Diagnosis and Management of Electrolyte Emergencies

9

Diagnosis and management of electrolyte

emergencies

Eva-Maria Weiss-Guillet MD

Consultant

Jukka Takala MD, PhD

Head of Department

Stephan M. Jakob* MD, PhD

Senior Consultant

Department of Intensive Care Medicine, Inselpital, University Hospital Bern, CH-3010 Bern, Switzerland

Electrolyte and fluid imbalances are disorders frequently observed in critical care patients. Inmany instances patients are asymptomatic, but they may also present with neurologicalalterations, severe muscle weakness, nausea and vomiting or cardiovascular emergencies.Therefore, a pathophysiological understanding of these disorders is necessary for initiating anappropriate therapy. After a precise history—including drug prescriptions—has been obtainedfrom the patient or his/her relatives, determination of the hydration status of the patient andmeasurement of acid–base status, plasma and urine osmolality and electrolytes are the first stepsin the assessment of the disease. Once a diagnosis has been established, great attention has to bepaid to the rate at which the disorder is corrected because this—if inappropriate—may causemore severe damage to the patient than the disease itself. This chapter addresses the initialdiagnostic 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 finelymaintained in the narrow range of 135–145 mmol/l despite great variations in water andsalt intake. Along with its accompanying anions, it accounts for 86% of the extracellularfluid osmolality, normally 285–295 mosm/kg of water, which is calculated as:

2 £ ½Naþ� ðmmol=lÞ þ urea nitrogen ðmmol=lÞ þ glucose ðmmol=lÞ

1521-690X/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.

Best Practice & Research Clinical Endocrinology & MetabolismVol. 17, No. 4, pp. 623–651, 2003doi:10.1016/S1521-690X(03)00056-3, www.elsevier.com/locate/jnlabr/ybeem

* Corresponding author. Tel.: þ41-31-632-1176; Fax: þ41-31-632-9644.E-mail address: [email protected] (S. Jakob).

http://www.elsevier.com/locate/ybeem

In comparison with osmolality, plasma tonicity refers to those solutes that affect thetranscellular distribution of water, represented by sodium salts and glucose but not ureanitrogen or ethanol, the latter two of which can permeate cell membranes.

Sodium balance regulates the extracellular fluid volume, water balance regulates theintracellular fluid (ICF) volume, and both define the total body water (TBW), whichvaries 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 throughhormonal mechanisms (atrial natriuretic factor and aldosterone) in volume regu-lation.3,4

Hyponatraemia

Usually patients with a serum sodium concentration exceeding 120–125 mmol/l areasymptomatic, but those with lower values may have symptoms, especially if thedisorder has developed rapidly.5,6 The symptoms are largely related to dysfunction ofthe central nervous system and may include nausea and vomiting, headache, cognitiveimpairment, lethargy, restlessness, confusion, seizures and coma. Muscle cramps andrhabdomyolysis7 and non-cardiogenic pulmonary oedema may also be observed.8

Hypotonic hyponatraemia can be associated with hypervolaemia, euvolaemia orhypovolaemia. On the other hand, hyponatraemia can reflect a hyper-, iso- or hypo-osmotic state, depending on whether the osmotically active solutes are able topermeate the cell membranes.9,10 In establishing the aetiology of hyponatraemia, it is,therefore, recommended to determine the hydration status of the patient, to measureplasma 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 byhypotonicity, especially in patients with a predisposition.11 However, in patients withchronic hyponatraemia, central pontine myelinolysis from osmotic demyelination is arare but known complication. Alcoholics with malnutrition, hypokalaemic patients,burn victims, and pre-menopausal or elderly women on thiazide diuretics seem to bemore endangered.5,11 There is no consensus about the optimal treatment ofsymptomatic hyponatraemia, with a recommended correction of 8–12 mmol/l perday.5,12,13 Osmotic demyelination has been described most often after a too rapid risein sodium concentration (over 20 mmol/l in the first 24 hours); it is rare at a rate below10–12 mmol/l per day and isolated below 9–10 mmol/l, or is due to an excessivecorrection above 140 mmol/l.9,12–15 Neurological injury is typically delayed for 2–6

Table 1. Water content as a percentage of total

body weight in relation to age and sex.

Age Male (%) Female (%)

18–40 60 50

41–60 50–60 40–50

Over 60 50 40

624 E.-M. Weiss-Guillet et al

days after elevation of the plasma sodium concentration.13 The symptoms are oftenirreversible or only partially reversible and include dysarthria, dysphagia, spastic para orquadriparesis, lethargy, coma and occasionally seizures.16 Imaging by CT scan orpreferably, because it is more sensitive, magnetic resonance, may be negative for as longas 4 weeks, however.17

As the duration of hyponatraemia is often difficult to judge, it is not the laboratoryvalues that should guide the treatment strategy but rather the presence of symptoms

EuvolaemiaTBW ↑ ,TBNA+↔

Hypo-osmolality

Hyperosmolality – Hypertonic hyponatraemia - Hyperglycaemia - Mannitol, Maltose, Glycine

Hypervolaemia TBW ↑↑ ,TBNA+↑

HypovolaemiaTBW ↓ ,TBNA+↓↓

U[Na]+ > 20

Extra-renal loss Sweating Diarrhoea Vomiting Third space loss -Trauma -Burn -Peritonitis -Pancreatitis

Renal salt loss Diuretics Mineralocorticoid deficiency Salt-losing nephropathyProximal type II renal tubular acidosis Cerebral salt wasting syndrome Ketonuria Osmotic diuresis

Syndrome of inappriateADH secretion (SIADH)Glucocorticoid deficiency Hypothyroidism Psychogenic polydypsia Stress Drugs - Desmopressin - Psychoactive agents - Anti-cancer agents - Idiosyncratic ACE inhibitor reactions, etc.

Iso-osmolality - Isotonic hyponatraemia- 'Pseudohyponatraemia'- Hyperlipidaemia (chylomicrons, triglycerides, not cholesterol)- Paraproteinaemia

Hyponatraemia

Acute or chronic renal failure

Congestive heart failure Cirrhosis Nephrotic syndrome

U[Na]+ < 20 U[Na]+ < 10U[Na]+ > 20 U[Na]+ > 20

Figure 1. Diagnostic algorithm for hyponatraemia.

Electrolyte emergencies 625

and their severity, the estimation that the imminent risk of hypotonicity exceeds thepotential 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 inbody water.19

Change in serum Naþ ¼ ½infusate Naþ 2 serum Naþ� : ½TBW þ 1�

or

Change in serum Naþ ¼ ½ðinfusate Naþ þ infusate KþÞ2 serum Naþ� : ½TBW þ 1�

Hypernatraemia

The presence of severe symptoms usually requires an acute and large elevation in theplasma sodium concentration to above 158–160 mmol/l.20 Intense thirst as animportant back-up defence may be absent, especially in patients with altered mentalstatus, or with hypothalamic lesions affecting the thirst centre, and in infants and elderlypersons. Non-specific symptoms such as anorexia, muscle weakness, restlessness,nausea and vomiting tend to occur early. More serious central nervous systemdysfunction follows, with altered mental status, lethargy or irritability, stupor or coma.Also, acute brain shrinkage can induce vascular rupture with cerebral bleeding andsubarachnoid haemorrhages.21

The cerebral adaptation response, initiated promptly to restore cell volume, explainswhy chronic hypernatraemia is much less likely to induce neurological symptoms.6

As hypernatraemia reflects a net water loss or a hypertonic sodium gain, it invariablydenotes hypertonic hyperosmolality. Often the cause is evident from the history;measurement of the urine osmolality in relation to the plasma osmolality and the urinesodium concentration help if the aetiology is unclear20,22 (Figure 2).

Table 2. Emergency treatment in hyponatraemia—symptomatic hyponatraemia, serum sodium

,120 mmol/l (120–125 mmol/l).

