Calvin was first diagnosed with diabetes when he was 10 years old. He had initially responded well to the need to comply with his treatment regimen of dietary control and regular doses of insulin given by self-injection. He was familiar with these problems as both his father and grandfather also had diabetes.

However, by the time Calvin reached 18 years old his diabetes did not fit well with his own self-image. He wanted to be out enjoying life with his friends and did not like to feel he was ‘an invalid’. This led to him becoming lax with his medication and his blood glucose control became less rigorous.

There were a number of occasions on which Calvin felt unwell and over a period of 5 years there was a series of eight emergency hospital admissions. On one such occasion he had been drinking more water than usual (polydipsia) and had been producing greater than normal amounts of urine (polyuria) for about 3 weeks. He had become drowsy and lethargic and, for the 3 days prior to the hospital admission, he had been vomiting.

The doctor in the emergency room noted that he was underweight for his age and build. Initial observations included a pulse rate of 142 beats/min, a blood pressure of 100/60 mm Hg and abnormally deep breathing. A venous blood sample provided the following data:

[Glucose] = 37 mmol/L (3.5–5.5 fasting)

[Na⁺] = 132 mmol/L (135–145)

[K⁺] = 5.5 mmol/L (3.5–5.0)

[Haemoglobin] = 17.5 g/100 mL (13.5–18.0)

Normal reference values are shown in brackets.

A urine dipstick test also showed the presence of glucose and ketones.

This case history raises the following questions:

1. What evidence is there in this history of body fluid volume depletion?

2. What is the link between volume depletion, Calvin’s low blood pressure and his fast heart rate?

3. What aspects of this history give immediate cause for concern and form the basis for clinical management strategies?

Aspects of the answers to these questions are discussed in Case 1.1:2 and in the text of this chapter.

Some fundamental concepts in relation to these opening paragraphs need further explanation.

Textbook person

Textbooks of basic biomedical sciences are inherently sexist, ageist and do not recognize either relatively small or large individuals. They are written primarily about male, 70 kg subjects in the age range 20–25 years. Textbooks contain statements such as ‘cardiac output is 5 L/min’. This is a figure which may well apply to the textbook person at rest, but there are wide variations which all represent perfectly normal values for a given individual within the population at large.

Oxygen consumption

Our textbook subject at rest consumes about 250 mL O₂/min and generates 200 mL CO₂/min. This gives rise to the concept of a respiratory quotient (RQ):

The precise value for RQ in any individual will reflect the composition of their diet but for a typical person consuming a mixed diet of carbohydrate, fat and protein the RQ would be about 0.8. This means that we normally consume more oxygen than we produce carbon dioxide. During exercise oxygen consumption may increase to about 10 times the resting value and the RQ may move closer to a value of 1 due to preferential metabolism of carbohydrate.

Interesting facts

30–40% of all the food we consume in our lifetime is used to generate ATP to drive the sodium pump which maintains the sodium and potassium concentration gradients across cell membranes.

Oxygen is used within the mitochondria of cells to generate adenosine triphosphate (ATP). This provides the energy for movement, for the synthesis of macromolecules and to drive the movement of ions, particularly Na⁺ ions, across cell membranes against a concentration gradient. The distribution of Na⁺ and K⁺ inside and outside cells is summarized in Figure 1.1. The ion gradients are maintained by the sodium pump which expels three Na⁺ ions and pulls two K⁺ ions into the cell each time it operates. As both of these ion movements are against a concentration gradient, an ATP molecule is hydrolysed to provide the energy. For some cells there may be about a million sodium pumps each operating at about thirty times a second. In the body as a whole the sodium pump accounts for about 30% of all of our energy intake over our lifetime. In this way, ionic gradients are maintained which are essential for the continuing function of nerves and muscles, including the heart. Failure to maintain ATP generation in hypoxic tissues leads to osmotic swelling of cells and to a loss of normal cellular function (see p.7). To serve all the requirements, the quantities of ATP which must be synthesized are quite prodigious and amount to something roughly equivalent to an individual’s body weight every day.

Fig. 1.1 The left hand side of this diagram shows typical concentrations of Na and K inside and outside cells. The right hand side depicts the sodium pump which uses ATP to maintain the ionic gradients across cell walls. Concentration units are mmol/L.

Diffusion

Diffusion is the movement of particles from an area of high concentration to an area of low concentration. The concentration of a gas in solution is actually the product of the partial pressure and the solubility coefficient (a constant at a given temperature). Two sets of units are in common usage for gas pressures. The appropriate conversion factors are as follows:

Some important parameters determining rate of diffusion are:

• the diffusive gradient (concentration difference between two points)

• the solubility of the particle in the solvent; if it is not very soluble the concentration will be low

• the size of the solute particle (small particles will diffuse faster than large particles)

• temperature: diffusion is faster at high temperatures than at low temperatures; body temperature is about 37°C in normal human subjects.

