Electrolyte Abnormalities

1.0 Disorders of Sodium

Definitions (Serum Na Concentration mmol/l):

Normal: 135‐145 Hyponatraemia: < 135 Hypernatraemia: > 145 Moderate Hypernatraemia: 145 ‐ 160 Severe Hypernatraemia: > 160

Sodium is primarily an extracellular cation, diffusing rapidly across the capillary membrane, other than in the cerebral circulation. As such, serum concentrations are used to represent those in the extracellular space, and changes in either the sodium content, or total body water can result in clinically significant dysnatraemia.

Sodium has an essential role in excitable tissues (such as nerves and muscle) where influx across the plasma membrane results in depolarisation of the resting membrane potential. The movement of sodium in this respect is governed by the electro‐chemical gradients established by the high extracellular concentration, and the relative negative charge of the cell interior.

Ion Intracellular Extra-cellular Equilibrium Potential Concentration Concentration

Na+ 15.0 mmol/L 150 mmol/L +60mV

K+ 150.0 mmol/L 5.5 mmol/L -90mV

Cl- 9.0 mmol/L 125.0mmol/L -70mV

1.1 Hyponatraemia

Symptoms can include delirium, seizures, coma and signs and symptoms of raised intracranial pressure.

Most categorisation schemas involve determining whether the plasma osmolality is normal (isotonic hyponatraemia), low (hypotonic hyponatraemia), or high (hypertonic hyponatraemia). The following diagram visually demonstrates the processes involved.

A useful flow diagram for considering the causes of hypontraemia on the basis of biochemical and clinical findings is summarised below:

1.2 Syndrome of Inappropriate Anti‐diuretic Hormone (SIADH)

Common diagnostic criteria for this syndrome include:

Common Causes Include the following:

1.3 Management of Hyponatraemia

This depends on the underlying cause, and rapidity of onset. A general 'rule of thumb' is to correct hyponatraemia over a similar time frame to that which it developed. If the patient is asymptomatic, and the hyponatraemia appears to be chronic, there is no urgency to increase the plasma concentration into the normal range.

 Hypovolaemic hypotonic hyponatraemia will usually respond to isotonic (0.9% Saline) fluid replacement.  Fluid overloaded patients may require fluid restriction and/or gentle diuresis.  Adrenal insufficiency will respond rapidly to corticosteroid replacement.  SIADH resulting in asymptomatic hyponatraemia should initially be treated with fluid restriction to 1 ‐ 1.5 L per twenty‐fours, and withdrawal of any likely causative agents.  The indications for using hypertonic (3%) saline to more rapidly raise the plasma Na concentration include signs of raised intra‐cranial pressure or cerebral oedema.  The aim in this scenario is to raise the Na concentration by 1‐2 meq/l/hour, not exceeding 10‐15 meq/l/day. The following equations can be used to estimate the volume of 3% saline needed:  Amount of NaCl needed = 0.6 x Wt (kg) x (desired Na ‐ actual Na)  Volume of 3% saline needed (ml) = (meq NaCl needed x 1000) / 513  In the setting of seizures directly related to hyponatraemia, a more aggressive approach may be needed, including the use of a bolus. Senior advice should be sort in this setting.  Central pontine myelinolysis is a dreaded complication of overly rapid correction of serum sodium concentrations.  Risk factors other than the rate of correction include; chronic EtOH consumption, malnutrition, liver disease, severe hyponatraemia (< 105 meq/l), and hypokalaemia.  Importantly, it is the daily, rather than hourly rate of correction that determines risk.  This is highest in those in which the Na concentration is raised more than 20 meq/l in the first 24hrs, or is overcorrected to above 140meq/l.

1.4 Hypernatraemia This is often iatrogenic in nature. Clinical features can include confusion, seizures, coma and neuromuscular irritability (hyper‐reflexia, tremor, ataxia, myoclonus). Severe hypernatraemia can be associated with acute renal failure, rhabdomyolysis, and subdural haemorrhage.

Common causes are summarised below:

1.5 Management of Hypernatraemia  If the patient is 'shocked', volume resuscitation with 0.9% saline may be required (20ml/kg bolus PRN).  It is important to remember that the concentration of sodium in 0.9% saline is approximately 150meq/l, which still may be lower that the patients. Too rapid reduction in sodium can precipitate cerebral oedema and seizures, although this is more commonly seen in the paediatric population. Ideally, the aim is to lower the sodium concentration at a rate of 0.5‐1meq/l/hr.  If the patient is not haemodynamically unstable, 0.45% saline / 5% dextrose IV and / or free water enterally can be used to slowly correct the sodium concentration over 72hrs. During this period, there should be regular measurement of plasma sodium concentrations.

