Category Archives: Water and electrolytes and acid-base homeostasis

The concentration of hydrogen ions in both extracellular and intracellular compartments is extremely tightly controlled; very small changes may lead to major cell dysfunction. Hydrogen ion concentration has traditionally been expressed as pH, the negative logarithm of [H+], but this may contribute to complacency about the real magnitude of changes in [H”]

Basic principles

CARBOHYDRATE AND FAT METABOLISM. Complete combustion of carbohydrate and fat in the liver and muscle produces CO2, which forms carbonic acid. If respiratory function is normal, the partial pressure of CO2 remains constant.
• Respiratory acidosis is due to decreased removal of CO2,
• Respiratory alkalosis is due to increased removal of CO2,
Incomplete combustion of these metabolic fuels results in the formation of organic acids such as lactic acid, hydroxybutyric acid, acetoacetic acid and free fatty acids. These may cause significant acidosis if their production exceeds the capacity of the liver to metabolize them completely, as in lactic acidosis and diabetic ketoacidosis.
AMINO ACID METABOLISM. Amino acids, by definition, contain -COOH and -NH2 groups; metabolism of amino acids produces HC03- and NH/ ions. These may be combined to form urea:

resulting in no net acid or base production (assuming CO2 is removed by respiration). Alternatively, if NH4+ is excreted in the urine, this leaves HC03- within the body, resulting in alkali retention, which is equivalent to H+ excretion. Both the liver and the kidney appear to have important regulatory roles in acid-base balance. The liver regulates the degree to which NH4+ and HC03- are metabolized to urea in response to acid-base balance; ureagenesis is increased by alkalosis (thus consuming bicarbonate) and decreased by acidosis (thus sparing bicarbonate). NH.+ not utilized for ureagenesis is incorporated into glutamine, which is transported to the kidney: hydrolysis of glutamine in the kidney also appears to be regulated by acid-base balance and is an important mechanism by which NH4+ is excreted in the urine. NH4+ excretion in urine increases in response to acidosis, and defective NH4+ excretion in tubular diseases (distal renal tubular acidosis) causes systemic acidosis.

Some amino acids also contain sulphur and chlorine groups, metabolism of which yields sulphuric acid and hydrochloric acid. Metabolism of phosphorus-containing compounds yields phosphoric acid. These are all known as ‘fixed acids’ because they cannot be metabolized further to CO2 and removed by respiration; removal requires renal excretion both of sulphate, phosphate, or chloride and of H+. EXOGENOUS ACIDS. Absorption of ingested acids and alkalis results in acidosis and alkalosis respectively. The commonest example is ingestion of salicylic acid. RENAL H+ HANDLING. Secretion of H+ into the distal nephron is dependent on an aldosterone-sensitive pump which exchanges Na” for H+ or K+. Excretion of hydrogen ions is therefore dependent on delivery of sodium to the distal tubule:
• Increased sodium delivery (for instance caused by diuretics) and hyperaldosteronism cause increased excretion of H+ and K+, leading to hypokalaemia and alkalosis.
• Decreased sodium delivery (e.g. hypovolaemia) or aldosterone deficiency cause hyperkalaemia and acidosis. By the same mechanism, increased K+ delivery leads to acidosis and alkaline urine. In this respect, the requirement for control of acid-base balance is overridden by the requirement to maintain extracellular volume.
RENAL HC03- HANDLING. Bicarbonate filtered at the glomerulus must be reabsorbed, otherwise there would be massive losses of bicarbonate causing severe acidosis. Sodium bicarbonate reabsorption in the proximal tubule is complicated by the fact that CO2 diffuses freely across the membrane of the tubular cell, whereas HC03- and H+ cannot diffuse freely. The capacity for bicarbonate reabsorption is limited, so that bicarbonate is lost into the urine if the plasma concentration exceeds the threshold of around 28 mmol litre-I. This threshold is lowered by parathyroid hormone and raised by intracellular acidosis (allowing bicarbonate retention to balance CO2 retention in respiratory acidosis).
BUFFERING SYSTEMS. Buffers are weak acids, present in blood and urine, which prevent large fluctuations of hydrogen ion concentration.

In blood hydrogen ions are buffered partIy by phosphate and haemoglobin but mainly by the bicarbonate/carbonic acid system:

Equilibrium between bicarbonate and carbonic acid is related to hydrogen ion concentration by the Henderson- Hasselbach relationship:

where k is the dissociation coefficient of carbonic acid. If [H+] is expressed in nmoles per litre, [H2C03] as Pco, in kPa, and [HC03-] in mmoles litre-“,

Alternatively the relationship may be expressed as

where pK = 6.1.

Control of the concentration of CO2 by the respiratory system and of HC03- by the liver and kidneys results in tight control of [H+].
In urine, hydrogen ions are buffered mainly by the phosphate buffer system:

Some textbooks refer to NH3 and NH. + as a buffer system. This is not strictly accurate, although, as discussed above, NH.+ excretion in the urine results in HC03- retention.

CAUSES AND DIAGNOSIS

Acid-base disturbances may be caused by:
• Abnormal CO2 removal in the lungs (,respiratory’ acidosis and alkalosis), or by
• Abnormalities in the regulation of bicarbonate and other buffers in the blood (,metabolic’ acidosis and alkalosis) .
Both may, and usually do, coexist. For instance, metabolic acidosis causes hyperventilation (via medullary chemoreceptors, leading to increased removal of CO2 in the lungs and partial compensation for the acidosis. Conversely, respiratory acidosis is accompanied by renal bicarbonate retention, which could be mistaken for primary metabolic alkalosis. The situation is even more complex if a patient has both respiratory disease and a metabolic disturbance.
Clinical history and examination usually point to the correct diagnosis. In complicated patients, the acid-base nomogram (Fig. 10.6) is invaluable. The H+ and Pac02 are measured in arterial blood (for precautions) as well as the bicarbonate. If the values from a patient lie in one of the bands in the diagram, it is likely that only one abnormality is present. If the [W] is high (pH low) but the Pco, is normal, the intercept lies between two bands:
the patient has respiratory dysfunction, leading to failure of CO2 elimination, but this is partly compensated for by metabolic acidosis, stimulating respiration and CO2 removal (this is the commonest ‘combined’ abnormality in practice).

Respiratory acidosis

This is caused by retention of CO2, The PaC02 and [H+] rise. Renal retention of bicarbonate may partly compensate, returning the [H+] towards normal.

Respiratory alkalosis

Increased removal of CO2 is caused by hyperventilation so there is a fall in Paco2 and [H+].

Metabolic acidosis

This is due to the accumulation of any acid other than carbonic acid (see above). The most common cause islactic acid production during shock or following cardiac arrest.
Differential diagnosis of metabolic acidosis: the anion gap The first step is to identify whether the acidosis is due to retention of H+Cl- or to another acid. This is achieved by calculation of the anion gap. The principles underlying this calculation are straightforward:
• The normal cations present in plasma are Na”, K+,
Ca2+, Mg2+.
• The normal anions present in plasma are Cl-, HC03-, negative charges present on albumin, phosphate, sulphate, lactate, and other organic acids.
• The sum of the positive and negative charges are equal.
• Measurement of Na”, K+, Cl- and HC03- are usually easily available.

