Physiology for ED practice

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Physiology for ED practice

David Corkill

Introduction

This chapter explores some of the physiological mechanisms that support normal body function, the failure of which may necessitate nursing intervention in the ED patient. The basic physiological concepts of homeostasis are examined and a number of homeostatic mechanisms described. The importance of temperature regulation is discussed and the homeostatic mechanisms that maintain normal levels of fluids and electrolytes, glucose, blood pressure and haemostasis are outlined. The mechanisms of oxygen and carbon dioxide transport to and from the cells are discussed. Finally, the breakdown of homeostatic mechanisms is considered in a discussion of physiological shock.

Homeostasis

A single-celled organism, such as an amoeba, requires warmth, oxygen, nutrients and fluids in order to survive and must be able to rid itself of waste products. It interacts directly with the outside world in order to achieve this (Fig. 23.1). The human body is a highly complex collection of millions of cells, very few of which are in direct contact with the outside world, and yet each individual cell has the same survival requirements as the amoeba – a constant supply of fluids, nutrients, oxygen and warmth in order to live and the ability to remove waste products. The external environment (the ‘outside world’) of the cells in the body is the interstitial fluid that surrounds them (see Fig. 23.2 for body fluid compartments) and this fluid must be kept supplied with all the components that the cells might need. Individual cells need to maintain a constant environment within relatively narrow limits in order to function optimally and this constant state must be maintained whatever is happening to the body as a whole. The term ‘homeostasis’, first used by an American physiologist, Walter Cannon, in 1932, refers to the physiological mechanisms that maintain the body in a relatively constant state despite changes in the environment. The word comes from the Greek and means ‘standing the same’, something of a misnomer since physiological function is never static but constantly fluctuating. Homeostasis is essential if the metabolic activities that occur constantly in all cells are to continue.

Figure 23.1 Cell homeostasis.

Figure 23.2 Body fluid compartments.

Throughout the body there are many self-regulating homeostatic mechanisms that aim to maintain an internal ‘steady state’. Most homeostatic mechanisms within the body work by ‘negative feedback’, where a deviation from normal will cause a response to restore the steady state – thus too little of something will cause more to be produced, too much of something will trigger mechanisms to reduce the amount. Once steady state is reached, the homeostatic mechanisms are switched off. An example of a see-saw is commonly used to illustrate this concept (Fig. 23.3). In order to function, homeostatic mechanisms require specialized receptors to detect deviations from the ‘steady state’; they also require a control centre to receive and process the information and the ability to stimulate appropriate body organs and structures to redress the imbalance.

Figure 23.3 Homeostasis: maintaining a steady state.

The homeostatic mechanisms involved in temperature regulation, fluid and electrolyte balance, oxygen and carbon dioxide transport and maintenance of blood glucose and blood pressure will be examined in more detail.

Temperature control

Maintenance of a constant core body temperature, within the internal organs, is essential for optimal functioning of cellular enzymes. Humans are homeothermic and normally maintain a constant core temperature of 37 C regardless of the external temperature. The skin temperature may be several degrees different from the core temperature and varies between areas of the body, as those who always seem to have cold feet and hands will know. Body temperature is usually lower, by about 0.5°C at night and is 0.5–1°C higher in women during the second half of the menstrual cycle as a result of normal circadian rhythms. Children have higher core temperatures than neonates and the elderly, and core temperature can rise by up to 2°C during strenuous exercise. Despite all these normal variations, the body must maintain a careful balance between heat gained and heat lost. A summary of factors influencing heat gain and loss is given in Box 23.1.

Temperature homeostasis

Temperature-sensitive receptors, thermoreceptors, are found peripherally in the skin (sensitive to external temperature changes) and centrally in the hypothalamus in the brain (sensitive to changes in temperature of blood bathing them and thus to core temperature). When stimulated, the thermoreceptors initiate impulses via afferent nerves to the control centre, the temperature-regulating area in the anterior hypothalamus.

When core temperature falls below normal, the hypothalamus acts to conserve heat in the following ways:

• peripheral vasoconstriction mediated via the sympathetic nervous system closes down the surface blood vessels, ensuring that blood is kept closer to the warm core and heat loss through the skin is minimized

• shivering is initiated by the posterior hypothalamus and results in uncoordinated muscle activity that generates heat

• the thyroid gland is stimulated to produce the hormone thyroxin, which raises the basal metabolic rate of cells, thus increasing heat production

• information is relayed to the cerebral cortex and we become conscious of the cold and will take steps to warm ourselves such as putting on extra clothes, turning on the fire, exercising or having a warm drink.