Most diffusion in living systems takes place in an environment in which water is the solvent, although molecules such as oxygen and carbon dioxide also have to diffuse through the lipid bilayer which makes up cell membranes. Special provision, in the form of transport proteins and ion channels, is made for ions which carry a charge and are therefore not lipid soluble.

Einstein (1905) showed that the time taken for a molecule to diffuse between two points varies as the square of the distance between the points. In physiological terms, diffusion is fine as a process for moving molecules short distances. A typical cell diameter in the body is about 10 μm and the time taken for an oxygen molecule to diffuse this distance would be a few milliseconds. Diffusion of oxygen over longer distances, however, such as the approximately 10 mm (a thousand times 10 μm) thickness of the ventricular wall of the heart, would take a million times as long, a time measured in hours. This would be inconsistent with maintaining life as, given the composition of the atmosphere, the diffusive gradients of oxygen available to us would be too small. The solution to these problems is to have an amazingly profuse circulatory system which delivers the oxygen and other nutrients very close to the cells where they will be used. Cells in the body are rarely more than 50 μm from a capillary and most are not more than 10–20 μm away.

The diffusive gradients concerned with loading of oxygen into pulmonary capillary blood at the lungs and the delivery of oxygen into the tissues are shown in Figures 1.2 and 1.3. Figure 1.2 shows the events at the interface between an alveolus and a pulmonary capillary. A typical Po₂ in the alveolus is 13.3 kPa (100 mm Hg). Blood returning to the lungs has a Po₂ of about 5.3 kPa (40 mm Hg) and so oxygen diffuses into the pulmonary capillary blood from the alveolus. The diffusive gradient for unloading CO₂ at the lungs is much smaller than for O₂. Mixed venous blood Pco₂ is about 6.1 kPa (46 mm Hg) whilst alveolar Pco₂ is typically 5.3 kPa (40 mm Hg). The diffusive gradient for CO₂ (0.8 kPa) is 10% of the diffusive gradient for O₂ (8 kPa). Both diffuse at about the same rate because CO₂ is 20 times as soluble in water as O₂. The transit time for red blood cells through pulmonary capillaries at rest is about 1 second but the diffusive exchange of O₂ and CO₂ is normally complete in about 0.25 seconds.

Fig. 1.2 Loading of oxygen by diffusion from the alveolae into pulmonary capillaries.

Fig. 1.3 Diffusive gradient. Diffusive gradient for oxygen from arterial blood to the mitochondrion of a cell where the oxygen is used. The interstitial fluid outside the cell is part of the way down this diffusive gradient. When blood leaves the tissue as venous blood it has equilibrated with the interstitial fluid.

Delivery of O₂ into the tissues (Fig. 1.3) starts with the arterial blood which has picked up O₂ in the lungs (Po₂ = 13.3 kPa; 100 mm Hg). Oxygen is used inside the mitochondria and the Po₂ here is of the order of 0.1 kPa (about 1 mm Hg). The interstitial fluid outside a cell is part of the way down a continuous diffusive gradient between the arterial blood and the inside of a mitochondrion. A typical Po₂ in the interstitial fluid is 5.3 kPa (40 mm Hg). Blood leaving a capillary has equilibrated with this fluid and so venous Po₂ is the same as in the interstitial fluid.

Interesting facts

Under normal circumstances, the lungs have spare capacity for several of their functions. For example, completion of the exchange of oxygen and carbon dioxide at the pulmonary capillary: alveolus interface only takes about a quarter of the approximately 1 second available for gas exchange. These safety factors mean that some degree of malfunction of the heart and lungs can be tolerated.

Carriage of oxygen in blood

A further consequence of the poor solubility of oxygen in water is that we have evolved with an oxygen-carrying pigment, haemoglobin (Hb). The oxygen-binding characteristics of haemoglobin are such that it is nearly fully saturated with oxygen at the partial pressure of oxygen normally present in the alveoli of the lungs. Figure 1.4 shows the oxyhaemoglobin dissociation curve. At a Po₂ of 13.3 kPa (100 mm Hg), a typical figure for the alveolus, Hb is 97–98% saturated with O₂. This information can be used to calculate the amount of oxygen carried bound to haemoglobin as follows:

Fig. 1.4 Oxygen–haemoglobin dissociation curve.

Typical values for [Hb] are 120 g/L (women), 140 g/L (men). The figure 1.34 mL/g is the volume (mL) of oxygen bound to 1 g Hb when it is fully saturated. These figures mean that arterial blood contains about 200 mL O₂ bound to Hb per litre blood. A small amount (0.3 mL/L) is carried as dissolved O₂

Reference to the oxyhaemoglobin dissociation curve (Fig. 1.4) shows that venous blood is about 75% saturated with O₂ at Po₂ = 5.3 kPa (40 mm Hg) and therefore about one quarter of the O₂ carried in arterial blood has moved into the tissues. One quarter of the 200 mL O₂/L present in arterial blood is 50 mL. If 50 mL of O₂ is typically deposited in the tissues from each litre of arterial blood, and the textbook person’s cardiac output (volume of blood pumped per minute from each side of the heart—see Chapter 4) is 5 L/min, then 250 mL O₂/min is delivered to the tissues. This is the amount of oxygen identified previously as a figure for O₂ consumption rate for the textbook person at rest.

