Diagnosis and Management of Electrolyte Emergencies

Best Practice & Research Clinical Endocrinology & Metabolism Vol. 17, No. 4, pp.
623 651, 2003

doi:10.1016/S1521-690X(03)00056-3, www.elsevier.com/locate/jnlabr/ybeem
9 Diagnosis and management of electrolyte emergencies

Eva-Maria Weiss-Guillet
Consultant
MD
Jukka Takala
MD, PhD
Head of Department
Stephan M. Jakob*
Senior Consultant
MD, PhD
Department of Intensive Care Medicine, Inselpital, University Hospital Bern, CH-3010 Bern, Switzerland
Electrolyte and uid imbalances are disorders frequently observed in critical care patients. In many instances patients are asymptomatic, but they may also present with neurological alterations, severe muscle weakness, nausea and vomiting or cardiovascular emergencies. Therefore, a pathophysiological understanding of these disorders is necessary for initiating an appropriate therapy. After a precise historyincluding drug prescriptionshas been obtained from the patient or his/her relatives, determination of the hydration status of the patient and measurement of acid base status, plasma and urine osmolality and electrolytes are the rst steps in the assessment of the disease. Once a diagnosis has been established, great attention has to be paid to the rate at which the disorder is corrected because thisif inappropriatemay cause more severe damage to the patient than the disease itself. This chapter addresses the initial diagnostic and therapeutic steps of the most common electrolyte emergencies. Key words: sodium; hyponatraemia; hypernatraemia; potassium; hypokalaemia; hyperkalaemia; calcium; hypocalcaemia; hypercalaemia; magnesium; hypomagnesaemia; hypermagnesaemia; phosphorus; hypophosphataemia; hyperphosphataemia.
SODIUM Sodium is the predominant extracellular cation. Under normal conditions it is nely maintained in the narrow range of 135 145 mmol/l despite great variations in water and salt intake. Along with its accompanying anions, it accounts for 86% of the extracellular uid osmolality, normally 285 295 mosm/kg of water, which is calculated as: 2 Na mmol=l urea nitrogen mmol=l glucose mmol=l
* Corresponding author. Tel.: 41-31-632-1176; Fax: 41-31-632-9644. E-mail address: stephan.jakob@insel.ch (S. Jakob). 1521-690X/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
624 E.-M. Weiss-Guillet et al
Table 1. Water content as a percentage of total body weight in relation to age and sex. Age 18 40 41 60 Over 60 Male (%) 60 5060 50 Female (%) 50 4050 40
In comparison with osmolality, plasma tonicity refers to those solutes that affect the transcellular distribution of water, represented by sodium salts and glucose but not urea nitrogen or ethanol, the latter two of which can permeate cell membranes. Sodium balance regulates the extracellular uid volume, water balance regulates the intracellular uid (ICF) volume, and both dene the total body water (TBW), which varies with sex and by changes in the ICF with age (Table 1). Hypothalamic osmoreceptors control the secretion of antidiuretic hormone (ADH, vasopressin) in osmoregulation1,2, and the kidneys control natriuresis through hormonal mechanisms (atrial natriuretic factor and aldosterone) in volume regulation.3,4 Hyponatraemia Usually patients with a serum sodium concentration exceeding 120 125 mmol/l are asymptomatic, but those with lower values may have symptoms, especially if the disorder has developed rapidly.5,6 The symptoms are largely related to dysfunction of the central nervous system and may include nausea and vomiting, headache, cognitive impairment, lethargy, restlessness, confusion, seizures and coma. Muscle cramps and rhabdomyolysis7 and non-cardiogenic pulmonary oedema may also be observed.8 Hypotonic hyponatraemia can be associated with hypervolaemia, euvolaemia or hypovolaemia. On the other hand, hyponatraemia can reect a hyper-, iso- or hypoosmotic state, depending on whether the osmotically active solutes are able to permeate the cell membranes.9,10 In establishing the aetiology of hyponatraemia, it is, therefore, recommended to determine the hydration status of the patient, to measure plasma and urine osmolality and to look at the urine sodium concentration5 (Figure 1). Management of hyponatraemia Hyponatraemia developing within 48 hours carries a greater risk of cerebral oedema by hypotonicity, especially in patients with a predisposition.11 However, in patients with chronic hyponatraemia, central pontine myelinolysis from osmotic demyelination is a rare but known complication. Alcoholics with malnutrition, hypokalaemic patients, burn victims, and pre-menopausal or elderly women on thiazide diuretics seem to be more endangered.5,11 There is no consensus about the optimal treatment of symptomatic hyponatraemia, with a recommended correction of 8 12 mmol/l per day.5,12,13 Osmotic demyelination has been described most often after a too rapid rise in sodium concentration (over 20 mmol/l in the rst 24 hours); it is rare at a rate below 10 12 mmol/l per day and isolated below 9 10 mmol/l, or is due to an excessive correction above 140 mmol/l.9,12 15 Neurological injury is typically delayed for 2 6
Electrolyte emergencies 625
Hyponatraemia
Iso-osmolality Isotonic hyponatraemia - 'Pseudohyponatraemia' - Hyperlipidaemia (chylomicrons, triglycerides, not cholesterol) - Paraproteinaemia
Hypo-osmolality
Hyperosmolality Hypertonic hyponatraemia - Hyperglycaemia - Mannitol, Maltose, Glycine
Hypervolaemia TBW ,TBNA+
Euvolaemia TBW ,TBNA+
Hypovolaemia TBW ,TBNA+
U[Na]+ > 20
U[Na]+ < 20
U[Na]+ > 20
U[Na]+ < 10
U[Na]+ > 20
Acute or chronic renal failure Congestive heart failure Cirrhosis Nephrotic syndrome Syndrome of inappriate ADH secretion (SIADH) Glucocorticoid deficiency Hypothyroidism Psychogenic polydypsia Stress Drugs - Desmopressin - Psychoactive agents - Anti-cancer agents - Idiosyncratic ACE inhibitor reactions, etc. Extra-renal loss Sweating Diarrhoea Vomiting Third space loss -Trauma -Burn -Peritonitis -Pancreatitis Renal salt loss Diuretics Mineralocorticoid deficiency Salt-losing nephropathy Proximal type II renal tubular acidosis Cerebral salt wasting syndrome Ketonuria Osmotic diuresis
Figure 1. Diagnostic algorithm for hyponatraemia.
days after elevation of the plasma sodium concentration.13 The symptoms are often irreversible or only partially reversible and include dysarthria, dysphagia, spastic para or quadriparesis, lethargy, coma and occasionally seizures.16 Imaging by CT scan or preferably, because it is more sensitive, magnetic resonance, may be negative for as long as 4 weeks, however.17 As the duration of hyponatraemia is often difcult to judge, it is not the laboratory values that should guide the treatment strategy but rather the presence of symptoms
Table 2. Emergency treatment in hyponatraemiasymptomatic hyponatraemia, serum sodium , 120 mmol/l (120125 mmol/l). Keep the rate of correction in any case under 812 mmol/l per day, avoid excessive correction (serum sodium . 125130 mmol/l) Use normal saline ( 154 mmol/l) sodium), strictly avoid NaCl solutions with higher concentration Seizures, agitated confusion, coma: permitted initial rate of correction 12 mmol/l per hour until clinical improvement is achieved9,11 Calculate the correcting factor for hyperglycaemia in hypertonic hyponatraemia: an increase of 5.6 mmol of glucose (100 mg/dl) is associated with a fall of 2.4 mmol/l in sodium124 Closely monitor the sodium concentration Treat the underlying illness Restoration of euvolaemia in hypovolaemia Water restriction and diuretics in hypervolaemic states Water restriction in euvolaemia Discuss V2-receptor antagonists in chronic heart failure, cirrhosis and SIADH125 127 Hormonal repletion in deciency
and their severity, the estimation that the imminent risk of hypotonicity exceeds the potential risks of osmotic demyelination9,11,18 (Table 2). Formulas that estimate the effect of 1 l of any infusate on serum sodium are helpful, although they have limitations because they do not provide information on shifts in body water.19 Change in serum Na infusate Na 2 serum Na : TBW 1 or Change in serum Na infusate Na infusate K 2 serum Na : TBW 1 Hypernatraemia The presence of severe symptoms usually requires an acute and large elevation in the plasma sodium concentration to above 158 160 mmol/l.20 Intense thirst as an important back-up defence may be absent, especially in patients with altered mental status, or with hypothalamic lesions affecting the thirst centre, and in infants and elderly persons. Non-specic symptoms such as anorexia, muscle weakness, restlessness, nausea and vomiting tend to occur early. More serious central nervous system dysfunction follows, with altered mental status, lethargy or irritability, stupor or coma. Also, acute brain shrinkage can induce vascular rupture with cerebral bleeding and subarachnoid haemorrhages.21 The cerebral adaptation response, initiated promptly to restore cell volume, explains why chronic hypernatraemia is much less likely to induce neurological symptoms.6 As hypernatraemia reects a net water loss or a hypertonic sodium gain, it invariably denotes hypertonic hyperosmolality. Often the cause is evident from the history; measurement of the urine osmolality in relation to the plasma osmolality and the urine sodium concentration help if the aetiology is unclear20,22 (Figure 2).
Hypernatraemia
Hypovolaemia TBW , TBNa+
Euvolaemia TBW , TBNa+
Hypervolaemia TBW , TBNa+
U[Na]+ > 20
U[Na]+ < 20
U[Na]+ variable
U[Na]+ > 20
Renal losses Osmotic diuresis Loop diuretics Post-obstruction Acute and chronic renal disease
Extra-renal losses Diarrhoea Lactulose Vomiting Excess sweating Fistulas Burns
Sodium gains Iatrogen - Hypertonic solutions 3% NaCl, NaHCO3, Intra-amniotic instillation for abortion - Accidental salt ingestion - Tube feedings - Antibiotics containing sodium - Hypertonic dialysis Hyperaldosteronism Cushings syndrome
Renal losses Diabetes insipidus - Central - Nephrogenic - Gestational Hypodipsia
Extra-renal losses - Fever - Hyperventilation - Mechanical ventilation
Figure 2. Diagnostic algorithm for hypernatraemia.
Management of hypernatraemia In patients with hypernatraemia that has developed over a period of hours, rapid correction improves the prognosis without the risk of convulsions and cerebral oedema.23 In those patients with hypernatraemia of longer or unknown duration, it is prudent to reduce the serum sodium concentration slowly (Table 3). The formulas, as mentioned above, are helpful for estimating the change in serum sodium concentration in relation to 1 l of an infusate.
POTASSIUM With 98% of total body potassium predominantly an intracellular cation, potassium has a serum concentration of 3.5 5.0 mmol/l. The ratio of intracellular to extracellular potassium, created by active transport, is important in determining the cellular membrane potential, and is inuenced by insulin, b-adrenergic catecholamines, thyroid
Table 3. Emergency treatment in hypernatraemiasymptomatic hypernatraemia, serum sodium . 158160 mmol/l. Acute hypernatraemia Reduction in sodium concentration by 1 mmol/hour without risk Chronic hypernatraemia Reduce the serum sodium concentration at a maximal rate of 0.5 mmol/hour20,128 until a target of 145 mmol/l is reached Hypovolaemic hypernatraemia Use isotonic saline to stabilize systemic haemodynamics Use 0.45% NaCl or 5% dextrose to correct water decit Euvolaemic or hypervolaemic states Administer hypotonic uids, preferably orally or enterally Consider hormonal and pharmacological therapy for the specic causes of the dysnatraemia Desmopressin acetate 24 mg intravenously in central diabetes insipidus Monitor the sodium concentrations closely
hormone, acidosis and alkalosis.24,25 The long-term balance is regulated by aldosterone in the kidneys.26,27 Hypokalaemia The loss of just 1% (35 mmol) of total body potassium content seriously disturbs the transcellular distribution and results in profound physiological changes. On the other hand, the presence of low levels of potassium in serum is not necessarily synonymous with whole-body potassium deciency.28 In addition, there is a wide variation in the degree to which a given reduction in the plasma potassium concentration will produce symptoms29, but the likelihood of symptoms seems to correlate with the rapidity of the decrease in serum potassium.30 In mild disorders (serum K 3.0 3.5 mmol/l), physiological effects often cannot be assessed. However, patients with underlying cardiovascular diseases31 or uncorrected pre-operative hypokalaemia , 3.5 mmol/l seem to show an increased risk in the likelihood of arrhythmia.32 With more severe hypokalaemia, the tissues most affected by potassium imbalance are muscles and renal tubular cells.30 Symptoms include generalized muscle weakness, paralytic ileus, andespecially in patients with underlying heart diseasecardiac arrhythmias with atrial tachycardias with or without block, atrioventricular dissociation, ventricular tachycardia and brillation. In the electrocardiogram, at or inverted T-waves, ST-segment depression and prominent U-waves must attract attention. In severe hypokalaemia (serum K , 2.5 mmol/l), myopathy may progress to rhabdomyolysis with myoglobinuria and acute renal failure, and at serum concentrations of , 2.0 mmol/l an ascending paralysis can develop with the risk of impairment of respiratory function.30 In the approach to treating the patient, it is helpful to have the patients history, including drug prescriptions, to check for acid base disorders and hormonal abnormalities, and to assess the renal response to hypokalaemia in measuring the potassium excretion (Figure 3).
