Fluid and Electrolytes

Pathophysiology

• Total body water = 60% BW (closer to 50% in females)
  • Decreases with age
  • ICF = 2/3 = 40% BW
  • ECF = 1/3 = 20% BW
    • Plasma = ¼ = 5% BW
    • Interstitial = ¾ = 15% BW
• Three homeostatic equilibriums govern fluid behaviours
  • Osmotic equilibrium
  • Electrical equilibrium
  • Acid-base equilibrium
• Intracellular Na 10 vs extracellular 140

Water homeostasis

• Intake controlled by thirst centres that respond to plasma osmolality
  • <280 = Impaired ADH release allowing maximal urinary dilution
  • >280 = ADH release
  • >295 = Maximal ADH release
  • An increase in osmolality due to permeant solutes (e.g. urea) does not stimulate ADH release
• Excretion controlled by renal action of ADH
  • Renal response to ADH depends upon functional distal nephron/collecting duct, hypertonic medullary interstitium and delivery of an osmolar load to the distal nephron

Disorders of osmolality

• Tonicity
  • Osmolality is osmol/kg and due largely to sodium salts
  • Permeant solutes
    • Distribute throughout all fluid compartments
    • Urea, alcohol
  • Impermeant solutes
    • ECF only
    • Result in shift of fluid from ICF to ECF
    • Hyperosmolality due to impermeant solutes = hypertonicity

Sodium

• Principle cation of the body and accounts for 86% of ECF osmolality

Sodium homeostasis

• 65% of filtered sodium reabsorbed with equivalent water reabsorption in proximal convoluted tubule
• Thin ascending limb of Loop of Henle
  • Early part permeable to water and enables water reabsorption driven by high osmolality interstitium
  • Later part impermeable to water but Na diffuses into medullary interstitium along concentration gradient (dependent on medullary recirculation of urea)
• Thick ascending limb of Loop of Henle
  • 25% of filtered sodium is reabsorbed here
  • Impermeable to water so get dilution of intratubular fluid as electrolytes reabsorbed
  • The higher the delivery of chloride, the greater the activity of NaK2Cl and the higher the rate of hyperosmotic Na reasborption

Sodium homeostasis

• Counter-current exchange mechanism
  • At any level in the vasa recta, the solute concentration in the descending limb is less than the ascending limb, causing NaCl to diffuse from ascending to descending while water moves from descending to ascending
  • This maintains the hyperosmolar medullary interstitium
• Counter-current multiplier
  • The above exchange of water only works as the osmolarity in the vasa recta increases at the bottom thanks to the multiplier effect of the loop of Henle
  • NaCl is moved out of the ascending limb and DCT, creating a hyperosmolar medullary interstitium
  • NaCl then diffuses into the descending limb of the Loop of Henle

Formation of concentrated urine

• In presence of ADH, AQP-2 allows free water transport from hypo-osmotic late DCT into the hyperosmolar interstitium
• NaCl is continually reabsorbed along length of DCT until fluid isotonic at end of cortical collecting duct
• Relatively small amount of isotonic fluid at medullary collecting duct continues to lose water to hyperosmolar interstitium

Formation of dilute urine

• In absence of ADH, hypo-osmotic fluid in DCT continues to be diluted further by transport of NaCl along collecting duct
• Water reabsorption is limited so tubular fluid becomes more and more dilute along remainder of tubules

Pathophysiology

• Effective osmolality = Tonicity
  • = 2xNa + Urea + Glucose

Hyponatraemia

• Condition of excess water relative to sodium
• Defined as <138 (symptoms <135)
• Urine osmolality is always >100 except in psychogenic polydipsia
• Mild hyponatraemia 15-30% of hospitalised patients
• 1-4% of hospitalised patients have Na <130
• 50% of cases are iatrogenic due to hypotonic fluids
• Differential based on serum osmolality and then fluid status
• Hyperosmolar hyponatraemia (Posm >295)
  • Large quantities of impermeant solutes accumulate in ECF and get fluid shift from ICF to ECF, thus diluting ECF sodium
  • Glucose, mannitol, glycerol, maltose can all dilute ECF sodium
  • If raised osmolar gap, this will cause an osmotic diuresis with loss of Na requiring saline rehydration
  • Other agents like methanol, ethanol, urea and ethylene glycol may cause a raised osmolar gap but do not cause an osmotic diuresis and do not cause hyponatraemia
• Iso-osmolar hyponatraemia (Posm 275-295)
  • Pseudohyponatraemia due to severe hyperproteinaemia or hypertriglyceridaemia
  • Cause laboratory misinterpretation rather than actual hyponatraemia
  • Can be seen in TURP syndrome
  • TURP syndrome
    • Hyponatraemia, cardiovascular disturbance (hypertension, hypotension, bradycardia), ALOC (agitation, confusion, nausea, vomiting, myoclonic and generalised seizures) and transient visual disturbance (blurred vision, blindness and fixed dilated pupils– seen with glycine only)
    • Due to intravesical glycine irrigation fluid with subsequent venous sinus absorption (also seen following endometrial ablation
    • Glycine can act as GABA agonist and potentiate NMDA receptors
    • Can present 15 minutes to 24 hours after procedure
    • Usually fluid overloaded + iso-osmolar hyponatraemia
    • Rx: Supportive
      • If hypotensive, bradycardic or unresolving neurological disturbance – consider HD
      • If measured osmolality <260mOsm/kg, with severe non-visual neurological disturbance – hypertonic saline
• Hypo-osmolar hyponatraemia (Posm <275)
  • Develops due to increased ADH with impaired water excretion and increased water reabsorption
  • In CCF, cirrhosis, nephrotic syndrome, effective arterial blood volume is reduced as fluid accumulates in ECF with subsequent ADH release, sodium and water reabsorption and reduced water excretion
  • SIADH and cerebral salt wasting are diagnoses of exclusion
  • MDMA intoxication is an important cause  as induces inappropriate ADH release and increased gut water absorption
  • Hypervolaemic hypo-osmolar hyponatraemia (urine Na normally <20)
    • CCF, cirrhosis, nephrotic syndrome, acute and chronic kidney disease
  • Euvolaemic hypo-osmolar hyponatraemia (normally urine Na >20; Uosm >100)
    • Psychogenic polydipsia (urine Na <10)
    • Glucocorticoid deficit
    • Hypokalaemia
    • Drugs (thiazides most commonly)
    • SIADH
    • Beer potomania (tea and toast diet)
      • Low solute intake means kidneys cannot excrete free water without adequate solute excretion
  • Hypovolaemic hypo-osmolar hyponatraemia
    • Urine Na >20; Uosm >100
      • Renal: Diuretics, mineralocorticoid deficit (decreased cortisol), salt-losing nephropathy (low urate), cerebral salt-wasting, post-obstructive diuresis, hypokalaemia
    • Urine Na <20; Uosm >100
      • Extra-renal: Vomiting (metabolic alkalosis), diarrhoea (metabolic acidosis), excessive sweating (no acidosis/alkalosis)
        • In vomiting get renal Na loss to counteract metabolic alkalosis as Na needs to be excreted with bicarb in urine

