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
Distribution of water in an adult man, weighing 70 kg
Body weight (%)
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.
Intake of water
Output of water
Water in food
Water contents of faeces
Water from metabolism of food
Loses in expired air and insensible perspiration
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 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
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
Decreased total body Na +
loss of Na+ > H2O)
1. Extrarenal losses of Na+
(urine Na+ <20 mmol/l
Burns, severe dermatitis
Paralytic ileus, Peritoneal fluid
2. Renal losses of Na+
(urine Na+ >20 mmol/l
Diuretic phase of renal tubular necrosis
Normal or near-normal total body Na+
1. Acute conditions
Parenteral administration of water, after surgery or trauma, or during or after delivery
2. Chronic conditions
Chronic renal failure
Low settings in carcinomatosis
Increased total body Na+
1. Acute conditions
Acute renal failure
2. Chronic conditions
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.
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.
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.
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.
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
Natriuresis may also occur in hyponatraemic states associated with SIADH or acute water intoxication and where ECF volume is normal or even increased.
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.
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.
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.
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.
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 vein near to a site of an IV infusion, where the fluid has alow[K+].
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 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.
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 in nonprotein nitrogen (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)
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
Best sources – Milk and milk products
Good sources – Beans, leafy vegetables, fish, cabbage, egg yolk
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.
Ñà (corrected) = [mmol/l] = Ñà (measured) + 0,02×(40 – albumin measured)
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.
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.
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:
- Parathyroid disease: hyperparathyroidism; multiple endocrine neoplasia syndromes (MEN)
- Malignant disease: myeloma, breast carcinoma, lymphomas, ets.
- 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
- Addison's disease
4. Artefact: Poor venepuncture technique (excessive venous stasis)
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.
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)
5. Irritability, personality changes
6. EGG changes (prolonged Q-T interval)
The causes of hypocalcaemia:
- Artefact (EDTA contamination of sample)
- Renal diseases
- Inadequate intake of Ca
- 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'.
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:
- age (1.4-1.8-fold increase per decade)
- sex (female > male)
2. Modifiable (environmental):
- nutritional calcium deficiency
- physical inactivity
- Alcohol excess; drugs (glucocorticoids, anticonvulsants)
3. Modifiable (endogenous):
- endocrine (oestrogen or androgen deficiency, hyperthyroidism)
- chronic diseases (gastrectomy, cirrhosis, rheumatoid arthritis)
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.
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.
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
Adult – 800 mg/day
Milk, cereals, leafy vegetables, meat, eggs
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 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.
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.
Adult man – 350 mg/day
Adult woman – 300 mg/day
Milk, cereals, nuts, beans, cabbage, cauliflower, meat, fruits
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 in non-renal causes of magnesium deficiency.
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].
The total body contains about 20 mg iodine, most of it (80%) being present in the thyroid gland.
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.
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).
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.
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 brain necrosis
- 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
The adult body contains about 2 g of zinc.
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.
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 is only important as constituent of vit-B12. The functions of cobalt is same as that of vit B12.
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.
The total human body contains about 6 mg chromium.
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 PCO2, in the alveoli is maintained at a low level by ventilation. The PCO2 in the blood of the pulmonary capillaries is therefore higher than the PC02 in the alveoli, so the PC02 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 PC02 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 PC02 in arterial or arterialised capillary blood specimens; [HCO3-] is then obtained by calculation:
[H+] = 180 × PCO2 / [HCO3-], so [HCO3-] = 180 × PCO2 / [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 PO2 and a fall in PCO2.
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.
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+], PCO2 and PO2 , 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 PCO2.
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).
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 PCO2 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.
This is due to hyperventilation (Table 3.3). The reduced PC02 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 PC02 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
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 PCO2 , 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.
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 PCO2 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 PCO2 or fall in PO2 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 PCO2 (even if 'arterialised') bears no constant relationship to alveolar PCO2. 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 PCO2 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 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 PO2, Hb concentration and percentage oxygen saturation. Hb measurements are widely available, and PO2 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 PO2 in arterial blood (reference range 12-15 kPa) are important, and are often valuable in assessing the efficiency of oxygen therapy, when high PO2 values may be found. Above a PO2 of 10.5 kPa, however, Hb is almost fully saturated with O2 (Figure 3.4), and further increases in PO2 do not result in greater O2 carriage. Conversely, as PO2 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 PO2 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 PO2 under these circumstances.
Figure 3.4 The oxygen dissociation curve of Hb. It is important to note that, above a PO2 of approximately 9 kPa, Hb is over 95 % saturated with O2. Also shown in the figure is the value of the PO2 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 PO2 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.