Investigation of fluid and electrolyte balance –I

Investigation of fluid and electrolyte balance –I

 

Fluid loss, retention or redistribution are common clinical problems in many areas of clinical prac­tice. The management of these conditions is often urgent, and requires a rapid assessment of the his­tory and examination, and of biochemical and other investigations.

Biological role of water:

1.    Water is an essential constituent of cell structures and provides the media in which the chemical reactions of the body take place and substances are transported.

2.    It has a high specific heat for which, it can absorb or gives off heat without any appreciable change in temperature.

3.    It has a very high latent heat. Thus, it provides a mechanism for the regulation of heat loss by sensible or insensible perspiration on the skin surface.

               4. The fluidity of blood is because of water

               5. Water is the most suitable solvent in human body

               6. Dielectric constant : Oppositely charged particles can coexist in water. Therefore, it is a good  ionizing medium. This increases the chemical reactions.

               7. Lubricating action: Water acts as lubricant in the body to prevent friction in joints, pleura, conjunctiva and peritoneum

Internal distribution of water and sodium

There are two water compartments in the body:

1.    Intracellular water

2.    Extracellular water

Extracellular fluid is divided into:

1.    interstitial fluid

2.    plasma

Distribution of water in an adult man, weighing 70 kg

 

The total body Na⁺ is about 4200 mmol and is mainly extracellular – about 50 % is in the ECF, 40 % in bone and 10 % in the ICF.

Two important factors influence the distribu­tion of fluid between the ICF and the intravascular and extravascular compartments of the ECF:

1. Osmolality This affects the movement of water across cell membranes.

2. Colloid osmotic pressure Together with hydrodynamic factors, this affects the movement of water and low molecular mass solutes (predominantly NaCl) between the intravascular and extravascular compartments.

Osmolality, osmolarity and tonicity

The osmolality is the number of solute particles per unit weight of water, irrespective of the size or nature of the particles. Therefore, a given weight of low molecular weight solutes contributes much more  to the osmolality than the same weight of high  molecular weight solutes. The units are mmol/kg of water. This determines the osmotic pressure exerted by a solution across a membrane.

Most laboratories can measure plasma osmolality, but it is also possible to calculate the approximate osmolality of plasma using a number of formulae of varying complexity. The following formula has the benefit of being easy to calculate and performs as well as more complex versions (all concentrations must be in mmol/L):

calculated osmolality = 2[Na⁺] + 2[K⁺] +[glucose] + [urea]

Plasma osmolality: 280-290  mOsm/kg

The osmolality of urine is usually measured directly, but is also linearly related to its specific gravity (SG) (which can be measured using urine dipsticks), unless there are significant amounts of glucose, protein or X-ray contrast media present.

Urine osmolality (24 -hour): 300-900  mOsm/kg

Osmolarity This is the number of particles of solute per litre of solution. Its units are mmol/L. Its mea­surement or calculation has been largely replaced by osmolality.

Tonicity This is a term often confused with osmo­lality. However, it should only be used in relation to the osmotic pressure due to those solutes (e.g. Na⁺) that exert their effects across cell mem­branes, thereby causing movement of water into or out of the cells. Substances that can readily dif­fuse into cells down their concentration gradients (e.g. urea, alcohol) contribute to plasma osmolality but not to plasma tonicity, since after equilibra­tion their concentration will be equal on both sides of the cell membrane. Tonicity is not readily measurable.

The tonicity of ICF and ECF equilibrate with one another by movement of water across cell membranes. An increase in ECF tonicity causes a reduction in ICF volume as water moves from the ICF to the ECF to equalise the tonicity of the two compartments, whereas a decrease in ECF tonicity causes an increase in ICF volume as water moves from the ECF to the ICF.

Colloid osmotic pressure (oncotic pressure)

The osmotic pressure exerted by plasma proteins across cell membranes is negligible compared with the osmotic pressure of a solution containing NaCl and other small molecules, since they are present in much lower molar concentrations. In contrast, small molecules diffuse freely across the capillary wall, and so are not osmotically active at this site, but plasma proteins do not readily do so. This means that plasma [protein] and hydrodynamic factors together determine the distribution of water and solutes across the capillary wall, and hence between the intravascular and interstitial compartments.

Regulation of external water balance

Typical daily intakes and outputs of water are given in Table 2.1.

 

Water intake is largely a conse­quence of social habit and is very variable, but is also controlled by the sensation of thirst. Its out­put is controlled by the action of vasopressin, also known as antidiuretic hormone (ADH). In states of pure water deficiency, plasma tonicity increases causing a sensation of thirst and stimulating vaso­pressin secretion, both mediated by hypothalamic osmoreceptors. Vasopressin then promotes water reabsorption in the distal nephron, with conse­quent production of small volumes of concen­trated urine. Conversely, a large intake of water causes a fall in tonicity, suppresses thirst and reduces vasopressin secretion, leading to a diuresis, producing large volumes of dilute urine.

Secretion of vasopressin is normally controlled by small changes in ECF tonicity, but it is also under tonic inhibitory control from baroreceptors in the left atrium and great vessels on the left side of the heart. Where haemodynamic factors (e.g. excessive blood loss, heart failure) reduce the stretch on these receptors, often without an accompanying change in ECF tonicity, a reduction in tonic inhibitory control stimulates vasopressin secretion. The resulting water retention causes hyponatraemia and is relatively ineffective in expanding the intravascular compartment, since water diffuses freely throughout all compartments (Figure 2.2).

Regulation of external sodium balance

 

A typical Western diet provides 100-200 mmol of both Na⁺ and Cl^– daily, but the total body Na⁺ can be maintained even if intake is less than 5 mmol or greater than 750 mmol daily.

Urinary losses or Na⁺ normally closely match intake. There is normally little loss of these ions through the skin or in the faeces, but in disease the gastrointestinal tract can become a major source of Na⁺ loss.

The amount of Na⁺ excreted in the urine con­trols the ECF volume since, when osmoregulation is normal, the amount of extracellular water is controlled to maintain a constant concentration of extracellular Na⁺. A number of mechanisms are important regulators of Na⁺ excretion:

1. The renin-angiotensin-aldosterone system Renin is secreted in response to a fall in renal afferent arteriolar pressure or to a reduction in supply of Na⁺ to the distal tubule. It converts angiotensinogen in plasma to angiotensin I (AI), which in turn is converted to angiotensin II (AII) by angiotensin-converting enzyme (ACE). Both AII and its metabolic product angiotensin III (AIII) are pharma­cologically active, and stimulate the release of aldosterone from the adrenal cortex. Aldosterone acts on the distal tubule to promote Na⁺ reabsorp­tion in exchange for urinary loss of H⁺ or K⁺. Since Na⁺ cannot enter cells freely, its retention (with iso-osmotically associated water) con­tributes solely to ECF volume expansion, unlike pure   water   retention   (Figures   2.2   and   2.3).

2. The glomerular filtration rate (GFR) The rate of Na⁺ excretion is often related to the GFR. When the GFR falls acutely, less Na⁺ is filtered and excreted, and vice versa. However, this only becomes a limiting factor in Na⁺ excretion at very low levels of GFR.

3. Atrial natriuretic peptide (ANP) This peptide secreted by cardiocytes of the right atrium of the heart pro­motes Na⁺ excretion by the kidney, apparently by causing a marked increase in GFR. The importance of the ANP regulatory mechanism is not yet clear, but it probably only plays a minor role. Other structurally similar peptides have been identified, including brain or B-type natriuretic peptide (BNP), secreted by the cardiac ventricles and with similar properties to ANP. BNP is increasingly being used in the assessment of patients suspected of having cardiac failure.

Disorders of water and sodium homeostasis

It is important to remember that the concentra­tion of any substance is a consequence of both the amount of the solute (here Na⁺) and of the solvent (here water). The concentration of the solute may change because of changes in either the amount of solute, or the amount of solvent, or both. Although the physiological control mechanisms for water and for Na⁺ are distinct, they need to be considered together when seeking an understand­ing of a patient’s Na⁺ and water balance, and of the plasma [Na⁺]. Whereas losses or gains of pure water are distributed across all fluid compartments, losses or gains of Na⁺ and water, as isotonic fluid, are borne by the much smaller ECF compartment (Figures 2.2 and 2.3). Thus, it is usually more urgent to replace losses of isotonic fluid than losses of water. For the same reason, circulatory overload is more likely with excessive administra­tion of isotonic Na⁺-containing solutions than with isotonic dextrose (the dextrose is metabolised, saving water behind).

Plasma [Na⁺] cannot be used as a simple mea­sure of body Na⁺ status since it is very often abnormal as a result of losses or gains of water rather than of Na⁺. The plasma [Na⁺] must be interpreted in relation to the patient’s history and the findings on clinical examination, and if neces­sary backed up by other investigations.

The reference range for plasma sodium [Na⁺] is 135-145 mmol/L.

The main causes of depletion and excess of water are summarised in Table 2.2, and of Na⁺ in Table 2.3. Although some of these conditions may be associated with abnormal plasma [Na⁺], it must be emphasised that this is not necessarily always the case. For example, patients with acute losses of iso­tonic fluid (e.g. plasma, ECF, blood) may be severely and dangerously hypovolaemic and Na⁺-depleted and very possibly in shock, but their plasma [Na⁺] may nevertheless be normal or even raised.

Hyponatraemia

Hyponatraemia is the commonest clinical bio­chemical abnormality. Most patients with hypona­traemia also have a low plasma osmolality. Unless an unusual cause of hyponatraemia is suspected,  measurement of plasma osmolality contributes lit­tle or no extra information.

Patients with hyponatraemia can be divided into three categories, on the basis of the ECF vol­ume being low, normal or increased. These cate­gories in turn reflect a total body Na⁺ that is low, normal or increased, respectively. The value of this classification is two-fold. First, the clinical history and examination often indicate the ECF volume and therefore the total body Na⁺ status. Second, treatment often depends on the total body Na” status rather than the [Na⁺]. One possible way of narrowing the differential diagnosis of a patient with hyponatraemia, based on this subdivision, is shown in Figure 2.4.