Hypokalaemia S[K]+ < 3.5 mmol/l U[K]+ < 15 mmol/day Metabolic alkalosis Diuretics Selective chloride depletion - Vomiting - Nasogastric drainage U[K]+ > 25 - 30 mmol/day
Losses in stool Diarrhoea Laxatives Tumours - Vipoma -Villous adenoma of the colon -ZollingerEllison syndrome Jejuno-ileal bypass Enteric fistulas Malabsorption Cancer therapy Increased sweating
Metabolic alkalosis Primary hyperaldosteronism Cushings syndrome Genetic disorders - Liddles syndrome - 11-hydroxysteroid dehydrogenase deficiency - Bartters syndrome - Gitelmans syndrome Metabolic acidosis Type I distal renal tubular acidosis Type II proximal renal tubular acidosis Diabetic ketoacidosis
Drugs - Penicillin and derivatives - Aminoglycosides - Amphotericin B - Foscarnet - Cisplatin Magnesium depletion Hypothermic diuresis Leukaemia
Transcellular shifts Alkalosis Drug-induced - 2-adrenergic drugs (epinephrine,(adrenalin) decongestants,bronchodilators, theophylline) - Caffeine - Tocolytic agents - Verapamil, chloroquine and barium intoxication - Insulin overdose - Barbiturate coma Thyrotoxicosis Hypothermia Acute brain injury Treatment of severe pernicious anaemia Hypokalaemic periodic paralysis
Figure 3. Diagnostic algorithm for hypokalaemia.
Dialysis Plasmapheresis
Management of hypokalaemia Loss of potassium, either in stool or urine, and hypokalaemic periodic paralysis33 are primary indications for substitution. In the case of depletion, hypokalaemia is accompanied in nearly all disorders by loss of other components of body uids, including sodium, chloride, bicarbonate, or acid. The magnitude of the potassium decit in body stores correlates with the absence of an independent factor, causing transcellular shifts with the degree of hyokalaemia.30,34 On average, serum K decreases by 0.3 mmol/l for each 100 mmol reduction in total body stores.29,30 In acidosis, however, the average decit may be heavily underestimated and will be uncovered in the setting of the acid base disorder correction.35 While treating the underlying disease, oral potassium supplementation by potassium-rich food and tablets (ranging between 40 and 120 mmol/day) should be favoured whenever possible, because potassium enters the circulation more slowly and therefore, the administration route is safer.28,36 Strategies for minimizing the risk of potassium depletion also include minimizing the dosage of non-potassium-sparing diuretics and restricting sodium intake. Severe, symptomatic hypokalaemia not only demands aggressive intravenous substitution but also cardiovascular and close laboratory monitoring29,30 (Table 4). Potassium phosphate or preferably potassium chloride are recommended as potassium salts; potassium bicarbonate is recommended only in the specic setting of metabolic acidosis.30 Hyperkalaemia There is little agreement on what constitutes mild, moderate, or severe hyperkalaemia.37 Moreover, denitions have to take into account that the toxic effects of a given potassium concentration depend less on the baseline value than on the rate of increase in potassium concentration as well as the acid base status and the serum calcium and serum sodium concentrations.38 Frequently, the disorder is discovered as an incidental laboratory nding. Complaints in hyperkalaemia are related to impaired neuromuscular transmission, inducing cardiac and neurological symptoms. Patients may report general fatigue and weakness, paresthesias, muscular paralysis and palpitations. Electrocardiographic changes include peaked T-waves, a decrease in, or absence of, P waves, a prolonged PR interval, bundle branch blocks and a sequential progression in widening of the QRS complex to resemble a sine wave, ventricular brillation and nally asystole. In the diagnostic approach, one has to keep in mind that hyperkalaemia is rare in normal subjects because of a phenomenon, called potassium adaptation, that is mainly due to more rapid potassium excretion in the urine after a potassium load.38,39
Table 4. Emergency treatment in hypokalaemiasymptomatic hypokalaemia. Cardiovascular and close laboratory monitoring! Potassium chloride (KCl), up to 20 mmol/l per hour intravenously.129 Adapt the infusion rate to the severity of the clinical disorder 10 mmol/l KCl over 510 minutes intravenously in life threatening hypokalaemia130 Magnesium repletion89 Favour oral potassium repletion as soon as possible
The disorder is, therefore, due to decreased or impaired potassium excretion and may be drug-induced40; it is observed when large amounts of potassium are added to the extracellular space, in transmembrane shifts or in pseudohyperkalaemia, and it may be factitious. Pseudohyperkalaemia can be excluded by simultaneous measurements of potassium in plasma and in serum. If the serum potassium concentration exceeds that in the plasma by more than 0.3 mmol/l, pseudohyperkalaemia can be diagnosed39,41 (Figure 4).
Management of hyperkalaemia The initial step in the clinical management of hyperkalaemia is to determine the presence of a potentially life threatening situation that requires urgent therapy. Although severe symptoms of hyperkalaemia do not occur until the serum potassium concentration is above 7.0 mmol/l (unless the rise has been very rapid), there is substantial inter-patient variability. In addition, there is a poor correlation between ECG ndings and the concentration of serum potassium42, and potentially fatal ventricular arrhythmias and asystole may occur without warning.39 Therefore, it is recommended that any patient with ECG changes consistent with hyperkalaemia, as well as any patient with a serum potassium level greater than 6 mmol/l, should undergo immediate treatment.38,43 Taking a careful history to assess the probable aetiology of the hyperkalaemia is mandatory, and therapy should be adjusted accordingly. The three main approaches for acute treatment are antagonizing the membrane toxic effects of potassium, shifting potassium from the extracellular environment to the intracellular compartment, and promoting the renal excretion and gastrointestinal loss of potassium39,43 (Table 5). Intravenous infusion of calcium, as either calcium gluconate or calcium chloride, directly opposes the membrane actions of hyperkalaemia and is indicated in those patients who manifest signicant electrocardiographic abnormalities. Calcium gluconate and calcium chloride are both 10% solutions, but 10 ml of calcium chloride contains approximately three times more calcium than calcium gluconate and has more damaging effects on tissues upon extravasation of the solution during infusion, which is why calcium gluconate is favoured. Calcium, however, should be administered with extreme caution (in 100 ml of 5% dextrose over 20 30 minutes) in patients taking digitalis because the myocardial toxicity of digoxin is potentiated. Direct activation of the Na K-ATPase to favour transcellular shift can be achieved with intravenous insulin along with glucose to prevent the development of hypoglycaemia and by application of albuterol, a b2-selective agonist.44 In up to 40% of dialysis, patients who have not taken b-blockers, however, there is resistance to albuterol.45 A potassium-lowering effect after infusion of sodium bicarbonate can be expected in patients with metabolic acidosis. When used in patients with advanced renal failure, however, bicarbonate showed a lack of efcacy.46 Haemodialysis is used if the hyperkalaemia is severe, and if the patient has marked tissue breakdown and conservative measures to remove potassium from the body (loop and thiazide diuretics, cation exchange resin with sorbitol to prevent constipation) are ineffective. In comparison to peritoneal dialysis, the rate of potassium removal is many times faster in haemodialysis47, up to 1.2 1.5 mmol/l/hour.48 Coexisting electrolyte disturbances have to be corrected.
Hyperkalaemia S[K]+ > 5.0 mmol/l
Pseudohyperkalaemia, P[K]+ 0.3 mmol/l > S[K]+? -Leukocytosis > 70,000/cm3 -Thrombocytosis > 1,000,000/cm3 -Familial disordered cation transport on erythrocyte membranes Factitious? -Improper isolation of serum before clotting -Long, tight tourniquet time
Increased potassium input? Potassium supplements and salt substitutes Stored packed red blood cells Penicillin G potassium
Reduced potassium secretion? Renal failure Drugs - ACE inhibitors, angiotensin-II blockers, spironolactone, amiloride, triamterene, non-steroidal anti-inflammatory drugs, cyclosporine and tacrolimus, heparin, trimethroprim, pentamidine, mitomycin C Addisons disease Type IV renal tubular acidosis (hyporeninaemic hypoaldosteronism) Type II pseudohypoaldosteronism (Gordons syndrome) Hyperkalaemic type I (distal) renal tubular acidosis - Urinary tract obstruction - Sickle cell disease Ureterojejunostomy Lupus nephritis Acute transplant rejection
Increased potassium release from cells? Cell and tissue catabolism - Haemolysis - Rhabdomyolysis - Tissue damage in trauma - Tumour lysis syndrome Transcellular potassium shifts - Acidosis - Exercise - Insulin deficiency - Hyperosmolality - Mutated sodium channel in hyperkalaemic familial periodic paralysis - Drugs Beta-adrenergic blockade Digitalis overdose Succinylcholine Intravenous amino acids (lysine, arginine, epsilon-aminocaproic acid) Cyclosporine and tacrolimus Rebound after barbiturate coma Somatostatin administration
Figure 4. Diagnostic algorithm for hyperkalaemia.
CALCIUM Calcium is required for the proper functioning of many intracellular, cAMP-mediated messenger systems and most cell organelle functions, and for extracellular processes, muscle contraction, nerve conduction and blood coagulation. In calcium homeostasis,
Table 5. Emergency treatment in hyperkalaemiahyperkalaemia and ECG abnormalities, acute hyperkalaemia . 6.0 mmol/l. Continuous ECG monitoring 1020 ml of 10% calcium gluconate intravenously over 25 minutes with abnormal ECG ndings. Effect within 13 minutes, lasting for 3060 minutes Can be repeated if there is no effect within 510 minutes Use extreme caution in patients taking digitalis! 10 U of regular insulin with 50 ml 50% dextrose intravenously No dextrose necessary in hyperglycaemic patients Effect onset within 15 20 minutes and peak within 30 60 minutes, lasting for 46 hours Expected fall in plasma potassium concentration: 0.51.5 mmol/l Careful monitoring of glucose! 1020 mg of nebulized albuterol Effect onset within 30 minutes and a peak within 90 120 minutes Expected fall in plasma potassium concentration: 0.61.0 mmol/l Possible resistance in dialysis patients! 2060 ml of 8.4% NaHCO3 intravenouslynot proven unanimously Haemodialysis Furosemid 40 80 mg intravenously or ethacrynic acid 50 100 mg intravenously Sodium polystyrene sulphonate Oral dose: 20 g with 100 ml of 20% sorbitol every 46 hours Effect after 46 hours Enema: 50 g with 50 ml of 70% sorbitol plus 100 150 ml of water, retained for at least 30 60 minutes, better 2 hours Intestinal necrosis and perforation described in the post-operative patient; laxatives other than sorbitol may be preferable131!
the extracellular calcium ion concentration is kept constant within a narrow physiological range (2.1 2.6 mmol/l 8.5 10.5 mg/dl; 1 mmol/l < 4 mg/dl calcium), regulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], calcitonin, phosphate and calcium itself through complex feedback loops, acting on the renal tubular re-absorption, the intestine and bone. The calcium-sensing receptors on parathyroid cells sense a small drop in the serum calcium ion concentration and this leads to secretion of PTH.49 PTH stimulates the reabsorption of calcium in the kidney and inhibits the re-absorption of phosphate. In bone, it increases the resorption of calcium and phosphate and, again in the kidney, it enhances the hydroxylation of 25OHD3 to the activated form of 1,25(OH)2D3. 1,25(OH)2D3 increases intestinal calcium and phosphate absorption, decreases renal calcium re-absorption and activates osteoclasts in concert with PTH to promote calcium release by bone resorption. The normalized calcium concentration exerts a negative feedback on the parathyroid cells. Calcitonin inhibits osteoclastic bone resorption, may also enhance osteoblast activity, and decreases renal tubular reabsorption of calcium and phosphate. Ninety-eight percent of total body calcium is present in bone, of which about 1% appears to be exchangeable with the extracellular uid. In the extracellular uid, the physiologically active ionized calcium concentration reects about 50% of the total serum calcium (1 1.5 mmol/l); 40% is protein-bound, predominantly to albumin, and