A rise in core temperature above 37°C will stimulate responses aimed at losing heat:

• peripheral blood vessels are dilated under the influence of the sympathetic nervous system and heat is lost through the skin by radiation, conduction and convection

• sweat glands are stimulated, again via the sympathetic nervous system, to increase secretion, and heat is lost by evaporation. Evaporation of sweat is reduced when humidity is high and this is consequently a less effective means of reducing temperature in hot climates

• again the cerebral cortex receives information and we take steps to cool down – removing clothes, taking a cold shower, drinking iced drinks.

Once temperature returns to normal levels, the physiological mechanisms are switched off. A diagrammatic representation of thermoregulatory mechanisms is given in Fig. 23.4.

Figure 23.4 Thermoregulation.

Hypothermia, a core temperature below 35°C, is dangerous and, if not treated, will result in failure of the negative-feedback mechanisms that maintain temperature homeostasis, and damage or death may ensue. The ability to shiver decreases when the core temperature falls below 34°C and consequently the core temperature will fall further. Hypothermia slows the chemical reactions of metabolism and reduces blood flow to all organs. The resultant hypoxia will cause drowsiness and loss of consciousness as a result of cerebral ischaemia. Cardiac arrhythmias can occur below 30°C and the heart will cease to beat at about 20°C.

The O₂ requirements of the tissues are substantially reduced at low temperatures, and gradual warming of the patient combined with controlled oxygen therapy may result in full recovery provided no physiological damage has occurred. The elderly and neonates are particularly prone to hypothermia because of less efficient thermoregulatory mechanisms, as are those who misuse drugs and alcohol or who live ‘rough’ and who are not always able to take voluntary measures to regain heat.

Pyrexia or fever occurs when body temperature rises above normal as a result of pyrogens produced by bacteria, viruses or necrotic tissue, which affect the temperature-regulating centre. Head injury and brain damage may have a similar effect. The temperature-regulating centre is ‘reset’ at a higher level by the pyrogens and the body will continue to produce heat to maintain the higher level until the pyrogens are removed from the body.

Hyperpyrexia, i.e., a core temperature above 40°C, is a dangerous condition. Cellular metabolism is greatly increased and the body is unable to lose the heat produced sufficiently to reduce the temperature. Cells throughout the body are destroyed by literally burning themselves out and irreversible brain damage can occur at about 42°C.

Fluid and electrolyte balance

Water is the basis of all body fluids, e.g., plasma, tissue fluids and lymph, and accounts for approximately 60 % of total body weight. Body water contains many electrolytes, substances that dissolve and dissociate into ions (develop electrical charges). The main electrolytes in the body are sodium (Na⁺), potassium (K⁺), calcium (Ca²⁺) and magnesium (Mg²⁺), all of which are positively charged anions, and the negatively charged cations chloride (Cl^–), bicarbonate (HCO₃⁻), protein (Pr⁻) and phosphate (PO₄²⁻).

Fluid is either inside the cells (intracellular) or outside the cells (extracellular). Extracellular fluid includes blood plasma, interstitial or tissue fluid that bathes the cells (see above), and small amounts of transcellular fluid, found in body cavities such as intraocular, peritoneal and pleural fluid, cerebrospinal fluid and digestive juices. Figure 23.2 shows how these fluid compartments compare.

Intracellular fluid contains more positively charged potassium and magnesium and negatively charged protein and phosphate than extracellular fluid (which contains more positively charged sodium ions and negatively charged chloride ions) (Fig. 23.5). The ions are prevented from diffusing into other compartments by the selective permeability of the cell membranes and by the presence of a pumping mechanism within cell walls which actively pumps out sodium and exchanges it for potassium. This difference between intra- and extracellular fluids is essential in nerve and muscle cells (excitable tissues), since nerves would be unable to relay messages and muscles unable to contract without it.

Figure 23.5 Electrolytes in fluid compartments.

The interstitial fluid which bathes cells throughout the body must be maintained in a stable state as it provides the cells with nutrients and maintains the correct temperature for them to function effectively and receives their waste products. Disturbances in the electrolyte content and the concentration, osmolality and osmolarity of the extracellular fluid will affect the intracellular fluid and will impair cell and body function as a result. Normal cell function relies on fluid and electrolyte homeostasis.

Fluids normally enter the body only through the mouth. Thirst is a stimulus triggered when osmoreceptors in the hypothalamus detect a fall in the osmotic pressure of plasma passing over them. Fluid and electrolyte balance by intake alone would be inefficient, since either too much or too little may be ingested for any number of reasons. The body regulates levels of both water and electrolytes at the point of exit, mainly by the action of hormones on the distal tubules of the kidney.

Water balance is coordinated by the thirst centre in the hypothalamus, which controls the release of antidiuretic hormone (ADH). When the concentration of extracellular fluid rises as a result of a fluid intake below body requirements, osmoreceptors in the anterior hypothalamus sense the change and trigger impulses to allow the release of ADH from the posterior pituitary gland. ADH acts on the distal tubules of the kidney so that water is reabsorbed into the circulation. The mechanism is switched off once extracellular osmolarity returns to normal. This is another good example of negative feedback.