The sum is referred to as the anion gap. Because there are more
unmeasured anions than cations, the normal anion gap
is 10-18 mmol litre “,

• Beware: some textbooks leave [K+] out of the calculation, giving a lower ‘normal range’ .
If the anion gap is normal in the presence of acidosis, one may conclude that H+Cl- is being retained or Na+HC03- is being lost. Causes of a normal anion gap acidosis are given.
If the anion gap is increased, one may conclude that an unmeasured anion is present in increased quantities. This may either be one of the acids normally present in small, but unmeasured quantities, such as lactate, or an exogenous acid. Causes of a high anion gap acidosis are given.
The anion gap involves a number of assumptions and uncertainties, such as the negative charge attributable to albumin. An albumin concentration of 40 g litre-I gives a negative charge of around 10 mmol; a fall in albumin concentration to 20 g litre-I would lower the normal anion gap by 5 mmollitre-‘. Both types of acidosis may co-exist. For instance, cholera would be expected to cause a normal anion gap acidosis due to massive gastrointestinal losses of bicarbonate, but the anion gap is often increased due to renal failure and lactic acidosis as a result of hypovolaemia.

Lactic acidosis

Increased lactic acid production occurs when cellular respiration is abnormal, either due to lack of oxygen in the tissues (‘type A’) or to a metabolic abnormality, e.g. druginduced Ctype-B’) . The commonest cause septicaemic or cardi genic shock. Significant acidosis can occur despite a normal blood pressure and Pa02′ due to splanchnic and peripheral vasoconstriction. Acidosis worsens cardiac function and vasoconstriction further, contributing to a downward spiral and fulminant production of lactic acid.

Diabetic ketoacidosis

This is a high anion gap acidosis due to the accumulation of organic acids, acetoacetic acid and hydroxybutyric acid due to increased production and some reduced peripheral utilization.

Renal tubular acidosis

This term refers to systemic acidosis caused by impairment of the ability of the renal tubules to maintain acidbase balance. This group of disorders is uncommon and only rarely a cause of significant clinical disease. Renal tubular acidosis may be secondary to immunological, drug-induced or structural damage to the tubular cells, an inherited abnormality, or an isolated (‘primary’) abnormality. As with most disorders which are not well understood, the nomenclature is confusing.
TYPE 4 RENAL TUBULAR ACIDOSIS, also called hyporeninaemic hypo aldosteronism, is probably the commonest of these disorders. The cardinal features are hyperkalaemia and acidosis occurring in a patient with mild chronic renal insufficiency, usually caused by tubulointerstitial disease (e.g. reflux nephropathy) or diabetes. Plasma renin and aldosterone are found to be low even after measures which would normally stimulate their secretion (Table 10.21). An identical syndrome may be  caused by NSAIDs, which impair renin and aldosterone secretion. In the presence of acidosis, urine pH may be low. Treatment is with fludrocortisone, sodium bicarbonate, diuretics, or ion exchange resins to remove potassium, or some combination of these. Dietary potassium restriction alone is ineffective.
TYPE 3 RENAL TUBULAR ACIDOSIS is vanishingly rare, and represents a combination of type 1 and type 2.
TYPE 2 (‘PROXIMAL’) RENAL TUBULAR ACIDOSIS is very rare in adult practice. It is caused by failure of sodium bicarbonate reabsorption in the proximal tubule. The cardinal features are acidosis, hypokalaemia, an inability to lower the urine pH below 5.5 despite systemic acidosis, and the appearance of bicarbonate in the urine despite a subnormal plasma bicarbonate. This disorder normally occurs as part of a generalized tubular defect, together with other features such as glycosuria and amino aciduria. Treatment is with sodium bicarbonate: massive doses may be required to overcome the renal ‘leak’.
TYPE 1 (‘DISTAL’) RENAL TUBULAR ACIDOSIS is due to a failure of H+ excretion in the distal tubule and consists of:
• Acidosis
• Hypokalaemia
• Inability to lower the urine pH below 5.5 despite systemic acidosis
• Low urinary ammonium production
These features may only be present in the face of increased acid production; hence the need for an acid load test in diagnosis. Other features include:
• Low urinary citrate
• Hypercalciuria
These abnormalities result in osteomalacia, renal stone formation and recurrent urinary infections. Osteomalacia is caused by buffering of H+ by Ca2+ in bone resulting in depletion of calcium from bone. Renal stone formation is caused by hypercalciuria, hypocitraturia (citrate inhibits calcium phosphate precipitation), and alkaline urine (which favours precipitation of calcium phosphate).

Recurrent urinary infections are caused by renal stones. This disorder is associated with numerous diseases including any cause of nephrocalcinosis (causing structural tubular damage), immunological damage (for instance, in association with Sjogren’s syndrome), and a number of drugs. Treatment is with sodium bicarbonate, potassium supplements and citrate. Thiazide diuretics are useful by causing volume contraction and increased proximal sodium bicarbonate reabsorption.

Uraemic acidosis

Kidney disease may cause acidosis in several ways. Reduction in the number of functioning nephrons decreases the capacity to excrete NH! and H+ in the urine. In addition, tubular disease may cause bicarbonate wasting. Acidosis is a particular feature of those types of chronic renal failure in which the tubules are particularly affected, such as reflux nephropathy and chronic obstructive uropathy.
Chronic acidosis is most often caused by chronic renal failure, where there is a failure to excrete fixed acid. Up to 40 mmol of hydrogen ions may accumulate daily. These are buffered by bone, in exchange for calcium. Chronic acidosis is therefore a major risk factor for renal osteodystrophy and hypercalciuria. Chronic acidosis has also been shown recently to be a risk factor for muscle wasting in renal failure, and may also contribute to the inexorable progression of some types of renal disease.
Uraemic acidosis should be corrected because of the effects of chronic acidosis on growth, muscle turnover end bones, Sodium bicarbonate 2-3 mmol kg:’ daily is usually enough to maintain serum bicarbonate above 20 mmollitre-I, but may contribute to sodium overload. Calcium carbonate improves acidosis and also acts as a phosphate binder and calcium supplement, and is increasingly used. Acidosis in end-stage renal failure is usually fully corrected by adequate dialysis.

Clinical features of acidosis

Clinically the most obvious effect is stimulation of respiration, leading to the clinical sign of ‘air hunger’, or Kussmaul’s sign. Interestingly, patients with profound hyperventilation may not complain of breathlessness, although in others it may be a presenting complaint. Acidosis increases delivery of oxygen to the tissues by shifting the oxyhaemoglobin dissociation curve to the right, but also leads to inhibition of 2,3- DPG production, which returns the curve towards normal.
Cardiovascular dysfunction is common in acidotic patients, although it is often difficult to dissociate the numerou  possible causes of this. There is no doubt that  acidosis is negatively inotropic. Severe acidosis causes venoconstriction, resulting in redistribution of blood from the peripheries to the central circulation, and increased systemic venous pressure, which may worsen pulmonary oedema caused by myocardial depression . Arteriolar vasodilatation also occurs, further contributing to hypotension.
Cerebral dysfunction is variable. Severe acidosis is often associated with confusion and fits, but numerous other possible causes are usually present.
As mentioned earlier, acidosis stimulates potassium loss from cells, which may lead to potassium deficiency if renal function is normal or to hyperkalaemia if renal potassium excretion is impaired.