10% is complexed with anions. PTH decreases the binding of calcium to protein and therefore, increases ionized calcium.50 A lower albumin concentration will affect the total serum calcium (in general 1 g/dl albumin binds 0.2 mmol/l or 0.8 mg/dl calcium), and acidaemia will decrease protein binding and increase the ionized fraction (an 0.1 decrease in pH will increase ionized calcium by about 0.05 mmol/l)51, but the corrections for albumin and pH are only poor substitutes for measuring ionized calcium in the clinical laboratory. Hypocalcaemia The severity of symptoms and clinical signs of hypocalcaemia correlates with the magnitude and rapidity of the fall in serum calcium and is inuenced by acid base status, hypomagnesaemia52 and sympathetic overactivity. The symptoms are primarily determined by the biologically active ionized fraction but generally do not appear unless the serum ionized calcium concentration drops below 0.7 mmol/l (2.8 mg/dl), which usually corresponds to a serum total calcium concentration of 1.8 1.875 mmol/l (7.0 7.5 mg/dl).50 In acute hypocalcaemia, neuromuscular, neuropsychiatric and cardiovascular disorders predominate. The hallmark of increased neuromuscular irritability is tetany, with both sensory and muscular dysfunction clinically.53 Patients may complain of muscle weakness and wasting, myalgia and cramps, paresthesia in hands and feet, circumoral numbness, dysphagia, and biliary and intestinal colic. In the clinical status, carpopedal spasms, Trousseaus and Chvosteks sign and hyper-reexia are typical. Laryngospasm, bronchospasm, focal or generalized seizures and papilloedema54 can be observed. Cardiac manifestations consist of decreased myocardial contractility leading to congestive heart failure with or without hypotension55, bradycardia and ventricular dysrhythmias, and a typical nding in the electrocardiogram is a prolongation in the QT interval. The neuropsychiatric symptoms include anxiety, irritability, psychosis, dementia, depression and confusion. In the diagnostic approach, biochemical tests should be based on the patients history and the physical examination. Hypocalcaemia usually suggests an insufcient action of PTH and/or vitamin D, and measurements of serum creatinine, phosphate, magnesium, 24-hour urinary calcium, PTH, 25OHD3 and 1,25(OH)2D3 are helpful (Figure 5). Management of hypocalcaemia Rational therapy depends on the acuity and severity of the hypocalcaemia as well as the underlying aetiology. In acute hypocalcaemia, patients generally develop symptoms at concentrations in ionized calcium of less than 0.7 mmol/l (2.8 mg/dl), or if the total serum calcium concentration is about 1.8 1.875 mmol/l (7.0 7.5 mg/dl), and should be treated with parenteral calcium until the symptoms cease or the calcium concentration rises above this point50,53 (Table 6). The calcium should be given slowly because of the risk of serious cardiac dysfunction, including asystole.53 Patients treated with digoxin should be monitored carefully as calcium administration potentiates the digitalis toxicity. In renal failure and symptomatic hypocalcaemia, calcium can be added to the dialysis uid. Because hypomagnesaemia diminishes the secretion of PTH as well as induces end-organ resistance to PTH52 and makes hypocalcaemia refractory to therapy, the magnesium level should be checked and corrected if it is low. In hyperphosphataemia, the rst step should be the administration of a phosphate binder to avoid soft-tissue calcium phosphate precipitations and a calcium phosphate
Hypocalcaemia Ionized Ca+ < 1.1 mmol/l S-[PO4]3- S-[PO4 ]3- Osteoblastic metastasis? (Prostate, lung, breast cancer) Hungry bone syndrome 25OHD3 1,25(OH)2D3
PTH
PTH
25OHD3 1,25(OH)2D3
25OHD3 1,25(OH)2D3
Hypoparathyroidis Postsurgical Post-irradiation Hypomagnesaiemia (very rarely hypermagnesaiemia) Congenital Autosomal dominant Autosomal recessive X-linked recessive DiGeorges syndrome Polyglandular autoimmune syndrome I Storage diseases Haemochromatosis Wilsons disease Infiltrative Granulomas Metastatic cancer HIV infection
Creatinine
Creatinine
Secondary hyperpathyroidism Vitamin D deficiency Low sun exposure Malnutrition Malabsorption Hepatobiliary disease Nephrotic syndrome Anticonvulsants phenytoin, primidone Phenobarbital Ketoconazol Rifampicin, isoniazid
Genetic disorders Pseudohypoparathyroidism Type 1a and 1b Type 2 Renal 1-alpha-hydroxylase deficiency
Decreased bone resorption Fluoride poisoning Drugs - Chemotherapeutic drugs (cisplatin, carboplatin, 5-fluorouracil with leukovorin, mithramycin, dactinomycin, cyclophosphamide, ifosfamide, doxorubicin with cytarabine) - Bisphosphonates - Calcitonin - Amphotericin B - Cimetidine - Ethanol
Calcium chelation or precipitation Hyperphosphataemia - Phosphate ingestion - Tumour lysis syndrome - Rhabdomyolysis Citrate Lactate Foscarnet Ethylene diamine tetraacetate Multifactorial pathogenesis - Sepsis/toxic-shock syndrome - Pancreatitis - Severe burns
Figure 5. Diagnostic algorithm for hypocalcaemia.
Table 6. Emergency treatment in hypocalcaemiasymptomatic acute hypocalcaemia, ionized Ca2 , 0.7 mmol/l (2.8 mg/dl). 200 mg of elemental calcium slowly (!) intravenously over 10 20 minutes (10 ml calcium gluconate 10% contains 94 mg of elemental calcium; 10 ml calcium chloride 10% contain 272 mg of elemental calcium) Monitor patients under digitalis! Calcium solutions are irritating to veins, and should not contain bicarbonate or phosphate! Infusion with 0.51.5 mg elemental calcium/kg per hour diluted in dextrose or saline over 4 6 hours Expected rise in total serum calcium 0.50.75 mmol/l (23 mg/dl) Continue with oral supplementation Check for hypomagnesaemia Consider vitamin D supplementation Correct hyperphosphataemia, not hypocalcaemia in a hypercatabolic state Treat the underlying disease
product . 5.83 mmol2/l2 (7 mg2/dl2), and to delay calcium supplementation, if ever possible, until the serum phosphate has fallen below 1.5 mmol/l (6 mg/dl).50 Patients with mild, asymptomatic or chronic hypocalcaemia should be treated with oral calcium supplements of 1000 2600 mg (250 260 mmol) daily, divided into two, three or four doses and taken between meals.56 Hypercalcaemia Again, the extent of symptoms is a function of the disorders degree and the rate of onset of the elevation in the serum calcium concentration. Mild hypercalcaemia (serum total calcium until 3.0 mmol/l [12 mg/dl]) is generally asymptomatic. In higher elevations of serum calcium concentration, most symptoms are non-specic, including fatigue, weakness, anxiety, depression, anorexia, nausea, vomiting, vague abdominal pain and constipation.57 Peptic ulcers have been described, because calcium stimulates gastric secretion.58 Severe hypercalcaemia may lead to acute pancreatitis.59 Hypercalciuria induces nephrogenic diabetes insipidus with polyuria and polydipsia, type 1 (distal) renal tubular acidosis, nephrolithiasis and nephrocalcinosis.60 There is an increased frequency of hypertension.61 Cognitive dysfunctions and personality and affective changes are seen with calcium concentrations above 3.0 mmol/l (12 mg/dl), and confusion, hallucinations, organic psychosis, somnolence, stupor and coma can be expected with serum calcium concentrations above 4 mmol/dl (16 mg/dl).62 The observed shortening in the QT interval appears not to be of any clinical importance.63 Hypercalcaemia develops when an excess of calcium derived from bone and/or intestine cannot be excreted by the kidneys. Thus, hypercalciuria is usually important and precedes the development of symptoms, except in familial hypocalciuric hypercalcaemia, an autosomal dominant disorder in which the urinary fractional calcium excretion is disturbed and often less than 1%. The major causes of hypercalcaemia, accounting for about 80 90% of cases, are hyperparathyroidism and malignancy64,65, although an increasing factor is the milk-alkali syndrome, which is provoked by taking calcium carbonate to treat osteoporosis, dyspepsia and the hyperphosphataemia in chronic renal failure.66 In malignancy, osteoclast activity and proliferation are stimulated by the secretion of humoral mediators by the tumour cells.67,68 This may include cytokines (interleukin-1, interleukin-6 and tumour necrosis
factor), prostaglandins and PTH-related peptide (PTHrP), which binds to PTH receptors, and paracrine factors (transforming growth factors). In addition, the inhibition of osteoblast activity by cytokines (interleukin-6) may have an effect. Production of 1,25(OH)2D3 by alpha-vitamin D3 hydroxylase is found in granulomatous diseases69, in Hodgkins disease and in non-Hodgkins lymphoma.70 In the clinical setting, history and physical examination are the most helpful diagnostic tools to exclude correctable non-malignant causes of hypercalcaemia. When data from the chest X-ray and laboratory are combined with the determination of calcium, phosphate, intact PTH (iPTH), vitamin D, and the fractional excretion of calcium in the urine (FECa2), the correct diagnosis is provided in up to 99% of cases65,71 FECa2 UCa2 PCr : PCa2 UCr 100 U and P refer to the urine and plasma concentrations of calcium (Ca2) and creatinine (Cr). As pseudohypercalcaemia due to hyperalbuminaemia in dehydration states or binding to paraproteins in myeloma72 should be excluded, it is worthwhile to measure ionized calcium. Rare disorders not mentioned in the algorithm are the Jansen-type metaphyseal chondrodysplasia, which is due to a mutation in the PTH and PTH-related receptor gene with normal or low levels of PTH73, and congenital lactase deciency with hypercalcaemia and medullary nephrocalcinosis74 (Figure 6). Management of hypercalcaemia As clinical manifestations of hypercalcaemia vary, the therapeutic approach should reect these differences. The goals of treatment are adequate hydration, increased urinary calcium excretion, inhibition of osteoclast activity in the bone and, when possible, treatment of the underlying cause (Table 7). In moderate (serum Ca2 . 3.0 mmol/l; . 12 mg/dl) to severe (serum Ca2 . 3.375 mmol/l; 13.5 mg/dl) hypercalcaemia50, which generally constitutes an emergency, intravascular volume depletion becomes more and more important; therefore, rehydration with crystalloid intravenous uid is the initial therapy. In increasing the glomerular ltration rate, renal calcium excretion will also increase. Once extracellular volume decits are corrected, the addition of a loop diuretic that promotes calciuresis (not a thiazide, as it enhances calcium resorption) is indicated. Medications causing or contributing to hypercalcaemia should be discontinued and immobilization avoided. Bisphosphonates (pamidronate, clodronate, etidronate, zoledronic acid, ibandronate) are an effective therapy for patients with hypercalcaemia due to increased bone resorption; they inhibit bone turnover, directly, by inhibiting the recruitment and function of osteoclasts, and indirectly, by stimulating osteoblasts to produce an inhibitor of osteoclast formation. With pamidronate, normocalcaemia is achieved in more than 90% of patients with a median duration of 4 weeks.75 It requires only a single infusion, is well tolerated, and seems to be safe in patients with renal failure. Newer, more potent compounds under study are zoledronate and ibandronate.76 Zoledronic acid has a safety prole similar to that of pamidronate and is signicantly more effective in reducing serum calcium.77 Gallium nitrate is effective in both PTHrP-mediated and non-PTHrP-mediated, cancer-related hypercalcaemia.78 Calcitonin, safe and non-toxic, is an agent with a rapid onset of action but frequently observed tachyphylaxis within 2 3 days.79 Mithramycin is rarely used, in spite of its reliability and efcacy, because of its toxicity, especially in patients with bone marrow, liver and kidney disease.
Hypercalcaemia > 3.0 mmol/l Ionized Ca2+ FECa2+ FECa2+ Milk-alkali-syndrome Increased calcium intake in chronic renal failure Thiazide diuretics Lithium toxicity Familial Addisons crisis Hypothyroidism
History Physical examination Chest X-ray
iPTH
iPTH
PTHrP Hyperparathyroidism Multiendocrinic Reoplasias (MEN) type I and type II PTH-related protein circulation in pheochromocytoma Rhabdomyolysis and acute renal failure (diuretic phase) Non-small-cell lung cancer Breast cancer Squamous cell cancers (head, neck, oesophagus) Renal cell carcinoma T-cell tumours Prostate cancers Multiple myeloma
PTHrP
25OHD3 1,25(OH)2D3 25OHD3 1,25(OH)2D3 25OHD3 1,25(OH)2D3
1,25(OH)2D3 replacement therapy in patients on dialysis Granulomatous diseases (sarcoidosis, tuberculosis, leprosy, coccidioidomycosis, histoplasmosis, berylliosis) Malignant lymphoma
Increased bone resorption - Immobilization - Pagets disease - Oestrogens and anti-oestrogens (tamoxifen) in skeletal metastasis - Vitamin A excess - Hyperthyroidism - Theophylline toxicity
Vitamin D or calcidiol intoxication