Causes of SIADH

• Neuropsychiatric
  • Infections: Meningitis, encephalitis, brain abscess
  • Vascular: Thrombosis, haemorrhage, temporal arteritis, cavernous sinus thrombosis, stroke
  • Malignancy
  • Traumatic brain injury
  • Psychosis, delirium tremens
  • GBS
• Drugs: Cyclophosphamide, Carbamazepine, Vinca alkaloids, haloperidol, SSRI, SNRI, narcotics, amiodarone, desmopressin
• Lung disease: TB, lung abscess, acute respiratory failure
• Ectopic vasopressin release: Carcinoma of lung (small cell, bronchogenic), duodenum, pancreas, thymus, olfactory neuroblastoma, bladder, prostate, uterus, lymphoma, leukaemia, sarcoma

SIADH diagnosis

• Hypotonic hyponatraemia with Posm <275
• Inappropriately elevated Uosm >200 (usually)
• Urine Na >20
• Clinical euvolaemia
• Normal adrenal, renal, liver, cardiac and thyroid function

Beer potomania (tea and toast)

• Low solute/high fluid diet
• Lack of solute + alcohol and carb load suppresses protein breakdown and urea excretion (necessary for urinary water excretion)
• Daily solute excretion falls to 240mosm and even with maximally dilute urine (60mosm/kg) daily water excretion falls to 4L per day (240 / 60)
• If becomes dehydrated get ADH release and acute on chronic hyponatraemia ensues

Cerebral salt wasting

• Excessive renal loss of sodium and chloride in the setting of intracranial pathology
• Hyponatraemia is common but not necessary
• Diagnosed by elevated urine output, elevated urinary sodium in absence of physiological cause for increased sodium excretion
• Differentiated from SIADH
  • Cerebral salt wasting show hypovolaemia vs. SIADH euvolaemic
  • Need to replace sodium and fluid losses and consider fludrocortisone
• Acute onset
  • More common in young women
  • Na may change >0.5mmol/L/hr
  • Mortality 90%
• Chronic onset
  • More common. M=F
  • More common in the elderly
  • Mortality 10%

Reset osmostat syndrome

• Na 125-130 but stable
• Due to downward reset of Na at which ADH secretion ceases
• Causes
  • Pregnancy
  • Hypovolaemia
  • Quadriplegia
  • Psychosis
  • TB
  • Encephalitis
  • Malignancy
  • Malnutrition
• Diagnostic criteria
  • Normovolaemic hyponatraemia
  • Normal adrenal, renal, thyroid, cardiac, hepatic fx
  • Excretion of >80% of a 10-15mL/kg water load within 4 hours
  • Urine osmolality <100mosm/kg after water loading test (normal urine diluting ability)
  • Ability to concentrate urine at serum osmolality above reset level

Hyponatraemia treatment

• Guided by four variables:
  • Severity
  • Rate of onset
  • Volume status
  • Current serum Na
• Sodium deficit = (140-serum Na) x Total body water
  • Aim to replace over number of days it took to occur or maximum 6mmol/L/24hrs (12 in low-risk patients)

Hyponatraemia Treatment

• Expected change in Na = Infuse Na – serum Na/(Total body water +1)
  • Total body water = 60% of total body weight for males <65; 50% for females <65 and elderly males; and 45% for elderly females)
  • This is the expected change for 1L of solution so can then workout how much of specific solution is required to raise the Na a given amount
  • N/S = 154mmol/L
  • Half N/S = 77mmol/L
  • Hartmann’s = 130mmol/L
  • 3% sodium chloride = 513mmol/L
  • 5% dextrose = 0mmol/L