The hormone aldosterone, secreted from the adrenal cortex, is responsible for maintaining sodium levels in the body. A fall in blood sodium levels or a rise in serum potassium is detected by specialized cells in the adrenal cortex and increases the release of aldosterone, which acts to reabsorb sodium from the renal tubules and to reduce its excretion in saliva, gastric juices and the skin. Aldosterone production is also stimulated by a fall in the extracellular fluid volume via the renin-angiotensin system activated within the kidney. Potassium balance is closely linked with sodium and when sodium is reabsorbed, potassium is generally excreted. The body is inefficient at conserving potassium and blood levels are not indicative of total body potassium as most of this electrolyte is intracellular.

Optimal kidney function is vital for maintaining fluid and electrolyte homeostasis, and damage through whatever causes (trauma, disease, old age, etc.) will reduce the efficiency of the homeostatic system.

Fluid and sodium balance are closely linked and hormonal responses are triggered by both changes in extracellular fluid volumes and changes in plasma osmolality. A diagrammatic representation is given in Fig. 23.6.

Figure 23.6 Water and sodium balance.

Calcium levels in the body are regulated by the secretion of parathyroid hormone from the four parathyroid glands. The hormone is released directly in response to low extracellular fluid concentrations of calcium and stimulates the release of calcium from bone and its reabsorption from the kidney tubules. In addition, vitamin D is activated and increases the amount of calcium absorbed in the gut from food. When calcium is reabsorbed, phosphate is lost. High calcium levels stimulate the release of calcitonin from the thyroid gland. Calcitonin inhibits the release of calcium from bone and increases its excretion through the kidney until levels return to normal and the mechanism is switched off (Fig. 23.7).

Figure 23.7 Calcium homeostasis.

Oxygen and carbon dioxide homeostasis

All cells require oxygen in order to function, and produce carbon dioxide as a result of metabolic activity. These gases are carried to and from the cells in the blood and their values can be measured as partial pressures (PO₂ and PCO₂). Variations in arterial PO₂ and PCO₂ are sensed by chemoreceptors. Peripheral chemoreceptors in the aortic arch and at the bifurcation of the common carotid artery are particularly sensitive to falls in arterial oxygen levels (PaO₂), and rises in arterial carbon dioxide (PaCO₂). Once altered levels are sensed, the respiratory centre in the medulla of the brain is stimulated, via the vagal and glossopharyngeal nerves, and stimulates the phrenic and intercostal nerves to the diaphragm and intercostal muscles. The result is that the rate and depth of respiration are increased and more oxygen is inhaled and delivered to the blood. Once arterial blood oxygen levels are restored to normal, the mechanism is switched off.

Central chemoreceptors on the ventral surface of the medulla monitor the acidity of cerebrospinal fluid and are particularly sensitive to rises in PaCO₂. Inspiratory neurones in the respiratory centre of the medulla are again stimulated to increase both the rate and depth of respiration until the CO₂ is removed and blown off at the lungs and levels within the blood return to normal. The homeostatic mechanism is switched off once arterial CO₂ levels are normal again.

These homeostatic mechanisms are diagrammatically represented in Fig. 23.8.

Figure 23.8 Respiratory homeostasis.

In order to understand some common blood gas estimations, the means by which oxygen and carbon dioxide enter and are carried in the blood will be considered.

Oxygen transport

The atmosphere is composed of a mixture of gases of which the most important physiologically is oxygen. Inspired air consists of approximately 21 % oxygen, 79 % nitrogen and small amounts of carbon dioxide (0.04 %) and other gases, including water vapour. Each gas within this mixture exerts its own pressure, known as the partial pressure, and the total pressure of the mixture is equal to the sum of the pressures of all the gases within it (Dalton’s law of partial pressures). Atmospheric air pressure at sea level is known to be 101.3 kPa or 760 mmHg, and since oxygen comprises 21 % of the mixture, its partial pressure, usually written as PO₂, can be calculated thus:

The PN₂ and PCO₂ can be similarly calculated.

As atmospheric air passes through the respiratory tract, it becomes humidified with more water vapour, which reduces the partial pressure of the other gases as the pressure exerted by the water accounts for a larger proportion of the total pressure. The partial pressures are further modified as the gases combine with the air in the physiological ‘dead space’ in the respiratory tract before finally meeting and mixing with gases in the alveoli. As a result, the alveolar PO₂ is considerably less than atmospheric PO₂, and alveolar PCO₂ and water vapour pressure are measurably higher, although the total pressure remains the same as atmospheric pressure. Alveolar PO₂ is 13.3 kPa (100 mmHg) and alveolar PCO₂ is 5.3 kPa, (40 mmHg) and it is these amounts of gas that are available at the alveolar capillary membrane in the lungs where gaseous exchange takes place. Blood within the alveolar capillaries contains less oxygen and more carbon dioxide than alveolar air as a result of cellular metabolism, which removes oxygen from arterial blood and replaces it with carbon dioxide produced as a result of metabolic activity. Blood arriving at the lungs has a PO₂ of 5.3 kPa (40 mmHg) and a PCO₂ of 6.1 kPa (45 mmHg).