Figure 6. Diagnostic algorithm in hypercalcaemia.
Corticosteroids are the cornerstones of therapy in patients with chronic granulomatous diseases and lymphoma as they decrease calcitriol production by the activated mononuclear cells in the lung and lymph nodes.80 In patients with serum calcium concentration above 4.5 5.0 mmol/l (18 20 mg/dl) and neurological symptoms but a stable circulation, haemodialysis should be considered in addition to the abovementioned treatments.
Table 7. Emergency treatment in hypercalcaemiasymptomatic hypercalcaemia, Ca2 . 3.0 mmol/l (. 12 mg/dl). Isotonic saline, 12 l intravenously over a 1-hour period, afterwards approximately 46 l/day intravenously Consider cardiovascular status Furosemide, 20 40 mg intravenously, every 2 hours after correction of dehydration Anticipate potassium and magnesium depletion, consider water, sodium and chloride loss Measure urine volume, the urine calcium excretion and serum calcium concentration Expected fall in S[Ca]2 concentration: 0.250.75 mmol/l (2 6 mg/dl) after 24 hours Zoledronate 4 mg as a single short infusion over 515 minutes intravenously Expected effect after 2 days, median duration of action 33 days Do not repeat dose until after a minimum of 7 days or Pamidronate in 500 ml of isotonic saline as a single infusion over 12 hours intravenously 60 mg in S[Ca]2 concentrations , 3.38 mmol/l (, 13.5 mg/dl) 90 mg in higher S[Ca]2 concentrations Expected maximum effect in 24 days, median duration of action 24 weeks Do not repeat dose until after a minimum of 7 days Salmon calcitonin, 4 IU/kg subcutaneously or intramuscularly every 12 hours Additive effect when given with bisphosphonate Expected lowering in S[Ca]2 by a maximum of 0.30.5 mmol/l (12 mg/dl), beginning after 46 hours with a nadir within 1224 hours Effective only in 60 70% of patients, possible tachyphylaxis within 23 days Consider haemodialysis in S[Ca]2 concentrations . 4.5 5.0 mmol/l (18 20 mg/dl) and neurological symptoms, in patients with heart failure or renal insufciency Corticosteroids in vitamin D toxicity, multiple myeloma, lymphoma, granulomatous diseases Hydrocortisone 200300 mg intravenously for 35 days or prednisone 2040 mg/day Onset of action after 35 days
Calcimimetic drugs have potential in the future treatment of primary and secondary hyperparathyroidism in uraemia.81 They bind to the calcium-sensing receptor and suppress the release of PTH. Osteoprotegerin, shown to specically and potently inhibit osteoclast differentiation, represents a promising new option for the treatment of patients with bone metastasis.82 Non-calcaemic analogues of calcitriol, such as 22oxacalcitriol, showed suppression of neoplastic keratinocyte proliferation and PTHrP production in in vitro studies.83
MAGNESIUM Magnesium, like potassium, is a predominantly intracellular cation with stores in bone and muscle. Only 1% of the total amount of magnesium is located in the extracellular space, with a normal serum concentration of 0.74 0.95 mmol/l (1.7 2.2 mg/dl; 1 mmol/l 2.43 mg/dl). Magnesium is essential as a cofactor in numerous enzyme systems, and is involved in phosphate transfer, muscle contractility and neuronal transmission.84,85 In magnesium homeostasis, gastrointestinal absorption depends on dietary intake. The kidney resorption in the proximal tubulus is limited, and hormonal and
non-hormonal factors (PTH, calcitonin, glucagon, vasopressin, acid base changes, potassium-depletion) as well as the magnesium concentration itself inuence the uptake in Henles loop and the distal tubulus.86,87 The latter mechanism seems to be regulated by the Ca2/Mg2-sensing receptor.88 Hypomagnesaemia Magnesium depletion should be suspected in chronic diarrhoea, hypocalcaemia84, refractory hypokalaemia89 and ventricular arrythmias, particularly during myocardial ischaemia and cardiopulmonary bypass.90,91 Clinical manifestations overlap those of hypokalaemia and hypocalcaemia with corresponding neuromuscular and cardiovascular symptoms. As magnesium is vital to carbohydrate metabolism and the generation of both anaerobic and aerobic energy, and as it inuences glucose catabolism and insulin sensitivity, carbohydrate intolerance and hyperinsulinism are observed. Because deciency has been shown to cause hypertrigliceridaemia and hypercholesterolaemia as well, there is a risk for atherosclerosis.84 Bone is affected by osteoporosis and osteomalacia in chronic disorders. The diagnosis can usually be obtained from the history, as magnesium depletion is a result of either gastrointestinal or renal losses, often promoted by drugs. In less obvious cases, determination of the fractional excretion of magnesium or the measurement of the magnesium excretion in the 24-hour urine can help to distinguish between gastrointestinal and renal losses (Figure 7). FEMg2 {UMg2 PCr : 0:7 PMg2 UCr} 100 U and P refer to the urine and plasma concentrations of magnesium (Mg2) and creatinine (Cr). About 70% of PMg2 are not bound to albumin and therefore, ltered across the glomerulus (0.7 PMg2). A daily excretion of more than 4.1 12.3 mmol/day (10 30 mg/day) or a fractional excretion above 2% signals renal magnesium wasting.92,93 Management of hypomagnesaemia Symptoms of hypomagnesaemia overlap those of hypokalaemia and hypocalcaemia. As hypoxalaemia and hypocalcaemia often are associated with magnesium deciency, these deciencies should also be considered. The route of magnesium repletion depends on the severity of clinical manifestations. Correcting the hypomagnesaemia, especially by intravenous application, will partially remove the stimulus to magnesium retention in the kidney as the plasma magnesium concentration is the major regulator of active magnesium resorption in the loop of Henle.84 Thus, oral supplementation is preferred in symptom-free patients (5 20 mmol/day in divided doses as magnesium chloride or lactate). However, diarrhoea may become a dose-limiting side-effect. The indication for parenteral administration is symptomatic hypomagnesaemia with tetany or severe ventricular arrhythmia (Table 8). The underlying disease should be treated, if possible. Patients with hypomagnesaemia provoked by thiazide or loop diuretics as well as patients with persistent urinary magnesium wasting or cisplatin nephrotoxicity may benet from the prescription of a potassium-sparing diuretic such as amiloride.
S-[Mg]2+ < 0.75 mmol/l FEMg2+ FEMg 2+
Gastrointestinal losses Nasogastric suctioning Acute or chronic diarrhoea Malabsorption syndromes Steatorrhoea Short-bowel syndrome Malnutrition Intestinal fistula Acute pancreatitis Primary intestinal hypomagnesaemia (selective defect in Mg2+ adsorption)
Renal losses Alcohol Osmotic diuresis in diabetes mellitus, uraemia, after mannitol Post-obstructive diuresis, renal transplantation and recovery from acute tubular necrosis Correction of chronic systemic acidosis Hypercalcaemia and hypercalciuria Hypocalcaemia, phosphate depletion Hungry bone syndrome Hyperaldosteronism Chronic parenteral fluid nutrition and volume expanded status Diuretics Nephrotoxic drugs (aminoglycoside, cisplatin, amphotericin B, cyclosporin, foscarnet, pentamidine) Theophylline, -agonists Primary renal magnesium wasting (Gitelmans syndrome, Paracellin-1 mutation, Na-K-ATPase mutation)
Figure 7. Differential diagnosis of magnesium deciency.
Normomagnesaemic magnesium depletion has been described in patients with persistent, unexplained hypocalcaemia and/or refractory hypokalaemia and normal renal function, and it seems reasonable to try magnesium replacement.92
Hypermagnesaemia Hypermagnesaemia, as dened by a serum magnesium concentration above 0.95 mmol/l (2.2 mg/dl), is rare and usually iatrogenic after intravenous administration
Table 8. Emergency treatment in hypomagnesaemiasevere, symptomatic hypomagnesaemiaseizure or acute arrhythmia. 48 mmol magnesium intravenously over 510 minutes Infusion with 25 mmol magnesium intravenously over 1224 hours Maintainance of the treatment for 35 days in hypocalcaemic patients Aim to keep the plasma [Mg]2 over 0.4 mmol/l (1.0 mg/dl) Consider and treat associated electrolyte and acidbase disorders
of magnesium94 or after use of antacids and laxatives containing magnesium. The elderly and patients with renal insufciency are those most at risk.95 Clinical manifestations include confusion and depressed level of consciousness, muscular weakness, paralysis with absence of reexes, and respiratory depression in severe cases. Hypermagnesaemia causes vasodilatation and hypotension. The electrocardiogram shows bradycardia, complete AV-block and, in the end, asystole. The PR and QT intervals and the QRS duration are increased, while the decrease in Pwave voltage and the T-wave peaking show variable degrees. The patients complain of nausea and vomiting. Treatment should be based on discontinuation of magnesium intake, counteracting the effect of hypermagnesaemia on excitable membranes with calcium to reverse cardiac arrhythmias, respiratory depression and hypotension, and removing magnesium from the serum. In severe cases haemodialysis may be necessary.
PHOSPHATE Phosphate is the most abundant intracellular anion, and includes creatinine phosphate, adenosine monophosphates and triphosphates, among others. It is present mainly in bone (80%) and skeletal muscle (9%), and, to a lesser extent, in viscera and extracellular uid. Less than 1% of total body phosphate is present in plasma, ranging from 0.8 to 1.45 mmol/l (2.5 4.5 mg/dl; 1 mmol/l 3.125 mg/dl). The higher levels in children and the elderly reect a higher bone turnover. About 15% of the serum phosphate is protein-bound; the rest is ultraltrable. Phosphate is essential for bone mineralization, cellular structure and function, energy metabolism and genetic coding. In phosphate homeostasis, intestinal absorption (70 80% of dietary intake) occurs mainly in the duodenum and jejunum by both passive and active transport stimulated by 1,25(OH)2D3.96,97 Glucocorticoids, high magnesium diet, hypothyroidism and nonabsorbable antacids, binding dietary phosphate, inhibit the intestinal absorption of phosphate.98 In the kidney, phosphate is freely ltered. Some 80 90% of it is reabsorbed in the proximal tubule, and a small amount in the distal tubule by passive transport coupled to sodium. Two different Na PO4 transporters have been identied which are regulated mainly by phosphorus intake and PTH.96,99 Phosphate restriction and parathyroidectomy decrease urinary phosphate secretion, whereas a high intake of phosphate and PTH administration increase it.96,100,101 A very good overview concerning serum phosphate abnormalities in the emergency department has recently been published.102 Hypophosphataemia In hypophosphataemia, it is important to distinguish phosphate depletion occurring in renal wasting or in decreased intestinal resorption from a low serum phosphate concentration resulting from an enhanced re-distribution of phosphate from the extracellular uid into cells. The signicance of hypophosphataemia in the absence of phosphate depletion is not known103, but a combination of the three mechanisms is possible. Severe hypophosphataemia refers to a serum phosphate concentration less than 0.48 mmol/l (1.5 mg/dl).103 Clinically symptomatic hypophosphataemia depends upon the severity and chronicity and is observed with a plasma phosphate , 0.32 mmol/l
(1 mg/dl).84 Patients at risk are those with acute, chronic alcoholism and in alcohol withdrawal104, with chronic ingestion of phosphate-binding antacids103,105, recovering from diabetic ketoacidosis103, under total parenteral nutrition without phosphate supplementation, with extensive third-degree burns106, in the post-operative state107 109, with respiratory alkalosis, with hyperparathyroidism or with vitamin D deciency. Except for the effects on mineral metabolism (osteopenia and osteomalacia as a result of the direct effect of phosphate depletion on osteoclastic resorption of bone), the clinical manifestations can be explained by a decrease in intracellular adenosine triphosphates (ATP), leading to failure in those cell functions dependent upon energyrich phosphate compounds110, and a decrease in 2,3-diphosphoglycerate (2,3-DPG) reducing oxygen release at the tissue level with consequent tissue hypoxia.111 Peripheral neuropathy and metabolic encephalopathy with a wide range of neuropsychiatric disturbances, seizures, mental obtundation and coma are reported.84,98 Electroencephalogram abnormalities correlate with changes in the red cells 2,3-DPG.112 Cardiac arrhythmias and a depressed myocardial contractility113, leading to congestive heart failure, have been recognized in association with hypophosphataemia. Respiratory failure as a consequence of diaphragmatic weakness may explain failed weaning from the respirator in the ICU.114 In rhabdomyolysis as a complication in acute hypophosphataemia superimposed on a chronic phosphate depletion state115, the underlying deciency may be masked due to the release of phosphate from muscle breakdown. Dysphagia and ileus are common alterations of smooth muscle. Haemolysis is rare, but is described when serum phosphate concentrations fall below 0.16 mmol/l (0.5 mg/dl).116 Impaired phagocytosis and chemotaxis in white blood cells117 and platelet abnormalities118 have been demonstrated. In the clinical approach, the diagnosis is often evident from the patients history. If not obvious, the measurement of urinary phosphate excretioneither from a 24-hour urine collection or by calculation of the fractional excretion of ltered phosphate 2 (FEPO3 4 ) from a random urine specimenis helpful. Urinary phosphate excretion above 32 mmol/day (100 mg/day) or a FEPO4 above 20% proves renal phosphate loss98 (Figure 8).
2 32 32 FEPO3 4 UPO4 PCr : PPO4 UCr 100
2 U and P refer to the urine and plasma concentrations of phosphate (PO3 4 ) and creatinine (Cr).
Management of hypophosphataemia Treatment is indicated in patients with hypophosphataemia and depletion. Oral supplementation is safest and should be preferred whenever possible. With about 60 mmol of phosphate daily, divided in three or four doses, repletion may be achieved over a period of 7 10 days.98 Oral phosphate can be administered with cows milk (1 mg phosphate per ml) or in tablets of sodium or potassium phosphate. Parenteral phosphate repletion is potentially dangerous, with risk of precipitations with calcium, symptomatic hypocalcaemia and renal failure84, and should therefore, be reserved for patients with severe symptomatic hypophosphataemia. In the literature, the beginning of substitution is recommended at a phosphate concentration below 0.32 mmol/l (1 mg/dl)84, but in clinical practice, it is initiated at a phosphate
S-[PO4] 3- < 0.48 mmol/l