Hyponatraemia treatment

• If Na <120 with severe neurological symptoms and hyponatraemia is acute, 3% saline is indicated
  • Typically a rise of 4-6mmol/L is sufficient to improve neurological symptoms
  • In seizures or coma, give 100mL 3% saline over 10-15 minutes and re-measure Na/reassess patient
  • Can repeat up to 3 times until improvement in symptoms or Na risen by 4-6
  • Most commonly required if self-induced water intoxication, MDMA intoxication, intracranial pathology or increased intracranial pressure

Hyponatraemia treatment

• If not severe symptoms or once symptoms settled or Na risen by 4-6, need to stop or reduce 3% saline
  • If acute hyponatraemia and ongoing mild/moderate symptoms can run 3% saline at 0.5-2mL/kg/hr with frequent Na checks and replacement of any K/Na lost in urine
  • If no symptoms, can just run N/S TKVL and institute cause-specific therapy
  • If chronic hyponatraemia, need to limit Na rise to <6mmol/24 hours in high-risk patients and <12mmol/24 hours in low-risk patients
    • Can provide 3% saline at 0.5-1mL/kg/hr, normal saline or institute cause-specific therapy

Hyponatraemia treatment

• Cause-specific therapy
  • CCF/cirrhosis: Loop diuretics and water restriction
  • Nephrotic syndrome: Water restriction
  • Acute or chronic kidney disease: Water restriction
  • Psychogenic polydipsia: Water restriction
  • Hypothyroidism: Thyroxine
  • Glucocorticoid deficiency: Hydrocortisone
  • SIADH: Water restriction
  • Diarrhoea/vomiting: N/Saline +- KCl
  • Diuretics (thiazides): Stop diuretic. KCl if hypokalaemic +- oral NaCl
  • Mineralocorticoid deficiency: Replace volume deficit and fludrocortisone once confirmed
  • Salt-losing nephropathies: N/S
  • Cerebral salt wasting: N/S +- fludrocortisone once diagnosis confirmed

Hyponatraemia treatment

• Osmotic demyelination syndrome
  • Intracellular dehydration due to too rapid Na correction (>12/24 hours)
  • Risk factors include:
    • Na <120
    • Elderly
    • CCF
    • Alcoholism
    • Cirrhosis
    • Hypokalaemia
    • Malnutrition
    • Treatment with vasopressin antagonists
  • Presentation: Dysarthria, dysphagia, lethargy,paraparesis, quadriparesis, seizures, coma and death
  • Treatment: 5% dextrose at 3mL/kg/hr + loop diuretics + desmopressin to drop Na again
• Pontine myelinolysis
  • Dysarthria
  • Dysphagia
  • Flaccid quadriparesis
• Extra-pontine myelinolysis
  • Tremor
  • Ataxia
  • Mutism
  • Parkinsonism
  • Dystonia
  • Catatonia

Hypernatraemia

• Na >145 with hyperosmolality (>295)
• Results from deficit in total body water and/or net gain of sodium
• Causes
  • Impaired ability to drink free water
  • Impaired thirst
  • Impaired kidney concentrating ability
  • Increased salt intake
  • Loss of free water in stools or urine
• Risk factors
  • Elderly
  • Decompensated diabetics
  • Infants
  • Hospitalised patients
• Clinical features
  • If rapid onset, can shrink brain to cause ICH
  • If corrected too quickly can lead to cerebral oedema and raised ICP
  • General
    • Lethargy, vomiting, weakness, increased thirst, reduced water intake, polyuria (>3L/24 hours), coma and seizures
  • May have diabetes, hypercalcaemia, hypokalaemia,
  • May be on lactulose, loop diuretics, lithium, demeclocycline (DI) or NSAID’s (interstitial nephritis)
  • Signs of Cushing’s syndrome may be evident
• Diagnosis
  • BUN/creatinine ratio >40 suggests hyperosmolar dehydration
• Free water deficit = Total body water x (Posm – 285)/Posm
• Posm = 2x Na + Glucose + Urea
• Uosm can be measured or approximated by urine specific gravity (Pi) by using digits in hundredths and thousandths decimal places as a whole number and multiplying by 35

• Hypervolaemic hypernatraemia (UNa >20, Uosm >100)
  • Cushing’s
  • Primary hyperaldosteronism
  • Salt water intake
  • Iatrogenic
• Normovolaemic hypernatraemia (UNa >20)
  • Central diabetes insipudus (Uosm <300)
  • Nephrogenic DI
  • Hypodipsia or extrarenal water loss (urine osmolality >800)
• Hypovolaemic hypernatraemia (loss of Na > water)
  • Renal (Una >20, Uosm >100)
    • Osmotic diuretics, loop diuretics or post-obstructive diuresis
  • Extrarenal (Una <10; Uosm >800)
    • Vomiting, diarrhoea, GI fistulas, sweating, burns, DI

• Treatment
  • Treat any hypoperfusion with N/saline
  • Maintenance fluids 0.45% N/S
  • Treat any underlying cause (e.g. DI, fever, vomiting, fever)
  • Correct free water deficit reflecting acuity and duration of onset
    • If onset <48 hours, can correct at 1mmol/L/hr
      • If alert and capable of drinking, replace deficit 2/3 free water orally and 1/3 IV 5% dextrose
    • If onset >48 hours, correct at rate up to 0.5mmol/L/hr or 10-12mmol/24 hours using 5% dextrose
• Prognosis
  • Mortality 50-70% (75% if Na >160)

