15.2 Potassium, Magnesium & Phosphate Disorders
Key Takeaways
- Hyperkalaemia is stratified into mild (5.5–5.9 mmol/L), moderate (6.0–6.4 mmol/L), and severe (≥6.5 mmol/L or any hyperkalaemic ECG changes), requiring continuous cardiac monitoring and immediate tiered intervention.
- Emergency hyperkalaemia management follows a 3-step sequence: (1) myocardial membrane stabilisation with IV calcium gluconate 10% (does not lower potassium), (2) intracellular potassium shift with IV soluble insulin in dextrose and nebulised salbutamol, and (3) definitive potassium elimination with novel binders (patiromer, SZC), loop diuretics, or emergent haemodialysis.
- Hypokalaemia causes include GI losses (diarrhoea, vomiting via secondary renal wasting), renal losses (diuretics, hyperaldosteronism, RTAs), and transcellular shifts; ECG signs feature flattened T waves, ST depression, prominent U waves, and Torsades de Pointes.
- Refractory hypokalaemia is universally linked to concurrent hypomagnesaemia; intracellular magnesium is an essential cofactor for Na+/K+-ATPase and tonically inhibits ROMK channels, so potassium cannot correct until hypomagnesaemia is treated.
- Bartter and Gitelman syndromes are inherited hypokalaemic metabolic alkalosis tubulopathies with normal blood pressure: Bartter mimics loop diuretics (thick ascending limb NKCC2 defect, childhood onset, hypercalciuria, nephrocalcinosis), whereas Gitelman mimics thiazides (distal convoluted tubule NCCT defect, adult onset, hypocalciuria, profound hypomagnesaemia).
Potassium is the predominant intracellular cation (98% of total body potassium, ~140–150 mmol/L in myocytes and erythrocytes), with only 2% residing in the extracellular fluid (3.5–5.0 mmol/L). The ratio of intracellular to extracellular potassium ([K+]in / [K+]out) establishes the resting membrane potential (RMP) of excitable tissues via the Nernst equation. Minor shifts in extracellular potassium profoundly affect cardiac conduction and neuromuscular transmission.
1. Hyperkalaemia: Diagnostic Stratification & ECG Progression
Stratification of Hyperkalaemia
- Mild: 5.5–5.9 mmol/L
- Moderate: 6.0–6.4 mmol/L
- Severe: ≥6.5 mmol/L OR any hyperkalaemia accompanied by ECG changes.
Pseudohyperkalaemia
Pseudohyperkalaemia denotes an in vitro artefact caused by potassium release from cells after venepuncture. Causes include mechanical lysis from prolonged tourniquet time, fist clenching, small-gauge needles, delayed laboratory processing, severe thrombocytosis (>500 × 10^9/L), marked leukocytosis (>50 × 10^9/L), or contamination with potassium EDTA from full blood count tubes. If pseudohyperkalaemia is suspected in an asymptomatic, ECG-normal patient, confirm with an urgent repeat non-haemolysed sample or a heparinised blood gas.
Sequential Electrocardiographic (ECG) Progression
As extracellular potassium rises, the resting membrane potential becomes less negative (hypopolarisation), initially accelerating repolarisation and subsequently inactivating voltage-gated sodium channels, leading to impaired intracardiac conduction:
- 5.5–6.5 mmol/L: Tall, tented, symmetrical T waves with a narrow base (best seen in chest leads V2–V4 and lead II).
- 6.5–7.5 mmol/L: Prolongation of the PR interval, flattening and widening of P waves, and eventual complete disappearance of P waves (sinoventricular conduction).
- 7.5–8.0 mmol/L: Progressive QRS complex widening, merging with the tented T wave.
- >8.0 mmol/L: Classic 'sine wave' pattern, heralding imminent degeneration into ventricular fibrillation or asystolic cardiac arrest.
MRCP High-Yield Rule: ECG changes do not correlate strictly with absolute serum potassium levels. Fatal arrhythmias can occur abruptly without prior sequential warnings. Any ECG abnormality in hyperkalaemia constitutes an immediate medical emergency.