† Keep the rate of correction in any case under 8–12 mmol/l per day, avoid excessive correction

(serum sodium . 125–130 mmol/l)

† Use normal saline ( ¼ 154 mmol/l) sodium), strictly avoid NaCl solutions with higher concentration

† Seizures, agitated confusion, coma: permitted initial rate of correction 1–2 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 deficiency


Management of hypernatraemia

In patients with hypernatraemia that has developed over a period of hours, rapidcorrection improves the prognosis without the risk of convulsions and cerebraloedema.23 In those patients with hypernatraemia of longer or unknown duration, it isprudent to reduce the serum sodium concentration slowly (Table 3). The formulas, asmentioned above, are helpful for estimating the change in serum sodium concentrationin relation to 1 l of an infusate.

POTASSIUM

With 98% of total body potassium predominantly an intracellular cation, potassium hasa serum concentration of 3.5–5.0 mmol/l. The ratio of intracellular to extracellularpotassium, created by active transport, is important in determining the cellularmembrane potential, and is influenced by insulin, b-adrenergic catecholamines, thyroid

Hypernatraemia

Hypovolaemia TBW ↓↓ , TBNa+↓

Euvolaemia TBW ↓ , TBNa+↔

Hypervolaemia TBW ↑ , TBNa+↑↑

U[Na]+ variableU[Na]+ > 20 U[Na]+ < 20

Extra-renal lossesDiarrhoea Lactulose Vomiting Excess sweatingFistulas Burns

Renal losses Osmotic diuresis Loop diuretics Post-obstruction Acute and chronic renal disease

U[Na]+ > 20

Sodium gains Iatrogen - Hypertonic solutions 3% NaCl, NaHCO3, Intra-amniotic instillation for abortion - Accidental salt ingestion - Tube feedings - Antibiotics containing sodium- Hypertonic dialysis Hyperaldosteronism Cushing’s syndrome

Renal losses Diabetes insipidus - Central - Nephrogenic - GestationalHypodipsia

Extra-renal losses - Fever - Hyperventilation - Mechanical ventilation

Figure 2. Diagnostic algorithm for hypernatraemia.


hormone, acidosis and alkalosis.24,25 The long-term balance is regulated by aldosteronein the kidneys.26,27

Hypokalaemia

The loss of just 1% (35 mmol) of total body potassium content seriously disturbs thetranscellular distribution and results in profound physiological changes. On the otherhand, the presence of low levels of potassium in serum is not necessarily synonymouswith whole-body potassium deficiency.28 In addition, there is a wide variation in thedegree to which a given reduction in the plasma potassium concentration will producesymptoms29, but the likelihood of symptoms seems to correlate with the rapidity of thedecrease in serum potassium.30

In mild disorders (serum Kþ 3.0–3.5 mmol/l), physiological effects often cannot beassessed. However, patients with underlying cardiovascular diseases31 or uncorrectedpre-operative hypokalaemia ,3.5 mmol/l seem to show an increased risk in thelikelihood of arrhythmia.32 With more severe hypokalaemia, the tissues most affectedby potassium imbalance are muscles and renal tubular cells.30 Symptoms includegeneralized muscle weakness, paralytic ileus, and—especially in patients with underlyingheart disease—cardiac arrhythmias with atrial tachycardias with or without block,atrioventricular dissociation, ventricular tachycardia and fibrillation. In the electro-cardiogram, flat or inverted T-waves, ST-segment depression and prominent U-wavesmust attract attention. In severe hypokalaemia (serum Kþ,2.5 mmol/l), myopathy mayprogress to rhabdomyolysis with myoglobinuria and acute renal failure, and at serumconcentrations of ,2.0 mmol/l an ascending paralysis can develop with the risk ofimpairment of respiratory function.30

In the approach to treating the patient, it is helpful to have the patient’s history,including drug prescriptions, to check for acid–base disorders and hormonalabnormalities, and to assess the renal response to hypokalaemia in measuring thepotassium excretion (Figure 3).

Table 3. Emergency treatment in hypernatraemia—symptomatic hypernatraemia, serum sodium

.158–160 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 deficit

† Euvolaemic or hypervolaemic states

Administer hypotonic fluids, preferably orally or enterally

† Consider hormonal and pharmacological therapy for the specific causes of the dysnatraemia

Desmopressin acetate 2–4 mg intravenously in central diabetes insipidus

Monitor the sodium concentrations closely


HypokalaemiaS[K]+ < 3.5 mmol/l

U[K]+ < 15 mmol/day

Losses in stoolDiarrhoeaLaxativesTumours - Vipoma -Villous adenoma of the colon -Zollinger–Ellison syndromeJejuno-ileal bypassEnteric fistulasMalabsorptionCancer therapy

Increased sweating

U[K]+ > 25 - 30 mmol/day

Drugs - Penicillin and derivatives - Aminoglycosides- Amphotericin B - Foscarnet - Cisplatin Magnesium depletion Hypothermic diuresis Leukaemia

Metabolic alkalosisDiuretics Selective chloride depletion- Vomiting - Nasogastric drainage

Metabolic alkalosis Primary hyperaldosteronismCushing’s syndromeGenetic disorders- Liddle’s syndrome - 11β-hydroxysteroid dehydrogenase deficiency- Bartter’s syndrome- Gitelman’s syndrome

Metabolic acidosis Type I distal renal tubular acidosisType II proximal renal tubular acidosisDiabetic ketoacidosis

DialysisPlasmapheresis

Transcellular shifts Alkalosis Drug-induced - β2-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.


Management of hypokalaemia

Loss of potassium, either in stool or urine, and hypokalaemic periodic paralysis33 areprimary indications for substitution. In the case of depletion, hypokalaemia isaccompanied in nearly all disorders by loss of other components of body fluids,including sodium, chloride, bicarbonate, or acid. The magnitude of the potassium deficitin body stores correlates with the absence of an independent factor, causingtranscellular shifts with the degree of hyokalaemia.30,34 On average, serum Kþ

decreases by 0.3 mmol/l for each 100 mmol reduction in total body stores.29,30 Inacidosis, however, the average deficit may be heavily underestimated and will beuncovered in the setting of the acid–base disorder correction.35

While treating the underlying disease, oral potassium supplementation bypotassium-rich food and tablets (ranging between 40 and 120 mmol/day) should befavoured whenever possible, because potassium enters the circulation more slowly andtherefore, the administration route is safer.28,36 Strategies for minimizing the risk ofpotassium depletion also include minimizing the dosage of non-potassium-sparingdiuretics and restricting sodium intake.

Severe, symptomatic hypokalaemia not only demands aggressive intravenoussubstitution but also cardiovascular and close laboratory monitoring29,30 (Table 4).

Potassium phosphate or preferably potassium chloride are recommended aspotassium salts; potassium bicarbonate is recommended only in the specific setting ofmetabolic acidosis.30

Hyperkalaemia

There is little agreement on what constitutes mild, moderate, or severe hyperkalae-mia.37 Moreover, definitions have to take into account that the toxic effects of a givenpotassium concentration depend less on the baseline value than on the rate of increasein potassium concentration as well as the acid–base status and the serum calcium andserum sodium concentrations.38 Frequently, the disorder is discovered as an incidentallaboratory finding. Complaints in hyperkalaemia are related to impaired neuromusculartransmission, inducing cardiac and neurological symptoms. Patients may report generalfatigue and weakness, paresthesias, muscular paralysis and palpitations. Electrocardio-graphic changes include peaked T-waves, a decrease in, or absence of, P waves, aprolonged PR interval, bundle branch blocks and a sequential progression in widening ofthe QRS complex to resemble a sine wave, ventricular fibrillation and finally asystole.