1.6 Diabetes Insipidus

Diabetes insipidus (DI) is a relatively common condition in ICU with either a relative or absolute lack of anti‐diuretic hormone (ADH) leading to an inability to concentrate the urine and subsequent polyuria, polydypsia (in the awake patient), dehydration and hypernatraemia. It is most commonly encountered in neurosurgical patients, particularly those with severe traumatic brain injury. Some additional causes are outlined below.

Neurogenic DI ‐ Traumatic brain injury ‐ Pituitary apoplexy ‐ Pituitary adenoma ‐ Pituitary surgery ‐ Post cranio‐pharyngeal radiotherapy ‐ Meningitis ‐ Craniopharyngioma ‐ Fat embolism ‐ Grauloma Nephrogenic DI Congenital Acquired ‐ Long‐term Li treatment ‐ Amphotericin B ‐ Clozapine ‐ Hypercalcaemia ‐ Hypokalaemia ‐ Pyelonephritis ‐ Amyloid / Multiple Myeloma / Sarcoid ‐ Medullary Sponge Kidney Other (case reports) ‐ Electrical Burns ‐ Amiodarone ‐ Penetrating thoracic trauma ‐ CABG surgery

Typical clinical and laboratory features include: ‐ Compatible history / cause (always remember to exclude solute diuresis) ‐ Polyuria (urine volumes > 3ml/kg/hr for 4‐6hrs) ‐ Polydipsia ‐ Raised plasma osmolality (> 300) and sodium concentration (in those with a defect in thirst or water intake) ‐ Inappropriately low urinary osmolality (< 300) given the high plasma value ‐ response to ADH administration

Management options:

‐ Rehydration ‐ ensuring adequate replacement of free water (without overly rapid correction of the sodium concentration if hypernatraemia has been chronic)

‐ DDAVP administration ‐ This is a long acting analogue of ADH that acts on the distal tubules and collecting ducts of the kidney to increase water re‐absorption. ‐ Can be administered intra‐nasally, parenterally or orally. ‐ The effect is generally 'all or nothing', such that the dose determines the duration of action, not the degree of response. IV administration tends to be favoured in the acute setting, although lower doses should be used initially (0.5‐1mcg IV) ‐ Plasma sodium concentrations must be monitored regularly, in addition to strict attention to fluid balance.

2.0 Disorders of Potassium

Definitions (Plasma potassium concentration ‐ mmol/l):

Normal: 3.5‐5.0 Hyperkalaemia: > 5.0 Hypokalaemia: < 3.5

Potassium is primarily an intracellular cation (see above). This concentration gradient is maintained by the Na/K ATPase pump. It has an important role in allow repolarisation of excitable tissues.

2.1 Hypokalaemia Clinical Features: weakness, hypotonicity, depression, constipation, ileus. Prolonged severe hypokalaemia is associated with rhabdomyolysis, and nephrogenic diabetes insipidus.

ECG Features: Increased PR interval, ST segment depression, prominent 'U' wave, normal QT interval, T wave inversion

Causes:

Inadequate Intake / Supplementation (urinary K concentration < 20meq/l) Abnormal Losses GI losses (urinary K < 20meq/l) ‐ vomiting / high NG aspirates ‐ diarrhoea / fistulas ‐ villous adenoma ‐ laxative abuse Renal losses (urinary K > 20 meq/l) ‐ Conn's syndrome ‐ Cushings syndrome ‐ Bartters syndrome ‐ ectopic ACTH production ‐ loop diuretics ‐ corticosteroid use ‐ magnesium deficiency ‐ renal tubular acidosis (types I and II) Compartmental Shift ‐ alkalosis ‐ insulin therapy ‐ refeeding syndrome ‐ beta‐agonists ‐ methyl xanthines (theophylline) ‐ hypothermia ‐ toluene intoxication ‐ barbiturates

Management:

Requires IV or PO supplementation. Administration of concentrated solutions (40mmol KCL in 100ml 0.9% saline) require central venous access. The maximum rate of administration is 40mmol/hr, and rates > 15mmol/hr require hourly estimates of plasma potassium concentrations.