Treatment of acidosis

In lactic acidosis caused by poor tissue perfusion (‘type A’), treatment should be aimed at maximizing oxygen delivery to the tissues and usually requires inotropic agents, mechanical ventilation and invasive monitoring. In ‘type B’ lactic acidosis treatment is that of the underlyingdisorder, e.g.
• Insulin in diabetic ketoacidosis
• Treatment of methanol and ethylene glycol poisoning with ethanol
• Removal of salicylate by dialysis
The question of whether severe acidosis should be treated with bicarbonate is extremely controversial. Severe acidosis ([H+] >100 nmol litre-I, pH <7.0) is associated with a very high mortality, which makes many doctors keen to correct it. Since acidosis is known to impair cardiac contractility it would seem sensible to correct acidosis with bicarbonate in a sick patient. However:
• Rapid correction of acidosis may result in tetany and fits due to a rapid decrease in ionized calcium.
• Administration of sodium bicarbonate may lead to extracellular volume expansion, exacerbating pulmonary oedema.
• Bicarbonate therapy increases CO2 production and will therefore only correct acidosis if ventilation can be increased to remove the added CO2 load.
• The increased amounts of CO2 generated may diffuse more readily into cells than bicarbonate, worsening intracellular acidosis. Administration of sodium bicarbonate (50 mmol, as 50 ml of 8.4% sodium bicarbonate intravenously) is sometimes given during cardiac arrest and is often necesnecessary before arrhythmias can be corrected. Correction of hyperkalaemia associated with acidosis is also of undoubted benefit. In other situations there is no clinical evidence to show that correction of acidosis improves outcome, but it remains standard practice to administer sodium bicarbonate when [H”] is> 126 nmol litre ” (pH <6.9) using intravenous 1.26% (150 rnrnol litre'”) bicarbonate.

Metabolic alkalosis

Renal excretion of excess bicarbonate is normally very efficient, and for this reason metabolic alkalosis is much rarer than acidosis. A number of factors stimulate bicarbonate reabsorption and hydrogen ion excretion despite the presence of alkalosis:
• Extracellular volume depletion
• Potassium deficiency
• Excess mineralocorticoids
• Thiazide and loop diuretics
All of these may be thought of as increasing secretion of H+ in exchange for Na” in the distal tubule. Vomiting causes alkalosis both by causing volume depletion and by causing loss of gastric acid. Exogenous alkalis, such as those found in effervescent preparations of analgesics or in proprietary antacids, may also contribute to metabolic alkalosis, particularly if combined with another contributory factor.

Effects of alkalosis

Cerebral dysfunction is an early feature of alkalosis. The oxyhaemoglobin dissociation curve is shifted to the left. Respiration may be depressed.

Treatment of alkalosis

Replacement of sodium, potassium and chloride allows renal excretion of bicarbonate. Clearly sodium chloride administration should be avoided in patients on diuretics as appropriate treatment for heart failure. Acetazolamide may be useful in patients without sodium depletion.

 Further reading

Arieff AI (1993) Management of hyponatraemia. British Medical Journal 307, 305-308. Atkinson DE & Bourke E (1987) Metabolic aspects of the regulation of systemic pH. American Journal of Physiology 252, F947-F956.
Cameron et al. (eds) (1993) Water, electrolyte or acidbase disorders. In: Oxford Textbook of Clinical Nephrology, pp. 867-917. Oxford: Oxford University Press. Editorial (1988) What causes oedema? Lancet i, 1028- 1030.
Field MJ & Giebisch GJ (1985) Hormonal control of renal potassium excretion. Kidney International 27, 379- 387.
Jamieson MJ (1985) Clinical algorithms: Hyponatraemia. British Medical Journal 290, 1723-1728

HYPOPHOSPHATAEMIA

Significant hypophosphataemia may occur in a number of clinical situations, either due to redistribution into cells, to renal losses, or to decreased intake, and may cause:
• Muscle weakness-diaphragmatic weakness, decreased cardiac contractility, skeletal muscle rhabdomyolysis
• Left-shifted oxyhaemoglobin dissociation (reduced 2,3- diphosphoglycerate (2,3-DPG)).
• Confusion, hallucinations and convulsionsMild hypophosphataemia often resolves without specific treatment. However, diaphragmatic weakness may be severe in acute hypophosphataemia, and may impede weaning a patient from a ventilator. Interestingly, chronic hypophosphataemia (in X-linked hypophosphataemia) is associated with normal muscle power.

Treatment of acute hypophosphataemia, if warranted, is with intravenous phosphate at a maximum rate of 9 mmol every 12 hours, with repeated measurements of calcium and phosphate, as over-rapid administration of phosphate may lead to severe hypocalcaemia, particularly in the presence of alkalosis. Chronic hypophosphataemia can be corrected, if warranted, with oral effervescent sodium phosphate.

HYPERPHOSPHATAE MIA

Hyperphosphataemia is common in patients with chronic renal failure. Hyperphosphataemia is usually asymptomatic but may result in precipitation of calcium phosphate, particularly in the presence of a normal or raised calcium or of alkalosis. Uraemic itching may be caused by a raised calcium x phosphate product. Prolonged hyperphosphataemia causes hyperparathyroidism, and periarticular and vascular calcification.
No treatment is usually required for acute hyperphosphataemia, as the causes are self-limiting. Treatment of chronic hyperphosphataemia is with gut phosphate binders and dialysis.

Plasma magnesium levels are normally maintained within the range 0.7-1.1 mmol litre:”. Like potassium, magnesium is principally an intracellular cation.
Regulation of magnesium balance is mainly via the kidney. Primary disturbance of magnesium balanceis uncommon, hypo- or hypermagnesaemia usually developing on a background of more obvious fluid and electrolyte disturbances. Disturbance in magnesium balance should always be suspected in association with other fluid and electrolyte disturbances when the patient develops unexpected neurological signs or symptoms.

HYPOMAGNESAEMIA

This most often develops as a result of deficient intake, defective gut absorption, or excessive gut or urinary loss . It can also occur with acute pancreatitis,  possibly due to the formation of magnesium soaps in the areas of fat necrosis. Calcium deficiency usually develops with hypomagnesaemia.

CLINICAL FEATURES

Symptoms and signs include irritability, tremor, ataxia, carpopedal spasm, hyperreflexia, confusional and hallucinatory states and epileptiform convulsions. The serum magnesium is usually <0.7 mmol Iitre”. An ECG may show a prolonged QT interval, broad flattened T waves and occasional shortening of the ST segment.

TREATMENT

This involves the withdrawal of precipitating agents such as diuretics or purgatives and the parenteral infusion of 50 mmol of magnesium cWoride in 1 litre of 5% dextrose or other isotonic fluid over 12-24 hours. This should be repeated daily until the plasma magnesium level is normal.

HYPERMAGNESAEMIA

This primarily occurs in patients with acute or chronic failure given magnesium-containing laxatives or antacids. It can also be induced by magnesium-containing enemas. Mild hypermagnesaemia may occur in patients with adrenal insufficiency. Causes are given.

CLINICAL FEATURES

Symptoms and signs relate to neurological and cardiovascular depression, and include weakness with hyporeflexia proceeding to narcosis, respiratory paralysis and cardiac conduction defects. Symptoms usually develop when the plasma magnesium level exceeds 2 mmol litre “.

TREATMENT

Treatment requires withdrawal of any magnesium therapy. An intravenous injection of 10 ml of calcium gluconate 10% (2.25 mmol calcium), is given to antagonize the effects ofhypermagnesaemia and dextrose and insulin (as for hyperkalaemia) to lower the plasma magnesium level. Dialysis may be required in patients with severe renal failure. Respiratory failure requires artificial ventilation until the plasma magnesium level returns to normal level.