1. Hyponatraemia with low ECF volume

The patient has lost Na⁺ and water in one or more body fluids (e.g. GI tract secretions, urine, inflam­matory exudate) or may have been treated with a diuretic (Table 2.4). The low ECF volume leads to tachycardia, orthostatic hypotension, reduced skin turgor and oliguria. The hypovolaemia causes secondary aldosteronism with a low urinary [Na⁺] (usually less than 20 mmol/L), unless diuretic treat­ment is the cause when urinary [Na⁺] remains high. The hypovolaemia also provides a ‘volume stimulus’ to vasopressin secretion, resulting in oliguria and a concentrated urine.

Treatment requires administration of isotonic saline.

Hyponatraemia with normal ECF volume

The hyponatraemia results from excessive water retention, due to inability to excrete a water load. This may develop acutely, or it may be chronic (Table 2.4).

Acute water retention Plasma [vasopressin] is acutely increased after trauma or major surgery, as part of the metabolic response to trauma, and dur­ing delivery and postpartum. Administration of excessive amounts of water (e.g. as 5 % dextrose) in these circumstances may exacerbate the hypona­traemia and cause acute water intoxication.

Chronic water retention Perhaps the most widely known chronic ’cause’ of this form of hypona­traemia is the syndrome of inappropriate secre­tion of ADH (SIADH) (Table 2.5). Whether this concept is of value in understanding its aetiology, or valid in terms of altered physiology, is uncer­tain. As the name implies, ADH (or rather vaso­pressin) is being secreted in the absence of an ‘appropriate’ physiological stimulus, of either fluid depletion or hypernatraemia. As water is retained, the potential for expansion of the ECF volume is limited by a reduction in renin and an increase in sodium excretion. A new steady state is achieved, with essentially normal, or only mildly increased, ECF volume. If the causative disorder (Table 2.5) is transient, plasma [Na⁺] returns to normal when the primary disorder (e.g. pneumonia) is treated.

However, in patients with cancer, the hyponatraemia is presumably due to production of vasopressin or a related substance by the tumour, and is usually persistent. If symptoms are mild, they may be treated by severe fluid restric­tion (i.e. 500 mL/day or less), but if this is ineffec­tive, treatment with a drug that antagonises the renal effects of vasopressin (e.g. demeclocycline) may be tried.

Other causes  of chronic retention of water include:

Chronic renal disease Damaged kidneys may be unable to concentrate or to dilute urine normally, tending to produce a urine of osmolality about that of plasma. Thus, the ability to excrete a water load is severely impaired, and excess water intake (oral or IV) readily produces a dilutional hypona­traemia. These patients may also be overloaded with Na⁺.

Glucocorticoid deficiency Whether due to anterior pituitary disease or abrupt withdrawal of long-term glucocorticoid therapy, this may lead to inability to excrete a water load, and to hyponatraemia.

Resetting of the osmostat Some patients with malnu­trition, carcinomatosis and tuberculosis seem to have their osmostat reset at a low level, with plasma [Na⁺] of 125-130 mmol/L. The cause is uncertain.

Hyponatraemia with increased ECF volume

Significant increases in total body Na⁺ give rise to clinically detectable oedema (Table 2.4). Generalised oedema is usually associated with secondary aldos-teronism, caused by a reduction in renal blood flow, which stimulates renin production. Patients fall into at least three categories:

Renal failure Excess water intake in a poorly con­trolled patient with acute or chronic renal disease can lead to hyponatraemia with oedema.

Congestive cardiac failure In cardiac failure there is reduced renal perfusion and an ‘apparent’ volume deficit, and also increased venous pressure, with altered fluid distribution between the intravascular and interstitial compartments. These lead to secondary aldosteronism and increased vasopressin secretion, causing Na⁺ overload and hyponatraemia.

Hypoproteinaemic states Low plasma [protein], espe­cially low [albumin], leads to excessive losses of water and low molecular mass solutes from the intravascular to the interstitial compartments. Hence interstitial oedema is accompa­nied by reduced intravascular volume, with conse­quent secondary aldosteronism and stimulation of vasopressin release.

‘Sick cell syndrome’

Some ill patients may have a hyponatraemia that is very resistant to treatment, and has no immedi­ately obvious cause. The effective arterial plasma volume may be contracted with a consequent secondary hyperaldosteronism and Na⁺ retention. The total ECF volume may in contrast be increased, possibly because of stress-induced vasopressin secretion, or other causes of SIADH. These however nay not be the whole explanation for the observed r athophysiology, since plasma [aldosterone] and [vasopressin] are not always raised. The hyponatraemia may be due, at least in part, to the ‘sick cell syndrome’, in which there is an inability to maintain a Na⁺ gradient across the cell membrane, because of an increase in permeability, with or without impaired Na⁺ pump activity.

Other causes of hyponatraemia

In all the examples of hyponatraemia discussed above, the low plasma [Na⁺] occurs in association vith reduced plasma osmolality. Where this is not the case, the following possibilities should be

considered:

1. Artefact ‘Hyponatraemia’ is often caused by collection of a blood specimen from a vein close to a site at which fluid (typically 5% dextrose) is being administered intravenously

2. Pseudohyponatraemia This is an artefactual result due  to a reduction in plasma water caused by marked   hyperlipidaemia  or  hyperproteinaemia (e.g. multiple myeloma). Normally, lipids and pro-

teins make up a relatively small proportion, by volume, of plasma. Na⁺ and other electrolytes are dessolved in the plasma water, and do not enter the  lipid or protein fraction of the plasma. This means that methods which measure [Na⁺] in the plasma water give similar results to those which measure [Na⁺] in total plasma. Most commonly used

methods for measuring [Na⁺] measure the amount of Na⁺ in a given volume of plasma. These methods include flame photometry, and ion-selective electrode methods in which the plasma is diluted before measurement.

3. Hyperosmolar hyponatraemia This may be due to hyperglycaemia, administration of mannitol or occasionally other causes. The hyponatraemia mainly reflects the shift of water out of the cells into the ECF in response to osmotic effects, other than those due to Na⁺, across cell membranes. Treatment should be directed to the cause of the hyperosmolality rather than to the hyponatraemia.

Table 2.4 Causes of hyponatremia

Hypernatraemia

This is the commonest cause of increased tonicity of body fluids. It is nearly always due to water deficit rather than Na⁺ excess. The ICF volume is decreased due to movement of water out of the cells.

Hypernatraemia with decreased body sodium

It is usu­ally due to extrarenal loss of hypotonic fluid. The nature and effects of the disturbance of fluid bal­ance can be thought of as comprising the conse­quences of the combination of two components:

1  Loss of isotonic fluid, which causes reduction in ECF volume, with hypotension, shock and oliguria. The physiological response is high urine osmolality and  low urine  [Na⁺]   of less  than 20 mmol/L.

2  Loss of water, which causes volume reduction of both ICF and ECF and consequent hypernatraemia.

Urinary loss of hypotonic fluid sometimes occurs due to renal disease or to osmotic diuresis; in these patients, urine [Na⁺] is likely to be greater than 20 mmol/L. The commonest cause of hyper­natraemia associated with an osmotic diuresis is hyperglycaemia.

Treatment should initially aim to replace the deficit of isotonic fluid by infusing isotonic saline or, if the deficit is large, hypotonic saline.

Hypernatraemia with normal body sodium

These patients (Table 2.6) have a pure water deficit, as may occur when insensible water losses are very high (e.g. in hot climates, in unconscious patients or in patients with a high fever) and insufficient water is drunk as replacement. The urine has a high osmolality, and its Na⁺ content depends on Na⁺ intake.

Hypernatraemia with normal body Na⁺ also occurs in diabetes insipidus  due to excessive renal water loss. This loss is normally replaced by drinking. However, dehydration may develop if the patient is unable to drink, as may occur in very young children or in unconscious patients. The urine has a low osmolality and its Na⁺ content depends on Na⁺ intake.

Treatment should aim to rehydrate these patients fairly slowly, to avoid causing acute shifts of water into cells, especially those of the brain, which may have accommodated to the hyper-osmolality by increasing its intracellular solute concentration. Water, administered orally, is the simplest treatment. IV therapy may be necessary, with 5% glucose or glucose-saline.

Hypernatraemia with increased body sodium

This is relatively uncommon (Table 2.6). Mild hypernatraemia may be caused by an excess of min-eralocorticoids or glucocorticoids. More often, it occurs if excess Na⁺ is administered therapeutically

(e.g. NaHCO₃ during resuscitation). Treatment may be with diuretics or, rarely, by renal dialysis.

Other chemical investigations in fluid balance disorders

Several other chemical investigations, in addition-to plasma [Na⁺], may help when the history or clinical examination suggests that there is a disorder of fluid balance.

Blood specimens

Plasma albumin This may help to assess acute changes in intravascular volume, and may be use­ful in following changes in patients with fluid balance disorders over time. Plasma [albumin] should be measured in patients with oedema, to find out whether hypoalbuminaemia is pre­sent as a contributory cause, and to determine its severity.

Plasma urea and plasma creatinine Hypovolaemia is usually associated with a reduced GFR, and so with raised plasma [urea] and [creatinine]. Plasma [urea] may increase before plasma [creati­nine] in the early stages of water and Na⁺ depletion.

Plasma chloride Alterations in plasma [Cl-] parallel those in plasma [Na⁺], except in the presence of some acid-base disturbances. Chloride measurements are rarely of value in assessing disturbances of fluid balance.

Plasma osmolality Plasma osmolality usually parallels plasma [Na⁺] and can be estimated by calculatioin, but may be of value when a defect in

vasopressin action is suspected to be responsible for a fluid-electrolyte disorder.