2.2 Hyperkalaemia

Clinical Features: tingling / paraesthesiae, flaccid paralysis, hypotension, bradycardia and arrhythmia.

ECG changes: Tall peak T‐waves, widening to the QRS, paralysis of the atria (lack of p‐waves), sine waves, VT/VF, asystole. Typical ECG changes are demonstrated below:

Causes:

Collection Abnormality (Spurious) ‐ delay in lab processing / separating of cellular component ‐ specimen haemolysis ‐ thrombocytopaenia Excessive administration / intake ‐ massive transfusion ‐ 'elderly blood' Reduced excretion ‐ acute kidney injury ‐ potassium sparring diuretics ‐ NSAID use ‐ ACE inhibitor use ‐ Addisions disease ‐ Renal tubular acidosis (type IV) Compartmental shift ‐ acidosis ‐ insulin deficiency ‐ digoxin overdose ‐ suxamethonium use ‐ fluoride poisoning ‐ burns / trauma ‐ rhabdomyolysis ‐ tumor‐lysis syndrome

Management:

This is focused on two principles: a) Temporary stabilisation of cell membranes / intra‐cellular shift of potassium: ‐ Administration of calcium gluconate / calcium chloride (contra‐indicated in digoxin overdose) ‐ Insulin ‐ Dextrose administration (50ml 50% dextrose and 20 IU IV insulin) ‐ Sodium bicarbonate (50‐100mmol IV) ‐ Salbutamol (typically nebulised) b) Reduction in total body potassium content ‐ Loop diuretics ‐ Oral / rectal K+ binding resins (Resonium A ‐ 50g) ‐ Renal replacement therapy

3.0 Disorders of Magnesium

Magnesium is an important intra‐cellular cation that acts as a co‐factor for a number of energy dependant reactions, including the Na/K ATPase pump. The laboratory reference range is between 0.7 ‐ 1.1 mmol/l.

Hypomagnesaemia is a relatively common electrolyte abnormality in ICU, although the role of regular magnesium supplementation in improving outcomes has not been thoroughly investigated. Hypocalcaemia and hypokalaemia are often encountered in parallel, and common clinical features of severe hypomagnesaemia include confusion, irritability, delirium, tremors, confusion, and tachyarrhythmia. The following table summarises some commonly encountered causes:

Decreased Intake ‐ mal‐absorption syndromes ‐ malnutrition ‐ TPN Increased losses Gastrointestinal ‐ diarrhoea ‐ repeated NG suctioning ‐ vomiting ‐ fistulae ‐ villous adenoma Renal ‐ renal tubular acidosis ‐ diuretic phase of ATN ‐ diuretics ‐ Conns syndrome ‐ renal replacement therapy Increased Utilisation / chelating / intracellular shift ‐ refeeding syndrome ‐ hungry bone syndrome ‐ hyperthyroidism ‐ hyperparathyroidism ‐ aminoglycoside administration ‐ amphotericin B administration ‐ cyclosporin administration ‐ pancreatitis

Treatment largely involves intravenous or enteral replacement.

Hypermagnesaemia in contrast is almost always iatrogenic in nature. As a pharmacological agent, magnesium has primarily been used in high doses in the management of pre‐eclampsia, although potential toxicity may still occur with conventional doses and renal impairment. Clinical features include; drowsiness, hyporeflexia (a commonly used clinical indicator of toxicity), weakness, coma, vasodilation (particularly when administered rapidly), and hypotension. Conduction defects in the SA and AV node can also be recognised.

Treatment involves administration of calcium to rapidly treat the conduction deficit, followed by means to reduce the magnesium concentration, including diuretics and/or the use of renal replacement therapy.

4.0 Disorders of Calcium

Calcium is primarily stored in the bony skeleton, with a normal total plasma concentration of 2.15‐ 2.55mmol/l. A significant proportion is protein bound, and therefore the total concentration should be corrected for the albumin level. The free ionised fraction is the biologically active component, and normally ranges between 1.15‐1.35mmol/l.

4.1 Hypercalcaemia

Common clinical features: hypertension, arrhythmia, weakness, depression, psychosis, seizures, coma, anorexia, nausea and vomiting. Sequelae include nephrocalcinosis, tubular dysfunction and acute kidney injury. Of note the key laboratory findings in multiple myeloma will include; hypercalcaemia, elevated total protein concentration, and a low anion gap.