In the diagnostic approach, one has to keep in mind that hyperkalaemia is rare innormal subjects because of a phenomenon, called potassium adaptation, that is mainlydue to more rapid potassium excretion in the urine after a potassium load.38,39

Table 4. Emergency treatment in hypokalaemia—symptomatic 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 5–10 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 maybe drug-induced40; it is observed when large amounts of potassium are added to theextracellular space, in transmembrane shifts or in pseudohyperkalaemia, and it may befactitious. Pseudohyperkalaemia can be excluded by simultaneous measurements ofpotassium in plasma and in serum. If the serum potassium concentration exceeds that inthe 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 thepresence of a potentially life threatening situation that requires urgent therapy.Although severe symptoms of hyperkalaemia do not occur until the serum potassiumconcentration is above 7.0 mmol/l (unless the rise has been very rapid), there issubstantial inter-patient variability. In addition, there is a poor correlation between ECGfindings and the concentration of serum potassium42, and potentially fatal ventriculararrhythmias and asystole may occur without warning.39 Therefore, it is recommendedthat any patient with ECG changes consistent with hyperkalaemia, as well as any patientwith a serum potassium level greater than 6 mmol/l, should undergo immediatetreatment.38,43 Taking a careful history to assess the probable aetiology of thehyperkalaemia is mandatory, and therapy should be adjusted accordingly.

The three main approaches for acute treatment are antagonizing the membranetoxic effects of potassium, shifting potassium from the extracellular environment to theintracellular compartment, and promoting the renal excretion and gastrointestinal lossof potassium39,43 (Table 5). Intravenous infusion of calcium, as either calcium gluconateor calcium chloride, directly opposes the membrane actions of hyperkalaemia and isindicated in those patients who manifest significant electrocardiographic abnormalities.Calcium gluconate and calcium chloride are both 10% solutions, but 10 ml of calciumchloride contains approximately three times more calcium than calcium gluconate andhas more damaging effects on tissues upon extravasation of the solution during infusion,which is why calcium gluconate is favoured. Calcium, however, should be administeredwith extreme caution (in 100 ml of 5% dextrose over 20–30 minutes) in patients takingdigitalis because the myocardial toxicity of digoxin is potentiated.

Direct activation of the Na–K-ATPase to favour transcellular shift can be achievedwith intravenous insulin along with glucose to prevent the development ofhypoglycaemia 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 toalbuterol.45

A potassium-lowering effect after infusion of sodium bicarbonate can be expected inpatients with metabolic acidosis. When used in patients with advanced renal failure,however, bicarbonate showed a lack of efficacy.46

Haemodialysis is used if the hyperkalaemia is severe, and if the patient has markedtissue breakdown and conservative measures to remove potassium from the body(loop and thiazide diuretics, cation exchange resin with sorbitol to preventconstipation) are ineffective. In comparison to peritoneal dialysis, the rate of potassiumremoval is many times faster in haemodialysis47, up to 1.2–1.5 mmol/l/hour.48

Coexisting electrolyte disturbances have to be corrected.


CALCIUM

Calcium is required for the proper functioning of many intracellular, cAMP-mediatedmessenger systems and most cell organelle functions, and for extracellular processes,muscle contraction, nerve conduction and blood coagulation. In calcium homeostasis,

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 substitutesStored 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 CAddison’s disease Type IV renal tubular acidosis (hyporeninaemic hypoaldosteronism)Type II pseudohypoaldosteronism (Gordon’s 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.


the extracellular calcium ion concentration is kept constant within a narrowphysiological range (2.1–2.6 mmol/l ¼ 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 therenal tubular re-absorption, the intestine and bone.

The calcium-sensing receptors on parathyroid cells sense a small drop in the serumcalcium ion concentration and this leads to secretion of PTH.49 PTH stimulates the re-absorption of calcium in the kidney and inhibits the re-absorption of phosphate. Inbone, it increases the resorption of calcium and phosphate and, again in the kidney, itenhances the hydroxylation of 25OHD3 to the activated form of 1,25(OH)2D3.1,25(OH)2D3 increases intestinal calcium and phosphate absorption, decreases renalcalcium re-absorption and activates osteoclasts in concert with PTH to promotecalcium release by bone resorption. The normalized calcium concentration exerts anegative feedback on the parathyroid cells. Calcitonin inhibits osteoclastic boneresorption, may also enhance osteoblast activity, and decreases renal tubular re-absorption 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 fluid. In the extracellular fluid, thephysiologically active ionized calcium concentration reflects about 50% of the totalserum calcium (1–1.5 mmol/l); 40% is protein-bound, predominantly to albumin, and

Table 5. Emergency treatment in hyperkalaemia—hyperkalaemia and ECG abnormalities, acute

hyperkalaemia .6.0 mmol/l.

† Continuous ECG monitoring

† 10–20 ml of 10% calcium gluconate intravenously over 2–5 minutes with abnormal ECG

findings. Effect within 1–3 minutes, lasting for 30–60 minutes

Can be repeated if there is no effect within 5–10 minutes

Use extreme caution in patients taking digitalis!

þ

† 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 4–6 hours

Expected fall in plasma potassium concentration: 0.5–1.5 mmol/l

Careful monitoring of glucose!

þ

† 10–20 mg of nebulized albuterol

Effect onset within 30 minutes and a peak within 90–120 minutes

Expected fall in plasma potassium concentration: 0.6–1.0 mmol/l

Possible resistance in dialysis patients!

† 20–60 ml of 8.4% NaHCO3 intravenously—not 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 4–6 hours

Effect after 4–6 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!


10% is complexed with anions. PTH decreases the binding of calcium to protein andtherefore, increases ionized calcium.50 A lower albumin concentration will affect thetotal 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 0.1decrease in pH will increase ionized calcium by about 0.05 mmol/l)51, but thecorrections for albumin and pH are only poor substitutes for measuring ionized calciumin the clinical laboratory.

Hypocalcaemia

The severity of symptoms and clinical signs of hypocalcaemia correlates with themagnitude and rapidity of the fall in serum calcium and is influenced by acid–base status,hypomagnesaemia52 and sympathetic overactivity. The symptoms are primarilydetermined by the biologically active ionized fraction but generally do not appearunless 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 andcardiovascular disorders predominate. The hallmark of increased neuromuscularirritability is tetany, with both sensory and muscular dysfunction clinically.53 Patientsmay complain of muscle weakness and wasting, myalgia and cramps, paresthesia inhands and feet, circumoral numbness, dysphagia, and biliary and intestinal colic. In theclinical status, carpopedal spasms, Trousseau’s and Chvostek’s sign and hyper-reflexiaare typical. Laryngospasm, bronchospasm, focal or generalized seizures andpapilloedema54 can be observed. Cardiac manifestations consist of decreasedmyocardial contractility leading to congestive heart failure with or withouthypotension55, bradycardia and ventricular dysrhythmias, and a typical finding in theelectrocardiogram is a prolongation in the QT interval. The neuropsychiatricsymptoms include anxiety, irritability, psychosis, dementia, depression and confusion.

In the diagnostic approach, biochemical tests should be based on the patient’shistory and the physical examination. Hypocalcaemia usually suggests an insufficientaction 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 theunderlying aetiology. In acute hypocalcaemia, patients generally develop symptoms atconcentrations in ionized calcium of less than 0.7 mmol/l (2.8 mg/dl), or if the totalserum calcium concentration is about 1.8–1.875 mmol/l (7.0–7.5 mg/dl), and should betreated with parenteral calcium until the symptoms cease or the calcium concentrationrises above this point50,53 (Table 6). The calcium should be given slowly because of therisk of serious cardiac dysfunction, including asystole.53 Patients treated with digoxinshould be monitored carefully as calcium administration potentiates the digitalistoxicity. In renal failure and symptomatic hypocalcaemia, calcium can be added to thedialysis fluid. Because hypomagnesaemia diminishes the secretion of PTH as well asinduces 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 first step should be the administration of a phosphatebinder to avoid soft-tissue calcium phosphate precipitations and a calcium £ phosphate


S-[PO4]3- ↑

HypocalcaemiaIonized Ca+ < 1.1 mmol/l

PTH ↓ PTH ↑

25OHD3 ↔1,25(OH)2D3 ↔↓

Creatinine ↑

25OHD3 ↔1,25(OH)2D3 ↓

25OHD3 ↔↓1,25(OH)2D3 ↓

Vitamin D deficiencyLow sun exposure Malnutrition Malabsorption Hepatobiliary disease Nephrotic syndrome Anticonvulsants phenytoin, primidone Phenobarbital Ketoconazol Rifampicin, isoniazid

