Causes of combined hypocalcemia, hypokalemia and hypomagnesemia with normal phosphate and PTH

1. Hypomagnesemia (the unifying cause)

• Low Mg impairs PTH secretion and causes PTH resistance at bone and kidney. This produces hypocalcemia that won't correct until Mg is replaced.
• Low Mg also causes renal K wasting through ROMK channel disinhibition, so the hypokalemia is refractory too.
• Harrison's (22E, Hypomagnesemia) states that the hypocalcemia and hypokalemia seen with hypomagnesemia may not be easily corrected unless magnesium is given. Morgan and Mikhail's (7e) says the same: hypomagnesemia is frequently associated with hypocalcemia (impaired PTH secretion) and hypokalemia (renal K wasting).

2. Sepsis and critical illness (gallbladder empyema)

• Sepsis suppresses PTH release and causes hypocalcemia (Morgan and Mikhail's 7e; Harrison's 22E; Henry's lists sepsis, burns and acute renal failure).
• Cytokines, calcitriol resistance, and low albumin and vitamin D add to this.
• Sepsis also causes intracellular shifts and renal losses of K and Mg.

3. Why Mg and K are low (causes of depletion)

• Vomiting, nasogastric drainage, diarrhea, or biliary and cholecystostomy drain output.
• Poor intake or malnutrition. Stroke-related dysphagia and prolonged illness make this likely.
• Long-term PPI use, which is a common cause of low Mg.

• Diuretics (loop and thiazide), often used in hypertension, DM and stroke patients.
• Osmotic diuresis from uncontrolled hyperglycemia. Insulin therapy also drives K and Mg into cells.
• Diabetic tubulopathy or nephropathy.
• Nephrotoxic antibiotics for the sepsis: aminoglycosides, amphotericin B, and (for K) piperacillin-tazobactam and other penicillins. Cisplatin and foscarnet are other possible culprits.

• Alcohol use.
• Refeeding syndrome if nutrition was restarted. It usually also lowers phosphate, so check this.

4. Other causes of hypocalcemia with normal phosphate

• Hypoalbuminemia causes a low total but normal ionized Ca. Check ionized Ca or corrected Ca first.
• Vitamin D deficiency is common in the elderly and the bedbound. PTH is usually high, but it can look "normal" when Mg is low or in sepsis. Check 25-OH vitamin D.
• Acute pancreatitis, for example gallstone pancreatitis in a biliary patient, causes calcium saponification. Check lipase.
• Citrate from transfusion or CRRT, and bicarbonate or alkalosis, which lower ionized Ca.
• Drugs: loop diuretics (calciuric), bisphosphonates, denosumab, PPIs, foscarnet.
• Fat malabsorption from biliary disease can reduce Ca, Mg and vitamin D absorption.

Suggested workup

• Ionized Ca, albumin, and ABG for pH and bicarbonate.
• Spot urine Mg and creatinine. Fractional excretion of Mg above 2% means renal wasting. Below 2% means GI loss or poor intake.
• Urine K and creatinine (or TTKG) to separate renal from GI K loss.
• 25-OH vitamin D, lipase, creatinine and eGFR, and repeat phosphate.
• ECG for QT prolongation. Hypokalemia, hypomagnesemia and hypocalcemia together raise the risk of torsades.
• Review the drug chart (PPI, diuretics, antibiotics, insulin).

Management principle

Recent evidence check

IV magnesium, calcium and potassium replacement for this patient

Order of replacement

1. Start magnesium first, or at the same time as calcium and potassium. Ca and K usually stay low until Mg is replaced, because hypomagnesemia causes PTH failure and renal K wasting (Harrison's 22E, Hypomagnesemia).
2. Give calcium urgently only if the patient is symptomatic or has a prolonged QT.
3. Put the patient on continuous ECG monitoring, because QT-prolonging combinations can cause torsades.

1. IV magnesium sulfate

• Standard load: 1 to 2 g MgSO4 (8 to 16 mEq) IV over 10 to 60 minutes (Morgan and Mikhail's 7e, Treatment of Hypomagnesemia). Schwartz's 11th ed. and Tintinalli's give similar loading doses.
• Tintinalli's: if serum Mg is below 2.0 mEq/L (1.0 mmol/L) or symptoms are present, give 2 g IV over 1 hour.
• Dilute in at least 100 mL of D5 or NS.
• Torsades or seizures: 1 to 4 g in at least 100 mL, over 10 to 60 minutes under monitoring (Tintinalli's).

• Total body Mg is usually deeply depleted, so a single dose is not enough.
• A critical care review suggests a 1 to 2 g load, then 4 to 8 g (32 to 64 mEq) over 12 to 24 hours.
• Another common regimen is 2 to 4 g IV every 6 to 8 hours, or a continuous infusion (an EMCrit summary).
• A slower infusion (about 1 g/hour, no more than 2 g/hour in non-emergencies) gives better retention. Fast boluses are largely lost in urine.
• Continue for 3 to 5 days, because intracellular stores refill slowly.
• Target serum Mg of at least 2 mg/dL (0.8 mmol/L or higher).

