The normal value for the anion gap depends on the type of biochemical analyser used and whilst the upper limit of normal has been commonly quoted as 18, the mean range with some modern analysers is only 5–12.³ In the normal resting state the serum ionic proteins account for most of the anion gap, with a lesser contribution from other ‘unmeasured’ anions such as PO₄⁻ and SO₄⁻. In pathological conditions where there is an increase in the concentration of unmeasured anions, an anion-gap metabolic acidosis results. The anions responsible for the increase in the anion gap depend on the cause of the acidosis. Lactic acid is the predominant anion in hypoxia and shock, PO₄⁻ and SO₄⁻ in renal failure, ketoacids in diabetic and alcoholic ketoacidosis, oxalic acid in ethylene glycol poisoning and formic acid in methanol poisoning.

Of the causes of an anion-gap metabolic acidosis, lactic acidosis is the most commonly encountered in the ED and is defined as a serum lactate of >2.5 mmol/L. The presence of lactic acidosis is determined by the balance between lactate production and metabolism. In the seriously ill patient, it is common for increased production and decreased metabolism to be present simultaneously. Tissue hypoxia of any cause decreases oxidative phosphorylation and results in the increased conversion of pyruvate to lactate. This commonly occurs in major haemorrhage and in the presence of severe cardiorespiratory disease. An alternative cause for increased lactate production may be the uncoupling of oxidative phosphorylation following exposure to toxins, such as cyanide, salicylates, metformin and iron. Severe thiamine deficiency may result in a marked increase in lactate production known as warm beriberi. A mild metabolic acidosis is common in acute ethanol intoxication and is associated with an elevated anion gap in 80% of cases; however, it is multifactorial in origin. Metabolism of lactic acid occurs in the liver and kidney, and is reduced when these organs are diseased or in the presence of alkalosis, hypothermia and diabetes mellitus.

It is important to realize that, in many conditions, a variety of factors may produce the acidosis, and that multiple anions may be involved in the production of an anion-gap acidosis. For example, in a patient with severe diabetic ketoacidosis, poor tissue perfusion, renal failure, increased lactic and ketoacid production, decreased SO₄⁻ and PO₄⁻ elimination and decreased lactic acid metabolism may all be present. Lactic acidosis is generally considered to be severe if serum lactate is >4 mmol/L.

Respiratory acidosis

Respiratory acidosis is defined as an elevation of the arterial partial pressure of carbon dioxide (PCO₂) and is due to alveolar hypoventilation. The effects of mild-to-moderate hypercarbia are usually confined to its effect on decreasing the alveolar partial pressure of oxygen (see alveolar gas equation). With more significant elevations, sweating, tachycardia, confusion and mydriasis occur. When the PCO₂ is greater than 80 mmHg, the level of consciousness is usually depressed. There are many possible causes of alveolar hypoventilation. Central nervous system causes include severe hypotension, drugs with respiratory depressant effects (especially opioids and sedatives), cerebrovascular events, tumours, infections, neurotrauma and metabolic derangements. Ventilatory drive may also be reduced by high partial pressures of oxygen in patients with chronic obstructive airways disease (COAD) and chronic CO₂ retention. Lesions of the spinal cord, such as tumours, infections, trauma or demyelination, may also result in alveolar hypoventilation if the lesion is above the level of C4. Lower in the afferent limb of respiratory muscle innervation, lesions of peripheral nerves such as Guillain–Barré syndrome or trauma to both phrenic nerves may also be causative. Neuromuscular junction dysfunction following postsynaptic destruction of acetylcholine receptors in myaesthenia gravis, inactivation of cholinesterase in organophosphate poisoning or the effects of spider or snake venoms and muscle relaxant drugs may also cause ventilatory failure. Aminoglycoside antibiotics may also precipitate ventilatory failure in susceptible patients. Muscular dystrophy, myopathies and severe electrolyte disorders may cause muscular weakness, and lesions of the chest wall, such as flail chest, severe kyphoscoliosis or arthritis, may also impair effective ventilation.

Pleural abnormalities, such as tension pneumothorax, massive haemothorax/pleural effusion, pulmonary conditions, such as severe fibrosis, pulmonary oedema or pneumonia, and severe airway obstruction due to severe croup, asthma or the inhalation of a foreign body are additional causes. In the intubated patient, causes such as the improper connection of the anaesthetic circuit, mechanical ventilator failure and the use of inappropriate equipment in small children should be considered.

Treatment

The treatment of respiratory acidosis is directed towards reversal of the causative factors. Ventilatory assistance is usually indicated in the presence of severe hypoxia, depressed level of consciousness or an acute elevation of PCO₂ of greater than 80 mmHg.

Alkalosis

Alkalosis is defined as a decrease in [H⁺] in the blood. Its physiological effects are the same as those of the administration of HCO₃ except that it does not cause hyperosmolarity. In very severe cases altered mental state, seizures and respiratory depression may also occur. The most common symptoms of metabolic alkalosis are related to a decrease in the concentration of ionized calcium, and are more commonly present in respiratory alkalosis due to anxiety, than from other causes. Reduced levels of ionized calcium may cause neurological symptoms such as light headedness, dizziness, chest tightness and difficulty swallowing. On examination, the respiratory rate is elevated, muscular tremor is often present and, if severe, carpopedal spasm may also be observed. Chovstek’s and Trousseau’s signs may also be present.

Metabolic alkalosis

This is caused by loss of acid from the GIT or kidney, or the addition of exogenous alkali. Upper GIT acid losses as a result of severe and prolonged vomiting are the most common cause encountered in the ED. Other causes, such as hyperaldosteronism, Bartter’s and Gitelman’s syndromes and severe hypokalaemia, result in the loss of H⁺ in the urine due to increased H⁺−K⁺ exchange in the distal convoluted tubule. Diuretics may also induce alkalosis by the same mechanism; however, the pH is rarely raised to >7.5.

Alkali may be added to the body in the form of citrate by red cell transfusion, intravenous NaHCO₃ administration or as urinary alkalinizers. The milk alkali syndrome may occur as a result of the chronic ingestion of more than 2 g of calcium salts each day (commonly in conjunction with vitamin D).⁸ The metabolic derangement known as post-hypercapnic alkalosis is caused by the decrease of a chronically elevated PCO₂ to normal levels, when relative hyperventilation occurs. In such patients the HCO₃⁻ is usually elevated as a result of chronic hypercarbia, and when the PCO₂ is acutely lowered to normal levels the appearance on blood gas analysis is that of a metabolic alkalosis, rather than that of a relative respiratory alkalosis. The most common example of this in the ED occurs in a patient who has chronic CO₂ retention with an acute exacerbation of COAD. The ingestion of strong alkali is almost never a cause of systemic alkalosis.