3- FEPO4 3- > 5% FEPO4
History Patient at risk of depletion?
Decreased intestinal absorption Severe dietary phosphate restriction Chronic antacid use Vitamin D deficiency/resistance Chronic diarrhoea Steatorrhea Malabsorption
Other losses Extensive burns, pancreatitis
Transcellular shifts Respiratory alkalosis Hormonal effects - Calcitonin - Insulin - Glucagon - -adrenergics Carbohydra te infusions (glucose, fructose, glycerol, lactate) Rapid cellular proliferation/uptake - Hungry bone syndrome - Erythropoietin therapy - Leukaemic blast crisis Re-feeding syndrome
Renal losses Chronic alcohol use Osmotic diuresis due to hyperglycaemia Acute volume expansion Carbonic anhydrase inhibition (acetazolamide) Renal transplantation Metabolic or respiratory acidosis Alkaluria Primary/secondary hyperparathyroidism Vitamin D deficiency Vitamin-D-resistant rickets (X-linked) Oncogenic osteomalacia - Prostatic carcinoma - Sclerosing haemangiomas - Angiosarcomas - Haemangiopericytomas - Non-ossifying fibromas Renal tubular dysfunction (Fanconi syndrome) - Multiple myeloma - Wilsons disease - Cystinosis - Hereditary fructose intolerance - Amyloidosis Glucocorticoid/mineralocorticoid-therapy
Figure 8. Differential diagnosis in hypophosphataemia.
concentration below 0.5 mmol/l (1.56 mg/dl). The dose should not exceed 0.08 mmol/ kg body weight (2.5 mg/kg) over 6 hours84,98, and the serum phosphate and calcium concentrations should be monitored closely (Table 9). Hyperphosphataemia Hyperphosphataemia is considered signicant when levels are greater than 1.6 mmol/l (5 mg/dl) and occurs when the phosphate load exceeds renal excretion and tissue uptake. Pseudohyperphosphataemia due to interference with the biochemical assay
Table 9. Emergency treatment in hypophosphatemiasymptomatic hypophosphataemia with S[PO4]32 , 0.5 mmol/l (1 mg/dl) and depletion. Treat the underlying disease Do not exceed 0.08 mmol phosphate/kg body weight (2.5 mg/kg) in normal saline over 6 hours intravenously Check serum phosphate and calcium every 6 hours Switch to oral replacement when a phosphate level of 0.640.8 mmol/l (22.5 mg/dl) is reached84
m may occur in patients with hyperglobulinaemia (multiple myeloma, Waldenstro macroglobulinaemia, monoclonal gammopathy), extreme hypertriglyceridaemia, in vitro haemolysis and hyperbilirubinaemia.119 Symptoms of acute hyperphosphataemia may be those of associated hyperkalaemia and hypocalcaemia. A rise in the serum calcium phosphate product above 5 6 mmol2/l2 (60 72 mg2/dl2) results in precipitating calcium, decreasing circulating calcium levels.120,121 Moreover, renal 1a-hydroxylase is inhibited by phosphate, resulting in less 1,25(OH)2D3.84 Chronic hyperphosphataemia, especially associated with hypercalcaemia, provokes extraskeletal metastatic calcications in soft tissues, blood vessels and organ parenchyma, and contributes to the development of secondary hyperparathyroidism and renal dystrophy. Management of hyperphosphataemia In the approach to therapy, it is important to distinguish acute from chronic hyperphosphataemia. In acute hyperphosphataemia, posing a life threatening condition, haemodialysis should be considered, particularly if renal function is impaired. The administration of dextrose and insulin drives phosphate into cells. Phosphate excretion can be increased by saline infusion (although this carries the risk of a further decrease in serum calcium concentration), and by administration of acetazolamide (carbonic anhydrase inhibitor) in a dose of 15 mg/kg body weight every 3 4 hours.122 In chronic hyperphosphataemia, treatment consists of reducing intestinal absorption by a decrease in protein intake and the ingestion of phosphate-binding salts of aluminium, magnesium or calcium. In renal failure, calcium salts such as calcium carbonate are preferred because of the long-term toxic effects of aluminium accumulation. Excessive calcium loading, however, should be avoided and tight controls of phosphate and the calcium phosphate product are important. Elevated levels may result in increased mortality, and there is an increasing consensus that a cut-off of , 4.58 ol2/l2 (, 55 mg2/dl2) in the calcium phosphate product seems more reasonable.123
SUMMARY Electrolyte disorders are frequent emergencies with a broad range of clinical presentations. While a crude diagnosis based on history, clinical presentation and measured electrolytes and acid base status can usually be established quickly, primary and secondary events are sometimes difcult to differentiate. Mixed electrolyte, acid base and uid disorders are frequent. Often, drugs prescribed for a variety of diseases
S[PO4]3- > 1.6 mmol/l
Pseudohyperphosphataemia Multiple myeloma Waldenstrm macroglobulinaemia Monoclonal gammopathy Extreme hypertriglyceridaemia In vitro haemolysis Hyperbilirubinaemia
Massive acute phosphate load Rhabdomyolysis Tumour-lysis syndrome (Burkitts lymphoma, Non-Hodgkins lymphoma, leukaemias) Haemolysis Malignant hyperthermia Ischaemic bowel Lactic acidosis, ketoacidosis Hyperglycaemia Vitamin D intoxication Large amounts of phosphate salts (oral/ rectal laxatives, enemas, intravenous phosphate)
Renal failure (GFR < 20 25 ml/minute) Increased tubular re-absorption Hypoparathyroidism Pseudohypoparathyroidism Vitamin D intoxication Acromegaly Thyrotoxicosis Glucocorticoid withdrawal or deficiency Tumoral calcinosis syndrome Bisphosphonates Magnesium deficiency
Figure 9. Differential diagnosis in hyperphosphataemia.
are involved. Because very different clinical conditions can result in similar electrolyte abnormalities, diagnostic algorithms are helpful. Once the underlying diagnosis of an electrolyte disorder has been established, the rate of correction of the electrolyte abnormality is crucial because correction at too rapid a rate can result in complications, which are more severe than the underlying disturbance. Correction of electrolyte disturbances almost invariably interferes with acid base and uid homoeostasis. This has to be taken into account when effects of therapeutic interventions are assessed. Knowledge of the pathophysiological background of electrolyte emergencies should help to avoid them in patients at risk (Figure 9).
Practice point practice points for recognition and management of each individual electrolyte disorder discussed in the present overview are summarized in Tables 2 9
Research agenda trials are needed to explore whether vasopressin V2-receptor antagonists can be used for the treatment of hyponatraemia of origin other than chronic heart failure and liver cirrhosis efcacy and safety of second-generation calcimimetics with an enhanced pharmacokinetic prole for the treatment of various forms of hyperparathyroidism should be further investigated in long-term, controlled studies potential new therapeutics directed against osteoclastic bone resorption are osteoprotegerin, anti-PTHrP antibodies and inhibitors of peptides, which stimulate osteoclastic bone resorption. Further investigations and clinical trials are needed to conrm the efcacy and safety of these compounds gallium nitrate warrants further investigation for the treatment of cancerrelated hypercalcaemia
REFERENCES
1. Acher R. Water homeostasis in the living: molecular organization, osmoregulatory reexes and evolution. Annales dendocrinologie (Paris) 2002; 63: 197 218. 2. Toney GM, Chen QH, Cato MJ & Stocker SD. Central osmotic regulation of sympathetic nerve activity. Acta Physiologica Scandinavica 2003; 177: 43 55. 3. Beltowski J & Wojcicka G. Regulation of renal tubular sodium transport by cardiac natriuretic peptides: two decades of research. Medical Science Monitor: Internation Journal of Experimental and Clinical Research 2002; 8: RA39RA52. 4. Cappuccio FP, Strazzullo P, Giorgione N et al. Renal tubular sodium handling and plasma atrial natriuretic peptide, renin activity and aldosterone in untreated men under normal living conditions. European Journal of Clinical Investigation 1991; 21: 40 46. * 5. Kumar S & Berl T. Sodium. Lancet 1998; 352: 220228. 6. Strange K. Regulation of solute and water balance and cell volume in the central nervous system. Journal of the American Society of Nephrology 1992; 3: 12 27. 7. Trimarchi H, Gonzalez J & Olivero J. Hyponatraemia-associated rhabdomyolysis. Nephron 1999; 82: 274 277. 8. Ayus JC, Varon J & Arieff AI. Hyponatraemia, cerebral oedema, and noncardiogenic pulmonary oedema in marathon runners. Annals of Internal Medicine 2000; 132: 711 714. * 9. Adrogue HJ & Madias NE. Hyponatraemia. New England Journal of Medicine 2000; 342: 15811589. 10. Oster JR & Singer I. Hyponatraemia, hyposmolality, and hypotonicity: tables and fables. Archives of Internal Medicine 1999; 159: 333 336. * 11. Han DS & Cho BS. Therapeutic approach to hyponatraemia. Nephron 2002; 92(supplement 1): 9 13. 12. Laureno R & Karp BI. Myelinolysis after correction of hyponatraemia. Annals of Internal Medicine 1997; 126: 57 62. 13. Sterns RH, Cappuccio JD, Silver SM & Cohen EP. Neurologic sequelae after treatment of severe hyponatraemia: a multicenter perspective. Journal of the American Society of Nephrology 1994; 4: 15221530. 14. Karp BI & Laureno R. Pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatraemia. Medicine (Baltimore) 1993; 72: 359 373. 15. Oh MS, Kim HJ & Carroll HJ. Recommendations for treatment of symptomatic hyponatraemia. Nephron 1995; 70: 143 150. 16. Menger H & Jorg J. Outcome of central pontine and extrapontine myelinolysis n 44. Journal of Neurology 1999; 246: 700705. 17. Menger H, Mackowski J, Jorg J & Cramer BM. Pontine and extra-pontine myelinolysis. Early diagnostic and prognostic value of cerebral CT and MRI. Der Nervenarzt 1998; 69: 10831090. 18. Berl T. Treating hyponatraemia: damned if we do and damned if we dont. Kidney International 1990; 37: 10061018.