Urine specimens

Urine osmolality

Measurements of urine osmolality are of value in the investigation of:

Polyuria A relatively concentrated urine suggests that polyuria is due to an osmotic diuretic (e.g glucose), whereas a dilute urine suggests that there is primary polydipsia or diabetes insipidus. Patients with chronic renal failure may also have polyuria, with a urine osmolality that is usually within 50 mmol/kg of the plasma value.

Oliguria  Where acute renal failure is suspected.

SIADH  In patients with SIADH, the urine osmolality is not maximally dilute, despite a dilutional hyponatraemia.

Urine  sodium

The  normally varies with Na⁺ intake. Measurements of 24-h output, taken with the clinical findings, may be useful in the diagnosis of disturbances in Na⁺ and water handling, and in planning fluid replacement.

Patients with low urine [Na⁺] This is an appropriate response in patients who are volume-depleted, with oliguria and normally functioning kidneys; urine [Na⁺] is usually less than 10 mmol/L, and urine flow increases after volume repletion. Na⁺ retention and low urine [Na⁺] occur in the secondary hyperaldosteronism associated with con­gestive cardiac failure, liver disease and hypopro-teinaemic states, and in Cushing’s syndrome and Conn’s syndrome.

Patients with natriuresis In hyponatraemic patients with evidence of ECF volume depletion, continu­ing natriuresis (i.e. urine [Na⁺] greater than 20 mmol/L) suggests either:

1  Volume depletion that is so severe as to have led to acute renal failure. The patient will be oliguric, with rising plasma [urea] and [creatinine]; diuresis fails to occur after volume repletion.

2  In the absence of acute renal failure, this occurs with over-zealous diuretic use, with salt-losing nephritis, and with defects in the hypothalamic—pituitary-adrenal (HPA) axis, including Addison’s
disease.

Natriuresis may also occur in hyponatraemic states associated with SIADH or acute water intox­ication and where ECF volume is normal or even increased.

Potassium balance

Potassium is the main intracellular cation. About 98 % of total body K⁺ is in cells, the balance (about 50 mmol) being in the ECF. There is a large con­centration gradient across cell membranes, the ICF [K⁺] being about 150 mmol/L compared with about 4 mmol/L in ECF.

Internal distribution

This is determined by movements across the cell membrane. Factors causing K⁺ to move out of cells include hypertonicity, acidosis, insulin lack and severe cell damage or cell death. Potassium moves into cells if there is alkalosis, or when insulin is given.

External balance

This is mainly determined, in the absence of GI disease, by intake of K⁺ and by its renal excretion. A typical ‘Western’ diet contains 20-100 mmol K⁺ daily; this intake is normally closely matched by the urinary excretion. The control of renal K⁺ excretion is not fully understood, but the follow­ing points have been established:

1  Nearly all the K⁺ filtered at the glomerulus is reabsorbed in the proximal tubule. Less than 10 %  reaches the distal tubule, where the main regulation of K⁺ excretion occurs. Secretion of K⁺ in response to alterations in dietary intake occurs in the distal tubule, the cortical collecting tubule and the collecting duct.

2  The  distal  tubule  is  an  important  site  of Na⁺ reabsorption. When Na⁺ is reabsorbed, the tubular lumen becomes electronegative in relation to the adjacent cell, and cations in the cell (e.g. K⁺,  H⁺) move into the lumen to balance the charge. The rate of movement of K⁺ into the lumen depends on there being sufficient delivery
of Na⁺ to the distal tubule, as well as on the rate of urine flow and on the concentration of K⁺ in the tubular cell.

3 The concentration of K⁺ in the tubular cell depends   largely  on   adenosine   triphosphatase-dependent (ATPase-dependent) Na⁺/K⁺ exchange with  peritubular  fluid   (i.e.   the   ECF).   This   is affected by mineralocorticoids, by acid-base changes and by ECF [K⁺]. The tubular cell [K⁺] tends to be increased by hyperkalaemia, by miner-alocorticoid excess and by alkalosis, all of which tend to cause an increase in K⁺ excretion.

Abnormalities of plasma potassium concentration

The reference range for plasma [K⁺] is 3.4-5.0 mmol/L. The important, and often life-threatening, clinical manifestations of abnor­malities of plasma [K⁺] are those relating to disturbances of neuromuscular excitability and of cardiac conduction. Any patient with an abnormal plasma [K⁺], who also shows signs of muscle weakness or of a cardiac arrhythmia, should have cardiac monitoring with electrocar-diography (ECG). The abnormal plasma [K⁺] should be corrected, with appropriate monitoring during treatment.

Hypokalaemia (Table 2.7) must not be equated with K⁺ depletion, and hyperkalaemia must not be equated with K⁺ excess. Although most patients with K⁺ depletion have hypokalaemia, and most patients with K⁺ excess may have hyper­kalaemia, acute changes in the distribution of K⁺ in the body can offset any effects of depletion or excess. To generalise, acute changes in plasma [K⁺] are usually caused by redistribution of K⁺ across cell membranes, whereas chronic changes in plasma [K⁺] are usually due to abnormal external K⁺ balance.

 

Hypokalaemia

Altered internal distribution: shift of K⁺ into cells

Acute shifts of K⁺ into the cell may occur in alkalosis,  but the hypokalaemia may be more closely related to the increased renal excretion of K⁺. Patients with respiratory alkalosis caused by voluntary

hyperventilation rarely show hypokalaemia, but patients on prolonged assisted ventilation may have low plasma [K⁺] if the alveolar Pco₂ is low for a relatively long period.

Insulin   in   high   dosage,   given   intravenously, notes the uptake of K⁺ by liver and muscle. Acute  shifts of K⁺ into the cells may occur in DKA shortly after starting treatment.

Adrenaline  and other (ß-adrenergic agonists stimulate the uptake of K⁺ into cells. This may contribute to the hypokalaemia appearing in patients after myocardial infarction, since catecholamine levels are likely to be increased in these patients. Hypokalaemic effects of salbutamol (a synthetic ß-adrenergic agonist) have also been described.

Altered external balance: deficient intake of K⁺

Prolonged deficient intake of K⁺ can lead to a decrease in total body K⁺, eventually manifested as hypokalaemia. This may occur in chronic and severe malnutrition in the Third World, in the

elderly on deficient diets, and in anorexia nervosa.

Altered external balance: excessive losses of K⁺

Hyperaldosteronism, both primary and secondary, and Cushing’s syndrome (including that due to steroid administration) cause excessive renal K⁺ loss due to increased K⁺ transfer into the distal tubule in response to increased reabsorption of Na⁺ from the tubular lumen. Mineralocorticoid excess also favours transfer of K⁺ into the tubular cell from the interstitial fluid in exchange for Na*. Urinary K⁺ loss in hyperaldosteronism returns to normal if there is dietary Na~ restriction, which limits distal tubular delivery of Na⁺.

Diuretic therapy increases renal K⁺ excretion by causing increased delivery of Na⁺ to the distal tubule and increased urine flow rate. Diuretics may also cause hypovolaemia, with consequent secondary hyperaldosteronism.

Acidosis and alkalosis both affect renal K⁺ excre­tion in ways that are not fully understood. Acute acidosis causes K⁺ retention, and acute alkalosis causes increased K⁺ excretion. However, chronic acidosis and chronic alkalosis both cause increased K⁺ excretion.

Gastrointestinal fluid losses often cause K~ deple­tion. However, if gastric fluid is lost in large quan­tity, renal K⁺ loss (due to the combined effects of the resultant secondary hyperaldosteronism and the metabolic alkalosis) is the main cause of the K” depletion, rather than the direct loss of K⁺ in gastric juice. In diarrhoea or laxative abuse, the increased losses of K⁺ in faeces may cause K⁺ depletion.

Renal disease does not usually cause excessive K⁺ loss. However, a few tubular abnormalities are associated with K⁺ depletion, in the absence of diuretic therapy:

Renal tubular acidosis The K⁺ loss is caused both by the chronic acidosis and, in patients with proxi­mal renal tubular acidosis (p. 61), by increased delivery of Na⁺ to the distal tubule. In distal renal tubular acidosis, the inability to excrete H⁺ may cause a compensatory transfer of K⁺ to the tubular fluid.

Bartter’s syndrome The syndrome consists of persis­tent hypokalaemia with secondary hyperaldostero­nism in association with a metabolic alkalosis; patients are normotensive. There is increased deliv­ery of Na⁺ to the distal tubule, caused by an abnor­mality of chloride reabsorption in the loop of Henle.

Excessive sweating Sweat [K⁺] is higher than ECF concentrations, so excessive sweat losses can result in potassium depletion and hypokalaemia.

Other causes of hypokalaemia

Artefact Collection of a blood sample from a veiear to a site of an IV infusion, where the fluid has alow[K⁺].

Hyperkalaemia

Plasma [K⁺] over 6.5 mmol/L requires urgent treat­ment. IV calcium gluconate has a rapid but short­lived effect in countering the neuromuscular effects of hyperkalaemia. Treatment with glucose and insulin causes K⁺ to pass into the ICF. However, treatment with ion-exchange resins or renal dialysis may be needed.

 

Altered internal distribution of K⁺

Acidosis The effects of acidosis on internal K⁺ bal­ance are complicated. As a general rule, acidotic states are often accompanied by hyperkalaemia, as K⁺ moves from the ICF into the ECF. Although this is the case for acute respiratory acidosis, and for both acute and chronic metabolic acidosis, it is more unusual to find hyperkalaemia in chronic respiratory acidosis. It is important to note that a high plasma [K⁺] may be accompanied by a reduced total body K⁺ as a result of excessive uri­nary K⁺ losses in both chronic respiratory acidosis and in metabolic acidosis.

Hypertonic states In these, K⁺ moves out of cells, possibly because of the increased intracellular [K⁺] caused by the reduction in ICF volume.

Uncontrolled diabetes mellitus The lack of insulin prevents K⁺ from entering cells. This results in hyperkalaemia, despite the K⁺ loss caused by the osmotic diuresis.

Cellular necrosis This may lead to excessive release of K⁺ and may result in hyperkalaemia. Extensive cell damage may be a feature of rhab-domyolysis (e.g. crush injury), haemolysis, burns or tumour necrosis (e.g. in the treatment of leukaemias).