The causes of metabolic alkalosis can be further classified according to their response to intravenous saline (which is also related to the urinary chloride concentration). If the urinary Cl is <10 mmol/L, this is considered to be saline responsive and is usually caused by GIT losses, diuretics or the acute correction of chronic hypercapnia. If the urinary Cl is >10 mmol/L, the metabolic alkalosis is considered to be saline resistant and is usually caused by mineralocorticoid excess, oedema states or renal failure.

The treatment of metabolic alkalosis should be directed primarily towards correction of the underlying cause. In the presence of upper gastrointestinal fluid losses, intravenous fluids with high chloride content (such as 0.9% saline) should be used initially for rehydration, and correction of hypokalaemia may also be required.

Respiratory alkalosis

This is the only acid–base disturbance in which compensation may be complete. In a fully compensated chronic respiratory alkalosis the pH returns to 7.4 in approximately 4 days, and the reduction in serum HCO₃⁻ that occurs results in an increase in the anion gap.

Common causes of respiratory alkalosis in the general population include exercise, altitude-elated hypoxia and stimulation of the medullary respiratory centre by progesterones during pregnancy. In the ED setting, causes such as hypoxia, early sepsis, cerebral oedema, hepatic cirrhosis, mechanical ventilation, anxiety and salicylate, theophylline and carbon monoxide toxicity should be considered.⁹ Treatment is directed towards correction of the underlying cause and the treatment of hypokalaemia or hypocalcaemia as required. Hydrochloric acid can be administered to correct the metabolic abnormality, but it is rarely required. A dose of 1–3 mmol/kg of hydrochloric acid can be given through a central venous line at a rate of no faster than 1 mEq/min.¹⁰

Controversies

Whilst it was previously thought that, due to levels decreasing rapidly following sampling, serum lactate needed to be measured by immediate assay of arterial blood, more recent evidence has challenged this assumption with one study failing to demonstrate any significant difference in lactate levels measured at 15 min after sampling.¹¹

References

1 Natalini G, Seramondi V, Fassini P, et al. Acute respiratory acidosis does not increase plasma potassium in normokalaemic anaesthetized patients. A controlled randomized trial. European Journal of Anaesthesiology. 2001;18(6):394-400.

2 Herr RD, Swanson T. Pseudometabolic acidosis caused by underfill of vacutainer tubes. Annals of Emergency Medicine. 1992;21(2):177-180.

3 Paulson WD, Roberts WL, Lurie AA, et al. Wide variation in serum anion gap measurements by chemistry analyzers. American Journal of Clinical Pathology. 1998;110(6):735-742.

4 Cooper DJ. Bicarbonate does not improve haemodynamics in critically ill patients who have lactic acidosis: a prospective controlled clinical study. Annals of International Medicine. 1990;112:492-498.

5 Mathieu D, Neviere R, Billard V, et al. Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study. Critical Care Medicine. 1991;19(11):1352-1356.

6 Okuda Y, Adrogue HJ, Field JB, et al. Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis. Journal of Clinical Endocrinology and Metabolism. 1996;81(1):314-320.

7 Australian Resuscitation Council, Medications in cardiac arrest, February 2006.

8 Whiting SJ, Kim K, Wood R. Calcium supplementation. Journal of the American Academy of Nurse Practitioners. 1997;9(4):187-192.

9 Laffey JG, Kavanagh BP. Hypocapnia. New England Journal of Medicine. 2002;347(1):43-53.

10 Adrogue HJ, Madias NE. Management of life-threatening acid base disorders. New England Journal of Medicine. 1998;338(2):107-111.

11 Jones AE, Leonard MM, Hernandez-Nino J, et al. Determination of the effect of in vitro time, temperature, and tourniquet use on whole blood venous point-of-care lactate concentrations. Academic Emergency Medicine. 2007;14:587-591.

12.2 Electrolyte disturbances

John Pasco

ESSENTIALS

1 Sodium disorders are relatively common in hospitalized patients and elderly people.

2 The brain is most at risk from hyponatraemia because the osmotically expanded intracellular volume may induce increased intracranial pressure (hyponatraemic encephalopathy).

3 Treatment of hyponatraemia needs to be carefully individualized because of the risk of osmotic myelinolysis.

4 Hypernatraemia has a high in-hospital mortality rate, which often reflects severe associated medical conditions.

5 Although usually benign, hypokalaemia may cause cardiac arrhythmias and rhabdomyolysis. Oral replacement is usually sufficient, except where there is severe myopathy or cardiac arrhythmias.

6 Electrocardiogram changes in the presence of hyperkalaemia require urgent potassium-lowering measures and myocardial protection with calcium.

7 Management of severe hypercalcaemia includes enhancement of renal excretion of calcium, inhibition of osteoclast activity and treatment of the underlying condition.

8 Acute symptomatic hypocalcaemia should be treated with i.v. calcium.

9 Hypomagnesaemia is difficult to diagnose because its symptoms are non-specific and the serum level often does not reflect the true magnesium status of the patient. It usually exists as a ‘deficiency triad’ with hypokalaemia and hypocalcaemia.

10 Hypermagnesaemia is often iatrogenic, particularly in elderly patients or patients with renal impairment and/or chronic bowel conditions receiving magnesium therapy.

Hyponatraemia

Introduction

Hyponatraemia, defined as serum sodium concentration of less than 130 mmol/L, is a common condition. The prevalence is estimated at 2.5% in hospitalized patients, of which two-thirds develop the condition whilst in hospital.¹

Pathophysiology

Hyponatraemia is almost always associated with extracellular hypotonicity, with an excess of total body water relative to sodium. The exceptions are:

• Normotonic hyponatraemia (pseudohyponatraemia): an artefactually low sodium measurement seen in hyperlipidaemia and hyperproteinaemia. It is rarely seen now because of the routine use of direct ion-selective electrodes to measure sodium.

• Hypertonic hyponatraemia: a dilutional lowering of the measured serum sodium concentration in the presence of osmotically active substances, most commonly glucose, but also mannitol, glycerol and sorbitol. In the presence of hyperglycaemia the true serum sodium can be estimated by adjusting the measured serum sodium upwards by 1 mmol/L for each 3 mmol/L rise in glucose.