2. Emergency Management Algorithm (UK Kidney Association / RCUK)
Emergency management of severe hyperkalaemia (≥6.5 mmol/L or ECG changes) follows a mandatory three-step sequence:
Severe Hyperkalaemia
(K+ >= 6.5 mmol/L or ANY ECG Changes)
│
┌─────────────────────────┼─────────────────────────┐
▼ ▼ ▼
STEP 1 STEP 2 STEP 3
Membrane Stabilisation Intracellular Shift Potassium Elimination
│ │ │
IV Calcium Gluconate 10% IV Soluble Insulin (10U) Novel Binders (SZC/Patiromer)
10-30 mL over 5-10 min in 50 mL 50% Dextrose Loop Diuretics (Furosemide)
(Restores AP threshold, + Nebulised Salbutamol Urgent Haemodialysis
does NOT lower K+) (Drops K+ 0.5-1.0 mmol) (Gold standard in AKI/CKD)
| Step & Objective | Therapeutic Agent | Dose & Administration | Onset & Duration | Mechanism & Essential Practice Points |
|---|---|---|---|---|
| Step 1: Myocardial Membrane Stabilisation | Calcium Gluconate 10% OR Calcium Chloride 10% | 10–30 mL IV 10% Calcium Gluconate over 5–10 mins (or 10 mL 10% Calcium Chloride via central line) | Onset: 1–3 mins. Duration: 30–60 mins. | Antagonizes potassium-induced membrane excitability by raising the myocardial action potential threshold towards zero, restoring the normal threshold-to-resting potential difference. Does NOT lower serum potassium. Repeat dose after 5–10 mins if ECG changes persist. Calcium chloride has 3x higher elemental calcium but causes severe tissue necrosis if extravasated; gluconate is preferred peripherally. |
| Step 2: Intracellular Potassium Shift | Soluble Insulin (Actrapid) in Dextrose | 10 units Actrapid in 50 mL 50% Dextrose (or 100 mL 20% Dextrose) IV over 15–30 mins | Onset: 15–30 mins. Duration: 4–6 hours. | Insulin activates skeletal muscle and hepatocyte Na+/K+-ATPase pumps, shifting potassium into cells. Lowers serum potassium by 0.5–1.0 mmol/L. Co-infused dextrose prevents hypoglycaemia. Mandates hourly capillary blood glucose monitoring for at least 6 hours. |
| Step 2 (Adjunct): Intracellular Shift | Nebulised Salbutamol | 10–20 mg nebulised with oxygen | Onset: 15–30 mins. Duration: 2–3 hours. | Beta-2 adrenergic receptor stimulation drives cAMP-mediated activation of Na+/K+-ATPase. Drops potassium by 0.5–1.0 mmol/L. Synergistic with insulin. Avoid in severe tachyarrhythmias; ineffective in patients taking non-selective beta-blockers. |
| Step 2 (Adjunct): Intracellular Shift | Intravenous Sodium Bicarbonate (8.4%) | 50–100 mL IV over 15–30 mins | Onset: 30–60 mins. Duration: 2–4 hours. | Strictly reserved for hyperkalaemia complicated by profound metabolic acidosis (pH < 7.15, [HCO3-] < 10 mmol/L). Ineffective in non-acidotic patients. Risks fluid overload and hypocalcaemic tetany. |
| Step 3: Potassium Removal / Elimination | Novel Potassium Binders: Sodium Zirconium Cyclosilicate (SZC) OR Patiromer | SZC (Lokelma): 10 g TDS orally for 48h. Patiromer (Veltassa): 8.4 g OD orally. | Onset: 1–2 hours (SZC) vs 4–7 hours (Patiromer). | SZC is an inorganic crystalline compound that captures potassium in exchange for sodium and hydrogen ions throughout the GI tract. Patiromer is a cross-linked polymer that exchanges calcium for potassium in the colon. Both have superseded traditional Calcium Resonium (calcium polystyrene sulfonate), which carries a slow onset (24h) and a high risk of fatal intestinal ischaemia and colonic necrosis. |
| Step 3: Potassium Removal / Elimination | Loop Diuretics | Furosemide 40–80 mg IV bolus | Onset: 15–30 mins. Duration: 4–6 hours. | Inhibits NKCC2 in the thick ascending limb, enhancing distal sodium and fluid delivery to the collecting duct and stimulating potassium secretion via ROMK. Only effective in patients with preserved renal function who are euvolaemic or hypervolaemic. |
| Step 3: Potassium Removal / Elimination | Emergent Haemodialysis | Urgent renal replacement therapy via temporary dual-lumen vascath | Onset: Immediate upon circuit initiation. | The definitive gold standard for refractory hyperkalaemia, severe anuric AKI, end-stage renal disease, or massive ongoing tissue breakdown (rhabdomyolysis, tumor lysis syndrome). Removes 25–50 mmol of potassium per hour. |
3. Hypokalaemia: Etiology, ECG Changes & Replacement
Differential Diagnosis of Hypokalaemia (<3.5 mmol/L)
- Transcellular Intracellular Shifts: Insulin administration, beta-2 agonists (salbutamol, terbutaline), acute alkalosis (cellular H+ exchanged for extracellular K+), refeeding syndrome, hypokalaemic periodic paralysis (familial or thyrotoxic periodic paralysis), theophylline toxicity, chloroquine overdose.