Digoxin poisoning Causes hyperkalaemia by inhibit­ing the Na⁺/K⁺ ATP’ase pump. Therapeutic doses do not have this effect.

 

Altered external balance: increased intake of K⁺

Increased K⁺ intake only rarely causes accumulation of K⁺ in the body, since the normal kidney can excrete a large K⁺ load. However, if there is renal impairment, K⁺ may accumulate if salt substitutes are administered, or excessive amounts of some fruit drinks  are drunk or if excessive potassium replacement therapy accompanies diuretic administration.

Altered external balance: decreased excretion of K⁺

Intrinsic renal disease This is an important cause of hyperkalaemia. It may occur in acute renal failure and  in the later stages of chronic renal failure. In patients with renal disease that largely affects the renal medulla, hyperkalaemia may occur earlier. This may be because increased K⁺ secretion from the collecting duct, an important adaptive response in the damaged kidney, is lost earlier in patients with medullary disease

Mineralocorticoid   deficiency This   may   occur   in Addison’s disease and in secondary adrenocortical hypofunction. In both, K⁺ retention may occur. This is not an invariable feature,  presumably because other mechanisms can facilitate K⁺ excretion. Selective hypoaldosteronism, accompanied by normal glucocorticoid production, may occur in patients with diabetes mellitus in whom juxtaglomerular sclerosis probably interferes with renin production.   ACE   inhibitors,   by   reducing   AII (and therefore aldosterone) levels, may lead to increased plasma [K⁺], but severe problems are only likely to occur in the presence of renal failure.

Patients treated with K⁺-sparing diuretics (e.g.spironolactone, amiloride) may fail to respond to aldosterone. If the K⁺ intake is high in these patients, or if they have renal insufficiency or selective  hypoaldosteronism,   this  can  lead  to dangerous hyperkalaemia.

Other causes of hyperkalaemia

Artefact This is the commonest cause of hyperkalaemia. When red cells, or occasionally white cells or platelets, are left in contact with plasma or serum for too long, K⁺ leaks from the cells. In any blood specimen that does not have its plasma or serum separated from the cells within about 3 h, [K⁺] is likely to be spuriously high. Blood speci­mens collected into potassium EDTA, an anticoag­ulant widely used for haematological specimens, have greatly increased plasma [K⁺]. Sometimes, doctors decant part of a blood specimen initially collected by mistake into potassium EDTA into another container, and send this for biochemical analysis. A clue to the source of this artefact, which may increase plasma [K⁺] to ‘lethal’ levels (e.g. over 8 mmol/L), is an accompanying very low plasma [calcium], due to chelation of Ca²⁺ with EDTA.

Pseudohyperkalaemia Pseudohyperkalaemia can occur in acute and chronic myeloproliferative dis­orders, chronic lymphocytic leukaemia and severe thrombocytosis as a result of cell lysis during venepuncture, or if there is any delay in the sepa­ration of plasma following specimen collection, since there are large numbers of abnormally fragile white cells present.

Other investigations in disordered K⁺   metabolism

Urine K⁺ measurements may be of help in deter­mining the source of K⁺ depletion in patients with unexplained hypokalaemia, but are otherwise of little value. A 24-h urine collection should be made. If the patient is Na⁺-depleted, this will induce aldosterone secretion, making the results difficult or impossible to interpret, so urine [Na⁺] should also be checked to ensure this is adequate.

Plasma total [CO₂]  may prove helpful in the investigation of disorders of K⁺ balance, since metabolic acidosis and metabolic alkalosis are com­monly associated with abnormalities of K⁺ homeostasis. It is rarely necessary to assess acid-base status fully when investigating disturbances of K⁺ metabolism; plasma [total CO₂] often suffices.

Other investigations may be indicated by the history of the patient’s illness and the findings on clinical examination. Hypomagnesaemia may be associated with hypokalaemia, so [Mg²⁺] should be checked in cases of prolonged or unexplained hypokalaemia.

Fluid and electrolyte balance in surgical patients

Patients admitted for major elective surgery, who may be liable to develop disturbances of water and electrolyte balance post-operatively, require pre-operative determination of baseline values for plasma urea, creatinine, [Na⁺] and [K⁺].

Patients who present for emergency surgery, with disturbances of water and electrolyte metab­olism already developed, should have the severity of the disturbances assessed and corrective mea­sures instituted pre-operatively. This usually involves the measurement of plasma urea, creati­nine, [Na⁺] and [K⁺] as an emergency. Ideally, fluid and electrolyte disturbances should be cor­rected before surgery.

Metabolic response to trauma

Accidental and operative trauma produce several metabolic effects. These include breakdown of pro­tein, release of K⁺ from cells and a consequent K⁺ deficit due to urinary loss, temporary retention of water, use of glycogen reserves, gluconeogenesis, mobilisation of fat reserves and a tendency to ketosis that sometimes progresses to a metabolic acidosis. Hormonal responses include increased secretion of adrenal corticosteroids, with temporary abolition of negative feedback control and increased secre­tion of aldosterone and vasopressin.

The metabolic responses to trauma are physio­logical and appropriate. They are the reason why post-operative states are such frequent causes of temporary disturbances in electrolyte metabolism. Most patients after major surgery have a tem­porarily impaired ability to excrete a water load or a Na⁺ load; they also have a plasma [urea] that is often raised due to tissue catabolism. Injudicious fluid therapy, especially in the first 48 h after oper­ation, may ‘correct’ the chemical abnormalities, for example by lowering the plasma [urea], but only by causing retention of fluid and the possi­bility of acute water intoxication

Post-operatively, any tendency for patients to develop disturbances of water and electrolyte bal­ance can be minimised by regular clinical assess­ment. In addition to plasma ‘electrolytes’, fluid balance charts and measurement of 24-h urinary losses of Na⁺ and K⁺, or losses from a fistula, can provide information of value in calculating the approximate volume and composition of fluid needed to replace continuing losses.

Acute water intoxication This is a severe and danger­ous disorder associated with acute neurological symptoms (drowsiness, fits) and later with coma and often death. The symptoms are due to acute swelling of the brain cells caused by the entry of water from the ECF, which has become hypotonic relatively rapidly with respect to the ICR There is controversy about the appropriate treatment. However, in most centres this would be instituted as a matter of urgency with the infusion of hypertonic saline; a diuretic may also be given to avoid causing fluid overload.

Dehydration

Dehydration may be defined as a state in which loss of water exceeds that of intake, as a result of which body’s water content gets reduced. In this state, the body is in negative water balance.

Causes

1. Primary dehydration: There is purely water depletion and no salt depletion. It occurs in following states:

(a) Due to deprivation of water as generally happens during desert travelling.

(b) In mental patients who refuse to drink water/fluids.

(c) In those who keep such a ‘fast’ in which water/fluid is completely restricted.

(d) It occurs more quickly during fever or in the high temperature of the environment.

    (e) Excessive water loss due to vomiting, prolonged diarrhoea, gastroenteritis.

      (f) Due to excretion of large quantities of urine or sweat.

This type of dehydration raises the concentration and osmotic pressure of extra­cellular fluid as a result of which there is consequent outflow of the intracellular water to the ECF; thus, ECF volume gets largely restored but there becomes deficiency of water inside the cells as a result of which they suffer from osmoconcentration; symptoms of which include dry tongue, poor salivation, dry shrunken skin, nausea, reduced sweating and intense thirst.

When the blood becomes hypertonic, it lowers the urinary output and also makes the urine concentrated as a result of which there is less elimination of NPN and other acids which leads to acidosis and eventually coma. Death occurs in man due to renal failure, acidosis, intracellular hyperosmolality, circulatory collapse or neural depression, when body water falls by 20%.

Drinking of concentrated saline like sea-water or failure of Na⁺ excretion (e.g., in Cushing’s syndrome and Primary aldosteronism) may cause hypertonicity of ECF which in turn is responsible for withdrawal of water from tissue cells, dehydration of tissues, but a rise in ECF volume. Mg²⁺ of sea-water may be responsible for an increased intestinal loss of water due to its osmotic effect in the intestinal lumen.

2.Secondary dehydration: The concentration of the electrolytes of the body fluids is maintained constant either through The elimination or retention of water. The reduction or elevation in the total electrolytes, which affects the basic radicals chiefly i.e. Na (extracellular) and K (intracellular) and the acid radicals HCO₃ and Cl are accompanied by a corresponding increase or decrease in the volume of body water which is eventually the cause of intracellular edema; as a result of which there is slowing of circulation and impairment of urinal functions. All this causes an individual to become weak bodily.

3. Dehydration due to injection of hypertonic solution: When a highly concentrated solution of sugar or salt is injected into the body of an individual, the osmotic pressure of blood will increase which results in the flow of fluid from the tissues into the blood unless an equilibrium is reached. Consequently, the blood volume increases. This increased blood volume soon returns to normal by the loss of excess material through excretion which finally causes a net loss of body water producing dehydration.

Effects of dehydration

There are various side effects of dehydration as follows, which may be overcome as soon as the body gets hydrated; otherwise the consequences are serious and may even lead to death.

1. Disturbance in acid-base balance.

2. Loss of body weight due to the reduction in tissue water.

3. Rise ionproteiitrogen (NPN) of blood.

4. Dryness, wrinkling and looseness of the skin.

5. Elevation in the plasma protein concentration and chloride.

6. Rise in the temperature of body due to reduction of circulating fluid.

7. Increased pulse rate and reduced cardiac output.

8. Exhaustion and collapse i.e. death.

Correction of dehydration

1. Ordinarily, sodium chloride solution may be given parenterally to compensate the loss.

2. In several disorders like diarrhoea, gastroenteritis, pancreatic or biliary fistulas, etc., a mixture of two-thirds isotonic saline solution and one-third sodium lactate solution (M/6) should be administered intravenously.