Hyponatraemia causes cellular swelling as water moves down an osmotic gradient into the intracellular fluid. Most of the symptomatology of hyponatraemia is produced in the central nervous system (CNS) by the swelling of brain cells within the rigid calvarium, causing raised intracranial pressure (hyponatraemic encephalopathy). As intracranial pressure rises, adaptive responses come into play. Initially there is a reduction of the cerebral blood and cerebrospinal fluid (CSF) pools. Later, neuronal intracellular osmolality is reduced by extrusion of potassium, followed within hours to days by organic solutes such as amino acids, phosphocreatine and myoinositol. These processes return brain volume towards normal and restore cellular function.

Patients become symptomatic when hyponatraemia develops rapidly and the adaptive responses have not had time to develop, or when the adaptive responses fail.

Aetiology and classification

Hypotonic hyponatraemia may be classified according to the volume status of the patient (hypovolaemic, euvolaemic or hypervolaemic).

Hypovolaemic hyponatraemia

These patients have deficits in both total body sodium and total body water, but the sodium deficit exceeds the water deficit. Causes include renal and extra-renal fluid losses, and are listed in Table 12.2.1. Determination of the urinary sodium concentration can differentiate these two groups. Extrarenal losses are associated with low urinary sodium concentrations (<20 mmol/L) and hyperosmolar urine. The exception is with severe vomiting and metabolic alkalosis, where bicarbonaturia obligates renal sodium loss and urinary sodium is high (>20 mmol/L), despite volume depletion. However, urinary chloride, a better indicator of extracellular fluid (ECF) volume, is low.

Table 12.2.1 Causes of hypovolaemic hyponatraemia

Renal losses (urinary [Na] >20 mmol/L)

Diuretics

Mineralocorticoid deficiency—Addison’s disease

Salt-losing nephropathy

Ketonuria

Osmotic diuresis—glucose, mannitol, urea

Bicarbonaturia with metabolic alkalosis

Extrarenal losses (urinary [Na] <20 mmol/L)

Vomiting—self-induced, gastroenteritis, pyloric obstruction

Diarrhoea

Excessive sweating

Blood loss

Third-space fluid loss—burns, pancreatitis, trauma

Drugs (ADH analogues, potentiation of ADH release, unknown mechanisms)

Psychoactive agents: phenothiazines, SSRIs, TCAs, MAOIs, ‘ecstasy’

Oxytocin

Anticancer agents: cyclophosphamine, vincristine, vinblastine

NSAIDs

Carbamazepine

SIADH

TURP, transurethral resection of prostate; ADH, antidiuretic hormone; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; MAOI, monoamic oxidase inhibitor; SIAOH, syndrome of inappropriate antidiuretic hormone secretion.

Hypervolaemic hyponatraemia

Total body water is increased in excess of total body sodium. Causes include congestive cardiac failure, hepatic cirrhosis with ascites, nephrotic syndrome and chronic renal failure.

Clinical features

In addition to the features of the underlying medical condition and alteration in extracellular volume, clinical manifestations of hyponatraemia per se usually develop when serum sodium is less than 130 mmol/L. The severity of symptoms depends partly on the absolute serum sodium concentration and partly on its rate of fall. At sodium concentrations from 125 to 130 mmol/L the symptoms are principally gastrointestinal, whereas at concentrations below 125 mmol/L the symptoms are predominantly neuropsychiatric. The principal signs and symptoms of hyponatraemia are listed in Table 12.2.3.

Table 12.2.3 Clinical manifestations of hyponatraemia

Anorexia

Nausea

Vomiting

Lethargy

Muscle cramps

Muscle weakness

Headache

Confusion/agitation

Altered conscious state

Seizures

Coma

Mild chronic ‘asymptomatic’ hyponatraemia in the elderly contributes to an increased rate of falls, probably due to impairment of attention, posture and gait mechanisms.²

Hyponatraemic encephalopathy carries a high mortality (50%) if left untreated.³ Population groups prone to hyponatraemic encephalopathy have been identified (Table 12.2.4).³^–⁸

Table 12.2.4 Patient groups at risk of hyponatraemia

Postoperative

Menstruating females

Elderly women on thiazide diuretics

Prepubescent children

Psychiatric polydipsic patients

Hypoxaemic patients

AIDS patients

Patients taking ‘Ecstasy’ (MDMA)

Endurance athletes

Premenopausal women appear at risk of developing hyponatraemic encephalopathy because oestrogen and progesterone are thought to inhibit the brain Na-K-ATPase and increase circulating levels of antidiuretic hormone (ADH).⁵

Psychogenic polydipsia refers to a condition in which kidney function is normal and dilute urine is produced, but free water intake overwhelms the kidney’s capabilities and the serum sodium falls. It occurs primarily in patients which schizophrenia or bipolar disorder. These patients develop hyponatraemia with a far lower fluid intake than is usually necessary (over 20 L of water/day in a 60-kg man, in the absence of elevated levels of ADH)^4,⁵ and it may arise through a combination of factors: antipsychotics, increased thirst perception, enhanced renal response to ADH and a mild defect in osmoregulation.

Exercise-associated hyponatraemia occurs in endurance athletes and mainly relates to the consumption of excessive fluid although non-osmotic release of vasopression and other mechanisms may be implicated.^9,¹⁰

Hyponatraemia in AIDS is common and associated with a high mortality. It may be secondary to syndrome of inappropriate ADH (SIADH), adrenal insufficiency or volume deficiency with hypotonic fluid replacement.⁴

The use of ‘Ecstasy’ at ‘rave’ parties has been associated with acute hyponatraemia.^6,⁷ This may be due to a combination of drug effect and drinking large quantities of water in an attempt to prevent dehydration.

Syndrome of inappropriate ADH secretion

This is a diagnosis of exclusion and is characterized by inappropriately concentrated urine in the setting of hypotonicity. It accounts for approximately 50% of all cases of hyponatraemia. These patients have elevated serum ADH levels without an obvious volume or osmotic stimulus. The diagnostic criteria for SIADH secretion are shown in Table 12.2.5 and conditions associated with the syndrome are listed in Table 12.2.6.

Table 12.2.5 Diagnostic criteria for SIADH

Hypotonic hyponatraemia

Urine osmolality >100 mmol/kg (i.e. inappropriately concentrated)

Urine sodium >20 mmol/mL while on a normal salt and water intake

Absence of extracellular volume depletion

Normal thyroid and adrenal function

Normal cardiac, hepatic and renal function

No diuretic use

Table 12.2.6 Conditions associated with SIADH

Neoplasms (ectopic ADH production)

Bronchogenic carcinoma

Carcinoma of the bladder

Chronic obstructive airways disease

Positive-pressure ventilation

Guillain–Barré syndrome

Stroke

Subdural or subarachnoid belled

HIV infection

Pneumocystis carinii pneumonia

Clinical investigation

Measurement of serum and urine sodium concentrations and osmolalities, in addition to clinical assessment of volume status, are essential for the assessment of hyponatraemia (Fig. 12.2.1).