- Gastrointestinal Losses: Secretory diarrhoea, VIPoma, villous adenoma, chronic laxative abuse, enterocutaneous fistulae.
MRCP Clinical Pearl: The True Mechanism of Hypokalaemia in Vomiting: Gastric secretions contain very little potassium (only ~10 mmol/L). Hypokalaemia in vomiting or nasogastric suction is NOT caused by direct gastric potassium loss. Instead, loss of gastric HCl produces volume depletion and metabolic alkalosis. Volume depletion activates secondary hyperaldosteronism, while metabolic alkalosis delivers high loads of non-reabsorbable bicarbonate to the cortical collecting duct. This creates a lumen-negative electrical potential that drives massive secondary renal potassium wasting.
- Renal Potassium Losses: Loop and thiazide diuretics, primary aldosteronism (Conn's syndrome), secondary hyperaldosteronism (renovascular disease, malignant hypertension), Cushing's syndrome, Renal Tubular Acidosis (Types 1 and 2), Bartter and Gitelman syndromes, licorice / carbenoxolone ingestion (glycyrrhizic acid inhibits 11β-hydroxysteroid dehydrogenase type 2, allowing normal cortisol to stimulate mineralocorticoid receptors), Liddle syndrome, and hypomagnesaemia.
Electrocardiographic Features of Hypokalaemia
Progressive hypokalaemia hyperpolarises the resting membrane, delays repolarisation, and increases myocardial arrhythmogenicity:
- Flattened or inverted T waves
- ST segment depression
- Prominent U waves (deflections following the T wave, best visualized in V2–V4)
- Prolonged PR interval and broadened QRS
- Ventricular arrhythmias: ventricular ectopy, ventricular tachycardia, and polymorphic VT (Torsades de Pointes).
Potassium Replacement Regimens
- Mild / Asymptomatic Hypokalaemia (3.0–3.4 mmol/L): Oral potassium chloride (Sando-K tablets, 2 to 4 tablets three times daily; each tablet supplies 12 mmol K+ and 8 mmol Cl-).
- Severe (<2.5 mmol/L) or Symptomatic / Arrhythmic Hypokalaemia: Intravenous potassium chloride is mandatory:
- Rate Limit: Maximum 20 mmol/hour (infusion rates >20 mmol/h risk catastrophic hyperkalaemic arrest and mandate continuous cardiac telemetry in high-dependency/ICU settings).
- Concentration Limit: Maximum 40 mmol/L via a peripheral cannula (higher concentrations cause severe local chemical phlebitis and pain; concentrations >40 mmol/L mandate a central venous catheter).
The Indispensable Role of Magnesium in Hypokalaemia
Refractory hypokalaemia that fails to resolve despite aggressive potassium replacement is almost invariably due to unrecognised hypomagnesaemia. Intracellular magnesium plays two critical physiological roles:
- Magnesium is an obligatory intracellular cofactor for the basolateral Na+/K+-ATPase pump. In magnesium depletion, active cellular potassium uptake is impaired.
- Intracellular magnesium provides tonic, voltage-dependent inhibition of ROMK (renal outer medullary potassium) channels in the cortical collecting duct principal cells. When intracellular magnesium falls, this inhibition is removed; ROMK channels remain wide open, driving uncontrolled, accelerated potassium efflux into the tubular lumen. Potassium levels cannot be corrected until hypomagnesaemia is actively treated with magnesium replacement.