Regulation of serum potassium concentration

The usual dietary intake varies between 80 and 150 mmol daily depending upon fruit and vegetable intake. Most of the body’s potassium (3500 mmol in an adult man) is intracellular. Serum potassium levels are controlled by:

• Uptake of K+ into cells
• Renal excretion
• Extra-renal losses (e.g. gastrointestinal)
Uptake of potassium into cells is governed by the activity of the Na”, K+ ATPase in the cell membrane and by H+ concentration. Uptake is stimulated by:
• Insulin
• Beta-adrenergic stimulation
• Theophyllines
and decreased by:
• Alpha-adrenergic stimulation
• Acidosis=-K” exchanged for H+ across cell membrane
• Cell damage or cell death-resulting in massive K+ release.
Excretion of potassium is increased by aldosterone, which stimulates K+ and H+ secretion in exchange for Na” in the collecting duct. Because H+ and K+ are interchangeable in the exchange mechanism, acidosis decreases and alkalosis increases the secretion of K+. Aldosterone secretion is stimulated by hyperkalaemia and increased angiotensin II levels, as well as by some drugs, and acts to protect the body against hyperkalaemia and against extracellular volume depletion. The body adapts to dietary deficiency of potassium by reducing aldosterone secretion. However, because aldosterone is also influenced by volume status, conservation of potassium is relatively inefficient, and significant potassium depletion may therefore result from prolonged dietary deficiency.
A number of drugs affect K+ homeostasis by affecting aldosterone release (e.g. heparin, NSAIDs) or by directly affecting renal potassium handling. Normally only about 10% of daily potassium intake is excreted in the gastrointestinal tract. Vomit contains around 5-10 mmol litre-‘ K+, but prolonged vomiting may cause hypokalaemia by inducing sodium depletion, stimulating aldosterone, which increases renal potassium excretion. Potassium may be secreted by the colon, and diarrhoea contains 10-50 mrnol litre-‘ K+; profuse diarrhoea can therefore induce marked hypokalaemia. Villous adenomas may rarely produce profuse diarrhoea and K+ loss.

HYPOKAlAEMIA

CAUSES

The commonest causes of chronic hypokalaemia are diuretic treatment (particularly thiazides) and hyper  aldosteronism. Acute hypokalaemia is more often caused by redistribution into cells. The common causes are shown.

Rare causes

BARTTER’s SYNDROME consists of hypokalaemia, alkalosis, normal blood pressure, and elevated plasma renin and aldosterone. Numerous causes of this syndrome probably exist. Diagnostic pointers include high urinary potassium and chloride despite low serum values, increased plasma renin, hyperplasia of the juxtaglomerular apparatus on renal biopsy, and careful exclusion of
diuretic abuse. Excess production of renal prostaglandins is often found. Magnesium wasting may also occur.
LIDDLE’S SYNDROME is also characterized by potassium wasting, hypokalaemia, and alkalosis, but is associated with low aldosterone production and high blood pressure.

HYPOKALAEMIC PERIODIC PARALYSIS may be precipitated by carbohydrate intake, suggesting that insulinmediated potassium influx into cells may be responsible. This syndrome also occurs in association with hyperthyroidism in Chinese patients.

CLINICAL FEATURES

Hypokalaemia is usually asymptomatic, but severe hypokalaemia may cause muscle weakness. Potassium depletion may also cause symptomatic hyponatraemia.
Hypokalaemia is associated with an increased frequency of atrial and ventricular ectopic beats. This association may not always be causal, because adrenergic activation (for instance after myocardial infarction) causes both hypokalaemia and increased cardiac irritability. Hypokalaemia in patients without cardiac disease is unlikely to lead to serious arrhythmias.
Hypokalaemia seriously increases the risk of digoxin toxicity by increasing binding of digoxin to cardiac cells, potentiating its action, and decreasing its clearance. The same may be true of some other drugs which cause arrhythmias.
Chronic hypokalaemia is associated with interstitial renal disease, but the pathogenesis is not completely understood.

TREATMENT

The underlying cause should be identified and treated where possible; for examples.
Acute hypokalaemia may correct spontaneously. In most cases, withdrawal of oral diuretics or purgation, accompanied by the oral administration of potassium supplements in the form of slow-releasing potassium or effervescent potassium, is all that is required. Intravenous potassium replacement is only required in conditions such as cardiac arrhythmias, muscle wealcness or severe diabetic ketoacidosis when the potassium is <2.5 mmol litre “. When used, intravenous therapy must take account of renal function and replacement at rates >20 mmol hour” should only be used with hourly monitoring of serum potassium and ECG changes. The treatment of adrenal disorders is described.
Failure to correct hypokalaemia may be due to concurrent hypomagnesaemia; serum magnesium should be measured and deficiency corrected.

HYPERKALAEMIA

CAUSES

Acute self-limiting hyperkalaemia occurs normally after vigorous exercise and is of no pathological significance. Hyperkalaemia in all other situations is due either to increased release from cells or to failure of excretion . The commonest causes are renal impairment and drug interference with potassium excretion. The combination of ACE inhibitors with potassiumsparing diuretics or NSAIDs is particularly dangerous.

Rare causes

HYPORENINAEMIC HYPOALDOSTERONISM is also known as type 4 renal tubular acidosis . PSEUDOHYPOALDOSTERONISM is a disease of infancy apparently due to resistance to the action of aldosterone, characterized by hyperkalaemia and evidence of sodium wasting (hyponatraemia, extracellular volume depletion).HYPERKALAEMIC PERIODIC PARALYSIS is precipitated by exercise, and is caused by a genetically determined abnormality of the sodium pump.
GORDON’S SYNDROME appears to be a mirror image of Bartter’s syndrome, in which primary renal retention of sodium causes hypertension, volume expansion, low renin/aldosterone, hyperkalaemia and acidosis. The disorder may be due to deficiency of ANP.
SUXAMETHONIUM AND OTHER DEPOLARIZING MUSCLE RELAXANTS cause release of potassium from cells. Induction of muscle paralysis during general anaesthesia may result in a rise of plasma potassium of up to 1 mmol litre – I. This is not usually a problem unless there is preexisting hyperkalaemia.

CLINICAL FEATURES

Serum potassium of greater than 7.0 mmol litre-II is a medical emergency and is associated with ECG changes. Severe hyperkalaemia may be asymptomatic and may predispose to sudden death from asystolic cardiac arrest. Muscle weakness is often the only symptom, unless (as is commonly the case) the hyperkalaemia is associated with metabolic acidosis, causing Kussmaul respiration.
Hyperkalaemia causes hyperpolarization of cell membranes leading to decreased cardiac excitability, hypotension, bradycardia, and eventual asystole.

TREATMENT 

Treatments for hyperkalaemia are summarized in Practical Box 10.1 and should also include treatment of the cause.
Calcium ions protect the cell membranes from the effects of hyperkalaemia but do not alter the potassium concentration. Insulin drives potassium into the cell, but must be accompanied by glucose to avoid hypoglycaemia. Regular measurements of blood glucose must be used for at least 6 hours after use of insulin in this situation, and extra glucose must be available for immediate use. Intravenous salbutamol has not yet found widespread acceptance and may cause disturbing muscle tremor at the doses required. Correction of acidosis with hypertonic (8.4%) sodium bicarbonate causes volume expansion and should be used with extreme caution, particularly in renal failure.
Cation exchange resins (sodium and calcium resonium) make use of the ion fluxes which occur in the gut to remove potassium from the body, and are the only way short of dialysis of removing potassium from the body. They may cause sodium (extracellular fluid) overload and hypercalcaemia respectively. In general all of these measures are simply ways of buying time either to correct the underlying disorder or to arrange removal of potassium by dialysis, which is the definitive treatment for hyperkalaemia.
All of these measures may cause digoxin toxicity in patients receiving digoxin, in whom cardiac monitoring is essential.