All tissues do not have the same oxygen consumption rate relative to blood flow. The figure quoted above, that ‘venous blood is typically 75% saturated with oxygen’, refers to ‘mixed venous blood’, i.e. the blood in the right side of the heart which is a mixture of all the venous drainages for the whole body. Venous blood from the kidneys, which have a high flow rate but relatively low O₂ consumption, has an oxygen saturation of about 90%. By contrast, the blood in the venous drainage from the heart is only 25% saturated with O₂. This is an important concept in relation to physiological control mechanisms and to the pathological consequences of disturbances of coronary blood flow (see Chapter 5).

Case 1.1 A design specification for the cardiovascular system: 2

Calvin’s acute circulatory problems

Calvin’s fundamental problem was a lack of insulin, a hormone which moves glucose from the circulation into cells particularly in the liver and skeletal muscle. In addition, in the absence of insulin gluconeogenesis, the conversion of amino acids from the breakdown of protein into glucose is promoted. The high blood [glucose] leads to an osmotic diuresis, excessive urine production and hence body fluid volume depletion. Responses to volume depletion in the form of blood loss (haemorrhage) are discussed in Chapter 14.

The diuresis is the cause of a high [haemoglobin] due to loss of fluid from the extracellular compartment. An appropriate clinical test for volume depletion is to compare standing and lying arterial blood pressure measurements. Normally there will be no substantial difference but in the volume-depleted patient there is a drop in pressure (postural drop) on standing.

In Chapter 4 of this book the links between blood volume and cardiac output (the volume of blood pumped by the heart per minute) are discussed. Basically, the fall in blood volume (a decreased preload on the heart) leads to a decrease in cardiac output and, as a consequence, a fall in arterial blood pressure. The baroreceptor reflex (see Chapter 10) reacts to a fall in blood pressure with an increase in heart rate and constriction of peripheral blood vessels.

Body fluid replacement with a combination of 0.9% saline and 5% glucose is the first priority in order to avoid circulatory collapse. The apparent anomaly of giving extra glucose to a patient with an already high blood [glucose] is explained as follows.

The textbook person contains about 42 L of water. The factors which determine the distribution of this volume between different compartments are described in detail in Chapter 11. Basically, about 14 L is in the extracellular compartment, which includes blood plasma and 28 L is in the intracellular compartment. An increase in the osmotic strength of body fluids, due to high blood [glucose] combined with a decrease in capillary blood pressure associated with volume depletion, means that there is movement of water from the intracellular compartment to the extracellular compartment. As a consequence Calvin suffers both intracellular and extracellular volume depletion. There is a high [Na⁺] in extracellular fluid and a low [Na⁺] in the intracellular fluid. Infusion of saline into a patient will therefore selectively expand the extracellular compartment. Administration of 5% glucose solution initially does not substantially change the osmotic strength of body fluids but, once the glucose has become distributed around the body, insulin supplements will drive the glucose into cells where it can be metabolized to CO₂ and water. Giving 5% glucose is therefore equivalent to an infusion of pure water and will initially dilute the extracellular compartment. The osmotic gradient created will move water into the intracellular compartment. Infusion of 5% glucose will therefore expand both the intracellular and extracellular compartments. These ideas are explained in more detail in Chapters 11 and 14.

A further potential cause for concern is the increase in plasma [K⁺]. This is likely to be a result of a ketoacidosis, a form of metabolic acidosis. At a level of 5.5 mmol/L this is not a significant problem, but further increases in potassium as a result of acidosis-induced movement of K⁺ from inside to outside cells can lead to the development of cardiac arrhythmias and potentially cardiac arrest (see Chapters 2 and 7). Despite a raised plasma [K⁺] there may be whole body depletion of K⁺ as most of the K⁺ is in the intracellular compartment.

Interesting facts

The task of working out the three-dimensional structure of haemoglobin was undertaken by Max Perutz in Cambridge. It took him 23 years but the answer taught us a huge amount about how the oxygen carriage mechanism works. He was awarded the Nobel Prize in 1962.

The shape and position of the oxyhaemoglobin dissociation curve (Fig. 1.4) shows one of the safety factors in relation to lung function. The top of the curve is nearly flat from 13 kPa (100 mm Hg), normal arterial Po₂, down to about 10 kPa (75 mm Hg). This means that a decrease in Po₂ within this range makes little difference to the % saturation of haemoglobin with oxygen, that is little change to the total amount of oxygen carried in arterial blood. Put another way, we can afford to have a certain degree of lung malfunction before it makes any significant difference to oxygen delivery to the tissues.