3. Dehydration is a burning problem in several disorders like diabetes mellitus, Addison’s disease, uremia, shock and extensive burns which is difficult to correct by the above two  ways.

 

 

 

 

Investigation of fluid and electrolyte balance –II

 

Calcium is the most abundant mineral in the body: about 25 mol (1 kg) in a 70 kg man (about 2 % of body weight).  About 99 % of the body’s calcium is present in the bone, mainly as the mineral hydroxyapatite, where it is combined with phosphate.

Biological functions of calcium

1.     Calcium is a major mechanical constituent of the bone. Bone by itself is a specialised mineralised connectlve tissue containing cellular elements bone-forming osteoblasts and bone-resorbing osteoclasts), organic matrix (type I collagen, proteoglycan, etc.) and the calcium-containing mineral hydroxyapatite. Calcium salts in bone have a mechanical role, but are not metabolically inert. There is a constant state of turnover in the skeleton associated with deposition of calcium in sites of bone formation and release at sites of bone resorption (about 5 % per year of the adult skeleton is remodelled). Calcium in the bone also acts as a reservoir that helps to stabilise ECF [Ca²⁺]. Maintenance of extracellular [Ca²⁺] within narrow limits is necessary for normal excitability of nerve and muscle. While the ECF [Ca²⁺] is approximately 1 mmol/L (10^-3 M), cytosolic [Ca²⁺] is much lower, approximately 100 nmol/L (10^-7 M). Cells possess a number of transport mechanisms for Ca²⁺ that allow maintenance of this large gradient across the cell membrane.

2.     Muscle contraction

3.     Blood coagulation

4.     Nerve transmission

5.     Membrane integrity and permeability

6.     Activation of enzymes (pancreatic lipase)

7.     Calcium as intracellular messenger

8.     Release of hormones (insulin, PTH, calcitonin)

Dietary requirements:

Adult – 800 mg/day

Women during pregnancy, lactation and post menopause – 1,5 g/day

Infants – 300-500 mg/day

Children (1-18 yrs) – 0,8-1,2 g/day

Sourses:

Best sources – Milk and milk products

Good sources – Beans, leafy vegetables, fish, cabbage, egg yolk

Plasma calcium:

Reference range 2.12 – 2.62 mmol/L (9 – 11 mg/dl)

Calcium is present in plasma in three forms, in equilibrium with one another.

About half of this is in the ionized form [Ca²⁺], which is functionally the most active. The other part of Ca is bound to proteins, mostly albumin and  a small part of Ca is found in association with citrate or phosphate.  Because of technical difficulties associated with the measurement of [Ca²⁺], clinical biochemistry laboratories only measure plasma [calcium] rou­tinely, even though the physiologically important fraction is plasma [Ca²⁺].

Effects of plasma [albumin]. Because albumin is the principal binding protein for calcium, a fall in plasma [albumin] will lead to a fall in bound calcium and a decrease in total [calcium]. Under these circumstances, the unbound plasma [Ca²⁺], the physiologically important frac­tion, will be maintained at normal levels by PTH.

 

Са (corrected) = [mmol/l] = Са (measured) + 0,02×(40 – albumin  measured)

                                                   [mmol/l]                              [g/l]

Effects of plasma H⁺. In acidosis, the protonation of albumin reduces its ability to bind calcium, lead­ing to an increase in unbound [Ca²⁺] and vice versa,  without  any  change  in  total   [calcium]. Thus, hyperventilation with respiratory alkalosis can reduce plasma [Ca²⁺], with the development of tetany. In chronic states of acidosis or alkalosis, PTH acts to readjust the plasma [Ca²⁺] back to normal. When pH increases in  0.1, content of  [Ca²⁺] decreases in 0.05 mmol/l, and when pH decreases in  0.1 content of  [Ca²⁺] increases in 0.05 mmol/l.

The ratio of plasma Ca : P is important for calcification of bones.  THe product of Ca × P (in mg/dl) in children is around 50 and in adults around 40. This product is less than 30 in rickets.

Control of calcium metabolism:

 

1. Parathyroid hormone (PTH)

Parathyroid hormone is the principal acute regula­tor of plasma [Ca²⁺]. Plasma PTH levels exhibit a diurnal rhythm, being highest in the early hours of the morning and lowest at about 9 am. The active hormone is secreted in response to a fall in plasma [Ca²⁺], and its actions are directed to increase plasma [Ca²⁺]. An increase in plasma [Ca²⁺] suppresses PTH secretion.

In bone, PTH stimulates bone decalcification, a process carried out by resorption by osteoclasts.

In the kidney, PTH increases the distal tubular reabsorption of calcium.

Action on the intestine: It increases  the intestinal absorption of Ca by promoting the synthesis of calcitriol.

2. Calcitriol (1:25-Dihydroxycholecalciferol –1 :25-DHCC)

Most vitamin D₃ (cholecalciferol) is synthesised by the action of ultraviolet light on the vitamin D precursor 7-dehydrocholesterol in the skin. Vitamin D₃ is also present naturally in food (a rich source is fish oils).

The principal action of 1 : 25-DHCC is to induce synthesis of a Ca²⁺– binding protein in the intestinal epithelial cell necessary for the absorption of calcium from the small intestine.

Calcitonin

Although calcitonin can decrease plasma [Ca²⁺] by reducing osteoclast activity and decreasing renal reabsorption of calcium and phosphate, its actions are transient, and chronic excess or defi­ciency is not associated with disordered calcium or bone metabolism.

Hypercalcaemia

Increased plasma [Ca²⁺] is a potentially serious problem that can lead to renal damage, cardiac arrhythmias and general ill-health.

Clinical consequences of high  [Ca²⁺]:

1.     Neurological symptoms (inability to concentrate, depression, confusion)

2.     Generalised muscle weakness

3.     Anorexia, nausea, vomiting, constipation

4.     Polyuria with polydipsia

5.     Nephrocalcinosis, nephrolithiasis

6.     EGG changes (shortened Q-T interval), bradycardia

7.     Pancreatitis, peptic ulcer

The causes of hypercalcaemia:

1.     Common:

–         Parathyroid disease: hyperparathyroidism; multiple endocrine neoplasia syndromes (MEN)

–         Malignant disease: myeloma, breast carcinoma, lymphomas, ets.

2. Uncommon:

– Endogenous production of 1:25 DHCC: sarcoidosis

– Excessive absorption of calcium: vitamin D overdose

– Bone diseases: immobilisation

– Drug-induced: thiazide diuretics, lithium

3. Miscellaneous (mostly rare)

– familial hypocalciuric hypercalcaemia

– thyrotoxicosis

– Addison’s disease

4. Artefact: Poor venepuncture technique (excessive venous stasis)

PTH assay

The single most important test in the differential diagnosis of hypercalcaemia is the measurement of serum PTH . Immunometric (‘sand­wich’) assays that measure serum [intact PTH] (reference range 10–55 ng/L) are now in wide­spread use. They have a high diagnostic sensitiv­ity and up to 90 % of patients with primary hyperparathyroidism have an elevated level. Approximately 10 % of patients with primary hyperparathyroidism may have serum [intact PTH] in the upper part of the reference range. However, in the setting of persistent hypercal­caemia, such levels are considered to be inappro­priately high since serum [intact PTH] should be suppressed if hypercalcaemia is unrelated to increased parathyroid activity. If serum [intact PTH] is within reference limits or is only margin­ally elevated in an asymptomatic hypercalcaemic patient, the diagnosis of familial benign hypocalciuric hypercalcaemia (FBHH ) should also be considered.

 

Hypocalcaemia

Clinical consequences of low  [Ca²⁺]:

1. Enhanced neuromuscular irritability (positive Chvostek’s and Trousseau’s sign); tetany

2. Numbness, tingling (fingers)

3. Muscle cramps (legs, feet, lower back)

4. Seizures

5. Irritability, personality changes

6. EGG changes (prolonged Q-T interval)

The causes of hypocalcaemia:

–         Artefact (EDTA contamination of sample)

–         Hypoproteinaemia

–         Renal diseases

–         Inadequate intake of Ca

–         Hypoparathyroidism

–         Acute pancreatitis

–         Critical illness

Biochemical bone diseases

Generalised defects in bone mineralisation, fre­quently associated with abnormal calcium or phosphate metabolism, are sometimes grouped together under the term ‘biochemical or metabolic bone diseases’.

Osteoporosis

This is a very common disorder that affects about one in four women. It is characterised by low bone mass and susceptibility to vertebral, forearm and hip fractures in later life. Results of routine chem­ical investigations are usually all normal. The diagnosis should exclude primary hyperparathyroidism, thyrotoxicosis, corticosteroid excess, multiple myeloma and hypogonadism.

Risk factors for osteoporosis:

1.     Unmodifiable:

–         age (1.4-1.8-fold increase per decade)

–         genetic

–         sex (female > male)

2.     Modifiable (environmental):

–         nutritional calcium deficiency

–         physical inactivity

–         Smoking

–         Alcohol excess; drugs (glucocorticoids, anticonvulsants)

3.     Modifiable (endogenous):

–         endocrine (oestrogen or androgen deficiency, hyperthyroidism)

–         chronic diseases (gastrectomy, cirrhosis, rheumatoid arthritis)

Paget’s disease

This is a common disorder of the bone, affecting up to 5 % of the population over 55 years old in the United Kingdom. Bone turnover is focally increased, with disordered bone remodelling. Plasma [calcium] and   [phosphate]   are   usually   normal,  although hypercalcaemia can develop, especially as a result of immobilisation. The increased bone turnover leads to a high plasma ALP activity and an increase in indices of osteoclast activity.

Phosphate metabolism

85 % of body phosphorus is located in the mineral phase of bone. The remainder is present outside bone, largely in an intracellular location as phosphate compounds.