Hypernatraemia
 – Diabetes insipidus

• Inability to reabsorb free water
• Polyuria, polydipsia and increased volume hypo-osmolar urine
• Hypernatraemia results when thirst drive or ability to drink free water is impaired
• Central (inadequate ADH release)
  • Treated with PO or nasal spray desmopressin
• Nephrogenic (insensitivity to ADH)
  • Treated with combination low-salt, low-protein diet, adequate hydration, thiazide diuretic, amiloride and indomethacin
• May be congenital or acquired
• Diagnosis required water deprivation testing +- cerebral MRI

Nephrogenic DI

• Renal: Amyloid, medullary sponge kidney, PCKD, pyelonephritis
• Drug-related: Ethanol, phenytoin, lithium, amphotericin
• Electrolyte: Severe hypokalaemia, hypercalcaemia
• Congenital
• Myeloma
• Sarcoidosis

Potassium homeostasis

• 98% intracellular (70-75% intramuscular)
• Normal intracellular concentration = 150mmol/L
• Normal extracellular = 3.5-5.0mmol/L
• Filtered freely at glomerulus and reabsorbed in proximal and ascending tubules
• Secreted in distal tubule in exchange for sodium
• Estimated K deficit = Expected serum K – measured serum K ) x ICF volume (40% of total body weight)
  • Only reliable for well patients, as the critically ill have dramatic shifts
• It is possible to have serum hyperkalaemia in setting of total body deficit (e.g. DKA) and vice versa
• Most important factor in determining transmembrane potential
• Chronic changes allow intra/extracellular shifts to maintain normal resting membrane potential and therefore is far less dangerous than dramatic acute shifts

Hypokalaemia

• K <3.5
• Most common causes
  • Insufficient dietary intake
    • Eating disorders
    • Alcoholism
  • Intracellular shifts
    • Alkalosis, aldosterone
    • Insulin, beta-2 agonists
    • Hypokalaemic periodic paralysis (thyrotoxic or hypokalaemic)
  • Increased losses
    • GIT losses
      • Vomiting, diarrhoea, NG suction, fistulas
      • Spot urinary K < 20mmol/L
      • pH <7.4 = lower GI losses vs. pH >7.4 = upper GI losses
    • Renal losses
      • Spot urinary K >20mmol/L
      • Hyperaldosteronism – Hypertension in absence of renal impairment with associated metabolic alkalosis, hyperNa and hypoK
        • Primary or secondary (CCF, cirrhosis, chronic kidney disease, renal artery stenosis, Liquirice
        • Liddle’s syndrome
      • Normal BP
        • Metabolic alkalosis – Diuretics, Barterr’s
        • RTA – Type 1
      • Normal pH
        • HypoMg, following ATN, leukaemia
• Causes
  • Osmotic diuresis
  • Diuretics (CA inhibitors, thiazides, loops)
  • Licorice
  • Renal tubular acidosis (I and II)
  • Post-obstructive diuresis
  • Bartter’s syndrome (mimics loop diuretics)
  • Gitelman’s syndrome (mimics thiazides)
  • Apparent mineralocorticoid excess (Liddle’s, Conn’s)
  • Drugs (penicillin, aminoglycosides, lithium, steroids, theophylline)
• Clinical features
  • Resting membrane potential is more electronegative resulting in enhanced depolarisation, delayed repolarisation
  • Potentiates digitalis toxicity
  • Prolonged QTc, flat T waves and appearance of U waves
• Diagnosis
  • Urinary electrolytes, osmolarity and plasma osmolarity
  • If Una <30 + Uosm < Posm = Polyuria
  • Transtubular K gradient = (Uk x Posm)/(Uosm x Pk)
    • Normally 8-9mmol/L
    • If <5 suggests hyperaldosteronism
    • If <3 with paralysis, suggests hypokalaemic periodic paralysis
  • Ca/Phosphate ratio >1.7 on a spot urine is diagnostic of thyrotoxic hypokalaemic periodic paralysis

Hypokalaemia–Interpretation of urine K

• Uk <10
  • Decreased K intake; non-renal losses
    • GI, sweat, NG suction
    • Transcellular shift in alkalosis, hypomagnesaemia, hypokalaemic period paralysis
• Uk >20
  • Renal losses
    • Hyperaldosteronism
    • Massive GI losses

Hypokalaemia – Treatment

• Treat underlying cause
• Orally if K >3 and stable
• IV replacement if K <2.5 (severe) or if symptomatic at 2.5-3
  • Monitor rhythm while replacing
  • Avoid administering K with glucose (leads to insulin-induced K shift into cells)
  • Maximum 40mmol K/500mL of saline over 4 hours via single peripheral line
    • = Maximum 10mmol/hour via single IV
  • Can give identical solution via second peripheral IV if necessary
  • Can administer higher concentrations via CVL
  • Use large vein if peripheral replacement is necessary
• Most patients are also hypomagnesaemic so add 20-60mmol/24 hours to infusions
  • Also contrasts the pro-arrhythmic effect of hypokalaemia