4. Magnesium & Phosphate Disorders
Hypomagnesaemia (<0.7 mmol/L)
- Etiology: Long-term Proton Pump Inhibitor (PPI) therapy (omeprazole, lansoprazole; downregulates active intestinal TRPM6/7 cation channels in enterocytes, typically after >1 year of use), chronic alcohol misuse (poor nutritional intake plus alcohol-induced tubular wasting), loop and thiazide diuretics, malabsorption / chronic diarrhoea, nephrotoxic drugs (aminoglycosides, amphotericin B, cisplatin, ciclosporin, tacrolimus).
- Clinical Manifestations: Neuromuscular hyperexcitability (carpopedal spasm, hyperreflexia, Chvostek's and Trousseau's signs, tetany, seizures), cardiac arrhythmias (prolonged QT interval, ventricular ectopy, Torsades de Pointes), refractory hypokalaemia, and refractory hypocalcaemia (magnesium deficiency impairs both parathyroid hormone [PTH] release from chief cells and induces peripheral end-organ resistance to PTH).
- Treatment: Mild/chronic: oral magnesium aspartate or glycerophosphate. Severe/symptomatic or Torsades de Pointes: Intravenous Magnesium Sulphate (2 g [8 mmol] in 100 mL 5% Dextrose over 15–60 minutes; immediate IV bolus over 1–2 minutes in pulseless Torsades de Pointes).
Hypophosphataemia & Refeeding Syndrome
- Refeeding Syndrome Pathophysiology:
- During prolonged starvation or severe malnutrition (anorexia nervosa, chronic alcohol dependence, marasmus/kwashiorkor), glycogen stores deplete within 24–48 hours. The body transitions to fat and muscle protein catabolism. Whole-body stores of intracellular phosphate, potassium, and magnesium become severely depleted, although baseline serum concentrations may remain normal.
- Re-introduction of carbohydrates or enteral/parenteral nutrition stimulates a massive surge in insulin secretion.
- Insulin stimulates cellular uptake of glucose and activates anabolic intracellular protein and glycogen synthesis, which drives phosphate, potassium, and magnesium rapidly into cells.
- Acute, profound extracellular and intracellular phosphate depletion halts the synthesis of Adenosine Triphosphate (ATP) and 2,3-Diphosphoglycerate (2,3-DPG).
- Clinical Collapse: Acute myocardial failure, fatal ventricular arrhythmias, respiratory muscle paralysis and diaphragm failure (failure to wean from ventilation), acute rhabdomyolysis, acute haemolytic anaemia (loss of erythrocyte deformability), encephalopathy, seizures, and coma.
- Prevention & Management: Identify high-risk patients (NICE criteria: BMI <16 kg/m², unintentional weight loss >15%, starvation >10 days). Start nutrition slowly at 5–10 kcal/kg/24 hours, slowly titrating over 4–7 days. Prophylactically administer oral or IV phosphate, potassium, magnesium, and high-dose intravenous thiamine (Pabrinex) before commencing feeding.