In the alveoli, gaseous exchange is possible because of the very thin pulmonary membrane between the alveoli and capillaries and the vast network of capillaries surrounding them. The existence of a pressure gradient, i.e., different pressures on either side of the membrane, results in movement of oxygen into the blood and carbon dioxide out of the blood and into the alveoli ready to be expired. Blood leaving the lungs for the heart contains oxygen and carbon dioxide at virtually the same partial pressures as those contained within the alveoli, so that the normal pulmonary vein and systemic arterial partial pressure of oxygen (PaO₂) is 13.3 kPa (100 mmHg) and PaCO₂ is 5.3 kPa (40 mmHg) (Figs 23.9 and 23.10); these quantities of gas are carried within the blood to the tissues.

Figure 23.9 Capillary network surrounding the alveolus.

Figure 23.10 Oxygen and carbon dioxide exchange throughout the body.

At the tissues, gases diffuse in the opposite direction across pressure gradients and thin membranes. Oxygen is given up to the tissues and replaced with carbon dioxide produced by the tissues. Partial pressures of oxygen and carbon dioxide within the cells are the same as those in blood arriving at the lungs (Fig. 23.10), since the gases cannot cross the thicker membranes of blood vessels in the rest of the circulation.

Oxygen is not simply carried around the circulation dissolved in blood, as a blood volume in excess of 80 L would be required to supply the 250 mL of oxygen required every minute when the body is at rest. Oxygen carried by this means accounts for only 1 % of the total oxygen transported in the blood, but it is an important 1 % as this is the only oxygen that exerts a pressure: not only does it maintain the pressure gradients necessary for diffusion, but it is this that is recorded when arterial blood gases are measured. Normal PaO₂ and PaCO₂ are the same as the pressures within alveolar air. This PO₂ governs the far greater amount of oxygen that can be transported in the blood bound to haemoglobin. Normally, 99% of oxygen is carried bound to haemoglobin (Hb) and, once bound, is no longer free to exert a pressure or to be measured in blood analysis. As the O₂ in solution is used, some of the bound O₂ will be released so that the ratio of 1% in solution:99% bound to Hb is always maintained.

Haemoglobin is a conjugated protein found in red blood cells and consists of four haem groups containing iron and four polypeptide chains. Each of these haem groups can combine with one molecule of oxygen to form oxyhaemoglobin, which is bright red and gives arterial blood its distinctive colour. This process is known as oxygenation. Normal Hb is approximately 15 g/dL and each gram of Hb can carry 1.34 mL O₂, so that the total oxygen capacity of the blood, i.e., the total amount that could be carried, is 15 × 1.34 = 20.1 mL/dL. This equation is simpler if SI units are used – normal Hb is 2.2 mmol/L blood and each molecule of Hb can combine with four molecules of O₂, so the oxygen capacity is 8.8 mmol/L (1 mmol O₂ = 23.4 mL). Amounts of oxygen carried bound to Hb can thus be far in excess of the normal requirements of the body. A simple sum will allow us to see that the body, which needs 250 mL of O₂ each minute at rest, actually has theoretically available 8.8 × 23.4 (= 197.12 mL per litre) × 5 L pumped out of the heart each minute, i.e., 986 mL per minute.

In normal physiological circumstances, not quite all the available haemoglobin binding sites become bound with oxygen but about 97–98 % do; this is the ‘oxygen saturation’ that is recorded by pulse oximetry. There are many reasons why pulse oximetry may give misleading information, but an important physiological reason is that while Hb may be fully bound with O₂, Hb levels may be very low. In this case pulse oximetry readings will be within normal limits but the blood is unable to carry sufficient oxygen to supply the needs of the cells throughout the body; examples are severe anaemia or in hypovolaemia (see the section on shock below).

Oxygen does not bind to each haem molecule with the same ease, and a graph plotting Hb saturation against PO₂ is not linear. The rate at which they bind is dependent on the PO₂. The first haem group combines with O₂ with relative difficulty, the second and third groups combine more readily and the fourth combines with the greatest difficulty of all. It will be seen from Fig. 23.10 that at a PO₂ of 5.3 kPa, (40 mmHg) as in blood arriving at the lungs, almost 70 % of the Hb sites are bound with oxygen and exposure to a PO₂ of 13.3 kPa (100 mmHg) at the alveoli will allow up to 98 % of the Hb to become saturated with O₂. At the tissues, O₂ is unloaded from the haem molecules in response to the fall in PO₂, so that a tissue PO₂ of 5.3 kPa (40 mmHg) will mean that oxygen from the 70–97% range can be removed for use.