Biological functions:

1. Phosphorus is essential for the development of bones and teeth.

2. Formation and utilization of energy-rich phosphates such as ATP, GTP etc.

3. Phosphorus is required fr the formation of phospholipids, phosphoproteins, nucleic acids and nucleotides.

4. Cell signalling and enzyme activation by phosphorylation.

5. Phosphate buffer system

Dietary requirements:

Adult – 800 mg/day

Sourses:

Milk, cereals,  leafy vegetables, meat, eggs

Plasma phosphate:

Reference range 0.8-1.4 mmol/L (3 – 4 mg/dl)

It is interesting to know that the fasting serum phosphate levels are higher than the post-prandial. this is attributed to the fact that following the ingestion of carbohydrate (glucose), the phosphate from the serum is drawn by the cells for metabolism (phosphorylation reactions).

Hypo- and hyperphosphataemia

Phosphate and calcium homeostasis are inextri­cably linked. The causes of hypophosphataemia   and  hyperphosphataemia are summarised in Table 5.10.

A plasma [phosphate] below 0.4 mmol/L may be associated with widespread cell dysfunction and even death. Muscle pain and weakness, including respiratory muscle weakness, associated with a raised CK, are possible. Urgent phosphate supplementation is  required. Dietary deficiency is unusual (phosphate occurs widely in food), but antacids may bind phosphate. Movement of phosphate into the cell occurs with metabolic and respiratory acidosis. Hypophosphataemia in DKA may be worsened when insulin is administered (insulin promotes cellular uptake of – glucose   and   phosphate).   Hyperalimentation   or re-feeding starved patients is also accompanied by cellular utilisation of phosphate and the potential for serious hypophosphataemia in the absence of appropriate supplementation.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        

 

Magnesium metabolism

 

Magnesium is the second most abundant intracellular cation. The adult body contains about 20 g magnesium, 50 % of which is found in bones in combination with calcium and phosphorus.

Biological functions:

1. Magnesium is required for the formation of bones and teeth.

2. Mg²⁺ serves as a cofactor for several enzymes: hexokinase, phosphofructokinase.

3. Mg²⁺ is necessary for proper neuromuscular function.

Dietary requirements:

Adult  man – 350 mg/day

Adult  woman – 300 mg/day

Sourses:

Milk, cereals, nuts, beans, cabbage, cauliflower,  meat, fruits

Plasma magnesium:

Reference range 0,8-1,0 mmol/L (2 – 3 mg/dl)

Hypomagnesaemia and magnesium deficiency

Magnesium deficiency (Table 5.11) rarely occurs as an isolated phenomenon. Usually it is accompanied by disorders of potassium, calcium and phosphorus metabolism. It may therefore be difficult to identify signs and symptoms that can be specifically attrib­uted to magnesium deficiency. However, muscular weakness, sometimes accompanied by tetany, car­diac arrhythmias and CNS abnormalities (e.g. con­vulsions) may all be due to magnesium deficiency. Magnesium deficiency should be suspected in patients who present with hypocalcaemia and/or hypokalaemia without an obvious cause or who fail to respond to treatment of these abnormalities.

Plasma [magnesium] is usually below 0.5 mmol/L in patients with symptoms directly attributable to magnesium deficiency; its level should be mea­sured before treatment with magnesium salts is instituted.

Plasma [magnesium] may not reflect the true state of the body’s reserves, particularly in chronic disorders. Other tests have been advocated (e.g. erythrocyte [magnesiumj, muscle [magnesium], magnesium loading tests), but there is no general agreement on the best test to use. Urinary excretion of magnesium is relatively easy to measure, and it is useful in distinguishing renal losses of magnesium from the other causes of hypomagnesaemia and magnesium deficiency. Renal excretion of magne­sium often falls below 0.5 mmol/24 h ion-renal causes of magnesium deficiency.

 

Hypermagnesaemia

This is most often due to acute renal failure or the advanced stages of chronic renal failure. Its presence is readily confirmed by measuring plasma [magne­sium]. There may be no symptoms. However, if plasma [magnesium] exceeds 3.0 mmol/L, nausea and vomiting, weakness and impaired conscious­ness may then develop, but these symptoms may not necessarily be caused solely by the hypermagnesaemia.

Hypermagnesaemia may rarely be caused by IV injection of magnesium salts, and adrenocortical hypofunction may cause a slight increase in plasma [magnesium].

Iodine

The total body contains about 20 mg iodine, most of it (80%) being present in the thyroid gland.

Biological functions:

 The only known function of iodine is its requirement for the synthesis of thyroid hormone mainly thyroxin (T₄) and triiodothyronin (T₃).

Dietary requirements: Adults – 100-150 microgram per day

                                        Pregnant women – 200  microgram per day

Sources: Sea food, drinking water, iodized salt.

Plasma iodine: Reference range (4 – 10 μg/dl)

Diseases states:  Goiter.

Fluorine

Biological functions:

1.It prevents the development of dental caries.

2.It is necessary for the proper development of bones .

3.It inhibits the activities of certain enzymes (enolase, aconitase).

Dietary requirements: 1-2 mg per day.

Sources: Drinking water.

Diseases states: dental caries,  dental fluorosis (mottling of enamel, discoloration of teeth The teeth are weak and become rough with characteristic brown or yellow patches on their surface), skeletal fluorosis (hypercalcification).

Copper

Biological functions:

1.           Its an essential constituent of several enzymes (cytochrome oxidase, catalase, superoxide dismutase etc.)

2.           Its necessary for the synthesis of hemoglobin, melanin and phospholipids.

3.           Ceruplasmin has oxidase activity and thereby facilitates the incorporation of ferric iron into transferrin.

4.           Development of bone and nervous system (myelin requires Cu).

Dietary requirements: 2-3 mg per day.

Sources: Liver, kidney, meat, egg yolk, nuts and green leafy vegetables.

Plasma copper : Reference range 4 – 10 μg/dl. Most of this (95 %) is bound to ceruloplasmin. Normal concentration of ceruloplasmin is 25-50 mg/dl.

Disease states:

1.           Copper deficiency (demineralization of bones, demyelination of neural tissue, anaemia, greying of hair).

2.           Menke’s disease (defect in the intestinal absorption of copper). Symptoms: decreased copper in plasma and urine, anemia and depigmentation of hair.

3.           Wilson’s disease:

–         Copper is deposited in liver and brain, this may lead to hepatic cirrhosis and braiecrosis

–         Low level of copper and ceruloplasmin in plasma with increased excretion of copper in urine

–         Copper deposition in kidney causes renal damage.

Treatment: Administration of pencillamine, a naturally occuring copper chelating agent

Zinc

The adult body contains about 2 g of zinc.

Biological functions:

1.           It is an essential component of several enzymes (carbonic anhydrase, alcohol dehydrase etc.)

2.           The storage and secretion of insulin from the beta – cells of pancreas requires zinc.

3.           It is require for wound healing.

4.           It is essential for the proper reproduction.

Dietary requirements: 10-15 mg / day. It is increased (by about 50 %) in pregnancy and lactation.

Sources: Meat , fish, eggs, milk, nutts.

Disease states:

1.     Zinc deficiency: poor wound healing, anaemia, loss of appetite, loss of taste  sensation.

2.     Zink toxicity: nausea, gastric ulcer, pancreatitis, anemia and excessive salivation.

Cobalt

Cobalt is only important as constituent of vit-B₁₂. The functions of cobalt is same as that of vit B₁₂.

Selenium

 Biological functions:

1. Selenium along with vit E, prevents the development of hepatic necrosis and muscular dystrophy.

2. Selenium is involved in maintaining structure integrity of biological membranes.

3. Selenium prevents lipid peroxidation and protect the cells against the free radicals.

4. Selenium binds with certain heavy metals and protects the body from their toxic effects.

Dietary requirements: 60-250 micrograms/day.

Sources: Liver, kidneys, seafood.

Toxicity: Selenosis is a toxicity due to very excessive intake of selenium. The manifestation of selenosis includes weight loss, emotional disturbances, diarrhea, hair loss and garlic odour in breath.

Chromium

The total human body contains about 6 mg chromium.

Biological functions:

1.     In association with insulin, Cr promotes the utilization of glucose.

2.     liwers the total serum cholesterol level

3.     It is invilved in lipoprotein metabolism

Dietary requirements: is not known. It is estimated that an adult man consumes about 10 to 100 μg/day.

Sources: brewer’s yeast, grains, cereals, cheese and meat.

Plasma chromium : Reference range 20 μg/dl.

Disease states: Cromium deficiency causes disturbances in carbohydrate, lipid and protein metabolism. Excessive intake of chromium results in toxicity, leading to liver and kidney damage.

 

 

 

 

ACID-BASE BALANCE IN NORMAL AND PATHOLOGICAL CONDITIONS

An important property of blood is its degree of acidity or alkalinity. Body acidity increases when the level of acidic compounds in the body rises (through increased intake or production, or decreased elimination) or when the level of basic (alkaline) compounds in the body falls (through decreased intake or production, or increased elimination). Body alkalinity increases with the reverse of these processes. The body’s balance between acidity and alkalinity is referred to as acid-base balance.

The blood’s acid-base balance is precisely controlled, because even a minor deviation from the normal range can severely affect many organs. The body uses different mechanisms to control the blood’s acid-base balance.

One mechanism the body uses to control blood pH involves the release of carbon dioxide from the lungs. Carbon dioxide, which is mildly acidic, is a waste product of the metabolism of oxygen (which all cells need) and, as such, is constantly produced by cells. As with all waste products, carbon dioxide gets excreted into the blood. The blood carries carbon dioxide to the lungs, where it is exhaled. As carbon dioxide accumulates in the blood, the pH of the blood decreases. The brain regulates the amount of carbon dioxide that is exhaled by controlling the speed and depth of breathing. The amount of carbon dioxide exhaled, and consequently the pH of the blood, increases as breathing becomes faster and deeper. By adjusting the speed and depth of breathing, the brain and lungs are able to regulate the blood pH minute by minute.

The kidneys are also able to affect blood pH by excreting excess acids or bases. The kidneys have some ability to alter the amount of acid or base that is excreted, but because the kidneys make these adjustments more slowly than the lungs do, this compensation generally takes several days.