Fig. 12.2.1 Assessment of hyponatraemia.

(Adapted from Walmsley R, Guerin M. Disorders of fluid and electrolyte balance. Bristol: John Wright & Sons; 1984.)

Treatment

There is ongoing controversy over the treatment of hyponatraemia because of the risk of osmotic demyelination, which is discussed below.

Treatment should be carefully individualized and depends on the presence of symptoms, the duration of the hyponatraemia and the absolute value of sodium. Ideally correction of the serum sodium should be of a sufficient pace and magnitude to reverse the manifestations of hypotonicity but not be so rapid and large as to pose a risk of the development of osmotic demyelination.¹¹ Treatment of the underlying cause is obviously essential and may correct the hyponatraemia. For hypovolaemic hyponatraemia, adequate volume replacement is essential.

Acute symptomatic hyponatraemia

Symptomatic hyponatraemia developing within 48 h is a medical emergency requiring prompt and aggressive treatment. The risks of developing osmotic demyelination are clearly outweighed by those of the encephalopathy.⁴ An immediate increase in serum sodium concentration by 8 mEq/L over 4–6 h is recommended.¹² This can be achieved by infusing hypertonic saline (3% NaCl) at a rate of 1–2 mL/kg/h, which should raise the serum sodium by 1–2 mmol/L/h. Where neurological symptoms are severe, hypertonic saline can be infused at 4–6 mL/kg/h. Indications for ceasing rapid correction of hyponatraemia are cessation of life-threatening manifestations, moderation of other symptoms or the achievement of a serum sodium of 125–130 mEq/L.¹¹ Other measures to reduce intracranial pressure, such as intubation and intermittent positive pressure ventilation (IPPV), may also be required.

Chronic symptomatic hyponatraemia

Hyponatraemia present for more than 48 h, or where the duration is unknown, presents the greatest dilemma. Care must be taken with correction of sodium as these patients are at the greatest risk of developing osmotic demyelination, yet the presence of encephalopathy mandates urgent treatment.^4,^5,¹³ Hypertonic saline can be infused so that a correction rate of no more than 1–1.5 mmol/L/h is maintained. Therapy with hypertonic saline should be discontinued when (a) the patient becomes asymptomatic, (b) the serum sodium has risen by 20 mmol/L or (c) the serum sodium reaches 120–125 mmol/L. Thereafter, slower correction with water restriction should follow. The serum sodium should never be acutely elevated to hypernatraemic or normonatraemic levels, and should not be elevated by more than 25 mmol/L during the first 48 h of therapy.

Chronic asymptomatic hyponatraemia

In this situation saline infusion is usually not required, and patients can be managed by treating the underlying disorder, discontinuing diuretic therapy or restricting fluids. Fluid restriction is inexpensive and effective but is often limited by patient non-compliance. Other treatment options include pharmacological inhibition of ADH with demeclocycline, which is limited by its neuro- and nephrotoxic side effects, or increasing solute with the use of furosemide or urea.^4,¹⁴

Osmotic myelinolysis

This is an iatrogenic disorder which develops progressively over 3–5 days following the correction of hyponatraemia. It classically produces symmetrical lesions centred on the midline of the pons and was originally described as ‘central pontine myelinolysis’. However, about 10% of cases involve extrapontine lesions. It is reported as occurring in 25% of severely hyponatraemic patients following correction of serum sodium.¹⁵ Clinically, the disorder is initially manifested by dysarthria, mutism, lethargy and affective changes, which may be mistaken for psychiatric illness. Classically, pseudo-bulbar palsy and spastic quadriparesis are observed. Recovery is usually gradual and incomplete although both fatalities and complete recovery are reported.¹⁶ Demyelination in the central pons and extrapontine sites can be demonstrated on magnetic resonance imaging (MRI) scan or at autopsy.¹⁷

It appears that the risk of developing osmotic myelinolysis is associated with severity and chronicity of hyponatraemia. It rarely occurs if the serum sodium is >120 mmol/L or where hyponatraemia has been present for <48 h. Alcoholics, malnourished patients, hypokalaemic patients, burn victims and elderly patients on thiazides seem to be most at risk of developing osmotic demyelination.^3,⁴

Both the rate and the magnitude of sodium correction appear important in the development of osmotic myelinolysis. Although there is as yet no agreed rate of correction that is regarded as completely safe, most authorities suggest that the serum sodium concentration should not rise by more than 10–14 mmol/L during any 24-h period.^4,^5,¹³

Hypernatraemia

Introduction

Hypernatraemia is much less common than hyponatraemia and may be defined as a serum sodium concentration greater than 150 mmol/L.

It is important to recognize hypernatraemia because it is usually associated with severe underlying medical illness. It is a condition of hospitalized patients, elderly and dependent people. The incidence of hypernatraemia in hospitalized patients ranges from 0.3 to 1%, with from 60 to 80% of these developing hypernatraemia after admission.¹⁴ In-hospital mortality is high (40–55%) and may be due to a combination of hypernatraemia and the severity of the underlying disease.^14,¹⁸

Pathophysiology

Hypernatraemia is a relative deficiency of total body water compared to total body sodium, thus rendering the body fluids hypertonic. The normal compensatory response includes stimulated thirst—the most important response—and renal water conservation through ADH secretion. In the absence of ADH, water intake can match urinary losses because of increased thirst, but where the thirst mechanism is absent or defective, patients become hypernatraemic even in the presence of maximal ADH stimulation. Therefore, hypernatraemia is usually seen where water intake is inadequate, i.e. in patients too young, too old or too sick to drink, with no access to water or with a defective thirst mechanism.

Extracellular hypertonicity causes a shift of water from the intracellular space until there is osmotic equilibrium. The resultant cellular contraction may explain some of the clinical features of hypernatraemia. The brain is especially at risk from shrinkage because of its vascular attachments to the calvarium. Haemorrhage may occur if these vascular attachments tear.