Hyperkalaemia

• K >5.5
• Most common cause is factitious
• Clinical features
  • Resting membrane potential becomes less electronegative, with partial depolarisation and subsequent reduced activation of voltage-dependent Na channels leading to slower and reduced amplitude action potential + more rapid repolarisation
  • ECG effects 50% sensitive for K >6.0
  • Everything gets stretched apart from short QT
  • 6.5-7.5: Prolonged PR, tall T waves, short QT
  • 7.5-8: Flattened P wave, QRS widening
  • 10-12: QRS degradation into sinusoidal pattern
  • VF, sinoatrial and AV blocks, complete heart block and asystole can occur
  • Weakness, paraesthesias, areflexia, ascending paralysis and nausea/vomiting/diarrhoea are common
• Causes
  • Pseudohyperkalaemia: Tourniquet, haemolysis (in vitro), leukocytosis, thrombocytosis
  • Intra- to extracellular shift: Acidosis, exercise, beta-blockers, insulin deficiency, digitalis toxicity, hyperkalaemic period paralysis
  • Potassium load: Supplements, IV, old blood transfusion, GI bleeding, tumour lysis syndrome, rhabdo, necrosis, digoxin
  • Decreased excretion: Renal failure, potassium-sparing diuretics, beta-blockers, NSAID’s, ACEi, ARB
    • Aldosterone deficiency
    • Selective deficit in K excretion: SLE, sickle cell disease, obstructive uropathy, renal transplant, Type IV RTA
    • Uncommon for renal failure to be sole cause if Creatinine < 800micromol/L
    • K >5.5 uncommon if eGFR >20 and >10% of renal function remains
• Diagnosis
  • Usually evident on history
  • Spot urine K >20 suggests extrarenal cause (i.e. kidneys are trying to get rid of it)
  • Spot urine K <10 suggests oliguric kidney failure or drug effect e.g. ACEi/ARB
  • Stat ECG to determine level of treatment
• Treatment
  • ECG changes
    • IV CaCl 10% (3x more potent) 5-10mL or CaGluconate 10% 10-20mL over several minutes
      • Raises threshold potential, restoring the membrane potential and myocardial excitability to normal
      • Can repeat up to 4 times per hour
      • Takes 1-3 minutes to work and lasts 30-60min
      • Either drug is an option. No clear benefit of one over another
  • Cease all drugs contributing to hyperkalaemia
  • Administer fluids to enhance renal excretion
  • If on digitalis, hypercalcaemia may enhance cardiotoxic effects of this but in severe hyperkalaeia with ECG changes, need to still provide calcium +- digibind
    • Give slowly over 20-30 min in 100mL 5% dextrose in this situation
    • Alternatively can use MgSO4 to stabilise cardiac membrane instead
  • Continuous ECG monitoring

• Sodium bicarbonate 50-150mmol can be considered if life-threatening or concomitant severe acidosis (5-10min onset; 1-2hr duration)
  • No clear evidence of reduction in K but may be an option if acidotic
• Nebulised salbutamol 10-20mg over 10 minutes (15-30min onset; 2-4hr duration) – Single neb 5mg reduces K by 0.2-0.4mmol/L
• 10U Actrapid in 50mL 50% dextrose (30 min onset; 4-6 hour duration)
  • Most effective means of reducing K
• Frusemide 40-80mg IV stat
• Resonium 25-50g PO or PR (1-2 hour onset; 4-6 hour duration)
  • Significant sodium load
  • Affects absorption of other orally given medications (wait 6 hours after other meds)
• Haemodialysis

BRASH syndrome

• Bradycardia out of proportion to degree of hyperkalaemia
• Renal failure
• AV nodal blockers
• Shock/Hypovolaemia
• Hyperkalaemia

Magnesium homeostasis

• Intracellular 40mmol/L
• Serum Mg 1.5-2.5
  • 1/3 protein-bound
  • 10-15% complexed
  • 50-60% ionised (active portion)
  • 60% excreted in stool and 40% renal
    • Renal reabsorption is paired with sodium and water and unidirectional (impaired by volume overload, osmotic diuresis and diuretics as these are situations where sodium and water reabsorption are impaired)

Hypomagnesaemia – causes

• Redistribution – IV glucose, correction of DKA, refeeding, acute pancreatitis, post-parathyroidectomy (hungry bone syndrome)
• Extrarenal losses – NG suction, lactation, sweating, burns, sepsis, fistula, diarrhoea
• Decreased intake – Alcoholism, malnutrition, small bowel resection, malabsorptive syndrome
• Renal loss – Ketoacidosis, saline/osmotic diuresis, potassium depletion (K preferentially reabsorbed), phosphorous depletion (same), tubulointerstitial renal disease
• Drugs – Loop diuretics, aminoglycosides, Vitamin D intoxication, alcohol, theophylline, PPI, tacrolimus
• Endocrine – SIADH, hyperthyroidism, hyperparathyroidism, hypercalcaemic states, hyperaldosteronism

Hypomagnesaemia

• Respiratory alkalosis can cause rapidly reduced Mg and Ca
• Clinical features
  • <0.5 = Seizures, tetany, arrhythmias
  • 0.5-0.7 = Neuromuscular irritability
  • Neuromuscular – Tetany, paraesthesia, weakness, Chvostek/Trousseau signs, cerebellar signs, confusion, coma, seizures, depression, irritability
  • GI: Dysphagia, nausea, anorexia
  • CVS: HF, dysrhythmias, hypotension
    • 2-3x risk of AF and SVT following AMI (hence high-risk protocol)
    • Potentiates digoxin toxicity
    • Prolonges QT to increase risk of TdeP
    • Decreases risk of AV block in AMI
  • Hypokalaemia, hypocalcaemia, anaema
• Diagnosis
  • 12% of hospitalised patients and 65% in ICU patients
  • ECG changes can be similar to hypokalaemia
  • Enhances digitalis toxicity
  • Should correct for albumin level (affects ionised portion)
    • Corrected Mg = Measured Mg + 0.005 x (40-albumin)