Creatinine ↔

S-[PO4]3- ↔↓

Decreased bone resorptionFluoride poisoningDrugs - Chemotherapeutic drugs (cisplatin, carboplatin, 5-fluorouracil with leukovorin, mithramycin, dactinomycin, cyclophosphamide, ifosfamide, doxorubicin with cytarabine) - Bisphosphonates - Calcitonin - Amphotericin B - Cimetidine - Ethanol

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

HypoparathyroidisPostsurgical Post-irradiation Hypomagnesaiemia (very rarely hypermagnesaiemia)Congenital Autosomal dominant Autosomal recessive X-linked recessive DiGeorge’s syndromePolyglandular autoimmune syndrome I Storage diseases Haemochromatosis Wilson’s disease Infiltrative Granulomas Metastatic cancer HIV infection

Osteoblastic metastasis?(Prostate, lung, breast cancer)Hungry bone syndrome

Secondary hyperpathyroidism

Calcium chelation or precipitationHyperphosphataemia - 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.


product .5.83 mmol2/l2 (7 mg2/dl2), and to delay calcium supplementation, if everpossible, 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 withoral 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 disorder’s degree and the rate ofonset of the elevation in the serum calcium concentration. Mild hypercalcaemia (serumtotal calcium until 3.0 mmol/l [12 mg/dl]) is generally asymptomatic. In higher elevationsof serum calcium concentration, most symptoms are non-specific, including fatigue,weakness, anxiety, depression, anorexia, nausea, vomiting, vague abdominal pain andconstipation.57 Peptic ulcers have been described, because calcium stimulates gastricsecretion.58 Severe hypercalcaemia may lead to acute pancreatitis.59 Hypercalciuriainduces nephrogenic diabetes insipidus with polyuria and polydipsia, type 1 (distal) renaltubular acidosis, nephrolithiasis and nephrocalcinosis.60 There is an increased frequencyof hypertension.61 Cognitive dysfunctions and personality and affective changes areseen with calcium concentrations above 3.0 mmol/l (12 mg/dl), and confusion,hallucinations, organic psychosis, somnolence, stupor and coma can be expectedwith serum calcium concentrations above 4 mmol/dl (16 mg/dl).62 The observedshortening in the QT interval appears not to be of any clinical importance.63

Hypercalcaemia develops when an excess of calcium derived from bone and/orintestine cannot be excreted by the kidneys. Thus, hypercalciuria is usually importantand precedes the development of symptoms, except in familial hypocalciurichypercalcaemia, an autosomal dominant disorder in which the urinary fractionalcalcium excretion is disturbed and often less than 1%. The major causes ofhypercalcaemia, accounting for about 80–90% of cases, are hyperparathyroidism andmalignancy64,65, although an increasing factor is the milk-alkali syndrome, which isprovoked by taking calcium carbonate to treat osteoporosis, dyspepsia and thehyperphosphataemia in chronic renal failure.66 In malignancy, osteoclast activity andproliferation are stimulated by the secretion of humoral mediators by the tumourcells.67,68 This may include cytokines (interleukin-1, interleukin-6 and tumour necrosis

Table 6. Emergency treatment in hypocalcaemia—symptomatic acute hypocalcaemia, ionized Ca2þ

,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 0.5–1.5 mg elemental calcium/kg per hour diluted in dextrose or saline over 4–6 hours

Expected rise in total serum calcium 0.5–0.75 mmol/l (2–3 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


factor), prostaglandins and PTH-related peptide (PTHrP), which binds to PTHreceptors, and paracrine factors (transforming growth factors). In addition, theinhibition of osteoblast activity by cytokines (interleukin-6) may have an effect.

Production of 1,25(OH)2D3 by alpha-vitamin D3 hydroxylase is found ingranulomatous diseases69, in Hodgkin’s disease and in non-Hodgkin’s lymphoma.70

In the clinical setting, history and physical examination are the most helpful diagnostictools to exclude correctable non-malignant causes of hypercalcaemia. When data from thechest 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 (FECa2þ),the correct diagnosis is provided in up to 99% of cases65,71

FECa2þ ¼ ½UCa2þ £ PCr� : ½PCa2þ £ UCr� £ 100

U and P refer to the urine andplasmaconcentrations of calcium (Ca2þ) and creatinine (Cr).As pseudohypercalcaemia due to hyperalbuminaemia in dehydration states or

binding to paraproteins in myeloma72 should be excluded, it is worthwhile to measureionized calcium.

Rare disorders not mentioned in the algorithm are the Jansen-type metaphysealchondrodysplasia, which is due to a mutation in the PTH and PTH-related receptorgene with normal or low levels of PTH73, and congenital lactase deficiency withhypercalcaemia and medullary nephrocalcinosis74 (Figure 6).

Management of hypercalcaemia

As clinical manifestations of hypercalcaemia vary, the therapeutic approach shouldreflect these differences. The goals of treatment are adequate hydration, increasedurinary calcium excretion, inhibition of osteoclast activity in the bone and, whenpossible, treatment of the underlying cause (Table 7).

In moderate (serum Ca2þ .3.0 mmol/l; .12 mg/dl) to severe (serum Ca2þ

.3.375 mmol/l; 13.5 mg/dl) hypercalcaemia50, which generally constitutes an emer-gency, intravascular volume depletion becomes more and more important; therefore,rehydration with crystalloid intravenous fluid is the initial therapy. In increasing theglomerular filtration rate, renal calcium excretion will also increase. Once extracellularvolume deficits are corrected, the addition of a loop diuretic that promotes calciuresis(not a thiazide, as it enhances calcium resorption) is indicated. Medications causing orcontributing 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 boneresorption; they inhibit bone turnover, directly, by inhibiting the recruitment andfunction of osteoclasts, and indirectly, by stimulating osteoblasts to produce aninhibitor of osteoclast formation. With pamidronate, normocalcaemia is achieved inmore than 90% of patients with a median duration of 4 weeks.75 It requires only a singleinfusion, is well tolerated, and seems to be safe in patients with renal failure. Newer,more potent compounds under study are zoledronate and ibandronate.76 Zoledronicacid has a safety profile similar to that of pamidronate and is significantly more effectivein reducing serum calcium.77 Gallium nitrate is effective in both PTHrP-mediated andnon-PTHrP-mediated, cancer-related hypercalcaemia.78 Calcitonin, safe and non-toxic,is an agent with a rapid onset of action but frequently observed tachyphylaxis within2–3 days.79 Mithramycin is rarely used, in spite of its reliability and efficacy, because ofits toxicity, especially in patients with bone marrow, liver and kidney disease.


Corticosteroids are the cornerstones of therapy in patients with chronic granuloma-tous diseases and lymphoma as they decrease calcitriol production by the activatedmononuclear cells in the lung and lymph nodes.80 In patients with serum calciumconcentration above 4.5–5.0 mmol/l (18–20 mg/dl) and neurological symptoms buta stable circulation, haemodialysis should be considered in addition to the above-mentioned treatments.

iPTH ↑ iPTH ↓

Hypercalcaemia > 3.0 mmol/lIonized Ca2+ ↑

FECa2+ ↓

FECa2+ ↑

Milk-alkali-syndrome Increased calcium intake in chronic renal failureThiazide diuretics Lithium toxicity Familial Addison’s crisis Hypothyroidism

PTHrP ↑ PTHrP ↓

HyperparathyroidismMultiendocrinic Reoplasias (MEN) type I and type IIPTH-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

25OHD3 →1,25(OH)2D3 ↑

25OHD3 ↑1,25(OH)2D3 ↑

25OHD3 ↑ 1,25(OH)2D3 ↓

Increased bone resorption - Immobilization - Paget’s disease - Oestrogens and anti-oestrogens (tamoxifen) in skeletal metastasis- Vitamin A excess - Hyperthyroidism - Theophylline toxicity

History Physical examination Chest X-ray

Vitamin D or calcidiol intoxication

1,25(OH)2D3 replacement therapy in patients on dialysis Granulomatous diseases (sarcoidosis, tuberculosis, leprosy, coccidioidomycosis, histoplasmosis, berylliosis) Malignant lymphoma

Figure 6. Diagnostic algorithm in hypercalcaemia.