648 E.-M. Weiss-Guillet et al 19. Adrogue HJ & Madias NE. Aiding uid prescription for the dysnatremias. Intensive Care Medicine 1997; 23: 309316. * 20. Adrogue HJ & Madias NE. Hypernatraemia. New England Journal of Medicine 2000; 342: 14931499. 21. McManus ML, Churchwell KB & Strange K. Regulation of cell volume in health and disease. New England Journal of Medicine 1995; 333: 12601266. 22. Kang SK, Kim W & Oh MS. Pathogenesis and treatment of hypernatraemia. Nephron 2002; 92(supplement 1): 1417. 23. Palevsky PM. Hypernatraemia. In Greenberg A (ed.) Primer on Kidney Diseases. San Diego: Academic Press, 1998, pp 64 71. 24. Clausen T & Everts ME. Regulation of the Na,K-pump in skeletal muscle. Kidney International 1989; 35: 113. * 25. Halperin ML & Kamel KS. Potassium. Lancet 1998; 352: 135140. 26. Field MJ & Giebisch GJ. Hormonal control of renal potassium excretion. Kidney International 1985; 27: 379387. 27. Giebisch G. Renal potassium transport: mechanisms and regulation. American Journal of Physiology 1998; 274: F817F833. 28. Cohn JN, Kowey PR, Whelton PK & Prisant LM. New guidelines for potassium replacement in clinical practice: a contemporary review by the National Council on Potassium in Clinical Practice. Archives of Internal Medicine 2000; 160: 2429 2436. 29. Kim GH & Han JS. Therapeutic approach to hypokalemia. Nephron 2002; 92(supplement 1): 28 32. * 30. Gennari FJ. Hypokalemia. New England Journal of Medicine 1998; 339: 451 458. 31. Schulman M & Narins RG. Hypokalemia and cardiovascular disease. American Journal of Cardiology 1990; 65: 4E9E. 32. Wahr JA, Parks R, Boisvert D et al. Preoperative serum potassium levels and perioperative outcomes in cardiac surgery patients. Multicenter study of Perioperative Ischemia Research Group. JAMA 1999; 281: 2203 2210. 33. Stedwell RE, Allen KM & Binder LS. Hypokalaemic paralyses: a review of the etiologies, pathophysiology, presentation, and therapy. American Journal of Emergency Medicine 1992; 10: 143148. 34. Sterns RH, Cox M, Feig PU & Singer I. Internal potassium balance and the control of the plasma potassium concentration. Medicine (Baltimore) 1981; 60: 339354. 35. Adrogue HJ, Lederer ED, Suki WN & Eknoyan G. Determinants of plasma potassium levels in diabetic ketoacidosis. Medicine (Baltimore) 1986; 65: 163172. 36. Sopko JA & Freeman RM. Salt substitutes as a source of potassium. JAMA 1977; 238: 608610. 37. Charytan D & Goldfarb DS. Indications for hospitalization of patients with hyperkalemia. Archives of Internal Medicine 2000; 160: 1605 1611. 38. Rose BD & Post TW. Clinical Physiology of Acid Base and Electrolyte Disorders, 5th edn. New York: McGrawHill, 2001. * 39. Kim HJ & Han SW. Therapeutic approach to hyperkalemia. Nephron 2002; 92(supplement 1): 3340. * 40. Perazella MA. Drug-induced hyperkalaemia: old culprits and new offenders. American Journal of Medicine 2000; 109: 307314. 41. Weiner ID & Wingo CS. Hyperkalemia: a potential silent killer. Journal of the American Society of Nephrology 1998; 9: 15351543. 42. Martinez-Vea A, Bardaji A, Garcia C & Oliver JA. Severe hyperkalemia with minimal electrocardiographic manifestations: a report of seven cases. Journal of Electrocardiology 1999; 32: 4549. 43. Greenberg A. Hyperkalemia: treatment options. Seminars in Nephrology 1998; 18: 4657. 44. Allon M & Copkney C. Albuterol and insulin for treatment of hyperkalaemia in hemodialysis patients. Kidney International 1990; 38: 869 872. 45. Allon M, Dunlay R & Copkney C. Nebulized albuterol for acute hyperkalemia in patients on hemodialysis. Annals of Internal Medicine 1989; 110: 426 429. 46. Allon M & Shanklin N. Effect of bicarbonate administration on plasma potassium in dialysis patients: interactions with insulin and albuterol. American Journal of Kidney Disease 1996; 28: 508514. 47. Nolph KD, Popovich RP, Ghods AJ & Twardowski Z. Determinants of low clearances of small solutes during peritoneal dialysis. Kidney International 1978; 13: 117 123. 48. Blumberg A, Weidmann P, Shaw S & Gnadinger M. Effect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure. American Journal of Medicine 1988; 85: 507512. 49. Brown EM. Physiology and pathophysiology of the extracellular calcium-sensing receptor. American Journal of Medicine 1999; 106: 238253. * 50. Bushinsky DA & Monk RD. Electrolyte quintet: calcium. Lancet 1998; 352: 306 311. 51. Broadus AE. Mineral balance and homeostasis. In Favus MJ (ed.) Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia: Lippincott/Raven, 1996, pp 5763.
Electrolyte emergencies 649 52. Graber ML. Magnesium deciency: pathophysiologic and clinical overview. American Journal of Kidney Disease 1995; 25: 973. 53. Tohme JF & Bilezikian JP. Hypocalcemic emergencies. Endocrinology & Metabolism Clinics of North America 1993; 22: 363 375. 54. Sheldon RS, Becker WJ, Hanley DA & Culver RL. Hypoparathyroidism and pseudotumor cerebri: an infrequent clinical association. Canadian Journal of Neurological Science 1987; 14: 622625. 55. Bashour T, Basha HS & Cheng TO. Hypocalcemic cardiomyopathy. Chest 1980; 78: 663 665. 56. Sutton RAL & Dirks JH. Disturbances of calcium and magnesium metabolism. In Brenner BM & Rector FC (eds) The Kidney. Philadelphia: Saunders, 1996, pp 10381085. 57. Heath III H. Clinical spectrum of primary hyperparathyroidism: evolution with changes in medical practice and technology. Journal of Bone & Mineral Research 1991; 6(supplement 2): S63S70. 58. Gardner Jr EC & Hersh T. Primary hyperparathyroidism and the gastrointestinal tract. Southern Medcial Journal 1981; 74: 197199. 59. Carnaille B, Oudar C, Pattou F et al. Pancreatitis and primary hyperparathyroidism: forty cases. Australian & New Zealand Journal of Surgery 1998; 68: 117 119. 60. Caruana RJ & Buckalew Jr VM. The syndrome of distal (type 1) renal tubular acidosis. Clinical and laboratory ndings in 58 cases. Medicine (Baltimore) 1988; 67: 84 99. 61. Campese VM. Calcium, parathyroid hormone, and blood pressure. American Journal of Hypertension 1989; 2: 34S44S. 62. Petersen P. Psychiatric disorders in primary hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism 1968; 28: 14911495. 63. Rosenqvist M, Nordenstrom J, Andersson M & Edhag OK. Cardiac conduction in patients with hypercalcaemia due to primary hyperparathyroidism. Clinical Endocrinology (Oxford) 1992; 37: 2933. 64. Casez J, Pfammatter R, Nguyen Q, et al. Diagnostic approach to hypercalcemia: relevance of parathyroid hormone and parathyroid hormone-related protein measurements. European Journal of Internal Medicine 2001; 12(4): 344349.. 65. Lafferty FW. Differential diagnosis of hypercalcaemia. Journal of Bone & Mineral Research 1991; 6(supplement 2): S51S59. 66. Beall DP & Scoeld RH. Milk-alkali syndrome associated with calcium carbonate consumption. Report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcaemia. Medicine (Baltimore) 1995; 74: 8996. 67. Esbrit P. Hypercalcaemia of malignancynew insights into an old syndrome. Clinical Laboratory 2001; 47: 6771. 68. Strewler GJ. The physiology of parathyroid hormone-related protein. New England Journal of Medicine 2000; 342: 177185. 69. Sharma OP. Hypercalcaemia in granulomatous disorders: a clinical review. Current Opinion in Pulmonary Medicine 2000; 6: 442447. 70. Seymour JF & Gagel RF. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkins disease and non-Hodgkins lymphomas. Blood 1993; 82: 1383 1394. 71. Fukagawa M & Kurokawa K. Calcium homeostasis and imbalance. Nephron 2002; 92(supplement 1): 4145. 72. van Dijk JM, Sonnenblick M, Weissberg N & Rosin A. Pseudohypercalcemia and hyperviscosity with neurological manifestations in multiple myeloma. Israel Journal of Medical Science 1986; 22: 143144. 73. Schipani E, Langman CB, Partt AM et al. Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansens metaphyseal chondrodysplasia. New England Journal of Medicine 1996; 335: 708 714. 74. Saarela T, Simila S & Koivisto M. Hypercalcaemia and nephrocalcinosis in patients with congenital lactase deciency. Journal of Pediatrics 1995; 127: 920923. 75. Body JJ. Current and future directions in medical therapy: hypercalcemia. Cancer 2000; 88(supplement): 3054 3058. 76. Body JJ. Dosing regimens and main adverse events of bisphosphonates. Seminars in Oncology 2001; 28(4 supplement 11): 4953. 77. Berenson JR. Treatment of hypercalcemia of malignancy with bisphosphonates. Seminars in Oncology 2002; 29(6 supplement 21): 1218. 78. Leyland-Jones B. Treatment of cancer-related hypercalcaemia: the role of gallium nitrate. Seminars in Oncology 2003; 30(2 supplement 5): 1319. 79. Wisneski LA. Salmon calcitonin in the acute management of hypercalcaemia. Calcied Tissue International 1990; 46(supplement): S26 S30. 80. Gardner DG. Hypercalcemia and sarcoidosisanother piece of the puzzle falls into place. American Journal of Medicine 2001; 110: 736 737.