The ‘s’ shape of the oxygen–haemoglobin dissociation curve is important physiologically for a number of reasons. Normal physiological function occurs over only a small part of this curve (Fig. 23.11) and a large reserve is available in the event of a fall in arterial PO₂, such as in lung disease, during exercise or at altitude. Even at a PO₂ of only 8 kPa (60 mmHg), 90 % saturation of Hb with oxygen will be achieved in blood leaving the lungs (point I in Fig. 23.11). During strenuous exercise, it is possible to achieve a PO₂ at the tissues of as little as 2 kPa (15 mmHg) and this will allow 80 % of the bound oxygen to be released (point II in Fig. 23.11), thus supplying the increased amount of oxygen required by the tissues.

Figure 23.11 The oxygen dissociation curve.

Several factors affect the ease with which O₂ binds with Hb and will influence the position of the oxygen–haemoglobin dissociation curve. The factors influencing ‘shifts’ in the curve are summarized in Fig. 23.12. The result of a shift to the left is that loading of Hb with O₂ occurs more readily, i.e., at a lower PO₂, while a shift to the right facilitates release of the O₂ at the tissues.

Figure 23.12 Factors influencing a shift in the dissociation curve.

Carbon dioxide transport

Carbon dioxide is transported around the body in three ways:

• 7 % in simple solution

• 23 % bound to the globin portion of haemoglobin and influenced by PCO₂

• 70 % as bicarbonate (hydrogen carbonate) ions.

Tissue cells constantly produce CO₂ and this diffuses across a pressure gradient into the capillaries supplying the tissue. Some remains dissolved in the plasma or binds to Hb but most crosses into the red blood cells (erythrocytes), where the presence of an enzyme, carbonic anhydrase, promotes the conversion of CO₂ and water within the cells to carbonic acid. The carbonic acid then dissociates into hydrogen and bicarbonate according to the equation

is then removed to the plasma where it is transported combined with sodium found in the plasma as sodium bicarbonate NaHCO₃.

CO₂ carried in this way does not exert a pressure within the blood and the equation reverses readily when blood arrives at the lungs so that CO₂ is readily released to be blown off. Fig. 23.8 shows this process diagrammatically.

Oxygen therapy

The aim of oxygen therapy is to raise the PO₂ in the lungs, thus increasing the pressure gradient across the alveolar capillary membrane and allowing more oxygen to enter the blood for transport to the tissues. There are, however, potential hazards that should be considered when oxygen therapy is indicated.

Patients with long-term respiratory disease may rely on low PO₂ levels to stimulate the respiratory centre (hypoxic drive) rather than rises in PCO₂ levels. High levels of oxygen administered to these patients will cause respiratory depression and possibly apnoea.

High concentrations of O₂ over prolonged periods may cause lung damage with oedema. Concentrations of administered O₂ should be kept as low as possible whilst maintaining adequate blood gas levels.

Compressed O₂ is very drying and should be humidified prior to administration. Patients receiving O₂ will require regular mouth rinses.

In neonates, particularly premature infants, blindness caused by retrolental fibroplasia, i.e., fibrosis behind the lens of the eye, may develop as a result of high-level O₂ administration.

More recently there has been recognition of the harmful effects of hyperoxaemia. It is recommended that critically ill patients, except neonates, be resuscitated in 100 % oxygen. After the patient has been successfully resuscitated, the oxygen concentration is rapidly titrated down to ensure an oxygen saturation of 94–98 %.

Variations at altitude and depth

As altitude increases, for example, during flight or when ascending mountains, barometric pressure falls. At 10 000 ft (300 m) total atmospheric pressure is 70 kPa or 523 mmHg and the PO₂ will be 21 % of this, i.e., 15 kPa. Alveolar PO₂ at this height will be reduced to approximately 9 kPa, causing a marked reduction in the pressure gradient across the alveolar capillary membrane. Hypoxic hypoxia (a deficiency of O₂ at the tissues caused by low PaO₂ levels) may become apparent in anyone above 10 000 ft unless supplementary oxygen is administered. Normal blood oxygen saturation of 98 % at sea level will be reduced to 87 % at 10 000 ft and to only 60 % at 20 000 ft. In pressurized aircraft cabins, pressure is usually maintained at about 8000 ft and the fit adult can readily adjust to cope with the resultant physiological alterations.

The symptoms of hypoxia include increases in heart and respiratory rate, headache, fatigue, nausea and dizziness. Perhaps the most threatening factor is that the onset is insidious and may occur in the carer as well as the patient. Prevention of hypoxia should always be the primary concern.