Calcimimetic drugs have potential in the future treatment of primary and secondaryhyperparathyroidism in uraemia.81 They bind to the calcium-sensing receptor andsuppress the release of PTH. Osteoprotegerin, shown to specifically and potentlyinhibit osteoclast differentiation, represents a promising new option for the treatmentof patients with bone metastasis.82 Non-calcaemic analogues of calcitriol, such as 22-oxacalcitriol, showed suppression of neoplastic keratinocyte proliferation and PTHrPproduction in in vitro studies.83

MAGNESIUM

Magnesium, like potassium, is a predominantly intracellular cation with stores in boneand muscle. Only 1% of the total amount of magnesium is located in the extracellularspace, with a normal serum concentration of 0.74–0.95 mmol/l (1.7–2.2 mg/dl;1 mmol/l ¼ 2.43 mg/dl).

Magnesium is essential as a cofactor in numerous enzyme systems, and is involved inphosphate transfer, muscle contractility and neuronal transmission.84,85

In magnesium homeostasis, gastrointestinal absorption depends on dietaryintake. The kidney resorption in the proximal tubulus is limited, and hormonal and

Table 7. Emergency treatment in hypercalcaemia—symptomatic hypercalcaemia, Ca2þ .3.0 mmol/l

(.12 mg/dl).

† Isotonic saline, 1–2 l intravenously over a 1-hour period, afterwards approximately 4–6 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]2þ concentration: 0.25–0.75 mmol/l (2–6 mg/dl) after 24 hours

† Zoledronate 4 mg as a single short infusion over 5–15 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 1–2 hours intravenously

60 mg in S[Ca]2þ concentrations ,3.38 mmol/l (,13.5 mg/dl)

90 mg in higher S[Ca]2þ concentrations

Expected maximum effect in 2–4 days, median duration of action 2–4 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]2þ by a maximum of 0.3–0.5 mmol/l (1–2 mg/dl), beginning after

4–6 hours with a nadir within 12–24 hours

Effective only in 60–70% of patients, possible tachyphylaxis within 2–3 days

† Consider haemodialysis in S[Ca]2þ concentrations .4.5–5.0 mmol/l (18–20 mg/dl) and

neurological symptoms, in patients with heart failure or renal insufficiency

† Corticosteroids in vitamin D toxicity, multiple myeloma, lymphoma, granulomatous diseases

Hydrocortisone 200–300 mg intravenously for 3–5 days or prednisone 20–40 mg/day

Onset of action after 3–5 days


non-hormonal factors (PTH, calcitonin, glucagon, vasopressin, acid–base changes,potassium-depletion) as well as the magnesium concentration itself influence the uptakein Henle’s loop and the distal tubulus.86,87 The latter mechanism seems to be regulatedby the Ca2þ/Mg2þ-sensing receptor.88

Hypomagnesaemia

Magnesium depletion should be suspected in chronic diarrhoea, hypocalcaemia84,refractory hypokalaemia89 and ventricular arrythmias, particularly during myocardialischaemia and cardiopulmonary bypass.90,91 Clinical manifestations overlap those ofhypokalaemia and hypocalcaemia with corresponding neuromuscular and cardiovas-cular symptoms. As magnesium is vital to carbohydrate metabolism and the generationof both anaerobic and aerobic energy, and as it influences glucose catabolism and insulinsensitivity, carbohydrate intolerance and hyperinsulinism are observed. Becausedeficiency has been shown to cause hypertrigliceridaemia and hypercholesterolaemiaas well, there is a risk for atherosclerosis.84 Bone is affected by osteoporosis andosteomalacia in chronic disorders.

The diagnosis can usually be obtained from the history, as magnesium depletion is aresult of either gastrointestinal or renal losses, often promoted by drugs. In less obviouscases, determination of the fractional excretion of magnesium or the measurement ofthe magnesium excretion in the 24-hour urine can help to distinguish betweengastrointestinal and renal losses (Figure 7).

FEMg2þ ¼ {½UMg2þ £ PCr� : ½ð0:7 £ PMg2þÞ £ UCr�} £ 100

U and P refer to the urine and plasma concentrations of magnesium (Mg2þ)and creatinine (Cr). About 70% of PMg2þ are not bound to albumin and therefore,filtered across the glomerulus (0.7 £ PMg2þ).

A daily excretion of more than 4.1–12.3 mmol/day (10–30 mg/day) or a fractionalexcretion above 2% signals renal magnesium wasting.92,93

Management of hypomagnesaemia

Symptoms of hypomagnesaemia overlap those of hypokalaemia and hypocalcaemia. Ashypoxalaemia and hypocalcaemia often are associated with magnesium deficiency, thesedeficiencies should also be considered.

The route of magnesium repletion depends on the severity of clinical manifestations.Correcting the hypomagnesaemia, especially by intravenous application, will partiallyremove the stimulus to magnesium retention in the kidney as the plasma magnesiumconcentration is the major regulator of active magnesium resorption in the loop ofHenle.84 Thus, oral supplementation is preferred in symptom-free patients (5–20 mmol/day in divided doses as magnesium chloride or lactate). However, diarrhoeamay become a dose-limiting side-effect.

The indication for parenteral administration is symptomatic hypomagnesaemia withtetany or severe ventricular arrhythmia (Table 8).

The underlying disease should be treated, if possible. Patients with hypomagnesae-mia provoked by thiazide or loop diuretics as well as patients with persistent urinarymagnesium wasting or cisplatin nephrotoxicity may benefit from the prescription of apotassium-sparing diuretic such as amiloride.


Normomagnesaemic magnesium depletion has been described in patients withpersistent, unexplained hypocalcaemia and/or refractory hypokalaemia and normalrenal function, and it seems reasonable to try magnesium replacement.92

Hypermagnesaemia

Hypermagnesaemia, as defined by a serum magnesium concentration above0.95 mmol/l (2.2 mg/dl), is rare and usually iatrogenic after intravenous administration

FEMg2+ ↓ FEMg 2+ ↑

Gastrointestinal lossesNasogastric 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 lossesAlcohol 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 statusDiuretics Nephrotoxic drugs (aminoglycoside, cisplatin, amphotericin B, cyclosporin, foscarnet, pentamidine) Theophylline, β-agonists Primary renal magnesium wasting (Gitelman’s syndrome, Paracellin-1 mutation, Na-K-ATPase mutation)

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

Figure 7. Differential diagnosis of magnesium deficiency.

Table 8. Emergency treatment in hypomagnesaemia—severe, sympto-

matic hypomagnesaemia—seizure or acute arrhythmia.

† 4–8 mmol magnesium intravenously over 5–10 minutes

† Infusion with 25 mmol magnesium intravenously over 12–24 hours

† Maintainance of the treatment for 3–5 days in hypocalcaemic

patients

† Aim to keep the plasma [Mg]2þ over 0.4 mmol/l (1.0 mg/dl)

† Consider and treat associated electrolyte and acid–base disorders


of magnesium94 or after use of antacids and laxatives containing magnesium. The elderlyand patients with renal insufficiency are those most at risk.95

Clinical manifestations include confusion and depressed level of consciousness,muscular weakness, paralysis with absence of reflexes, and respiratory depression insevere cases. Hypermagnesaemia causes vasodilatation and hypotension. Theelectrocardiogram 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 P-wave voltage and the T-wave peaking show variable degrees. The patients complain ofnausea and vomiting.

