25–29.9)

• Obese (>30)

• Severely obese (>35)

• Very severely obese (>40)

Body density and fat percentage can be estimated using anthropometric measurements to estimate nutritional status. These include mid-upper-arm circumference and skin fold thickness to indirectly measure subcutaneous adipose tissue at specified anatomical sites such as the triceps or iliac crest. A functional measurement of nutritional status can also be made by fist grip strength.

Other than a subjective global assessment, severe malnutrition is defined by ESPEN criteria for severe undernutrition as including one of the following:

• Weight loss >10%–15% over the preceding 6 months

• BMI <18.5 kg m ^–2

• Serum albumin <30 g L ^–1 (with no hepatic or renal dysfunction)

Patients who are malnourished or at risk of undernutrition can be identified using screening tools such as the MUST (Malnutrition Universal Screening Tool). This comprises five steps:

• 1.

  Assess BMI.

• 2.

  Calculate percentage of unplanned weight loss.

• 3.

  Add acute disease effect.

• 4.

  Use tables to generate a score of overall risk of malnutrition.

• 5.

  Use this score to guide the plan of care.

The effects of chronic malnutrition on anaesthesia

Malnourished patients have increased risks of inadvertent perioperative hypothermia, increased susceptibility to infection with greater risk of wound infection and anastomotic breakdown, and increased risk of pressure ulceration. Malnutrition is associated with increased duration of hospital stay and duration of mechanical ventilation in the critically ill. Patients with decreased serum albumin have altered volume of distribution and altered fraction of protein-bound and unbound drug, potentially leading to unpredictable drug effects (see Chapter 1 ). Altered drug metabolism may also occur because of decreased microsomal enzyme activity and protein deficiency.

Malnourished patients are at risk of refeeding syndrome when feeding is re-established in hospital, either enterally or parenterally. This is associated with hypophosphataemia, as phosphate ions are taken intracellularly when a glucose substrate is restored. Adenosine triphosphate depletion and muscle weakness follow, with potential tissue hypoxia, seizures and cardiorespiratory arrest in severe cases. To avoid this, feeding should be started slowly in the malnourished patient, with 50% of calorie requirement given for the first 48 h before increasing to full feed.

Many elderly patients have nutritional deficits as well as being classed as frail. Some clinicians prescribe iron, folate and vitamin B12 replacement in the perioperative period to correct anaemia as well as protein and vitamin D supplements to minimise loss of muscle mass (sarcopenia) (see Chapter 31 ). Some units have instigated exercise programs sometimes known as prehabilitation to improve functional capacity before surgery.

The stress response to surgery

The physiological syndrome known as the stress response has evolved to enable humans to enter a catabolic state that mobilises energy stores and conserves water to enhance chances of survival in times of danger. The perioperative stress response to surgery varies in size and duration in proportion to the extent of injury or metabolic insult. If left unmodified in the perioperative period, it results in little benefit and much potential harm ( Fig. 13.6 ).

The two principal components of the stress response are the neuroendocrine response and the cytokine response ( Table 13.3 ). The neuroendocrine response is stimulated by painful afferent neural stimuli reaching the CNS. From baseline, serum cortisol concentrations reach a peak at around 4–6 h from the start of surgery. The stress response may be diminished by the use of a regional anaesthetic technique such as epidural or high-dose opioids (see later).

The cytokine (e.g. interleukin-6 and tumour necrosis factor) 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 Box 13.3 .