Pressures within body cavities alter with changes in barometric pressure. At altitude, gases within the cavities expand and then contract again during descent. These effects are particularly noticeable in the smaller body cavities, such as the middle ear and sinuses. Normally expanding and contracting gases will pass through the Eustachian tubes or the sinus cavities so that the pressure changes are equalized. In individuals with allergies, a cold or sinus infection, this movement of gases is limited or obstructed and painful otitis media or sinusitis may result. Those patients in whom respiration is compromised require careful monitoring and any pneumothorax must be treated prior to air transport as it will be likely to collapse further at altitude. Endotracheal tube balloons, intravenous fluid bags, anti-shock trousers and pneumatic splints are also subject to pressure changes and need close observation to ensure accurate functioning.

Gas pressures increase below sea level and at as little as 10 m deep in sea water (10.4 m in fresh water) atmospheric pressure is doubled (i.e., 202.6 kPa) and consequently all the partial pressures of the constituent gases are doubled. Divers and underwater tunnel workers breathe air at high pressure to equalize the pressures on the chest wall and abdomen. Nitrogen dissolves in plasma and interstitial fluid at these pressures but as long as ascent to the surface is slow and controlled, the dissolved N₂ will diffuse at the lungs and be breathed off. If ascent is too rapid, however, the N₂ forms bubbles in the tissues and decompression sickness results. With the current popularity of scuba diving, it is important to be aware of the symptoms of this sickness (joint pain, especially in the limbs, dizziness and fatigue, shortness of breath) as patients may present in departments a day or more after their dive and far from the coast.

Blood glucose homeostasis

Cells need a constant supply of nutrients from which to extract energy for cell work and glucose plays an important role in this as it is a major substrate for the manufacture of adenosine triphosphate (ATP) within the cells. This is particularly true in the brain, where 90 % of the cellular energy required for metabolism is derived from glucose. Glucose is obtained from food and food substrates and the body has efficient glucose storage mechanisms for use in times of plentiful supply (for example, following a meal) and equally efficient means of releasing the stores during fasting states. Two hormones – insulin and glucagon – are responsible for maintaining blood glucose within relatively narrow limits so that cells throughout the body receive a constant and adequate supply (Fig. 23.13).

Figure 23.13 Glucose homeostasis.

Following a meal, glucose crosses from the gut into the bloodstream and the high levels are detected in the pancreas where the specialized beta cells in the islets of Langerhans are stimulated to secrete insulin. Insulin has a number of ways of reducing blood sugar (by negative feedback):

• encourages the entry of glucose into cells throughout the body, especially the cells of skeletal muscle, to be used to manufacture ATP

• turns glucose into the storage form glycogen (this process is known as glycogenesis) for storage in cells and in the liver

• slows down the processes which turn fats and proteins into glucose.

If blood sugar is low, the alpha cells of the islets of Langerhans are stimulated and secrete the hormone glucagon. This leads to a number of physiological alterations aimed at raising the blood glucose levels:

• acts on liver cells to convert stored glycogen back to glucose (glycogenolysis) and release it back into the blood

• encourages the liver to manufacture glucose from lactic acid and from some amino acids (gluconeogenesis) and release it into the blood

• when blood levels have returned to normal, the mechanism is switched off.

Blood pressure homeostasis – a more complex mechanism

The maintenance of blood pressure is essential to life and the body initiates a number of mechanisms to restore pressure to normal resting state. A fall in blood pressure is detected by baroreceptors (pressure receptors) in the aortic arch and carotid arteries and information is relayed to the cardiovascular control centre in the medulla. The sympathetic nervous system is stimulated here and acts to bring about peripheral vasoconstriction so that blood pressure is increased in vessels supplying the vital organs.

The fall in blood pressure is also detected in the kidney where the juxtaglomerular cells release the enzyme renin. Renin converts a plasma protein, angiotensinogen, into angiotensin I and this, in turn, is converted into angiotensin II when it meets angiotensin-converting enzyme (ACE) in the blood vessels. Angiotensin II stimulates the release from the adrenal glands of aldosterone, which increases the amount of sodium and water reabsorbed into the blood as it passes through the kidneys. Angiotensin II also stimulates the release of adrenaline from the adrenal glands and this enhances and maintains the vasoconstrictor effect of sympathetic nervous stimulation described above. Two distinct negative-feedback mechanisms – vasoconstriction and fluid retention – can be seen acting together to increase venous return to the heart and maintain normal blood pressure.

A number of homeostatic mechanisms using negative feedback to maintain a relatively constant internal environment within which cells can function optimally have been examined. There are examples of physiological positive-feedback mechanisms, where too much produces more and too little produces even less, in the body and two of these will now be explored. In the first, the positive-feedback loop is broken once the desired effect has been achieved. In the second, the desired effect is unachievable and the positive feedback continues until the patient’s death unless appropriate interventions are made to break the loop.