As with hyponatraemia, the rate and magnitude of the rise in sodium determine the severity of the symptoms, which is a reflection of the brain’s capacity to adapt to the deranged osmotic conditions.¹⁴

Aetiology and classification

The clinical causes of hypernatraemia are listed in Table 12.2.7. Population groups at particular risk of developing hypernatraemia are listed in Table 12.2.8.^4,¹⁴

Table 12.2.7 Causes of hypernatraemia

Altered perception of thirst

Osmoreceptor damage/destruction

Exogenous: trauma

Endogenous: vasculitis, carcinoma, granuloma

Idiopathic: psychogenic, head injury

Drugs

Normal perception of thirst

Poor intake

Confusion

Coma

Depression

Dysphagia

Odynophagia

Increased water loss and decreased intake

Diuresis

Renal loss

Diabetes insipidus

Chronic renal failure

Diuretic excess

GIT loss: fistulae, diarrhoea

Exogenous increase in salt intake

Table 12.2.8 Groups at particular risk for hypernatraemia

Elderly or disabled, unable to obtain oral fluids independently

Infants

Inpatients receiving:

hypertonic infusions

tube feedings

osmotic diuretics

lactulose

mechanical ventilation

Altered mental status

Uncontrolled diabetes mellitus

Underlying polyuric disorders

Hypernatraemia is classified into these categories based on extracellular volume status: hypovolaemic, hypervolaemic and euvolaemic.^4,^14,¹⁹

Hypovolaemic hypernatraemia

This occurs where there is loss of both total body water and sodium, but with a greater loss of water. Renal causes include osmotic diuresis and diuretic excess. Urinary sodium is usually >20 mmol/L. Extrarenal losses include profuse diarrhoea, sweating, burns and fistulae. Urinary sodium is usually <20 mmol/L.

Euvolaemic hypernatraemia

This is the most common form of hypernatraemia. Patients have pure water losses, with intracellular dehydration as water shifts according to the osmotic gradient. Hypernatraemia in these patients occurs only when there is no accompanying water intake, i.e. restricted access to water or a defect in thirst sensation.

Extrarenal losses are usually seen in skin losses in burns patients and via the respiratory system in respiratory infections and at high altitude. Renal water loss is usually due to diabetes insipidus—a failure of ADH production or secretion (central diabetes insipidus), or a failure of the collecting duct of the kidney to respond to ADH (nephrogenic diabetes insipidus).

Hypervolaemic hypernatraemia

This is not very common. These patients are typically extracellular volume expanded but intracellular volume depleted. It is seen following resuscitation with sodium bicarbonate, with the use of hypertonic saline solutions, with excess salt intake, in primary hyperaldosteronism and in Cushing’s syndrome.

Clinical features

In addition to the features of the underlying medical condition and alteration in extracellular volume, the clinical features of hypernatraemia per se are primarily CNS. Early symptoms are anorexia, nausea and vomiting; lethargy, hyperreflexia, confusion, seizures and coma occur later.

Treatment

The speed at which hypernatraemia is corrected should take into account the rate of development and severity of symptoms. Too rapid correction, especially in chronic hypernatraemia, can cause cerebral oedema or isotonic water intoxication. The rate of correction of chronic hypernatraemia should not exceed 0.5–0.7 mmol/L/h.

Treatment is based on clinical assessment of the patient’s volume status.

Hypovolaemic hypernatraemia

These patients require restoration of the volume deficit with isotonic saline, colloid or blood in the first instance, to prevent peripheral vascular collapse, and treatment of the underlying cause. Following this, the water deficit is corrected with 0.45% saline, 5% dextrose or oral water.^4,¹⁴

The water deficit is calculated as follows:

where Na2 = desired sodium, Na1 = actual sodium and total body water is usually 60% of the body weight. The calculated normal daily maintenance fluids should be added to the above volumes.

Euvolaemic hypernatraemia

Calculate the water deficit as above and replace the deficit and ongoing losses with 5% dextrose, 0.45% saline or oral water.^4,¹⁴ To avoid cerebral oedema, particularly in chronic hypernatraemia, 50% of the water deficit should be replaced over the first 6–12 h and the rest given slowly over 1–2 days. Serum sodium estimations should be repeated at regular intervals.

Hypervolaemic hypernatraemia

Removal of sodium is required with the use of diuretics such as furosemide and discontinuation of causative agents. Furosemide causes excretion of more water than sodium, so a hypotonic fluid such as 5% dextrose may need to be infused. In severe cases, or in renal failure, dialysis may be required.

Hypokalaemia

Introduction

Hypokalaemia may be defined as a serum potassium concentration of less than 3.5 mmol/L. It is usually considered to be severe when this is less than 2.4 mmol/L.

Pathophysiology

Hypokalaemia may develop as a consequence of potassium depletion or a shift of potassium into cells. In either case there is an increase in the ratio of intracellular to extracellular potassium concentrations. This in turn produces hyperpolarization across excitable membranes, and is responsible for the effects of hypokalaemia on striated muscle and the cardiac conducting system.

Aetiology

The causes of hypokalaemia are listed in Table 12.2.9.

Table 12.2.9 Causes of hypokalaemia

Inadequate dietary intake

Abnormal losses

Gastrointestinal

Vomiting, nasogastric aspiration

Diarrhoea, fistula loss

Villous adenoma of the colon

Laxative abuse

Renal

Mineralocorticoid excess

Conn syndrome

Bartter syndrome

Ectopic ACTH syndrome

Small cell carcinoma of the lung

Pancreatic carcinoma

Carcinoma of the thymus

Renal tubular acidosis

Magnesium deficiency

Drugs

Diuretics

Corticosteroids

Gentamicin, amphotericin B

Cisplatin

Compartmental shift

Alkalosis

Insulin

Na-K-ATPase stimulation

Sympathomimetic agents with β₂ effect

Methylxanthines

Barium poisoning

Hypothermia

Toluene intoxication

Hypokalaemic periodic paralysis

Clinical presentation

Hypokalaemia commonly produces no symptoms in otherwise healthy subjects.

Clinical features may include weakness, constipation, ileus and ventilatory failure. Myopathy may develop, with weakness of the extremities which characteristically worsens with exercise. If the hypokalaemia is severe and untreated, rhabdomyolysis may occur. Polyuria and polydipsia may result from the effect of hypokalaemia on the distal renal tubule (nephrogenic diabetes insipidus of hypokalaemia). Cardiac effects include ventricular tachycardias and atrial tachycardias, with or without block. Characteristic electrocardiogram (ECG) changes include PR prolongation, T-wave flattening and inversion and prominent U waves.²⁰

Treatment

Oral replacement is safe for asymptomatic patients and 40–60 mmol of potassium every 1–4 h is usually well tolerated.