Different categorisation systems for hypercalcaemia exist, although a useful way of approaching the problem is to consider potential aetiologies related to malignancy versus non‐neoplastic processes. The table below summarises the causes associated with neoplasia.

Non‐neoplastic mediated mechanisms include:

‐ Post hypocalcaemic hypercalcaemia ‐ Addisons disease ‐ Prolonged immobilisation ‐ Hypovolaemia ‐ Granulomatous disease (Sarcoid) ‐ Vit A and Vit D intoxication ‐ Thyrotoxicosis ‐ Drugs (thiazides, lithium) ‐ Total parenteral nutrition ‐ Disorders of magnesium metabolism ‐ Benign hypocaliuric hypercalcaemia

The management of hypercalcaemic crisis involves two parallel processes: a) Management of the underlying disease process ‐ For multiple myeloma this involves ensuring adequate volume resuscitation, possible plasma exchange for hyperviscosity syndromes, administration of bisphosphonates, and the administration of corticosteroids. b) Reduction in the plasma calcium concentrations via: ‐ Increasing calcium excretion in the urine using volume expansion with normal saline, and forced diuresis with loop diuretics. In those patients with acute kidney injury, renal replacement therapy should be considered. ‐ Reduced bone re‐absorption by using bisphosphonates

4.2 Hypocalcaemia

Clinical features: circumoral and peripheral paraesthesiae, cramps, tetany, trousseau's sign, chvostek's sign, seizures, proximal myopathy, depression, anxiety, psychosis, arrhythmia, hypotension, apnoea, laryngospasm, bronchospasm and coagulopathy.

ECG changes: prolonged QT interval, T‐wave inversion.

Common causes:

Vitamin D Deficiency ‐ inadequate intake / UV exposure ‐ mal‐absorption syndromes ‐ liver disease ‐ renal disease Increased Excretion / Reduced Bony turnover ‐ Loop Diuretics ‐ Osteoperosis ‐ Cachexia ‐ Bisphosphonate administration ‐ Hypoparathyroidism Calcium chelation ‐ alkalosis ‐ citrate toxicity (massive red cell transfusion and concurrent liver surgery) ‐ hyperphosphataemia (rhabdomyolysis, tumor lysis syndrome) ‐ pancreatitis ‐ ethylene glycol poisoning ‐ EDTA administration

Hypoparathyroidism is infrequently encountered in the critically ill, other than post parathyroidectomy or thyroidectomy. In particular, chronic renal failure patients requiring parathyroidectomy for secondary hyperparathyroidism will often need intravenous infusions of calcium in the first 12‐24hours post op in order to prevent symptomatic hypocalcaemia. This will require repeated measurements of the ionised calcium concentration and adjustment of the infusion rate, aiming for a level of 1.25mmol/l.

5.0 Bibliography

E Ellison DH, Berl T. The syndrome of inappropriate antidiuresis. N Engl J Med 2007, 356:2064‐72.

Delaney A, Finfer S. Fluid and electrolyte therapy. In Oh's Intensive Care Manual, 6th edition. Eds: Berston AD and Soni N. Butterworth Heinemann Elsevier, 2009.

Stewart AF. Hypercalcaemia associated with cancer. N Engl J Med 2005, 352:373‐9.

Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000, 342:1493‐99.

6.0 MCQ Questions

1) Useful criteria to diagnose SIADH, include the following, EXCEPT: a) Urinary osmolality < plasma osmolality b) Urinary sodium concentration > 20 meq/l c) Hypotonic hyponatraemia d) Normal thyroid function e) Absence of adrenal insufficiency

2) With hyponatramia: a) The plasma sodium concentration should be corrected as rapidly as possible b) Patients should never receive hypertonic solutions c) Asymptomatic patients with chronic hyponatraemia can be fluid restricted d) All patients should receive hydrocortisone e) Central pontine myelinolysis is less common with chronic alcohol intake

3) A cause of hyperkalaemia includes: a) Vomiting or high nasogastric losses b) Cushings syndrome c) Hypothermia d) Thiopentone coma e) Digoxin overdose

4) The management of hypercalcaemia includes the following, EXCEPT: a) Fluid resuscitation b) Thiazide diuretics c) Loop diuretics d) Corticosteroids e) Bisphosphonates