Haemostasis – an example of positive feedback with a cut-off mechanism

Haemostasis, the arrest of bleeding, is a homeostatic process designed to maintain the body’s blood volume. Haemostasis takes place only where blood vessels are damaged as it is essential that blood in the rest of the circulation remains fluid. Normally the haemostatic process will control bleeding in all but large arteries and veins; intervention will be needed if bleeding is to be arrested in these large vessels.

The process of haemostasis can be divided into stages, although physiologically it occurs as a continuous process:

1. Myogenic reflex – damaged vessels will normally dilate immediately after injury under the influence of histamine released by mast cells in response to the trauma. Within seconds the vessels constrict and the cut ends retract as platelets within the vessels begin to clump together and release powerful vasoconstrictors, serotonin (also called 5-hydroxytryptamine or 5HT) and thromboxane A. This so-called ‘myogenic reflex’ occurs even in large vessels and lasts for approximately 20 minutes, enough time for stages two and three to commence.

2. Platelet plug formation – when blood vessels are cut, filaments of collagen and elastin are exposed and attract passing platelets which adhere to them. This adherence causes the release of adenosine diphosphate (ADP) from the platelets, red blood cells and vessel walls. ADP triggers a change in the shape of the platelets which encourages them to clump together. Other substances, including serotonin, also encourage platelet clumping until a plug of platelets is formed which is large enough to close the wounded vessel. A platelet plug is formed within a few seconds of injury and is sufficiently strong to stop bleeding in smaller vessels. The plug must then be stabilized by fibrin fibres or it will break down after about 20 minutes and bleeding will start again.

3. Fibrin clot – fibrin is an insoluble protein that is laid down as a mesh of fine threads which adhere to one another and to blood cells and platelets. They become entangled in the platelet plug, attract more cells to plug the damaged area and gradually make the clot firmer and more stable. Fibrin is formed by a complex process initiated when tissues are damaged. The complexity of the process is important since clotting within undamaged vessels would be highly undesirable. The early stages of fibrin formation also trigger the complicated clotting cascade involving 13 different factors, mostly blood constituents, which ultimately results in a blood clot. Blood is prevented from clotting, or the process is prolonged, if any of the factors are absent (as in haemophilia) or by the use of anticoagulants (such as heparin or aspirin), which prevent their production. The positive feedback of this clotting mechanism stops once the cascade is complete.

4. Fibrinolysis – during this stage fibrin is broken down and removed by phagocytes. The enzyme plasmin, which is responsible for this process, may be activated by streptokinase and other fibrinolytic agents.

Shock – where homeostasis fails and uncontrolled positive feedback ensues

Shock is a complex clinical syndrome characterized by a lack of adequate tissue and organ perfusion to such an extent that the oxygen and nutritional needs of the cells cannot be met. Cells and organs throughout the body are unable to function adequately and will fail and die unless both the cause and the symptoms of shock are treated.

Shock is commonly classified according to its pathophysiological cause, but any condition, physical or psychological, which reduces the blood supply to the tissues, is a potential cause of shock.

Classification of shock

There are three distinct mechanisms that may lead to hypoperfusion of the tissues:

• hypovolaemia – there is insufficient blood to carry the oxygen and nutrients needed

• pump failure (cardiogenic) – the heart is unable to pump the blood around the body effectively

• distribution problems – blood volume and cardiac output are essentially adequate but widespread vasoconstriction leads to pooling of blood and reduces venous return to the heart. Neurogenic, septic and anaphylactic shock all fall into this category.

Hypovolaemic shock

The causes of hypovolaemia are:

• loss of blood through haemorrhage

• loss of plasma as in severe burns and peritonitis

• loss of body fluids through diarrhoea, vomiting or sweating

• failure to drink sufficient fluids.

Fifteen per cent or more of total blood volume may be lost before signs of hypovolaemic shock are noted in an adult.

Cardiogenic shock (‘pump failure’)

Events which reduce the ability of the heart to pump efficiently result in cardiogenic shock. These include:

• myocardial infarction

• cardiac arrhythmias

• cardiac tamponade

• disorders in the lungs, e.g., tension pneumothorax or pulmonary embolus.

Neurogenic shock

In neurogenic shock, sympathetic and parasympathetic nervous control is lost. The venous ‘tone’ essential to the maintenance of normal blood pressure and venous return is lost and blood pools in the venules and capillaries. Common causes include:

• severe head injury

• spinal injury

• drug reaction and anaesthetics

• neurological illness, e.g., Guillain-Barreé syndrome.

Intense pain and severe fright may also result in neurogenic shock.