5. Inherited Tubulopathies: Bartter Syndrome vs Gitelman Syndrome
Bartter and Gitelman syndromes are autosomal recessive tubulopathies causing hypokalaemic metabolic alkalosis with normal or low blood pressure. Their differentiation is a perennial MRCP(UK) favourite:
| Clinical & Genetic Feature | Bartter Syndrome | Gitelman Syndrome |
|---|---|---|
| Molecular Defect | Inactivating mutations in the thick ascending limb (TAL): SLC12A1 (NKCC2), KCNJ1 (ROMK), CLCNKB (ClC-Kb), or BSND (Barttin) | Inactivating mutations in the distal convoluted tubule (DCT): SLC12A3, encoding the NCCT (sodium-chloride cotransporter) |
| Pharmacological Mimic | Mimics chronic Loop Diuretic (Furosemide) | Mimics chronic Thiazide Diuretic (Bendroflumethiazide) |
| Age of Onset | Antenatal, infantile, or early childhood (polyhydramnios, premature delivery) | Late childhood, adolescence, or adulthood (often discovered incidentally) |
| Clinical Severity | Severe polyuria, polydipsia, recurrent volume depletion, failure to thrive, growth retardation | Mild to moderate fatigue, muscle cramps, lethargy, carpopedal spasms, nocturia |
| Blood Pressure | Normal or low (hypotension) | Normal or low (hypotension) |
| Serum Potassium | Moderate to severe hypokalaemia | Moderate to severe hypokalaemia |
| Acid-Base Status | Metabolic alkalosis | Metabolic alkalosis |
| Urinary Calcium Excretion | Hypercalciuria (loss of lumen-positive potential in TAL impairs paracellular calcium reabsorption) | Hypocalciuria (enhanced proximal and DCT calcium reabsorption; urinary Ca:Creatinine < 0.2) |
| Nephrocalcinosis | Present in >80% (bilateral medullary nephrocalcinosis and nephrolithiasis) | Absent (protective hypocalciuria prevents calcification) |
| Serum Magnesium | Normal or mildly reduced | Profound hypomagnesaemia (hallmark; DCT TRPM6 channels downregulated) |
| Therapeutic Regimen | High-dose oral KCl, NaCl, magnesium, potassium-sparing diuretics, and NSAIDs (Indomethacin) to inhibit renal prostaglandin E2 | Lifelong oral magnesium supplementation, oral KCl, amiloride or spironolactone. (NSAIDs are ineffective). |
A 64-year-old man with end-stage renal disease secondary to diabetic nephropathy misses two consecutive maintenance haemodialysis sessions over a bank holiday weekend. He is brought to the emergency department by his family complaining of profound muscular weakness in both lower limbs. He is alert and oriented. On examination, his pulse is 54 bpm regular, blood pressure 156/88 mmHg, and respiratory rate 18 breaths/minute. Neurological examination reveals symmetrical lower limb flaccid paresis with absent knee and ankle reflexes. Urgent point-of-care venous blood gas analysis reveals: pH 7.26, potassium 7.4 mmol/L, bicarbonate 15 mmol/L. An immediate 12-lead electrocardiogram demonstrates tall, tented, symmetrical T waves, marked prolongation of the PR interval (310 ms), flattening of the P waves, and widening of the QRS complexes (144 ms). What is the most appropriate first-line therapeutic intervention to administer immediately?
A 38-year-old woman presents to the metabolic clinic for evaluation of chronic fatigue, diffuse muscle cramps, and recurrent episodes of carpopedal spasm. She takes no regular medications, uses no over-the-counter slimming aids, and denies vomiting or diarrhoea. On examination, her pulse is 72 bpm, blood pressure is 108/66 mmHg with no postural drop, and body mass index is 21 kg/m². Trousseau's sign is positive upon inflating a blood pressure cuff above systolic pressure. Laboratory investigations reveal: serum sodium 138 mmol/L, potassium 2.6 mmol/L, chloride 94 mmol/L, bicarbonate 32 mmol/L, urea 4.8 mmol/L, creatinine 72 mcmol/L, calcium 2.34 mmol/L, magnesium 0.45 mmol/L (normal 0.70–1.00 mmol/L). Arterial blood gas demonstrates a metabolic alkalosis (pH 7.48, PaCO2 5.8 kPa, HCO3- 32 mmol/L). A 24-hour urine collection reveals: urinary potassium 48 mmol/24h (elevated), urinary sodium 140 mmol/24h, and urinary calcium excretion 1.1 mmol/24h (normal 2.5–7.5 mmol/24h; urinary calcium:creatinine ratio <0.15). Renal ultrasonography is entirely normal with no evidence of nephrocalcinosis. What is the most likely diagnosis?
A 52-year-old woman with chronic alcohol misuse and poor dietary intake is admitted to the medical ward following a fall. Routine admission biochemistry reveals a serum potassium concentration of 2.7 mmol/L (normal 3.5–5.0 mmol/L). She is commenced on intravenous potassium chloride supplementation (80 mmol/24h in 0.9% sodium chloride). Despite 48 hours of continuous intravenous potassium administration, her repeat serum potassium remains persistently low at 2.8 mmol/L. She has had no episodes of vomiting or diarrhoea, and her 24-hour urine collection demonstrates inappropriately elevated potassium excretion (58 mmol/24h). What is the underlying physiological mechanism explaining this patient's refractory hypokalaemia?