Hypomagnesaemia – Treatment

• Need to replace deficits in Mg, K, Phosphate and Ca together usually
• Treat or stop cause
• Oral supplementation if asymptomatic (multiple low doses throughout day to avoid diarrhoea)
• 1g = 4mmol = 8mEq 
• In an emergency
  • 5mmol IV bolus
  • 10mmol over 10-15 min if less acute
• 1-4g in 100mL of 5% dextrose or N/S over 10-60min under ECG monitoring if severe/eclampsia
  • Need continuous ECG and BP monitoring
  • Monitor for hypoventilation due to paralysis
• Chronic deficiency may require >50mmol (6g MgSO4) per day
  • May give 8-12g over first day with first 1.5-2g over 1-2 hours then 4-6g per day
• Spironolactone is effective at maintaining Mg levels in CCF

Hypomagnesaemia – Treatment

• Adverse effects of MgSO4
  • Flushing, hypotension, flaccid paralysis, weakness, respiratory weakness
  • Bradycardia
  • Worsening hypocalcaemia

Hypermagnesaemia

• Rarely seen in ED as kidney can increase fractional excretion to 100%
• Causes
  • Mostly seen in kidney failure or treatment of pre-eclampsia
  • Possible life-threatening consequence of magnesium-containing laxative abuse
  • Lithium, volume depletion or familial hypocalciuric hypercalcaemia
• Consider if hyperkalaemic or hypercalcemic
• Only accumulates if eGFR <30
• Treatment
  • Cease Mg
  • IV fluids + Frusemide
  • Calcium directly antagonists cardiac effects by reverting the calcium channel block induced by magnesium
  • Treat as per hyperkalaemia with Calcium 10-20mL of CaGluconate 10% = 5mL CaCl2
  • Dialysis if necessary

Hypermagnesaemia

• Clinical effects
  • 3.0 – Nausea, vomiting, cutaneous flushing
  • 4.0 – Deep tendon reflex depression, drowsy, unsteady, sweating
  • 5.0 – QRS widening, PR prolongation
  • 6-7 – Stupor, hypotension, bradycardia
  • 10 – Absent reflexes, skeletal muscle paralysis
  • 15 – Complete HB, apnoea

Calcium homeostasis

• 99% bound in bone as phosphate and carbonate
• 1/3 absorbed by small bowel by active Vitamin-D dependent mechanism and passive concentration-dependent absorption
• Excretion is primarily via stools
• Plasma calcium is 2.2-2.7mmol/L. iCa is 1.1-1.4mmol/L (50% of total)
• Protein-bound makes up 40% and complexed (10%) to phosphate, carbonate and citrate
• Alkalosis reduces the ionised portion, resulting in paraesthesia
  • Each 0.1 pH rise in pH lowers ionised Ca by 3-8%
  • Opposite in acidosis
• 1,25-Vitamin D3
  • Formed in distal tubule
  • Promotes small intestinal absorption, increases renal calcium reabsoption and increases osteoclastic Calcium release from bone
• PTH
  • Secreted by parathyroid when serum calcium low regulated by Ca-SR, Vitamin D3 and Mg (hypomagnesaemia inhibits PTH)
  • Stimulates bone demineralisation to release Ca via osteoclasts, increases VitD3 synthesis and increases Ca reabsorption from kidneys while increasing phosphate excretion
• Calcitonin
  • Peptide by C-cells of thyroid released when Ca is high to inhibit osteoclastic bone resorption, 1 alpha Vitamin D hydroxylase activity, gastric motility, gastrin secretion and jejunal absorption of Ca and Phosphate
  • Increases ALP synthesis by osteoblasts
• Ca-sensing receptor (Ca-SR)
  • Activated in hypercalcaemia to inhibit PTH release, promotes hypercalciuria and polyuria to prevent nephrocalcinosis + stimulates calcitonin release
• Urinary calcium secretion
  • Enhanced by hypercalciuria, metabolic acidosis, hypervolaemia, loop diuretics
  • Inhibited by PTH, Vitamin D3, alkalosis, hypovolaemia and chronic thiazide use

Hypocalcaemia

• iCa <1.1mmol/L
• Causes
  • Decreased absorption:
    • Vit D deficiency (malnutrition, gastrectomy, liver failure, renal failure), malabsorptive syndrome
  • Increased excretion/reduced bone resorption
    • Alcoholism: Hypomagnesaemia inhibits PTH release
    • Hypoparathyroidism (post-surgical, autoimmune, parathyroid infiltration, hungry bone syndrome, HIV)
    • Pseudohypoparathyroidism (resistant to effect)
    • Hypomagnesaemia (inhibits PTH release)
    • Drugs (Phosphates, phenytoin, gentamicin, cisplatin, citrate, loop diuretics, glucocorticoids, magnesium sulfate, bisphosphonates, calcitonin
    • Sepsis
    • Acute pancreatitis (saponification)
    • Massive transfusions (Citrate excess)
    • Rhabdomyolysis
• Causes
  • Low PTH
    • Post-surgical 
    • Autoimmune hypoPTH
    • Parathyroid gland infiltration
    • Radiation-induced hypoPTH
    • Hungry bone syndrome
    • HIV infection
  • High PTH
    • Vitamin D deficiency or resistance
    • PTH resistance
    • Renal disease – Phosphate retention, impaired Vit D conversion
    • Hyperphosphataemia, tumor lysis syndrome, acute pancreatitis, osteoblastic metastases, acute respiratory alkalosis, sepsis
  • Drugs
    • Chelators (citrate, lactate, EDTA)
    • Cinacalcet
    • Phenytoin
    • Fluoride poisoning
  • Disorders of Magnesium metabolism
    • Can reduce PTH release or inhibit response
  • Spurious
    • Gadolinium-based contrast can interfere with calcium assays