These are best thought of as disorders of body water content. As discussed above, sodium content is regulated by volume receptors; water content is adjusted to maintain, in health, a normal osmolality and (in the absence of abnormal osmotically active solutes) a normal sodium concentration. Disturbances of sodium concentration are caused by disturbances of water balance.

HYPONATRAEMIA

Hyponatraemia is one of the commonest abnormalities detected in biochemistry laboratories. It may be associated with normal, decreased, or increased extracellular volume and total body sodium content. The differential diagnosis of hyponatraemia depends on an assessment of extracellular volume. Rarely hyponatraemia may be pseudohyponatraemia, where in hyperlipidaemia or hyperproteinaemia there is a spuriously low measured sodium concentration, the sodium being confined to the aqueous phase but having its concentration expressed in terms of the total volume of plasma. In this situation plasma osmolality is normal and therefore treatment of ‘hyponatraemia’ is unnecessary. It is also important to exclude artefactual ‘hyponatraernia’ caused by taking blood from the limb into which fluid of low sodium concentration is being infused.

Salt-deficient hyponatraemia

This is due to salt loss in excess of water; the causes are listed in Table 10.7. In this situation ADH secretion is initially suppressed (via the hypothalamic osmoreceptors), but as fluid volume is lost, volume receptors override the osmoreceptors and stimulate both thirst and the release of ADH. This is an attempt by the body to defend circulating volume at the expense of osmolality.

With extrarenal losses and normal kidneys, the urinary excretion of sodium falls in response to the volume depletion, as does water excretion, leading to concentrated urine containing less than 10 mmol litre”! of sodium. However, in salt wasting kidney disease, renal compensation cannot occur and the only physiological protection is increased water intake in response to thirst.

CLINICAL FEATURES

With sodium depletion the clinical picture is usuallydominated by features of volume depletion.  The diagnosis is usually obvious where there is a history of gut losses, diabetes mellitus or diuretic abuse.  the potential daily losses of water and electrolytes from the gut. Losses due to renal or adrenocortical disease may be less easily identified and are suggested by a urinary sodium concentration of more than 20 mmol litre.” in the presence of clinically evident volume depletion.

TREATMENT

This is directed at the primary cause whenever possible.Increased salt intake as Slow Sodium 60-80 mmol daily is all that is required in the relatively healthy patient who can take this by mouth. In the face of vomiting or severe  volume depletion, intravenous infusion of normal saline is given. Potassium supplements and correction of acidbase abnormalities may also be required.

Hyponatraemia due to water excess

This results from an intake of water in excess of the kidney’s ability to excrete it. It is uncommon with normal kidney function, requiring an intake of approximately 1 litre hour-I. Overgenerous infusion of 5% glucose into postoperative patients is one of the commonest causes, in which situation it is exacerbated by increased ADH secretion in response to stress. Some degree of hyponatraemia is usual in acute oliguric renal failure, while in chronic renal failure it is most often due to ill-given advice to ‘push’ fluids.
The commonest presentation of hyponatraemia due to water excess is in patients with severe cardiac failure, hepatic cirrhosis or the nephrotic syndrome in which there is evidence of volume overload. In all these conditions there is usually an element of reduced glomerular filtration rate with avid reabsorption of sodium and chloride in the proximal tubule. This leads to reduced delivery of chloride to the ‘diluting’ ascending limb of Henle’s loop and a reduced ability to generate ‘free water’, with a consequent inability to excrete dilute urine. This is commonly compounded by the administration of diuretics that block chloride reabsorption and interfere with the dilution of filtrate either in Henle’s loop (loop diuretics) or distally (thiazides),

CLINICAL FEATURES

Symptoms are common with dilutional hyponatraemia when this develops acutely. They are principally neurological and are due to the movement of water into brain cells in response to the fall in extracellular osmolality. Symptoms rarely occur until the serum sodium is less than 120 mmol litre-‘ and are more usually associated with values around 110 mmol litre ” or lower. Symptoms and signs of hyponatraemia are non-specific and include headache, confusion, and restlessness leading to drowsiness, myoclonic jerks, generalized convulsions and eventually coma. Other features depend on the cause, e.g. signs of congestive cardiac failure or liver disease.

INVESTIGATION

No further investigation of hyponatraemia is usually necessary if it is associated with clinically detectable extracellular volume excess. The cause of hyponatraemia with apparently normal extracellular volume is usually less obvious, and this category requires careful investigation to:
• exclude Addison’s disease
• exclude hypothyroidism
• consider ‘syndrome of inappropriate ADH secretion’ (SIADH) (p. 821) and drug-induced water retention
• remember potassium and magnesium depletion potentiate ADH release and are an important cause of diuretic-associated hyponatraemia The syndrome of inappropriate ADH secretion is often over-diagnosed. Some causes are associated with a lower set point for ADH release, rather than completely autonomous ADH release; an example is chronic alcohol abuse.

TREATMENT

The underlying cause should be corrected where possible. Most cases are simply managed by restriction of water intake (to 1000 or even 500 ml per day) with review of diuretic therapy. Magnesium and potassium deficiency must be corrected. The use of hypertonic saline is restricted to patients with acute water retention in which there are severe neurological.signs, e.g. fits and coma. It must be given slowly (not more than 70 mmol per hour) the aim being to increase the serum sodium to more than 125 mmol litre :’. If hyponatraemia has developed slowly, as in the majority of patients, the brain will have adapted by decreasing intracellular osmolality; a rapid rise in extracellular osmolality, particularly if there is an ‘overshoot’ to high serum sodium and osmolality will then result in severe shrinking of brain cells, and the syndrome of ‘central pontine myelinolysis’, which may be fatal. Hypertonic saline must not be given to patients who are already fluid overloaded because of the risk of acute heart failure; in this situation 100 ml of 20% mannitol may be infused in an attempt to increase renal water excretion. Syndrome of inappropriate AD H secretion This is described.

HYPERNATRAEMIA

This is much rarer than hyponatraemia and nearly always indicates a water deficit. This may be due to:
• Pituitary diabetes insipidus (see p. 820) (failure of ADH secretion)
• Nephrogenic diabetes insipidus (failure of response to ADH)
• Osmotic diuresis
• Excessive loss of water through the skin or lungs Excessive administration of hypertonic sodium may also contribute, for example:
• Excessive reliance on 0.9% (150 mmol litre “) saline for volume replacement
• Administration of drugs with a high sodium content, e.g, piperacillin
• Use of 8.4% sodium bicarbonate after cardiac arrest

Hypernatraemia is always associated with increased plasma osmolality, which is a potent stimulus to thirst. None of the above causes hypernatraemia unless thirst sensation is abnormal or access to water limited. For instance, a patient with diabetes insipidus will maintain a normal serum sodium concentration by maintaining a high water intake until an intercurrent illness prevents this. Thirst is frequently deficient in elderly people, making them more prone to water depletion. Hypernatraemia may occur in the presence of normal, reduced or expanded extracellular volume, and does not necessarily imply that total body sodium is increased.

CLINICAL FEATURES

SYMPTOMS of hypernatraemia are non-specific. Nausea, vomiting, fever and confusion may occur. A history of long-standing polyuria, polydipsia and thirst suggests diabetes insipidus. There may be clues to a pituitary cause. A drug history may reveal ingestion of nephrotoxic drugs. SIGNS. Assessment of extracellular volume status is important in guiding resuscitation. Mental state should be assessed. Convulsions occur in severe hypernatraemia.