Intravenous administration of potassium is recommended when hypokalaemia is associated with cardiac arrhythmias, familiar periodic paralysis or severe myopathy. Usual infusion rates are 10–20 mmol/h. Rates greater than 40 mmol/h are not recommended. Potassium is a slerosant and should, therefore, be given via a large peripheral or central vein. Lignocaine, heparin and hydrocortisone can be used to ameliorate symptoms. Serum potassium estimations every 1–4 h and continuous cardiac monitoring are mandatory.

Hyperkalaemia

Introduction

Hyperkalaemia, defined as a serum potassium concentration greater than 5.5 mmol/L, is less common than hypokalaemia. Moderate (6.1–6.9 mmol/L) and severe (>7 mmol/L) hyperkalaemia can have grave consequences, particularly if acute.

Pathophysiology

Two homeostatic mechanisms are responsible for maintaining potassium balance. The renal system maintains external potassium balance by excreting 90–95% of the average daily potassium load (100 mmol/day); the gut excretes the remainder. This is a relatively slow process: only half the administered load of potassium will have been excreted in the urine after 3–6 h.^21,²² The extra-renal system involves hormonal and acid–base mechanisms that rapidly translocate potassium intracellularly. This system is critical in the management of acute hyperkalaemia.

Aetiology

The causes of hyperkalaemia are listed in Table 12.2.10.

Table 12.2.10 Causes of hyperkalaemia

Pseudohyperkalaemia

Delay in separating red cells

Specimen haemolysis during or after venesection

Severe leukocytosis/thrombocytosis

Excessive intake

Exogenous: i.v. or oral KCI, massive blood transfusion

Endogenous: tissue damage

Burns

Trauma

Rhabdomyolysis

Tumour lysis

Decrease in renal excretion

Drugs

Spironolactone, triamterene, amiloride

Indometacin

Captopril, enalapril

Renal failure

Addison’s disease

Hyporeninaemic hypoaldosteronism

Compartmental shift

Acidosis

Insulin deficiency

Digoxin overdose

Succinylcholine

Fluoride poisoning

Hyperkalaemic periodic paralysis

Clinical features

The clinical features of hyperkalaemia are often non-specific. Diagnosis depends on clinical suspicion, measurement of potassium concentration in the plasma and the characteristic changes on the ECG.

Generalized muscle weakness, flaccid paralysis and paraesthesiae of the hands and feet are common, but there is poor correlation between the degree of muscle weakness and serum potassium concentration.

The ECG changes (Table 12.2.11) are characteristic, but are an insensitive method of evaluating hyperkalaemia.

Table 12.2.11 ECG changes of hyperkalaemia

Plasma potassium (mmol/L)	ECG characteristics
6–7	Tall peaked T waves (>5 mm)
7–8	QRS widening, small-amplitude P waves
8–9	Fusion of QRS complex with T wave producing sine wave
9	AV dissociation, ventricular tachycardia, ventricular fibrillation

Serum biochemistry in almost all patients with hyperkalaemia shows some degree of renal impairment and metabolic acidosis. In dialysis patients, hyperkalaemia may develop without concomitant metabolic acidosis.

Treatment

Pseudohyperkalaemia is common and, if hyperkalaemia is an unexpected finding, the serum potassium should be remeasured.

Hyperkalaemia with ECG changes requires urgent management. The priorities are as follows:^20,²³

1 Antagonize potassium cardiac toxicity:

• i.v. calcium chloride 10%, 5–10 mL or

• i.v. calcium gluconate 10%, 5–10 mL. The effects of calcium should be evident within minutes and last for 30–60 min. A calcium infusion may be required. Calcium antagonizes the myocardial membrane excitability induced by hyperkalaemia. It does not lower serum potassium levels.

2 Shift potassium into cells:

• i.v. soluble insulin, 20 U with dextrose 50 g or

• salbutamol nebulized (10–20 mg) or i.v. (0.5 mg diluted in 100 mL over 10–15 min)^20,²⁴ or

• i.v. sodium bicarbonate, 50–200 mmol.

3 Enhance potassium excretion:

• oral and/or rectal resonium A 50 g. This is a cation exchange resin; as the resin passes through the gastrointestinal tract Na and K are exchanged and the cationically modified resin is then excreted in the faeces.

• furosemide diuresis

• haemodialysis. This is usually reserved for cases of acute renal failure or end-stage renal disease. It is the most effective treatment for acutely lowering serum potassium, but there is usually a time delay in instituting dialysis and the temporizing measures outlined above must be employed in the interim.

The use of insulin and glucose is well supported in the literature.^19,²² A response is usually seen within 20–30 min, with lowering of plasma potassium by up to 1 mmol/L and reversal of ECG changes. Transient hypoglycaemia may be observed within 15 min of insulin administration. In some patients, particularly those with end-stage renal failure, late hypoglycaemia may develop. For this reason, a 10% dextrose infusion at 50 mL/h is recommended and the blood glucose should be monitored closely. The exact mechanism by which insulin translocates potassium is not known; it is thought to be stimulation of Na-K-ATPase independent of cAMP.

β₂-Agonists significantly lower plasma potassium when given intravenously or via a nebulizer.^21,²² Potassium levels are reduced by up to 1.00 mmol/L within 30 min following 10–20 mg of nebulized salbutamol. The effect is sustained for up to 2 h. Adverse effects of salbutamol administration include tachyarrhythmias and precipitation of angina in patients with coronary artery disease. Patients on non-selected β-blockers may not respond. Some patients with end-stage renal disease are also resistant to this therapy. The reason for this is unknown. Greater decreases in potassium have been observed when salbutamol treatment is combined with insulin and glucose. The additive effect is thought to be due to stimulation of Na-K-ATPase via different pathways. Transient hyperglycaemia may occur with combined therapy, but delayed hypoglycaemia does not occur.

HypocalCaemia

Introduction

A reduction in serum calcium concentration manifests principally as abnormal neuromuscular function.

Pathophysiology

Calcium is involved in smooth and skeletal muscle contraction and relaxation, platelet aggregation, neurotransmission, hepatic and adipose glycogenolysis, thermogenesis and neutrophil function. In addition, most endocrine and exocrine gland function is calcium dependent.

Aetiology

Hypocalcaemia occurs when calcium is lost from the extracellular fluid at a rate greater than can be replaced by the intestine or bone. The major cause of severe hypocalcaemia is hypoparathyroidism, as a result of surgery for thyroid disease, autoimmune destruction or from developmental abnormalities of the parathyroid glands. Other causes are listed in Table 12.2.12.