• Hypocalcaemia with metabolic acidosis narrows differential significantly
  • Acute renal failure
  • Tumor lysis syndrome
  • Rhabdomyolysis
  • Pancreatitis
  • Ethylene glycol poisoning
  • Hydrofluoric acid intoxication
• Clinical features
  • Weakness, fatigue, spasms, cramps
  • Tetany, Chvostek’s, Trousseau’s, paraesthesia, confusion, dementia, seizures, extrapyramidal disorders
  • Trousseau’s is 90% sensitive and specific
  • Hyperpigmentation, dry skin
  • CCF, ventricular arrhythmias, torsades
  • Osteodystrophy, Rickets, osteomalacia
  • Dental hypoplasia, cataracts, decreased insulin secretion
  • ECG: Prolonged QTc (ST segment specifically)
    • Like hypomagnesaemia
• Diagnosis
  • Full Chem20
  • Albumin levels
  • Blood gas (pseudohypocalcaemia in alkalosis)
  • PTH and Vitamin D3 levels (results not required prior to treatment)
• Treatment
  • If not severely symptomatic or >10 days duration – Oral supplementation +- Vit D
    • 500-3000mg elemental calcium in 1-3 divided doses per day
  • If symptomatic or severe (iCa <0.95mmol/L)
    • IV calcium gluconate in non-emergency
      • 10-30mL of 10% over 10-20 minutes q1h until symptoms resolved
    • IV calcium chloride if emergent (risk of calcinosis cutis if extravasates)
      • 10mL of 10% over 10-20 minutes until symptoms resolved
  • Use with caution if on digitalis as may potentiate digoxin toxicity
  • Replace magnesium with calcium as hypomagnesaemia inhibits PTH and Ca release from bone

Hypercalcaemia

• iCa >1.4mmol/L
• Neuromuscular weakness, reduced cardiac automaticity, shortened refractory period and increased sensitivity to digoxin
  • Bones (osteolysis), stones, moans (psychic) and groans (peptic ulcer disease, pancreatitis, constipation)
• ECG:
  • ST depression, widened T waves, shortened ST segments and shortened QTc
  • Bradyarrhythmias, BBB, second-degree and third-degree heart block
• Get loss of concentrating ability of kidney and osmotic diuresis leading to polyuria and volume depletion + potassium wasting in 1/3 of patients
• Nephrocalcinosis and nephrolithiasis can exacerbate volume depletion
• Causes (90% due to cancer or primary hyperparathyroidism)
  • Malignancy (50% of ED cases)
    • Humoral hypercalcaemia of malignancy: Tumour secretion of PTH-related peptide (PTHrP – most common cause of hyperCa in cancer patients)
    • Local osteolytic hypercalcaemia: Release of local factors, including PTHrP by bony metastases
    • Vitamin D-mediated hypercalcaemia: Autonomous production of Vit D by lymphoma cells
    • Ectopic hyperparathyroidism: Tumour production of PTH
    • Commonly multiple myeloma, leukaemia, lung cancer, breast cancer
    • Often severe, poor survival and nearly always due to paraneoplastic syndromes vs. bony mets
    • PTH levels are low
  • Primary hyperparathyroidism (25% of ED cases)
    • 80% due to single parathyroid adenoma, 15% parathyroid hyperplasia
    • <1% due to parathyroid carcinoma 
    • Usually mild-moderate elevations in serum calcium
    • Inherited forms in 10-20% (e.g. MEN-1, MEN-2, MEN-4)
    • Usually elderly females
  • Secondary hyperparathyroidism
    • Severe CKD with parathyroid hyperplasia
    • Usually low-normal serum calcium
    • May have hypercalcaemia in setting of calcium carbonate use as a phosphate binder
  • Tertiary hyperparathyroidism
    • Advanced and prolonged renal failure results in autonomous overproduction of PTH that is not suppressible by elevated serum calcium concentrations
  • Vitamin D toxicity – Ingestion, lymphoma
  • Hyperthyroidism – Due to rapid bone turnover
  • Milk-alkali syndrome – Excess dietary milk or alkali or excessive calcium supplementation
  • Sarcoidosis – Vitamin D toxicity as increases activation of 1,25
  • Immobilisation in younger people leading to bone demineralisation
  • Paget’s disease
  • Vitamin A toxicity – Increased bone turnover
  • Lithium – Reduced feedback inhibition of PTH secretion through calcium sensing leading to syndrome akin to primary hyperparathyroidism even after drug ceased
  • Thiazides – Usually after many years (Vs. frusemide causing hypocalcaemia)
  • Familial hypocalciuric hypercalcaemia
  • Rhabdomyolysis
    • Follows the early hypocalcaemic period
  • Chronic kidney disease
    • Renal failure alone usually does not lead to hypercalcaemia due to concurrent hyperphosphataemia and decreased calcitriol production
    • Can occur if receiving calcium supplementation, Vitamin D supplementation or tertiary hyperparathyroidism
  • Adrenal insufficiency
• Diagnosis
  • Most common cause of acute severe hypercalcaemia is malignancy (leukaemia, lymphoma, metaststic bone cancer)
  • Correct for albumin
    • Corrected Ca = Measured total Ca + 0.02 (40-serum albumin)
  • Serum PTH and iCa
    • PTH elevated in primary hyperPTH and low in all other states
  • Consider imaging for malignancy
  • Vitamin D levels for Vit D intoxication
  • CXR for sarcoidosis
  • Creatinine and kidney USS for chronic renal failure and Ix for secondary or tertiary hyperPTH
• Treatment
  • Symptomatic or severe: N/S at 500-1000mL/hour for 2-4 hours
    • 3-4L over first 24 hours until urine output 2L/day is achieved
    • Frusemide 20-40mg IV to promote diuresis 150-200mL/hr
    • Monitor for hypokalaemia/hypomagnesaemia
  • Steroids can limit osteoclastic activity in Addison’s, Sarcoidosis or steroid-responsive malignancies (haematological mostly +- breast Ca)
  • Haemodialysis in very severe cases
  • IV bisphosphonates in hypercalcaemia of malignancy (e.g. zoledronic acid 4mg IV over 15 minutes)
    • Normalises serum calcium in <3 days in 80-100% of patients
    • Relatively contraindicated in renal failure
  • Calcitonin works quicker at dose of 4U/kg SC or IM
    • Third-line therapy. Salmon-derived
    • Effective in only 10-30% of patients and only lasts 24-48 hours due to tolerance 