INVESTIGATION

Simultaneous urine and plasma osmolality and sodium should be measured. Serum osmolality is high in hypernatraemia. Passage of urine with an osmolality lower than that of plasma in this situation is clearly abnormal and indicates diabetes insipidus. In pituitary diabetes insipidus, urine osmolality will increase after administration of desmopressin; the drug (a vasopressin analogue) has no effect in nephrogenic diabetes insipidus. If urine osmolality is high this suggests either an osmotic diuresis due to an unmeasured solute (e.g. in parenteral feeding) or excessive extra-renal loss of water (e.g. heat stroke).

TREATMENT

Treatment is that of the underlying cause: replacement of ADH in the form of desmopressin, a stable non-pressor analogue of ADH, in ADH deficiency; withdrawal of nephrogenic drugs where possible; and replacement of water, either orally, if possible, or intravenously. In severe (>170 mmol litre-I) hypernatraemia 0.9% (150 mmol litre-I) saline should be used initially, to avoid too rapid a drop in serum sodium concentration; the aim is correction over 48 hours, as over-rapid correction may lead to cerebral oedema. In less severe (e.g. > 150 mrnol litre -I) hypernatraemia the treatment is 5% dextrose or 0.45% saline; the latter is obviously preferable in hyperosmolar diabetic coma. Very large volumes-5 litres a day or more-may need to be given in diabetes insipidus. If there is clinical evidence of volume depletion, this implies that there is a sodium deficit as well as a water deficit. Treatment of this is discussed

Deficiency of sodium and water causes shrinkage both of the interstitial space and of the blood volume and may have profound effects on organ function.

CLINICAL FEATURES

SYMPTOMS are variable. Thirst, muscle cramps, nausea and vomiting, and postural dizziness may occur. Severe depletion of circulating volume causes hypotension and impairs cerebral perfusion, causing confusion and eventual coma.
SIGNS can be divided into those due to loss of interstitial fluid and those due to loss of circulating volume. Loss of interstitial fluid leads to loss of skin elasticity (‘turgor’) -the rapidity with which the skin recoils to normal after being pinched. Skin turgor decreases with age, particularly at the peripheries. The turgor over the anterior triangle of the neck or on the forehead is a very useful sign in all ages. Loss of circulating volume leads to decreased pressure in the venous and (if severe) arterial compartments. Loss of up to 1 litre of extracellular fluid in an adult may be compensated for by venoconstriction and may cause no physical signs. Loss of more than this causes:

POSTURAL HYPOTENSION. Normally the blood pressure rises if a subject stands up, as a result of increased venous return due to venoconstriction (this maintains cerebral perfusion). Loss of extracellular fluid prevents this and causes a fall in blood pressure. This is one of the earliest and most reliable signs of volume depletion, as long as the other causes of postural hypotension are excluded.
Low JUGULAR VENOUS PRESSURE. In hypovolaemic patients, the jugular venous pulsation can only be seen with the patient lying completely flat, or even head down, because the left atrial pressure is lower than 5 cmH20.
PERIPHERAL VENOCONSTRICTION causes cold skin with empty peripheral veins, which are difficult to cannulate, just when the patient needs intravenous therapy the most! This sign is absent in sepsis, where peripheral vasodilatation contributes to effective hypovolaemia.
TACHYCARDIA (not always reliable). Beta-blockers and other antiarrhythmics may prevent this and hypovolaemia may activate vagal mechanisms and actually cause bradycardia.
ARTERIAL HYPOTENSION. A late sign.

CAUSES

Salt and water may be lost either from the kidneys, from the gastrointestinal tract, or from the skin. Examples are given.
In addition to these causes, there are a number of situat ions where signs of volume depletion occur despite a normal or increased body content of sodium and water:
1 Septicaemia causes vasodilatation both of arterioles and veins, resulting in greatly increased capacitance of the vascular space. In addition, increased capillary permeability to plasma proteins leads to loss of fluid from the vascular space to the interstitium.
2 Diuretic treatment of heart failure or nephrotic syndrome may lead to rapid reduction in plasma volume; mobilization of oedema may take much longer.
3 Inappropriate diuretic treatment of oedema e.g. when the cause is local rather than systemic.

INVESTIGATION

Blood tests are in general not helpful in assessment of extracellular volume. Blood urea may be raised due to increased urea reabsorption and, later, to prerenal failure (when the creatinine rises as well) but is very non-specific. Urinary sodium is low if the kidneys are functioning normally, but is misleading if the cause of the volume depletion involves the kidneys (e.g. diuretics, intrinsic renal disease). Urine osmolality is high in volume depletion (due to increased water reabsorption) but may also often mislead.

TREATMENT

The overriding principle IS: aim to replace what is missing.
HAEMORRHAGE involves the loss of whole blood. The rational treatment of acute haemorrhage is therefore whole blood, or a combination of red cells and a plasma substitute. (Chronic anaemia causes salt and water retention rather than volume depletion; correction therefore involves replacement of red cells with the minimum of salt, water and albumin, combined with diuretics.)
Loss OF PLASMA, as in burns or severe peritonitis, should be treated with human plasma or a plasma substitute
Loss OF WATER AND ELECTROLYTES, as in vomiting, diarrhoea, or excessive renal losses, should be treated by replacement of water and electrolytes. If possible, this should be done with oral water and sodium salts. These are available as slow sodium 600 mg (approximately 10 mmol NaCI per tablet). The usual dose per day with 2-3 litres of water. It is used in mild or chronic salt and water depletion, e.g. associated with renal salt wasting.
Sodium bicarbonate 500 mg (6 mmol NaHC03 per tablet) is used in doses of 6-12 tablets per day with 2-3 litres of water. This is used in milder chronic sodium depletion with acidosis, e.g. chronic renal failure, postobstructive renal failure, renal tubular acidosis. Sodium bicarbonate is less effective in causing positive sodium balance than sodium chloride.
Oral rehydration solutions are described. Intravenous fluids may sometimes be required. Rapid infusion (e.g. 1000 ml hour-lor even faster) is necessary if there is hypotension and evidence of impaired organ perfusion (e.g. oliguria, confusion); in these situations plasma expanders (colloids) are often used in the first instance to restore an adequate circulating volume. Repeated clinical assessments are vital in this situation, usually complemented by frequent measurements of central venous pressure (see Management of Shock). Severe hypovolaemia induces venoconstriction, which maintains venous return; overrapid correction does not give time for this to reverse, resul.ting in signs of circulatory overload le.g. pul.monary oedema) even if a total body ECF deficit remains. In less severe ECF depletion, (e.g. a patient with postural hypotension complicating acute tubular necrosis) the fluid should be replaced at a rate of 1000 ml every 4-6 hours, again with repeated clinical assessment. If all that is required is avoidance of fluid depletion during surgery, 1-2 litres may be given over 24 hours, remembering that surgery is a stimulus to sodium and water retention and that over-replacement may be as dangerous as underreplacement.
Loss OF WATER ALONE only causes extracellular volume depletion in severe cases, because the loss is spread evenly between all the compartments of body water. In the rare situations where there is a true deficiency of water alone, as in diabetes insipidus in a patient who is unable to drink (after surgery, for instance), the correct treatment is to give water. If intravenous treatment is required, water is given as 5% dextrose, because pure water would lead to osmotic lysis of blood cells.