Treatment should be based on discontinuation of magnesium intake, counteractingthe effect of hypermagnesaemia on excitable membranes with calcium to reversecardiac arrhythmias, respiratory depression and hypotension, and removing magnesiumfrom 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 inbone (80%) and skeletal muscle (9%), and, to a lesser extent, in viscera and extracellularfluid. Less than 1% of total body phosphate is present in plasma, ranging from 0.8 to1.45 mmol/l (2.5–4.5 mg/dl; 1 mmol/l ¼ 3.125 mg/dl). The higher levels in children andthe elderly reflect a higher bone turnover. About 15% of the serum phosphate isprotein-bound; the rest is ultrafiltrable. Phosphate is essential for bone mineralization,cellular structure and function, energy metabolism and genetic coding. In phosphatehomeostasis, intestinal absorption (70–80% of dietary intake) occurs mainly in theduodenum and jejunum by both passive and active transport stimulated by1,25(OH)2D3.

96,97 Glucocorticoids, high magnesium diet, hypothyroidism and non-absorbable antacids, binding dietary phosphate, inhibit the intestinal absorption ofphosphate.98 In the kidney, phosphate is freely filtered. Some 80–90% of it is re-absorbed in the proximal tubule, and a small amount in the distal tubule by passivetransport coupled to sodium. Two different Na–PO4 transporters have been identifiedwhich are regulated mainly by phosphorus intake and PTH.96,99 Phosphate restrictionand parathyroidectomy decrease urinary phosphate secretion, whereas a high intake ofphosphate and PTH administration increase it.96,100,101 A very good overviewconcerning serum phosphate abnormalities in the emergency department has recentlybeen published.102

Hypophosphataemia

In hypophosphataemia, it is important to distinguish phosphate depletion occurring inrenal wasting or in decreased intestinal resorption from a low serum phosphateconcentration resulting from an enhanced re-distribution of phosphate from theextracellular fluid into cells. The significance of hypophosphataemia in the absence ofphosphate depletion is not known103, but a combination of the three mechanisms ispossible.

Severe hypophosphataemia refers to a serum phosphate concentration less than0.48 mmol/l (1.5 mg/dl).103 Clinically symptomatic hypophosphataemia depends uponthe 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 alcoholwithdrawal104, with chronic ingestion of phosphate-binding antacids103,105, recoveringfrom diabetic ketoacidosis103, under total parenteral nutrition without phosphatesupplementation, with extensive third-degree burns106, in the post-operativestate107–109, with respiratory alkalosis, with hyperparathyroidism or with vitamin Ddeficiency.

Except for the effects on mineral metabolism (osteopenia and osteomalacia as aresult of the direct effect of phosphate depletion on osteoclastic resorption of bone),the clinical manifestations can be explained by a decrease in intracellular adenosinetriphosphates (ATP), leading to failure in those cell functions dependent upon energy-rich 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 ofneuropsychiatric disturbances, seizures, mental obtundation and coma arereported.84,98 Electroencephalogram abnormalities correlate with changes in the redcells 2,3-DPG.112 Cardiac arrhythmias and a depressed myocardial contractility113,leading to congestive heart failure, have been recognized in association withhypophosphataemia. Respiratory failure as a consequence of diaphragmatic weaknessmay explain failed weaning from the respirator in the ICU.114 In rhabdomyolysis as acomplication in acute hypophosphataemia superimposed on a chronic phosphatedepletion state115, the underlying deficiency may be masked due to the releaseof phosphate from muscle breakdown. Dysphagia and ileus are commonalterations of smooth muscle. Haemolysis is rare, but is described whenserum phosphate concentrations fall below 0.16 mmol/l (0.5 mg/dl).116 Impairedphagocytosis and chemotaxis in white blood cells117 and platelet abnormalities118

have been demonstrated.In the clinical approach, the diagnosis is often evident from the patient’s history. If not

obvious, the measurement of urinary phosphate excretion—either from a 24-hoururine collection or by calculation of the fractional excretion of filtered phosphate(FEPO4

32) from a random urine specimen—is helpful. Urinary phosphate excretionabove 32 mmol/day (100 mg/day) or a FEPO4 above 20% proves renal phosphate loss98

(Figure 8).

FEPO324 ¼ ½UPO32

4 £ PCr� : ½PPO324 £ UCr� £ 100

U and P refer to the urine and plasma concentrations of phosphate (PO432) and

creatinine (Cr).

Management of hypophosphataemia

Treatment is indicated in patients with hypophosphataemia and depletion. Oralsupplementation is safest and should be preferred whenever possible. With about60 mmol of phosphate daily, divided in three or four doses, repletion may be achievedover a period of 7–10 days.98 Oral phosphate can be administered with cow’s milk(1 mg phosphate per ml) or in tablets of sodium or potassium phosphate.

Parenteral phosphate repletion is potentially dangerous, with risk of precipitationswith calcium, symptomatic hypocalcaemia and renal failure84, and should therefore, bereserved for patients with severe symptomatic hypophosphataemia. In the literature,the beginning of substitution is recommended at a phosphate concentration below0.32 mmol/l (1 mg/dl)84, but in clinical practice, it is initiated at a phosphate


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 calciumconcentrations should be monitored closely (Table 9).

Hyperphosphataemia

Hyperphosphataemia is considered significant when levels are greater than 1.6 mmol/l(5 mg/dl) and occurs when the phosphate load exceeds renal excretion and tissueuptake. Pseudohyperphosphataemia due to interference with the biochemical assay

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

FEPO43- ↓ FEPO4

3- > 5%

HistoryPatient at risk of depletion?

Renal lossesChronic 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 - Wilson’s disease - Cystinosis - Hereditary fructose intolerance - Amyloidosis Glucocorticoid/mineralocorticoid-therapy

Decreased intestinal absorptionSevere dietary phosphate restrictionChronic antacid use Vitamin D deficiency/resistanceChronic diarrhoea Steatorrhea Malabsorption

Other lossesExtensive burns, pancreatitis

Transcellular shiftsRespiratory alkalosisHormonal effects- Calcitonin- Insulin- Glucagon- β-adrenergics Carbohydra te infusions (glucose, fructose, glycerol, lactate)Rapid cellular proliferation/uptake- Hungry bone syndrome - Erythropoietin therapy- Leukaemic blast crisisRe-feeding syndrome

Figure 8. Differential diagnosis in hypophosphataemia.


may occur in patients with hyperglobulinaemia (multiple myeloma, Waldenstrommacroglobulinaemia, monoclonal gammopathy), extreme hypertriglyceridaemia, invitro haemolysis and hyperbilirubinaemia.119

Symptoms of acute hyperphosphataemia may be those of associated hyperkalaemiaand hypocalcaemia. A rise in the serum calcium £ phosphate product above 5–6 mmol2/l2 (60–72 mg2/dl2) results in precipitating calcium, decreasing circulatingcalcium levels.120,121 Moreover, renal 1a-hydroxylase is inhibited by phosphate,resulting in less 1,25(OH)2D3.

84 Chronic hyperphosphataemia, especially associatedwith hypercalcaemia, provokes extraskeletal ‘metastatic’ calcifications in soft tissues,blood vessels and organ parenchyma, and contributes to the development of secondaryhyperparathyroidism and renal dystrophy.

Management of hyperphosphataemia

In the approach to therapy, it is important to distinguish acute from chronichyperphosphataemia.

In acute hyperphosphataemia, posing a life threatening condition, haemodialysisshould be considered, particularly if renal function is impaired. The administration ofdextrose and insulin drives phosphate into cells. Phosphate excretion can be increasedby saline infusion (although this carries the risk of a further decrease in serum calciumconcentration), 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 absorptionby 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 arepreferred because of the long-term toxic effects of aluminium accumulation. Excessivecalcium loading, however, should be avoided and tight controls of phosphate and thecalcium £ phosphate product are important. Elevated levels may result in increasedmortality, 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 clinicalpresentations. While a crude diagnosis based on history, clinical presentation andmeasured electrolytes and acid–base status can usually be established quickly, primaryand secondary events are sometimes difficult to differentiate. Mixed electrolyte, acid–base and fluid disorders are frequent. Often, drugs prescribed for a variety of diseases

Table 9. Emergency treatment in hypophosphatemia—symptomatic 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 0.64–0.8 mmol/l (2–2.5 mg/dl) is reached84


are involved. Because very different clinical conditions can result in similar electrolyteabnormalities, diagnostic algorithms are helpful. Once the underlying diagnosis of anelectrolyte disorder has been established, the rate of correction of the electrolyteabnormality is crucial because correction at too rapid a rate can result in complications,which are more severe than the underlying disturbance. Correction of electrolytedisturbances almost invariably interferes with acid–base and fluid homoeostasis. Thishas to be taken into account when effects of therapeutic interventions are assessed.Knowledge of the pathophysiological background of electrolyte emergencies shouldhelp to avoid them in patients at risk (Figure 9).