Table 12.2.12 Causes of hypocalcaemia

Factitious EDTA contamination

Hypoalbuminaemia

Decreased PTH activity

Hypoparathyroidism

Pseudohypoparathyroidism

Hypomagnesaemia

Decreased vitamin D activity

Acute pancreatitis

Hyperphosphataemia

Renal failure

Phosphate supplements

‘Hungry bone’ syndrome

Drugs

Mithramycin

Diuretics: furosemide, ethacrynic acid

Clinical features

Patients with acute hypocalcaemia are more likely to be symptomatic than those with chronic hypocalcaemia. Symptomatic hypocalcaemia is characterized by abnormal neuromuscular excitability and neurological sensations.²⁴ Early signs are perioral numbness and paraesthesia of distal extremities. Hyperreflexia, muscle cramps and carpopedal spasm follow. Chvostek’s sign (ipsilateral contraction of the facial muscles elicited by tapping the facial nerve just anterior to the ear) and Trousseau’s sign (carpopedal spasm with inflation of a blood pressure cuff for 3–5 min) are signs of neuromuscular irritability. If muscle contractions become uncontrollable tetany results, and this can prove fatal if laryngospasm occurs. Seizures may occur when there is CNS instability. Cardiovascular manifestations include hypotension, bradycardia, impaired cardiac contractility and arrhythmias. ECG evidence of hypocalcaemia includes prolonged QT interval, and possibly ST prolongation and T-wave abnormalities.

Treatment

Acute symptomatic hypocalcaemia

In the emergency situation where seizures, tetany, life-threatening hypotension or arrhythmias are present, i.v. calcium is the treatment of choice. Infusion of 15 mg/kg of elemental calcium over 4–6 h increases the total serum calcium by 0.5–0.75 mmol/L.²⁴

Administration of 10–20 mL of 10% calcium gluconate (89 mg elemental calcium per 10 mL) i.v. over 5–10 min is recommended. This should be followed by a continuous infusion because the effects of a single i.v. dose last only about 2 h. The infusion rate should be adjusted according to serial calcium measurements obtained every 2–4 h. Over-rapid infusion may cause facial flushing, headache and arrhythmias.

Calcium chloride 10% may also be used. This contains more calcium per ampoule (272 mg in 10 mL), resulting in a more rapid rise in serum calcium, but is more irritant to veins and can cause thrombophlebitis with extravasation.

Where hypcalcaemia and metabolic acidosis are present (usually in sepsis or renal failure) correction of the acidosis with bicarbonate may result in a rapid fall in ionized calcium as the number of calcium-binding sites is increased. Therefore, hypocalcaemia must be corrected before the acidosis. Bicarbonate or phosphate should not be infused with calcium because of possible precipitation of calcium salts.

Cardiac monitoring is recommended during rapid calcium administration, especially if the patient is taking digoxin, when calcium administration may precipitate digitalis toxicity.

If coexisting magnesium deficiency is suspected, or when symptoms do not improve after calcium administration, MgSO₄ 1–5 mmol i.v. over 15 min may be given.

Chronic asymptomatic hypocalcaemia

These patients are usually managed with oral calcium supplements taken between meals. Calcitriol, the active hormonal form of vitamin D, 0.5–1.5 mg daily, can also be given.

Hypercalcaemia

Introduction

The normal total serum calcium concentration is 2.15–2.55 mmol/L. Hypercalcaemia is a relatively common condition with a frequency estimated at 1:1000–1:10 000.²⁵ Although there are many causes, the most frequent are malignancy and hyperparathyroidism, with the former the most likely to cause hypercalcaemia requiring urgent attention.²⁵

Pathophysiology

Total serum calcium is made up of protein-bound calcium (40%, mostly albumin and not filterable by the kidneys), ion-bound complexes (13%, bound to anions such as bicarbonate, lactate, citrate and phosphate), and the unbound, ionized fraction (47%). The ionized fraction is the biologically active component of calcium and is closely regulated by parathyroid hormone (PTH). Total serum calcium is affected by albumin and does not necessarily reflect the level of plasma ionized calcium. Normal ionized calcium levels are 1.14–1.30 mmol/L. Protein binding in turn is influenced by extracellular fluid pH and alterations in serum albumin. Acidaemia decreases protein binding and increases the level of ionized calcium.

To correct for pH:

ionized calcium rises 0.05 mmol/L for each 0.1 decrease in pH.

To correct for serum albumin:

Corrected calcium is used for all treatment decisions except where direct measurement of ionized calcium using an ion-specific electrode is available.

Three pathophysiological mechanisms may produce hypercalcaemia:²⁵

• Accelerated osteoclastic bone resorption. This is the most common cause of severe hypercalcaemia. Osteoclasts are activated by PTH and various humoral tumour products, the most common being parathyroid hormone-related protein (PTHRP).

• Increased gastrointestinal absorption (rarely important).

• Decreased renal excretion of calcium. PTH and PTHRP stimulate renal tubular reabsorption of calcium. Hypercalcaemia per se causes polyuria by interfering with renal mechanisms for reabsorption of water and sodium. If there is inadequate fluid intake to compensate, extracellular volume depletion occurs, reducing glomerular filtration and exacerbating the hypercalcaemia.

Aetiology

The majority of cases of hypercalcaemia requiring urgent treatment are due to malignancy or, less commonly, primary hyperparathyroidism (parathyroid crisis). Malignant hypercalcaemia is most commonly seen with the solid tumours: lung and breast cancer, squamous cell carcinoma of the head and neck and cholangiocarcinoma and the haematological malignancies multiple myeloma and lymphoma.²⁴ Other causes of hypercalcaemia are uncommon (Table 12.2.13).

Table 12.2.13 Causes of hypercalcaemia

Factitious

Haemoconcentration

Postprandial

Malignancy

Primary hyperparathyroidism

Drugs

Thiazides

Vitamin D

Lithium

Vitamin A

Hormonal

Thyrotoxicosis

Acromegaly

Hypoadrenalism

Phaeochromocytoma

Granulomas

Tuberculosis

Sarcoidosis

Renal failure

Milk alkali syndrome

Immobilization

Clinical features

Hypercalcaemia causes disturbances of the gastrointestinal, cardiovascular, renal and central nervous systems.^24,²⁶

Gastrointestinal manifestations include anorexia, nausea, vomiting and constipation. Cardiovascular manifestations include hypertension and a shortened QT interval on the ECG. Renal manifestations include polyuria, polydipsia and nephrocalcinosis (rare). CNS symptoms include psychotic behaviour, seizures, apathy, cognitive difficulties, obtundation and coma. Renal elimination of digoxin is also impaired.