Yet another mechanism for controlling blood pH involves the use of buffer systems, which guard against sudden shifts in acidity and alkalinity. The pH buffer systems are combinations of a weak acid and weak base that exist in balance under normal pH conditions. The pH buffer systems work chemically to minimize changes in the pH of a solution by adjusting the proportion of acid and base. The most important pH buffer system in the blood involves carbonic acid (a weak acid formed from the carbon dioxide dissolved in blood) and bicarbonate ions (the corresponding weak base).

 

The hydrogen ion concentration of ECF is nor­mally maintained within very close limits. To achieve this, each day the body must dispose of:

1.     About 20 000 mmol of CO₂ generated by tissue metabolism. CO₂ itself is not an acid, but combines with water to form the weak acid, carbonic acid;

2.     About 40-80 mmol of non-volatile acids, mainly sulphur-containing   organic   acids,    which   are excreted by the kidneys.

 

Transport of carbon dioxide

The CO₂ produced in tissue cells diffuses freely down a concentration gradient across the cell membrane into the ECF and red cells. This gradi­ent is maintained because red blood cell metabo­lism is anaerobic, so that no CO₂ is produced there, and the concentration remains low. The fol­lowing reactions then occur:

CO₂ + H₂O « H₂CO₃             (3.1)

H₂CO₃  « H⁺ + HCO₃^–               (3.2)

Reaction 3.1, the hydration of CO₂ to form car­bonic acid (H₂CO₃), is slow, except in the presence of the catalyst carbonate dehydratase (also known as carbonic anhydrase). This limits its site in the blood mainly to erythrocytes, where carbonate dehydratase is located. Reaction 3.2, the ionisation of carbonic acid, then occurs rapidly and spontaneously. As a result, erythrocytes are the principal site of H⁺ and HCO₃^–  formation in the blood. The H⁺ ions are mainly buffered inside the red cell by haemoglobin (Hb). Hb is a more effec­tive buffer when deoxygenated, so its buffering capacity increases as it passes through the capil­lary beds and gives up oxygen to the tissues. Bicarbonate ions, meanwhile, pass from the ery­throcytes down their concentration gradient into plasma, in exchange for chloride ions to maintain electrical neutrality.

In the lungs, the P_CO2, in the alveoli is maintained at a low level by ventilation. The P_CO2 in the blood of the pulmonary capillaries is therefore higher than the P_C02 in the alveoli, so the P_C02 gradient is reversed. CO₂ then diffuses into the alveoli down its concentration gradient, and is excreted by the lungs. The above reaction sequence shifts to the left, carbonate dehydratase again catalysing reac­tion 3.1, but this time in the reverse direction.

Renal mechanisms for HCO₃^– reabsorption and H   excretion

Glomerular filtrate contains the same concentra­tion of HCO₃^–  as plasma. At normal HCO₃^–, renal tubular mechanisms are responsible  for reabsorbing virtually all this HCO₃^–. If this fails to occur, large amounts of HCO₃^–  would be lost in the urine, resulting in an acidosis and reduction in the body’s buffering capacity. In addition, the renal tubules are responsible for excreting 40-80 mmol of acid per day under normal circumstances. This will increase when there is an acidosis.

The mechanism of reabsorption of HCO₃^–  is shown in Figure 3.1. HCO₃^–  is not able to cross the luminal membrane of the renal tubular cells. H⁺ is pumped from the tubular cell into the lumen, in exchange for Na⁺. The H⁺ combines with HCO₃^–   to form H₂CO₃ in the lumen. This dissociates to give water and CO₂, which readily diffuses into the cell. In the cell, CO₂ recombines with water under the influence of carbonate dehydratase to give H₂CO₃. This dissociates to H⁺ and HCO₃^–  .

The HCO₃^–  then passes across the basal membrane of the cell into the interstitial fluid. This mecha­nism results in the reabsorption of filtered HCO₃^– , but no net excretion of H⁺

The net excretion of H⁺ relies on the same renal tubular cell reactions as HCO3 reabsorption, but occurs after luminal HCO₃^–  has been reabsorbed, and depends on the presence of other suitable buffers in the urine (Figure 3.2). The main urinary buffer is phosphate, most of which is present as HPO₄², which can combine with H⁺ to form H₂PO₄^–. Ammonia can also act as a urinary buffer, and is formed by the deamination of glutamine in renal tubular cells under the influence of the enzyme glutaminase. Ammonia readily diffuses across the cell membrane into the tubular lumen, where it combines with H⁺ to form NH₄⁺. This does not pass across cell membranes, so passive reabsorption is prevented. Glutaminase is induced in chronic acidoses, stimulating increased ammonia production and therefore increased H⁺ excretion in the form of NH₄⁺  ions.

Fig. 3.1 Reabsorption of bicarbonate in the renal tubule

Buffering of hydrogen ions

The lungs and the kidneys together maintain overall acid-base balance. However, the ECF needs to be protected against rapid changes in [H⁺]. This is achieved by various buffer systems. A buffer system consists of a weak (incompletely dissociated) acid in equilibrium with its conjugate base and H⁺. The capacity of a buffer for H⁺ is related to its concentration and the position of its equilibrium, being most effective at the [H⁺] at which the acid and conjugate base are present in

equal concentrations. Thus, Hb and plasma pro­teins act as efficient buffers in blood, since they are abundant and at a physiological [H⁺] of approximately 40 nmol/L have side groups that exist in an appropriate equilibrium. At this [H⁺], the bicarbonate buffer system has an equilibrium that is far removed from the ideal, with [HCO₃^–] being about 20 times greater than [H₂CO₃]. However, the effectiveness of the bicarbonate sys­tem is greatly enhanced in vivo by the fact that H₂CO₃ is readily produced or disposed of by interconversion with CO₂. Furthermore, physiological control mechanisms act on this buffer system to maintain both P_C02 and [HCO₃^– ] within limits, and hence to control [H⁺].

Any physiological buffer system could be used to investigate and define acid-base status, but the H₂CO₃/HCO₃^– buffer system has proved to be the most appropriate for this purpose, due to its physiological importance.

 

 

Investigating acid-base balance

The acid-base status of a patient can be fully characterised by measuring [H⁺] and P_C02 in arterial or arterialised capillary blood specimens; [HCO₃^–] is then obtained by calculation:

[H⁺] = 180 × P_CO2  / [HCO₃^–], so [HCO₃^–] = 180 × P_CO2  / [H⁺]

 Although standard bicarbonate, base excess and base deficit are still sometimes reported, these derived values are not necessary for the under­standing of acid-base disturbances.

Collection and transport of specimens

Arterial blood specimens are the most appropriate for assessing acid-base status. However, unless an arterial cannula is in situ, these specimens may be difficult to obtain for repeated assessment of patients whose clinical condition is changing rapidly. Arterialised capillary blood specimens are also widely used, especially in infants and chil­dren. It is essential for the capillary blood to flow freely, and collection of satisfactory samples may be impossible if there is peripheral vasoconstriction or the blood flow is sluggish.

Patients must be relaxed, and their breathing pattern should have settled after any temporary disturbance (e.g. due to insertion of an arterial cannula), before specimens are collected. Some patients may hyperventilate temporarily because they are apprehensive.

Blood is collected in syringes or capillary tubes that contain sufficient heparin to act as an antico­agulant; excess heparin, which is acidic, must be avoided. If ionised Ca²⁺ is to be measured on the same specimen, as is possible with some instru­ments, calcium-balanced heparin must be used. Specimens must be free of air bubbles, since these will equilibrate with the sample causing a rise in P_O2 and a fall in P_CO2.

Acid-base measurements should be performed immediately after the sample has been obtained, or the specimen should be chilled until analysis.

Otherwise, glycolysis (with the production or lac­tic acid) occurs, and the acid-base composition of the blood alters rapidly. Specimens chilled in iced water can have their analysis delayed for as long as 4 h. However, the clinical reasons that gave rise to the need for full acid-base studies usually demand much more rapid answers.

 

 

Temperature effects

Acid-base measurements are nearly always made at 37°C, but some patients may have body temper­atures that are higher or lower than 37°C. Equations are available to relate [H⁺], P_CO2 and P_O2 , determined at 37°C, to ‘equivalent’ values that correspond to the patient’s body temperature. However, reference ranges for acid-base data have only been established by most laboratories for measurements made at 37°C. Adjustment of ana­lytical results to values that would have been obtained at the patient’s temperature, according to these equations, may therefore be difficult to interpret. If treatment aimed at reducing an acid-base disturbance (e.g. NaHCO₃ infusion) is given to a severely hypothermic patient, the effects of the treatment should be monitored fre­quently by repeating the acid-base measurements (at 37°C).

Disturbances of acid-base status

Acid-base disorders fall into two main categories, respiratory and metabolic.

1 Respiratory disorders A primary defect in ventila­tion affects the P_CO2.

2 Metabolic disorders The primary defect may be the production of non-volatile acids, or ingestion of substances that give rise to them, in excess of the kidney’s ability to excrete these substances. Alternatively, the primary defect may be the loss of H⁺ from the body, or it may be the loss or reten­tion of HCO₃^–.

 

Acidosis is excessive blood acidity caused by an overabundance of acid in the blood or a loss of bicarbonate from the blood (metabolic acidosis), or by a buildup of carbon dioxide in the blood that results from poor lung function or slow breathing (respiratory acidosis).

Alkalosis is excessive blood alkalinity caused by an overabundance of bicarbonate in the blood or a loss of acid from the blood (metabolic alkalosis), or by a low level of carbon dioxide in the blood that results from rapid or deep breathing (respiratory alkalosis).

 

 

 

Respiratory acidosis

This is caused by CO₂ retention due to hypoventilation (Table 3.2). It may accompany defects in the control of ventilation, or diseases affecting the nerve supply or muscles of the chest wall or diaphragm, or disorders affecting the ribcage or intrinsic lung disease.