S[PO4]3- > 1.6 mmol/l

Massive acute phosphate load RhabdomyolysisTumour-lysis syndrome (Burkitt’s lymphoma, Non-Hodgkin’s 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 PseudohypoparathyroidismVitamin D intoxication Acromegaly Thyrotoxicosis Glucocorticoid withdrawal or deficiency Tumoral calcinosis syndrome Bisphosphonates Magnesium deficiency

PseudohyperphosphataemiaMultiple myelomaWaldenström macroglobulinaemiaMonoclonal gammopathyExtreme hypertriglyceridaemiaIn vitro haemolysisHyperbilirubinaemia

Figure 9. Differential diagnosis in hyperphosphataemia.

Practice point

† practice points for recognition and management of each individual electrolytedisorder discussed in the present overview are summarized in Tables 2–9


REFERENCES

1. Acher R. Water homeostasis in the living: molecular organization, osmoregulatory reflexes andevolution. Annales d’endocrinologie (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 Research2002; 8: RA39–RA52.

4. Cappuccio FP, Strazzullo P, Giorgione N et al. Renal tubular sodium handling and plasma atrial natriureticpeptide, renin activity and aldosterone in untreated men under normal living conditions. European Journalof Clinical Investigation 1991; 21: 40–46.

* 5. Kumar S & Berl T. Sodium. Lancet 1998; 352: 220–228.6. 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: 1581–1589.10. 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 severehyponatraemia: a multicenter perspective. Journal of the American Society of Nephrology 1994; 4:1522–1530.

14. Karp BI & Laureno R. Pontine and extrapontine myelinolysis: a neurologic disorder following rapidcorrection of hyponatraemia. Medicine (Baltimore) 1993; 72: 359–373.

15. Oh MS, Kim HJ & Carroll HJ. Recommendations for treatment of symptomatic hyponatraemia. Nephron1995; 70: 143–150.

16. Menger H & Jorg J. Outcome of central pontine and extrapontine myelinolysis ðn ¼ 44Þ. Journal ofNeurology 1999; 246: 700–705.

17. Menger H, Mackowski J, Jorg J & Cramer BM. Pontine and extra-pontine myelinolysis. Early diagnosticand prognostic value of cerebral CT and MRI. Der Nervenarzt 1998; 69: 1083–1090.

18. Berl T. Treating hyponatraemia: damned if we do and damned if we don’t. Kidney International 1990; 37:1006–1018.

Research agenda

† trials are needed to explore whether vasopressin V2-receptor antagonists canbe used for the treatment of hyponatraemia of origin other than chronic heartfailure and liver cirrhosis

† efficacy and safety of second-generation calcimimetics with an enhancedpharmacokinetic profile for the treatment of various forms of hyperparathyr-oidism should be further investigated in long-term, controlled studies

† potential new therapeutics directed against osteoclastic bone resorption areosteoprotegerin, anti-PTHrP antibodies and inhibitors of peptides, whichstimulate osteoclastic bone resorption. Further investigations and clinical trialsare needed to confirm the efficacy and safety of these compounds

† gallium nitrate warrants further investigation for the treatment of cancer-related hypercalcaemia


19. Adrogue HJ & Madias NE. Aiding fluid prescription for the dysnatremias. Intensive Care Medicine 1997;23: 309–316.

* 20. Adrogue HJ & Madias NE. Hypernatraemia. New England Journal of Medicine 2000; 342: 1493–1499.21. McManus ML, Churchwell KB & Strange K. Regulation of cell volume in health and disease. New England

Journal of Medicine 1995; 333: 1260–1266.22. Kang SK, Kim W & Oh MS. Pathogenesis and treatment of hypernatraemia. Nephron 2002;

92(supplement 1): 14–17.23. 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:

1–13.* 25. Halperin ML & Kamel KS. Potassium. Lancet 1998; 352: 135–140.

26. Field MJ & Giebisch GJ. Hormonal control of renal potassium excretion. Kidney International 1985; 27:379–387.

27. Giebisch G. Renal potassium transport: mechanisms and regulation. American Journal of Physiology 1998;274: F817–F833.

28. Cohn JN, Kowey PR, Whelton PK & Prisant LM. New guidelines for potassium replacement in clinicalpractice: a contemporary review by the National Council on Potassium in Clinical Practice. Archives ofInternal 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: 4E–9E.

32. Wahr JA, Parks R, Boisvert D et al. Preoperative serum potassium levels and perioperative outcomes incardiac 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: 143–148.

34. Sterns RH, Cox M, Feig PU & Singer I. Internal potassium balance and the control of the plasmapotassium concentration. Medicine (Baltimore) 1981; 60: 339–354.

35. Adrogue HJ, Lederer ED, Suki WN & Eknoyan G. Determinants of plasma potassium levels in diabeticketoacidosis. Medicine (Baltimore) 1986; 65: 163–172.

36. Sopko JA & Freeman RM. Salt substitutes as a source of potassium. JAMA 1977; 238: 608–610.37. 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: McGraw-

Hill, 2001.* 39. Kim HJ & Han SW. Therapeutic approach to hyperkalemia. Nephron 2002; 92(supplement 1): 33–40.* 40. Perazella MA. Drug-induced hyperkalaemia: old culprits and new offenders. American Journal of Medicine

2000; 109: 307–314.41. Weiner ID & Wingo CS. Hyperkalemia: a potential silent killer. Journal of the American Society of

Nephrology 1998; 9: 1535–1543.42. 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: 45–49.43. Greenberg A. Hyperkalemia: treatment options. Seminars in Nephrology 1998; 18: 46–57.44. 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: 508–514.47. 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; 85:507–512.

49. Brown EM. Physiology and pathophysiology of the extracellular calcium-sensing receptor. AmericanJournal of Medicine 1999; 106: 238–253.

* 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 57–63.


52. Graber ML. Magnesium deficiency: pathophysiologic and clinical overview. American Journal of KidneyDisease 1995; 25: 973.

53. Tohme JF & Bilezikian JP. Hypocalcemic emergencies. Endocrinology & Metabolism Clinics of North America1993; 22: 363–375.

54. Sheldon RS, Becker WJ, Hanley DA & Culver RL. Hypoparathyroidism and pseudotumor cerebri: aninfrequent clinical association. Canadian Journal of Neurological Science 1987; 14: 622–625.

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 1038–1085.57. 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): S63–S70.58. Gardner Jr EC & Hersh T. Primary hyperparathyroidism and the gastrointestinal tract. Southern Medcial

Journal 1981; 74: 197–199.59. 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 findings in 58 cases. Medicine (Baltimore) 1988; 67: 84–99.61. Campese VM. Calcium, parathyroid hormone, and blood pressure. American Journal of Hypertension

1989; 2: 34S–44S.62. Petersen P. Psychiatric disorders in primary hyperparathyroidism. Journal of Clinical Endocrinology and

Metabolism 1968; 28: 1491–1495.63. Rosenqvist M, Nordenstrom J, Andersson M & Edhag OK. Cardiac conduction in patients with

hypercalcaemia due to primary hyperparathyroidism. Clinical Endocrinology (Oxford) 1992; 37: 29–33.64. 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 Medicine2001; 12(4): 344–349..

65. Lafferty FW. Differential diagnosis of hypercalcaemia. Journal of Bone & Mineral Research 1991;6(supplement 2): S51–S59.