Septic shock

Damage is caused by overwhelming bacterial infection, usually by Gram-negative bacilli such as Escherichia coli, Pseudomonas and Klebsiella. The bacteria cause damage by releasing endotoxins that cause vasodilatation and increased capillary permeability. Fluid leaks out of the capillaries, causing hypotension and ultimately hypovolaemia. Septic shock often has an insidious rather than a sudden onset and is sometimes referred to as ‘hot shock’ because sufferers are pyrexial as a result of the precipitating infection. ‘Toxic shock’ is a type of septic shock and is generally associated with menstruation and prolonged use of tampons. The causative organism in this instance is Staphylococcus aureus.

Anaphylactic shock

Anaphylaxis occurs as the result of an antigen–antibody response in sensitive individuals. Antigens combine with immunoglobulin E (IgE) antibodies on the surface of mast cells throughout the body and these cells degranulate and release histamine and prostaglandins into the circulation. Under their influence, capillaries become more permeable, and widespread oedema results, including laryngeal oedema, which can rapidly cause death if not treated with adrenaline (epinephrine). Antigens may be introduced by the following routes:

• by injection, e.g., animal or insect bites and stings, drug therapy and mismatched blood transfusion

• by ingestion – food (shellfish, cheese, egg, nuts are some common causes of allergic reaction) or orally administered drugs

• by inhalation, e.g., dust and chemicals.

It will be noted that, whatever the initial cause of shock, venous return will be increasingly reduced and the cardiac output will continue to fall – a clear example of positive feedback at work.

Physiology of shock

Whatever the initial cause of shock, the pathophysiological response is the same (Fig. 23.14). Cells throughout the body are deprived of oxygen, resulting in cell membrane damage. Histamines and kinins are released in response to the damage and cause vasodilation and increased capillary permeability. White blood cells leak out of the capillaries and proteins pass into the extracellular fluid. Oedema occurs within the cells and the interstitial fluid volume increases as the fluid compartments break down. The result is a decrease in the circulating blood volume and a consequent reduction in venous return, in the amount of blood available for oxygenation and in cardiac output. Metabolism continues within the cells despite the lack of oxygen, and lactic acid, produced as a result of cellular metabolism, builds up causing metabolic acidosis.

Figure 23.14 The causative mechanisms of shock.

Compensatory mechanisms – the early stage

In the initial stages of shock, the body’s homeostatic mechanisms are triggered and attempt to return the body to ‘steady state’.

Sympathetic nerves are stimulated by the fall in arterial blood pressure and a fall in PO₂. They act to preserve blood supply to the vital organs, i.e., the heart and the brain, by vasoconstriction and by increasing heart rate, although stroke volume, the volume pumped by each contraction, diminishes. This may be felt as a rapid, weak pulse.

The skin becomes cold as blood is diverted to the vital organs and patients may become confused and disoriented as blood supply to the brain is reduced.

The fall in PO₂ levels triggers deep and rapid breathing (‘air hunger’) but this will only rectify the situation if sufficient blood is passing through the system for adequate oxygenation to occur.

The fall in PO₂ at the tissues means that more O₂ can be released from Hb, but demand will exceed supply unless intervention occurs. Administered O₂ will only partially rectify the situation.

In the early stages of shock, interstitial fluid is returned to the circulation through the capillary walls in an attempt to raise the circulating blood volume, but once cell damage begins this mechanism also fails. Sodium and water are preserved in the body by the production of ADH and aldosterone and this further helps to raise blood volume. Urine output falls as a result.

Progressive shock – when compensatory mechanisms are not enough

Without intervention, these compensatory mechanisms ultimately fail and cells throughout the body begin to malfunction. Some of the resulting effects are:

• metabolic acidosis causes hyperventilation and this causes respiratory acidosis in addition as too much CO₂ is blown off

• PCO₂ falls, causing a reduction in blood flow to the brain and a reduced level of consciousness

• adrenaline (epinephrine) and noradrenaline (norepinephrine) are produced in response to sympathetic nervous stimulation and cause vasoconstriction, which causes further hypoxia by decreasing blood flow through the lungs. Surfactant production in the lungs starts to fail and the lungs begin to collapse, making breathing more difficult. Fluid leaks from the pulmonary capillaries and pulmonary oedema results

• reduced blood volume and flow result in poor renal perfusion with resultant oliguria

• in the liver, cells can eventually no longer conjugate bilirubin; it is returned to the circulation and jaundice becomes apparent

• poor blood flow through the gut leads to breakdown of the gut lumen. Gut contents cross into the circulation and blood passes into the gut – haematemesis and melaena are indications that this is happening

• disseminated intravascular coagulation occurs when the clotting system is activated by enzymes released from the breakdown of cells and this further reduces blood flow

• the heart’s pumping ability is so reduced that it is unable to supply even the needs of the cardiac muscle and it becomes weaker and weaker.

Irreversible shock – the final stage

The vicious circle described above, with its many positive-feedback mechanisms, is illustrated in Fig. 23.15. Early intervention may mean that homeostasis can be restored but once cell breakdown and acidosis reach a critical level, the damage is irreversible and death will ensue despite all intervention.