650 E.-M. Weiss-Guillet et al 81. Urena P & Frazao JM. Calcimimetic agents: review and perspectives. Kidney International 2003; 85(supplement): 9196. 82. Sezer O, Heider U, Zavrski I et al. RANK ligand and osteoprotegerin in myeloma bone disease. Blood 2003; 101: 20942098. 83. Yu J, Papavasiliou V, Rhim J et al. Vitamin D analogs: new therapeutic agents for the treatment of squamous cancer and its associated hypercalcemia. Anticancer Drugs 1995; 6: 101 108. * 84. Weisinger JR & Bellorin-Font E. Magnesium and phosphorus. Lancet 1998; 352: 391396. 85. White RE & Hartzell HC. Magnesium ions in cardiac function. Regulator of ion channels and second messengers. Biochemical Pharmacology 1989; 38: 859 867. 86. de Roufgnac C & Quamme G. Renal magnesium handling and its hormonal control. Physiological Reviews 1994; 74: 305 322. 87. Quamme GA. Control of magnesium transport in the thick ascending limb. American Journal of Physiology 1989; 256: F197 F210. 88. Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney International 1997; 52: 11801195. 89. Whang R, Whang DD & Ryan MP. Refractory potassium repletion. A consequence of magnesium deciency. Archives of Internal Medicine 1992; 152: 40 45. 90. England MR, Gordon G, Salem M & Chernow B. Magnesium administration and dysrhythmias after cardiac surgery. A placebo-controlled, double-blind, randomized trial. JAMA 1992; 268: 2395 2402. 91. Kafka H, Langevin L & Armstrong PW. Serum magnesium and potassium in acute myocardial infarction. Inuence on ventricular arrhythmias. Archives of Internal Medicine 1987; 147: 465 469. 92. al Ghamdi SM, Cameron EC & Sutton RA. Magnesium deciency: pathophysiologic and clinical overview. American Journal of Kidney Disease 1994; 24: 737752. 93. Elisaf M, Panteli K, Theodorou J & Siamopoulos KC. Fractional excretion of magnesium in normal subjects and in patients with hypomagnesemia. Magnesium Research 1997; 10: 315320. 94. Morisaki H, Yamamoto S, Morita Y et al. Hypermagnesemia-induced cardiopulmonary arrest before induction of anesthesia for emergency cesarean section. Journal of Clinical Anesthesia 2000; 12: 224226. 95. Schelling JR. Fatal hypermagnesemia. Clinical Nephrology 2000; 53: 61 65. 96. Danisi G & Murer H. Inorganic phosphate absorption in the small intestine. In Field M & Fritzel RA (eds) Handbook of Physiology. Bethesda, MD: American Physiology Society, 1991, pp 323336. 97. Wesson LG. Homeostasis of phosphate revisited. Nephron 1997; 77: 249 266. * 98. Subramanian R & Khardori R. Severe hypophosphatemiapathophysiologic implications, clinical presentations, and treatment. Medicine 2000; 79: 18. 99. Murer H, Markovich D & Biber J. Renal and small-intestinal sodium-dependent symporters of phosphate and sulfate. Journal of Experimental Biology 1994; 196: 167 181. 100. Murer H. Cellular mechanisms in proximal tubular P(I) reabsorptionsome answers and more questions. Journal of the American Society of Nephrology 1992; 2: 1649 1665. 101. Murer H & Biber J. Cellular mechanisms in renal tubular transport of divalent inorganic anions. Nephrologie 1996; 17: 365369. * 102. Shiber GR & Mattu A. Serum phosphate abnormalities in the emergency department. The Journal of Emergency Medicine 2002; 23(4): 395400. 103. Knochel JP & Agarwal R. Hypophosphatemia and hyperphosphatemia. In Brenner BM (ed.) Brenner and Rectors the kidney. Philadelphia: WB Saunders, 1996, pp 10861133. 104. Knochel JP. Hypophosphatemia in the alcoholic. Archives of Internal Medicine 1980; 140: 613615. 105. Lotz M, Zisman E & Bartter FC. Evidence for a phosphorus-depletion syndrome in man. New England Journal of Medicine 1968; 278: 409415. 106. Lennquist S, Lindell B, Nordstrom H & Sjoberg HE. Hypophosphatemia in severe burnsprospective study. Acta Chirurgica Scandinavica 1979; 145: 16. 107. George R & Shiu MH. Hypophosphatemia after major hepatic resection. Surgery 1992; 111: 281286. 108. Goldstein J, Vincent JL, Leclerc JL et al. Hypophosphatemia after cardiothoracic surgery. Intensive Care Medicine 1985; 11: 144148. 109. Halevy J & Bulvik S. Severe hypophosphatemia in hospitalized patients. Archives of Internal Medicine 1988; 148: 153 155. 110. Fuller TJ, Carter NW, Barcenas C & Knochel JP. Reversible myopathy associated with phosphorus (P) depletion. Clinical Research 1975; 23: A535. 111. Benesch R & Benesch RE. Effect of organic phosphates from human erythrocyte on allosteric properties of hemoglobin. Biochemical and Biophysical Research Communications 1967; 26: 162. 112. Travis SF, Sugerman HJ, Ruberg RL et al. Alterations of red-cell glycolytic intermediates and oxygen transport as a consequence of hypophosphatemia in patients receiving intravenous hyperalimentation. New England Journal of Medicine 1971; 285: 763768.
Electrolyte emergencies 651 113. Oconnor LR, Wheeler WS & Bethune JE. Effect of hypophosphatemia on myocardial performance in man. New England Journal of Medicine 1977; 297: 901903. 114. Aubier M, Murciano D, Lecocguic Y et al. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. New England Journal of Medicine 1985; 313: 420 424. 115. Knochel JP. Hypophosphatemia and rhabdomyolysis. American Journal of Medicine 1992; 92: 455457. 116. Klock JC, Williams HE & Mentzer WC. Hemolytic anemia and somatic-cell dysfunction in severe hypophosphatemia. Archives of Internal Medicine 1974; 134: 360364. 117. Craddock PR, Yawata Y et al. Acquired phagocyte dysfunction resulting from parenteral hyperalimentation. New England Journal of Medicine 1974; 290: 14031407. 118. Yawata Y, Hebbel RP, Silvis S et al. Blood-cell abnormalities complicating hypophosphatemia of hyperalimentationerythrocyte and platelet ATP deciency associated with hemolytic anemia and bleeding in hyperalimented dogs. Journal of Laboratory and Clinical Medicine 1974; 84: 643 653. 119. Larner AJ. Pseudohyperphosphatemia. Clinical Biochemistry 1995; 28: 391 393. 120. Boivin MA & Kahn SR. Symptomatic hypocalcaemia from oral sodium phosphate: a report of two cases. American Journal of Gastroenterology 1998; 93: 25772579. 121. Sutters M, Gaboury CL & Bennett WM. Severe hyperphosphatemia and hypocalcemia: a dilemma in patient management. Journal of the American Society of Nephrology 1996; 7: 20562061. 122. Yamaguchi T, Sugimoto T, Imai Y et al. Successful treatment of hyperphosphatemic tumoral calcinosis with long-term acetazolamide. Bone 1995; 16(supplement 4): 247S250S. 123. Uhlig K, Sarnak MJ & Singh AK. New approaches to the treatment of calcium and phosphorus abnormalities in patients on hemodialysis. Current Opinion in Nephrology & Hypertension 2001; 10: 793 798. 124. Hillier TA, Abbott RD & Barrett EJ. Hyponatraemia: evaluating the correction factor for hyperglycemia. American Journal of Medicine 1999; 106: 399 403. 125. Gerbes AL, Gulberg V, Gines P et al. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial. Gastroenterology 2003; 124: 933939. 126. Gheorghiade M, Niazi I, Ouyang J et al. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation 2003; 107: 26902696. 127. Verbalis JG. Vasopressin V2 receptor antagonists. Journal of Molecular Endocrinology 2002; 29: 1 9. 128. Sterns RH. Hypernatremia in the intensive care unit: instant qualityjust add water. Critical Care Medicine 1999; 27: 1041 1042. 129. Kruse JA & Carlson RW. Rapid correction of hypokalemia using concentrated intravenous potassium chloride infusions. Archives of Internal Medicine 1990; 150: 613 617. 130. Wingo CSWID, Disorders of potassium balance. In Brenner BM (ed.) The Kidney. Philadelphia: Saunders, 2000, pp 9981035. 131. Rashid A & Hamilton SR. Necrosis of the gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate (Kayexalate) in sorbitol: an underrecognized condition. The American Journal of Surgical Pathology 1997; 21: 6069.