Moderately elevated total serum calcium (3.00–3.50 mmol/L) is usually associated with symptoms. Markedly elevated total serum calcium (>3.5 mmol/L) mandates urgent treatment regardless of symptoms.

Treatment

Irrespective of the cause, the management of hypercalcaemic crisis is the same. There are four primary treatment goals:²⁶^–²⁹

1 hydration of the patient

2 enhancement of renal excretion of calcium

3 inhibition of accelerated bone resorption

4 treatment of the underlying problem.

Hydration and diuresis

Hydration expands intravascular volume, dilutes calcium and increases calcium clearance. Infusion rates of 200–300 mL/h of 0.9% saline, depending on the degree of hypovolaemia and the ability of the patient to tolerate fluid, may be required.

Frusemide 20–40 mg i.v. every 1–4 h, or by infusion, is usually added once the patient is adequately hydrated. This inhibits the function of the ascending loop of Henle and increases the excretion of calcium and sodium. This treatment, although effective, results in a relatively modest reduction in serum calcium, and patients with severe hypercalcaemia usually require additional treatment.

Enhancement of renal excretion

Haemodialysis is the treatment of choice to rapidly decrease serum calcium in patients with heart failure or renal insufficiency.³⁰

Inhibition of bone resorption

Pharmacological inhibition of osteoclastic bone resorption is the most effective treatment for hypercalcaemia, particularly hypercalcaemia of malignancy. Bisphosphonates, analogues of pyrophosphate, are the principal agents used. They inhibit osteoclast function and hydroxyapatite crystal dissolution. Unfortunately, normalization of calcium levels may take 3–6 days, which is too slow in critically ill patients.

Etidronate given as a dose of 7.5 mg/kg daily over 4 h for 3–7 days produces normocalcaemia in most patients after a 7-day course. Adverse reactions include a transient elevation in serum creatinine, a metallic taste and transient hyperphosphataemia.

Disodium pamidronate is more potent and lowers serum calcium more rapidly and predictably than etidronate. It is currently the bisphosphonate of choice. The dose is 60 mg i.v. (in 500 mL 0.9% saline over 4 h) if serum calcium is <3.5 mmol/L, and 80 mg i.v. if serum calcium is >3.5 mmol/L. Calcium levels normalize in up to 80% of patients within 7 days, and this effect can persist for up to a month. Common adverse reactions include a mild transient elevation in temperature, local infusion site reactions, mild gastrointestinal symptoms and mild hypophosphataemia, hypokalaemia and hypomagnesaemia.

An alternative treatment to pamidronate is sodium clodronate 1500 mg in 500 mL 0.9% saline i.v. (4–6 mg/kg daily) over 4 h.

Glucocorticoids are the treatment of choice in selected patient populations where the production of 1.25-dihydroxy-vitamin D is the known mechanism for causing hypercalcaemia. Such conditions include vitamin D toxicity, sarcoidosis, other granulomatous diseases, and haematological malignancies such as multiple myeloma and lymphoma. The usual dose is 200–300 mg hydrocortisone i.v. for 3–5 days. However, the maximal calcium-lowering effect does not occur for several days, and glucocorticoids should only be regarded as adjunctive therapy in hypercalcaemic crises.

Treat the underlying disorder

The definitive treatment for hypercalcaemia is to treat the underlying disease: surgery for hyperparathyroidism and tumour-specific therapy for hypercalcaemia of malignancy.

Hypomagnesaemia

Introduction

The diagnosis of magnesium deficiency is difficult and often overlooked largely because the symptoms are non-specific and do not usually appear until the patient is severely deficient.

Serum magnesium concentration (normal range: 0.76–0.96 mmol/L) is not a sensitive indicator of magnesium deficiency as it may not truly reflect total body stores. However, it is commonly used in the absence of other reliable methods to estimate the ‘true’ magnesium status. A low serum magnesium concentration is usually present in symptomatic magnesium deficiency, but it is important to remember that it may be normal in the presence of significant intracellular depletion.

Pathophysiology

Magnesium plays a critical role in metabolism; as an enzyme co-factor, in the maintenance of cell membranes and in electrolyte balance. It is the fourth most common cation in the body and is predominantly an intracellular ion with the majority found in bone (>50%) and soft tissue. Only 0.3% of total body magnesium is located extracellularly, of which 33% is protein bound, 12% is complexed to anions such as citrate, bicarbonate and phosphate, and 55% is found in the free ionized form.

Hypokalaemia is present in 40–60% of cases of magnesium deficiency, due to renal wasting of potassium. The hypokalaemia is resistant to potassium replacement alone, as a result of a combination of factors, including impaired cellular cation pump activity and increased cellular permeability to potassium.

Hypocalcaemia is usually present at serum magnesium concentrations below 0.49 mmol/L. This may be due to impaired PTH synthesis or secretion, or to PTH resistance as a result of magnesium deficiency.

Aetiology

From an emergency medicine perspective, hypomagnesaemia is most frequently encountered in the context of acute and chronic diarrhoea, acute pancreatitis, diuretic use, in alcoholics and in diabetic ketoacidosis, secondary to glycosuria and osmotic diuresis. Table 12.2.14 details causes of magnesium deficiency.

Table 12.2.14 Causes of magnesium deficiency ³¹

Gastrointestinal losses

Acute and chronic diarrhoea

Acute pancreatitis

Severe malnutrition

Intestinal fistulae

Extensive bowel resection

Prolonged nasogastric suction

Renal losses

Osmotic diuresis – diabetes, urea, mannitol

Hypercalcaemia and hypercalciuria

Volume expanded states

Chronic parenteral fluid therapy

Drugs

ACE inhibitors

Alcohol

Aminoglycosides

Amphotericin B

Cisplatin

Ciclosporin

Diuretics – thiazide or loop

Other

Phosphate depletion

Hypomagnesaemia has been found in 30% of alcoholics admitted to hospital and results from a combination of the direct effect of alcohol on the renal tubule, which increases magnesium excretion, and associated malnutrition, diarrhoea and metabolic acidosis.³¹

Clinical features

The clinical manifestations of severe magnesium deficiency include metabolic, neurological and cardiac effects (Table 12.2.15).

Table 12.2.15 Clinical manifestations of severe magnesium deficiency³²

Cardiac effects	Metabolic effects	Neurological effects
Atrial fibrillation Atrial flutter Supraventricular tachycardia Ventricular tachycardia Torsades des pointes Coronary artery spasm Hypertension ECG changes Atherosclerosis