Hypercalcaemia

• Multiple myeloma
  • 80% present with bone pain and anaemia +- renal insufficiency, hypercalcaemia and/or infection

Phosphate homeostasis

• 85% as hydroxyapatite
• Regulated by gut absorption and renal excretion and tightly linked to calcium
• Duodenal absorption inhibited by calcitonin and stimulated by Vitamin D + low phosphate intake
• Jejunal and ileal absorption is passive and dependent on gut phosphate concentration only
• Urinary excretion enhanced by PTH
• Fibroblast growth factor-23 increases excretion and inhibits intestinal absorption (released by osteoclasts and blasts)
• Proximal tubule reabsorption increases with hypophosphataemia, volume depletion, hypocalcaemia or GH
• Excretion increases in volume expansion, hypercalcaemia, acidosis, hypomagnesaemia, hypokalaemia, glucocorticoids, diuretics, calcitonin and PTH

Hypophosphataemia – Causes

• Pseudohypophosphataemia in the setting of mannitol (binds to molybdate in serum causing artifically low phosphate level in lab
• Shift from ECF to ICF
  • Glucose, insulin, catecholamines and respiratory alkalosis
• Refeeding syndrome
• Reduced intestinal absorption – Low intake, malabsorption, vitamin D deficiency and chronic antacid use (calcium bicarbonate/aluminium hydroxide/MgOH)
• Increased renal excretion – HyperPTH, renal tubular acidosis, Fanconi’s syndrome, hypokalaemia, hypomagnesaemia, polyuria, acidosis
• Alcoholism, DKA (osmotic diuresis), toxic shock syndrome
• Drugs – Osmotic/loop/CA inhibitor diuretics, acyclovir, paracetamol, bisphosphonates, gentamicin (Fanconi’s-type syndrome), corticosteroids, cisplatin

Hypophosphataemia

• Seen in 30% of ICU patients and 80% of sepsis patients
• Occurs in 90% of DKA patients (usually 6-12 hours into therapy)
• Presentation
  • Haematological – Reduced survival and fx of platelets/WBC + Impaired macrophage function, impaired leukocyte/platelet function
  • Weakness, tremors, paraesthesias, decreased reflexes, confusion, anorexia
  • Impaired myocardial function and reduced threshold for ventricular arrhythmia
  • Insulin resistance
• Treatment
  • Treat underlying cause
  • IV therapy may result in hypocalcaemia (with subsequent myocardial depression, arrhythmias, acute kidney injury and calcifications)
  • If asymptomatic or mild, replace orally with 50mmol/day for 7-10 days (causes diarrhoea)

Hypophosphataemia

• Treatment
  • If moderate-severe/symptomatic
    • 8mmol Potassium phosphate over 6 hours
    • Maintenance 15mmol/day (alcoholics may require 30mmol/day)
    • 50mmol/day may be required in first 24 hours for DKA
    • Max rate 4.5mmol/hr via CVC
  • Adverse effects of infusion
    • Hypocalcaemia, hyperphosphataemia, metastatic calcification, hyperkalaemia

Hyperphosphataemia

• Causes
  • Reduced renal excretion: Acute and chronic renal failure, hypoparathyroidism, pseudohypoparathyroidism
  • Shifts from ICF to ECF: Haemolysis, rhabdo, tumor lysis syndrome, respiratory acidosis, DKA
  • Iatrogenic
    • Phosphate supplementation
    • Phosphate-containing laxatives/antacids
    • Excessive Vitamin D, GH or bisphosphate therapy
• Acute symptoms are due to hypocalcaemia, hypomagnesaemia and underlying renal failure
• May require dialysis
• Long-term treatment is with phosphate binders (calcium carbonate/calcium acetate)

Last Updated on July 3, 2024 by Andrew Crofton