Diagnosis and Management of Electrolyte Emergencies

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Diagnosis and Management of Electrolyte Emergencies

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Best Practice & Research Clinical Endocrinology & Metabolism Vol. 17, No. 4, pp.

623 651, 2003

9 Diagnosis and management of electrolyte emergencies

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Electrolyte emergencies 625

Hyperosmolality Hypertonic hyponatraemia - Hyperglycaemia - Mannitol, Maltose, Glycine

Hypervolaemia TBW ,TBNA+

Euvolaemia TBW ,TBNA+

Hypovolaemia TBW ,TBNA+

Figure 1. Diagnostic algorithm for hyponatraemia.

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Electrolyte emergencies 627

Hypovolaemia TBW , TBNa+

Euvolaemia TBW , TBNa+

Hypervolaemia TBW , TBNa+

Extra-renal losses Diarrhoea Lactulose Vomiting Excess sweating Fistulas Burns

Renal losses Diabetes insipidus - Central - Nephrogenic - Gestational Hypodipsia

Extra-renal losses - Fever - Hyperventilation - Mechanical ventilation

Figure 2. Diagnostic algorithm for hypernatraemia.

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Electrolyte emergencies 629

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Electrolyte emergencies 631

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Hyperkalaemia S[K]+ > 5.0 mmol/l

Figure 4. Diagnostic algorithm for hyperkalaemia.

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Electrolyte emergencies 635

Genetic disorders Pseudohypoparathyroidism Type 1a and 1b Type 2 Renal 1-alpha-hydroxylase deficiency

Figure 5. Diagnostic algorithm for hypocalcaemia.

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Electrolyte emergencies 637

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History Physical examination Chest X-ray

25OHD3 1,25(OH)2D3 25OHD3 1,25(OH)2D3 25OHD3 1,25(OH)2D3

Vitamin D or calcidiol intoxication

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Electrolyte emergencies 641

S-[Mg]2+ < 0.75 mmol/l FEMg2+ FEMg 2+

Figure 7. Differential diagnosis of magnesium deciency.

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S-[PO4] 3- < 0.48 mmol/l

History Patient at risk of depletion?

Other losses Extensive burns, pancreatitis

Figure 8. Differential diagnosis in hypophosphataemia.

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S[PO4]3- > 1.6 mmol/l

Figure 9. Differential diagnosis in hyperphosphataemia.

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