Water accounts for 50–60% of total body weight. This percentage varies with age, sex and body build, being less in women and the obese, as fat has a lower water content. Changes in total body water from one day to the next is, in an individual, reflected by changes in body weight. In a healthy, 70-kg male, total body water is approximately 42 litres, distributed between several compartments.
Two-thirds (28 litres) is intracellular fluid (I CF);
the remainder is extracellular fluid (ECF), comprising the interstitial fluid (10.5 litres) and the vascular compartment (3.5 litres).
There is no barrier to the passage of water between the extracellular and intracellular compartments as the distribution of water is governed by osmotic forces and all compartments have the same osmolality (280- 290 mosmol kg”). The major intracellular solute is potassium, balanced largely by phosphate and ionic protein, whilst the major extracellular solute is sodium chloride. Osmolality is determined by the concentration of osmotically active particles. Fully ionized (dissociated) molecules (e.g. NaCl) have twice the osmolality of undissociated particles (urea, glucose). The major determinant of plasma osmolality is sodium concentration: plasma osmolality can be approximated as (2 x [Na+l) + [urea] + [glucose], unless there is an unmeasured osmotically active substance present. For instance, plasma alcohol or ethylene glycol concentration can be estimated by subtracting calculated from measured osmolality.
The distribution of extracellular water between the vascular and extravascular (interstitial space) is determined by the equilibrium between hydrostatic and oncotic pressures (Fig. 10.1). The composition of intracellular and extracellular fluids.

the relative effect of the addition of identical volumes of water, saline and colloid solutions on the different compartments. Thus, 1 litre of water given intravenously as 5% dextrose is distributed equally into all compartments, whilst 1 litre of 0.9% saline remains in the extracellular compartment. The latter is thus the correct treatment for extracellular water depletion-sodium keeping the water in this compartment. The addition of 1 litre of colloid with its high oncotic pressure stays in the vascular compartment and is the treatment for hypovolaemia. Regulation of extracellular volume The extracellular volume is controlled by the total body content of sodium. Sodium is ‘diluted’ by water to keep it at the right concentration.
It is essential to distinguish between the concentration of sodium in the ECF (in practice the plasma sodium) and the amount of sodium. Concentration only implies the relative amounts of sodium to water and does not suggest the absolute amounts or volumes of either. Control of the body’s sodium is exerted by tight control over renal excretion. This is achieved by activation of receptors which respond to extracellular volume rather than the change in sodium concentration. These ‘volume’ receptors can be divided into extrarenal and intrarenal baroreceptors.

EXTRARENAL. These are located in the vascular tree in the left atrium and major thoracic veins and also in the sinus body and aortic arch. These volume receptors respond to a slight reduction in effective circulating volume and result in increased sympathetic nerve activity and a rise in catecholamines. In addition volume receptors in the cardiac atria control the release of a powerful natriuretic hormone-atrial natriuretic peptide (ANP)- from granules located in the atrial walls.
INTRARENAL. Receptors in the walls of the afferent glomerular arterioles respond, via the juxtaglomerular apparatus, to changes in renal perfusion, and control the activity of the renin-angiotensin-aldosterone system. In addition sodium concentration in the distal tubule and sympathetic nerve activity alter renin release from the juxtaglomerular cells. Prostaglandins 12 and E2 are also generated within the kidney in response to angiotensin II, acting to maintain glomerular filtration rate and sodium and water excretion, modulating the sodiumretaining effect of this hormone

The final common pathway for all the regulatory systems discussed is to increase or decrease the renal excretion of sodium in the event of an increase or decrease in effective circulating blood volume. An increase in the reabsorption of salt, with concomitant retention of water (due to a change in osmolality) expands the vascular and interstitial compartments while increased sodium excretion has the opposite effect..

Regulation of body water content

Body water homeostasis is effected by thirst and the urine concentrating and diluting functions of the kidney. These in turn are controlled by intracellular osmoreceptors, principally in the hypothalamus, to some extent by volume receptors in capacitance vessels close to the heart, and via the renin-angiotensin system. Of these, the major and best-understood control is via osmoreceptors. An increase in intracellular osmolality-for example after water deprivation-stimulates both thirst and release of anti-diuretic hormone (ADH) from the posterior pituitary. Thirst stimulates increased water intake while ADH increases the reabsorption of water from the tubular fluid by its action on the distal tubules of the kidney. This causes a reduction in the urine output. The increased intake of water and reduced urinary excretion results in a net gain of water that returns body fluid osmolality to normal. A decrease in intracellular osmolality in the osmoreceptors has the reverse effect. By this method the amount of water in body fluid is adjusted to ensure normal osmolality in the face of varying increase or loss of water or solute.
In addition non-osmotic stimuli may cause ADH release even if serum osmolality is normal or even low. These include hypovolaemia, stress (e.g. surgery, trauma), psychiatric disturbance and nausea. Increased extracellular volume.
Increased extracellular volume occurs in numerous disease states. The physical signs depend on the distribution of excess volume and on whether the increase is local or systemic. According to Starling principles, distribution depends on venous tone, which determines the capacitance of the blood compartment and thus hydrostatic pressure
• capillary permeability
• oncotic pressure-mainly dependent on serum albumm
• lymphatic drainage
Depending on these factors, fluid accumulation may result in expansion of interstitial volume, blood volume, or both.

CLINICAL FEATURES

Peripheral oedema is caused by expansion of the extracellular volume by at least 2 lit res (15%). The ankles are normally the first part of the body to be affected, although the ankles may be spared in patients with lipodermatosclerosis (where the skin is tethered and cannot expand to accommodate the oedema). Oedema may be noted in the face, particularly in the morning, and in a patient in bed oedema may accumulate in the sacral area. Expansion of the interstitial volume also causes pulmonary oedema, pleural effusion, pericardial effusion and ascites. Expansion of the blood volume causes a raised jugular venous pressure, cardiomegaly, added heart sounds and a raised arterial blood pressure in certain circumstances.

CAUSES

Extracellular volume expansion is due to sodium chloride retention. Increased salt intake does not normally cause volume expansion because of rapid homeostatic mechanisms which increase salt excretion. However, a rapid intravenous solution of a large volume of saline will cause volume expansion. Thus most causes of extracellular volume expansion are associated with renal sodium chloride retention:
HEART FAILURE: due to increased venous pressure causing oedema formation, activation of the reninangiotensin- aldosterone system, and increased activity of the renal sympathetic nerves.
HYPOALBUMINAEMIA : the major mechanism is loss of plasma on cotic pressure leading to loss of water from the vascular space to the interstitial space. This activates the renin-angiotensinaldosterone system. However, other factors may be involved as in the nephrotic syndrome measured plasma volume may be normal, decreased, or increased. There is some evidence that the nephrotic syndrome itself alters renal sodium handling.
HEPATIC CIRRHOSIS: the mechanism is again complex, but involves peripheral vasodilatation, possibly due to nitric oxide with activation of the renin-angiotensinaldosterone system causing sodium retention.
RENAL IMPAIRMENT: decreased glomerular filtrationrate decreases renal capacity to excrete sodium. This may be acute, as in the acute nephritic syndrome, or may occur as part of the presentation ofchronic renal failure. In end-stage renal failure extracellular volume is controlled by the balance between salt intake and its removal by dialysis. Mild sodium retention can also be caused by oestrogens which have a weak aldosterone-like effect. This produces weight gain in the premenstrual phase.
Numerous other drugs may cause renal sodium retention, particularly in patients whose renal function is already impaired:
• Mineralocorticoids and liquorice (which potentiates the sodium-retaining action of cortisol) have aldosterone- like actions
• NSAIDs, in the presence of activation of the reninangiotensin- aldosterone system by heart failure, cirrhosis and renal artery stenosis Substantial amounts of sodium and water may accumulate in the body without clinically obvious oedema or evidence of raised venous pressure. In particular, several litres may accumulate in the pleural space or as ascites; these spaces are then referred to as ‘third spaces’. Bone may also act as a ‘sink’ for sodium and water.