 

 

In acute respiratory acidosis, a rise in P_CO2 causes the equilibria in reactions 3.1 and 3.2 to shift to the right, as a result of which plasma [H⁺] and [HCO₃^–] both increase. Equilibration of H⁺ with body buffer systems limits the potential rise in [H⁺], and a new steady state is achieved within a few minutes.

Unless the cause of the acute episode of acidosis is resolved, or is treated quickly and successfully, renal compensation causes HCO₃^–  retention and H⁺ excretion, thereby returning plasma [H⁺] towards normal while [HCO₃^–] increases. These  compensatory changes can occur over a period of hours to days, by which time a new steady state is achieved and the daily renal H⁺ excretion and HCO₃^– retention return to normal. The patient then has the pattern of acid-base abnormalities of chronic respiratory acidosis.

Respiratory alkalosis

This is due to hyperventilation (Table 3.3). The reduced P_C02 that results causes the equilibrium posi­tions of reactions 3.1 and 3.2 to move to the left. As a result, plasma [H⁺] and [HCO₃^–] both fall, although the relative change in [HCO₃^–] is small.

If conditions giving rise to a low P P_C02 persist for more than a few hours, the kidneys increase HCO₃^– excretion and reduce H⁺ excretion. Plasma [H⁺] returns towards normal, whereas plasma [HCO₃^–] falls further. A new steady state will be achieved in hours to days, if the respiratory disorder persists. It is unusual for chronic respiratory alkalosis to be severe, and plasma [HCO₃^–] rarely falls below 12 mmol/L.

 

 

 

 

 

 

 

 

 

 

Table 3.3 Respiratory alkalosis

 

 

 

 

Metabolic acidosis

Increased production or decreased excretion of H⁺ leads to accumulation of H⁺ within the ECF (Table 3.4). The extra H⁺ ions combine with HCO₃^– to form H₂CO₃, disturbing the equilibrium in reac­tion 3.2, with a shift to the left. However, since there is no ventilatory abnormality, any increase in plasma [H₂CO₃] is only transient, as the related slight increase in dissolved CO₂ is immediately excreted by the lungs. The net effect is that a new equilibrium rapidly establishes itself in which the product, [H⁺] x [HCO₃^–], remains unchanged, since [H₂CO₃] is unchanged. In consequence, the rise in plasma [H⁺] is limited, but at the expense of a fall in [HCO₃^–], which has been consumed in this process and may be very low. Its availability for further buffering becomes progressively more lim­ited. Less often, metabolic acidosis arises from loss of HCO₃^– from the renal or GI tracts. Typically in these conditions, HCO₃^– does not fall to such a great extent, rarely being less than 15 mmol/L.

 

Table 3.4 Metabolic acidosis.

 

The rise in ECF [H⁺] stimulates the respiratory centre, causing compensatory hyperventilation. As a result, due to the fall in P_CO2 , plasma [H⁺] returns towards normal, while plasma  [HCO₃^–] falls even further. Plasma [H⁺] will not, however, become completely normal through this mecha­nism, since it is the low [H⁺] that drives the compensatory hyperventilation – as the [H⁺] falls, the hyperventilation becomes correspondingly reduced. In addition, if renal function is normal, H⁺ will be excreted by the kidney. It is quite common for patients with metabolic acidosis to have very low plasma [HCO₃^–], often below 10 mmol/L.

Metabolic alkalosis

This is most often due to prolonged vomiting, but may be due to other causes (Table 3.5). The loss of H⁺ upsets the equilibrium in reaction 3.2, causing it to shift to the right as H₂CO₃ dissociates to form H⁺ (which is being lost) and HCO₃^–. However, because there is no primary disturbance of ventila­tion, plasma P_CO2 remains constant, with the net effect that plasma [H⁺] falls and [HCO₃^–] rises. Respiratory compensation (i.e. hypoventilation) for the alkalosis is usually minimal, since any resulting rise in P_CO2 or fall in P_O2 will be a potent stimulator of ventilation. HCO₃^– is freely filtered at the glomerulus, and is therefore available for excretion in the urine, which would rapidly tend to restore the acid-base status towards normal. The continuing presence of an alkalosis means there  is  inappropriate reabsorption  of filtered  HCO₃^–  from the distal nephron. This can be due to ECF volume depletion, potassium deficiency or mineralocorticoid excess.

Table 3.5 Metabolic alkalosis.

 

Other investigations in acid-base assessment

The full characterisation of acid-base status requires arterial or arterialised capillary blood samples, since venous blood P_CO2 (even if ‘arterialised’) bears no constant relationship to alveolar P_CO2. However, other investigations can provide some useful information.

Total CO₂ (reference range 24-30 mmol/L)

This test, performed on venous plasma or serum, includes contributions from HCO₃^–H₂CO₃, dis­solved CO₂ and carbamino compounds. However, about 95 % of ‘total CO₂‘ is contributed by HCO₃^–. Total CO₂ measurements have the advantages of ease of sample collection and suitability for mea­surement in large numbers, but they cannot define a patient’s acid-base status, since plasma [H⁺] and P_CO2 are both unknown. For example, an increased plasma [total CO₂] may be due to either a respiratory acidosis or a metabolic alkalosis. However, when interpreted in the light of clinical findings, plasma [total CO₂] can often give an ade­quate assessment of whether an acid-base distur­bance is present and, if one is present, provide an indication of its severity. This is particularly true when there is a metabolic disturbance. However, patients with respiratory disturbances are much more likely to require full assessment of acid-base status, both for their definition and for monitor­ing and controlling their treatment.

Anion gap (reference range 10-20 mmol/L)

The anion gap (or ion difference) is obtained from plasma electrolyte results, as follows:

AG = ([Na+] + [K⁺]) – ([Cl] + [total CO₂)

The difference between the cations and the anions represents the unmeasured anions or anion gap and includes proteins, phosphate, sulphate and lactate ions. The anion gap may be increased because of an increase in unmeasured anions.

This may be of help in narrowing the differential diagnosis in a patient with metabolic acidosis (table 3.6). In the presence of metabolic acidosis, raised anion gap points to the cause being exessive production of hydrogen ions or failure to

excrete them. As the acid accumulates in the ECF (e.g.  in DKA), the HCO₃^– is titrated and replaced with unmeasured anions (e.g. acetoacetate) and the  anion gap increases. In contrast, if the cause is a loss of HCO₃^– (e.g. renal tubular acidosis), there is a compensatory increase in Cl^– and the anion gap remains unchanged (Table 3.4)

 

 Plasma chloride (reference range 95-107 mmol/L)

The causes of metabolic acidosis are sometimes divided into those with an increased anion gap and those with a normal anion gap. In the latter group, the fall in plasma [total CO₂], which  accompanies  the  metabolic  acidosis,   is associated with an approximately equal rise in plasma [Cl-]. Patients with metabolic acidosis and a normal anion gap are sometimes described as having hyperchloraemic acidosis.

Increased plasma [Cl ], out of proportion to any accompanying increase in plasma [Na⁺], may occur in patients with chronic renal failure, ureteric transplants into the colon, renal tubular acidosis, or in patients treated with carbonate dehydratase inhibitors. Increased plasma [Cl^–] may also occur in patients who develop respira­tory alkalosis as a result of prolonged assisted ventilation. An iatrogenic cause of increased plasma [Cl^–] is the IV administration of excessive amounts of isotonic or ‘physiological’ saline, which contains 155 mmol/L NaCl.

Patients who lose large volumes of gastric secretion (e.g. due to pyloric stenosis) often show a disproportionately marked fall in plasma [Cl^–] compared with any hyponatraemia that may develop. They develop metabolic alkalosis, and are often dehydrated.

Oxygen transport

Oxygen delivery to tissues depends on the combi­nation of their blood supply and the arterial O₂ content. In turn the O₂ content depends on the concentration of Hb and its saturation. Tissue hypoxia can therefore be caused not just by hypoxaemia, but also by impaired perfusion (e.g. because of reduced cardiac output or vasoconstric-tion), anaemia and the presence of abnormal Hb species. The full characterisation of the oxygen composition of a blood sample requires measure­ment of P_O2, Hb concentration and percentage oxygen saturation. Hb measurements are widely available, and P_O2 is one of the measurements automatically performed by most blood gas analy­sers as part of the full acid-base assessment of patients, and Hb saturation is measured using an oximeter.

Measurements of P_O2 in arterial blood (reference range 12-15 kPa) are important, and are often valuable in assessing the efficiency of oxygen ther­apy, when high P_O2 values may be found. Above a P_O2 of 10.5 kPa, however, Hb is almost fully satu­rated with O₂ (Figure 3.4), and further increases in  P_O2 do not result in greater O₂ carriage. Conversely, as P_O2 drops, initially there is little reduction in O₂ carriage on Hb, but when it falls below about 8 kPa, saturation starts to fall rapidly. In addition, results of P_O2 measurements may be misleading in conditions where the oxygen-carrying capacity of blood is grossly impaired, as in severe anaemia, carbon monoxide poisoning and when abnormal Hb derivatives (e.g. methaemoglobin) are present. Measurement of both the blood [Hb] and the per­centage oxygen saturation are required in addi­tion to P_O2  under these circumstances.

 

Figure 3.4 The oxygen dissociation curve of Hb. It is important to note that, above a P_O2 of approximately 9 kPa, Hb is over 95 % saturated with O₂. Also shown in the fig­ure is the value of the P_O2 3.8 kPa, that corresponds to 50 % saturation with O₂; this value is called the P₅₀ value.

 

 

 

Indications for full blood acid-base and oxygen measurements

The main indications for full acid-base assess­ment, coupled with P_O2 or oxygen saturation measurements, are in the investigation and man­agement of patients with pulmonary disorders, severely ill patients in intensive care units and patients in the operative and peri-operative peri­ods of major surgery who may often be on assisted ventilation. Other important applications include the investigation and management of patients with vascular abnormalities involving the shunt­ing of blood.

Full acid-base assessment is less essential in patients with metabolic acidosis or alkalosis, for whom measurements of plasma [total CO₂] on venous blood may give sufficient information.