66. Beall DP & Scofield RH. Milk-alkali syndrome associated with calcium carbonate consumption. Report of7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalizedwith hypercalcaemia. Medicine (Baltimore) 1995; 74: 89–96.

67. Esbrit P. Hypercalcaemia of malignancy—new insights into an old syndrome. Clinical Laboratory 2001; 47:67–71.

68. Strewler GJ. The physiology of parathyroid hormone-related protein. New England Journal of Medicine2000; 342: 177–185.

69. Sharma OP. Hypercalcaemia in granulomatous disorders: a clinical review. Current Opinion in PulmonaryMedicine 2000; 6: 442–447.

70. Seymour JF & Gagel RF. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin’s diseaseand non-Hodgkin’s lymphomas. Blood 1993; 82: 1383–1394.

71. Fukagawa M & Kurokawa K. Calcium homeostasis and imbalance. Nephron 2002; 92(supplement 1):41–45.

72. van Dijk JM, Sonnenblick M, Weissberg N & Rosin A. Pseudohypercalcemia and hyperviscosity withneurological manifestations in multiple myeloma. Israel Journal of Medical Science 1986; 22: 143–144.

73. Schipani E, Langman CB, Parfitt AM et al. Constitutively activated receptors for parathyroid hormoneand parathyroid hormone-related peptide in Jansen’s metaphyseal chondrodysplasia. New England Journalof Medicine 1996; 335: 708–714.

74. Saarela T, Simila S & Koivisto M. Hypercalcaemia and nephrocalcinosis in patients with congenital lactasedeficiency. Journal of Pediatrics 1995; 127: 920–923.

75. Body JJ. Current and future directions in medical therapy: hypercalcemia. Cancer 2000; 88(sup-plement): 3054–3058.

76. Body JJ. Dosing regimens and main adverse events of bisphosphonates. Seminars in Oncology 2001; 28(4supplement 11): 49–53.

77. Berenson JR. Treatment of hypercalcemia of malignancy with bisphosphonates. Seminars in Oncology2002; 29(6 supplement 21): 12–18.

78. Leyland-Jones B. Treatment of cancer-related hypercalcaemia: the role of gallium nitrate. Seminars inOncology 2003; 30(2 supplement 5): 13–19.

79. Wisneski LA. Salmon calcitonin in the acute management of hypercalcaemia. Calcified Tissue International1990; 46(supplement): S26–S30.

80. Gardner DG. Hypercalcemia and sarcoidosis—another piece of the puzzle falls into place. AmericanJournal of Medicine 2001; 110: 736–737.


81. Urena P & Frazao JM. Calcimimetic agents: review and perspectives. Kidney International 2003;85(supplement): 91–96.

82. Sezer O, Heider U, Zavrski I et al. RANK ligand and osteoprotegerin in myeloma bone disease. Blood2003; 101: 2094–2098.

83. Yu J, Papavasiliou V, Rhim J et al. Vitamin D analogs: new therapeutic agents for the treatment ofsquamous cancer and its associated hypercalcemia. Anticancer Drugs 1995; 6: 101–108.

* 84. Weisinger JR & Bellorin-Font E. Magnesium and phosphorus. Lancet 1998; 352: 391–396.85. White RE & Hartzell HC. Magnesium ions in cardiac function. Regulator of ion channels and second

messengers. Biochemical Pharmacology 1989; 38: 859–867.86. de Rouffignac 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: 1180–1195.89. Whang R, Whang DD & Ryan MP. Refractory potassium repletion. A consequence of magnesium

deficiency. 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.Influence on ventricular arrhythmias. Archives of Internal Medicine 1987; 147: 465–469.

92. al Ghamdi SM, Cameron EC & Sutton RA. Magnesium deficiency: pathophysiologic and clinical overview.American Journal of Kidney Disease 1994; 24: 737–752.

93. Elisaf M, Panteli K, Theodorou J & Siamopoulos KC. Fractional excretion of magnesium in normalsubjects and in patients with hypomagnesemia. Magnesium Research 1997; 10: 315–320.

94. Morisaki H, Yamamoto S, Morita Y et al. Hypermagnesemia-induced cardiopulmonary arrest beforeinduction of anesthesia for emergency cesarean section. Journal of Clinical Anesthesia 2000; 12: 224–226.

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 323–336.97. Wesson LG. Homeostasis of phosphate revisited. Nephron 1997; 77: 249–266.

* 98. Subramanian R & Khardori R. Severe hypophosphatemia—pathophysiologic implications, clinicalpresentations, and treatment. Medicine 2000; 79: 1–8.

99. Murer H, Markovich D & Biber J. Renal and small-intestinal sodium-dependent symporters of phosphateand sulfate. Journal of Experimental Biology 1994; 196: 167–181.

100. Murer H. Cellular mechanisms in proximal tubular P(I) reabsorption—some answers and morequestions. 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: 365–369.

* 102. Shiber GR & Mattu A. Serum phosphate abnormalities in the emergency department. The Journal ofEmergency Medicine 2002; 23(4): 395–400.

103. Knochel JP & Agarwal R. Hypophosphatemia and hyperphosphatemia. In Brenner BM (ed.) Brenner andRector’s the kidney. Philadelphia: WB Saunders, 1996, pp 1086–1133.

104. Knochel JP. Hypophosphatemia in the alcoholic. Archives of Internal Medicine 1980; 140: 613–615.105. Lotz M, Zisman E & Bartter FC. Evidence for a phosphorus-depletion syndrome in man. New England

Journal of Medicine 1968; 278: 409–415.106. Lennquist S, Lindell B, Nordstrom H & Sjoberg HE. Hypophosphatemia in severe burns—prospective

study. Acta Chirurgica Scandinavica 1979; 145: 1–6.107. George R & Shiu MH. Hypophosphatemia after major hepatic resection. Surgery 1992; 111: 281–286.108. Goldstein J, Vincent JL, Leclerc JL et al. Hypophosphatemia after cardiothoracic surgery. Intensive Care

Medicine 1985; 11: 144–148.109. 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: 763–768.


113. Oconnor LR, Wheeler WS & Bethune JE. Effect of hypophosphatemia on myocardial performance inman. New England Journal of Medicine 1977; 297: 901–903.

114. Aubier M, Murciano D, Lecocguic Y et al. Effect of hypophosphatemia on diaphragmatic contractility inpatients 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: 455–457.116. Klock JC, Williams HE & Mentzer WC. Hemolytic anemia and somatic-cell dysfunction in severe

hypophosphatemia. Archives of Internal Medicine 1974; 134: 360–364.117. Craddock PR, Yawata Yet al. Acquired phagocyte dysfunction resulting from parenteral hyperalimenta-

tion. New England Journal of Medicine 1974; 290: 1403–1407.118. Yawata Y, Hebbel RP, Silvis S et al. Blood-cell abnormalities complicating hypophosphatemia of

hyperalimentation—erythrocyte and platelet ATP deficiency associated with hemolytic anemia andbleeding 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: 2577–2579.121. Sutters M, Gaboury CL & Bennett WM. Severe hyperphosphatemia and hypocalcemia: a dilemma in

patient management. Journal of the American Society of Nephrology 1996; 7: 2056–2061.122. Yamaguchi T, Sugimoto T, Imai Y et al. Successful treatment of hyperphosphatemic tumoral calcinosis

with long-term acetazolamide. Bone 1995; 16(supplement 4): 247S–250S.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 receptorantagonist: a randomized double-blind multicenter trial. Gastroenterology 2003; 124: 933–939.

126. Gheorghiade M, Niazi I, Ouyang J et al. Vasopressin V2-receptor blockade with tolvaptan in patients withchronic heart failure: results from a double-blind, randomized trial. Circulation 2003; 107: 2690–2696.

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 quality—just 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 998–1035.131. 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 ofSurgical Pathology 1997; 21: 60–69.


Diagnosis and Management of Electrolyte Emergencies

Documents

Transcript of Diagnosis and Management of Electrolyte Emergencies