Other causes of oedema

Initiation of insulin treatment for type 1 diabetes and refeeding after malnutrition are both associated with the development of transient oedema; the mechanism is complex. Oedema may also result from increased capillary pressure due to relaxation of precapillary arterioles; the best example is the peripheral oedema caused by dihydropyridine calcium channel blockers such as nifedipine. Oedema may also be caused by increased interstitial oncotic pressure as a result of increased capillary permeability to proteins. This may occur as part of a rare complement-deficiency syndrome; as a result of septicaemia;
with therapeutic use of interleukin-2 in cancer chemotherapy; or in ovarian hyperstimulation syndrome. IDIOPATHIC OEDEMA OF WOMEN, by definition, occurs in women without heart failure, hypoalbuminaemia, renal or endocrine disease. Oedema is intermittent and often worse in the premenstrual phase. The condition remits after the menopause. Patients complain of swelling of the face, hands, breasts and thighs and a feeling of being bloated. Sodium retention during the day and increased sodium excretion during recumbency are characteristic; an abnormal fall in plasma volume on standing caused by increased capillary permeability to proteins may be the cause of this. The oedema may respond to diuretics, but returns when they are stopped. A similar syndrome of diuretic-dependent sodium retention can be caused by abuse of diuretics, for instance as part of an attempt to lose weight, but not all women with idiopathic oedema admit to having taken diuretics, and the syndrome was described before diuretics were introduced for clinical use.
LOCAL INCREASE IN OEDEMA does not reflect disturbances of extracellular volume control per se, but can cause clinical confusion, e.g. ankle oedema due to venous damage following thrombosis or surgery, ankle or leg oedema due to immobility, oedema of the arm due to subclavian thrombosis, facial oedema due to superior vena caval obstruction. Local loss of oncotic pressure may result from increased capillary permeability to proteins, caused by inflammatory mediators including histamine and interleukins, e.g. bee stings. Lastly, local loss of lymphatic drainage causes lymphoedema.

TREATMENT

The underlying cause should be treated where possible. For instance, treat heart failure, or withdraw offending drugs, e.g. NSAIDs. Sodium restriction has a limited role, but is useful in patients who are resistant to diuretics. Sodium intake can easily be reduced to approximately 100 mmol daily; reductions below this are often difficult to achieve without affecting the palatability of food. Manoeuvres which increase venous return stimulate salt and water excretion by effects on cardiac output and ANP release. This is the rationale for strict bed rest in congestive cardiac failure. Water immersion also causes redistribution of blood towards the central veins, but is seldom of practical use. Venous compression stockings or bandages may help to mobilize oedema in heart failure. The mainstay of treatment is the use of diuretic agents, which increase sodium, chloride and water excretion in the kidney. These agents act by interfering with membrane ion pumps which are present on numerous cell types, but most achieve specificity for the kidney by being secreted into the proximal tubule, resulting in much higher concentrations in the tubular fluid than in other parts of the body.

Clinical use of diuretics

Loop DIURETICS are widely used, potent diuretics which are useful in the treatment of any cause of systemic extracellular volume overload. They stimulate excretion of both sodium chloride and water, and are useful in stimulating water excretion in states of relative water overload.
They also act by causing increased venous capacitance, resulting in rapid clinical improvement in patients with left ventricular failure, preceding the diuresis. Unwanted effects include:
• Urate retention causing gout
• Hypokalaemia
• Hypomagnesaemia
• Decreased glucose tolerance
• Allergic tubulo-interstitial nephritis and other allergic reactions
• Myalgia (especially with bumetanide)
• Ototoxicity (due to an action on sodium pump activity in the inner earl-particularly frusemide
• Interference with excretion oflithium, resulting in toxicity In most situations there is little to choose between the drugs in this class. Ethacrynic acid is now very seldom used because of ototoxicity. Bumetanide has a better oral bioavailability, particularly in patients with severe peripheral oedema, and may have more beneficial effects on venous capacitance in left ventricular failure than frusemide. It may cause severe muscle cramps when used in high doses.

THIAZ IDE DIURETIC S are weaker diuretics than loop diuretics. They cause relatively more urate retention, glucose intolerance and hypokalaemia. They interfere with water excretion and may cause hyponatraemia, particularly if combined with amiloride or triamterene. This effect is clinically useful in diabetes insipidus. Thiazides reduce peripheral vascular resistance by mechanisms which are not completely understood but which do not appear to depend on their diuretic action, and are widely used in the treatment of essential hypertension. They are also used extensively in mild to moderate cardiac failure. Thiazides reduce calcium excretion. This effect is useful in patients with idiopathic hypercalciuria, but may cause hypercalcaemia. Numerous agents are available, with varying half-lives but little else to choose between them. Metolazone is not dependent for its action on glomerular filtration, and therefore retains its potency in renal impairment.
POTASSIUM-SPARING DIURETICS are relatively weak and are most often used in combination with thiazides or loop diuretics to prevent potassium depletion. These are of two types. Spironolactone, an aldosterone antagonist, competes with aldosterone in the collecting ducts reducing sodium absorption. Amiloride and triamterene inhibit sodium uptake in collecting duct epithelial cells and reduce renal potassium excretion.
CARBONIC ANHYDRASE INHIBITORS are relatively weak diuretics and are seldom used except in the treatment of glaucoma. They may cause metabolic acidosis and hypokalaemia.
RESISTANCE TO DIURETICS may occur as a result of:
• Poor bioavailability
• Reduced GFR, which may be due to decreased circulating volume despite oedema (e.g. nephrotic syndrome, local causes of oedema) or intrinsic renal disease
• Activation of sodium-retaining mechanisms, particularly aldosterone
Intravenous administration may establish a diuresis. High doses of loop diuretics may be required to achieve adequate concentrations in the tubule if GFR is depressed: the daily dose of frusemide must be limited to a maximum of 2 g for an adult, because of ototoxicity. Intravenous albumin solutions restore plasma oncotic pressure temporarily in the nephrotic syndrome and may allow mobilization of oedema. Combinations of different classes of diuretics are extremely helpful in patients with resistant oedema. A loop diuretic plus a thiazide inhibits two major sites of sodium reabsorption; this effect may be further potentiated by addition of a potassium-sparing agent. Metolazone in combination with a loop diuretic is particularly useful in refractory congestive cardiac failure, because its action is less dependent on glomerular filtration. However, this potent combination can cause severe electrolyte imbalance.
Both aminophylline and dopamine increase renal blood flow and may be useful in refractory cardiogenic sodium retention.
EFFECTS ON RENAL FUNCTION. All diuretics may increase blood urea concentrations by increasing urea reabsorption in the medulla. Thiazides may also promote protein breakdown. In certain situations diuretics may also decrease G FR:
• Excessive diuresis may cause volume depletion and prerenal failure.
• Diuretics may cause allergic tubulo-interstitial nephritis.
• Thiazides may directly cause a drop in G FR; the mechanism is complex.

Introduction

In health, the volume and biochemical composition of both extracellular and intracellular fluid compartments in the body remains remarkably constant. Many different disease states result in changes of control either of extracellular fluid volume, leading to clinical abnormalities such as oedema and hypotension or hypertension, or of the electrolyte composition of extracellular fluid. A sensible approach to these abnormalities is therefore essential in a wide range of clinical settings.