• Check creatinine first. This patient has diabetes, hypertension and sepsis, so AKI risk is real.
• With impaired renal function, reduce the dose by 25 to 50% and monitor Mg levels closely.

• Check deep tendon reflexes, respiratory rate, blood pressure and ECG.
• Recheck Mg 4 to 6 hours after dosing, then daily.
• Hypermagnesemia presents as loss of reflexes, hypotension, and respiratory depression. Its antidote is IV calcium gluconate.

2. IV calcium (only if symptomatic or QT prolonged)

• Calcium gluconate 10% is preferred. Each 10 mL ampule contains 90 mg (2.2 mmol) of elemental calcium.
• Give 1 to 2 ampules (10 to 20 mL) diluted in 50 to 100 mL of D5 or NS, IV over 10 to 20 minutes (Harrison's; Katzung's; Morgan and Mikhail's).
• Calcium chloride 10% has 3 times more elemental Ca (10 mL = 272 mg), but it is irritant. Use it only through a central line, and mostly in arrest or hemodynamic collapse.
• Do not push it fast. Rapid injection can cause arrhythmias.
• The bolus effect lasts only 2 to 3 hours, so follow it with an infusion if symptoms or low Ca persist.

• A common regimen is about 10 ampules (100 mL of 10% calcium gluconate, around 900 mg elemental Ca) in 1 L of D5 or NS, running at about 50 mL/hour.
• The usual range is 0.5 to 1.5 mg/kg/hour of elemental Ca. Titrate to the lower end of the normal range.
• Check Ca every 4 to 6 hours.

• Do not mix with bicarbonate or phosphate in the same line, because it precipitates.
• Avoid ceftriaxone co-infusion through the same line.
• Use caution with digoxin, because hypercalcemia raises toxicity risk.
• Extravasation causes tissue necrosis.
• Correct hypomagnesemia, or the calcium infusion will fail.

• In sepsis, mild asymptomatic hypocalcemia often does not need IV calcium. Some data suggest IV calcium may be harmful in sepsis, so treat only symptoms, QT prolongation, or severe ionized hypocalcemia.
• Always check ionized Ca or albumin-corrected Ca first. Corrected Ca = measured Ca + 0.8 × (4 − albumin).

3. Potassium (replace together with Mg)

• Peripheral line: up to 10 mEq/hour.
• Central line: up to 20 mEq/hour with cardiac monitoring if K is below 2.5 mEq/L or arrhythmias are present.
• Rosen's states that K repletion may fail unless Mg is replaced at the same time.
• Recheck K every 2 to 4 hours during active repletion.
• Check renal function before giving large amounts.

4. Adjuncts after stabilization

• Oral calcium (1 to 2 g elemental/day) and vitamin D (cholecalciferol, with calcitriol only if indicated), once 25-OH D is known.
• Stop or reduce PPI and diuretics if possible. Control glucose.
• Control the source: biliary drainage or cholecystectomy and antibiotics.
• Replete phosphate if it falls, especially with nutrition restart (refeeding risk).

Causes of hypomagnesemia

1. Reduced intake or intestinal absorption

• Malnutrition, protein-calorie malnutrition, and alcoholism. Dietary deficiency alone is unlikely except in alcoholism (Harrison's).
• Prolonged IV fluids or parenteral nutrition without Mg.
• Malabsorption (celiac disease, Crohn's, short bowel, fat malabsorption, biliary disease).
• Proton pump inhibitors. These impair intestinal Mg absorption, and the effect is more pronounced with long-term use.
• Vitamin D deficiency.
• Rare genetic cause: primary intestinal hypomagnesemia with secondary hypocalcemia (TRPM6 mutations).

2. Gastrointestinal losses

• Chronic diarrhea and laxative abuse.
• Vomiting and nasogastric suction.
• Intestinal or biliary fistulas and drain output.
• Acute pancreatitis (saponification of Mg in fat necrosis).

3. Renal losses

• Loop and thiazide diuretics.
• Aminoglycosides, amphotericin B, cisplatin and carboplatin, pentamidine, foscarnet.
• Calcineurin inhibitors (cyclosporine, tacrolimus).
• EGFR inhibitors (cetuximab, panitumumab).
• Digoxin is also listed in some tables.

• Uncontrolled diabetes mellitus (osmotic diuresis and glycosuria), including DKA.
• Hypercalcemia (competes for Mg reabsorption in the thick ascending limb).
• Volume expansion, hyperaldosteronism, SIADH.
• Hyperthyroidism and hyperparathyroidism.

• Post-obstructive diuresis, recovery from acute tubular necrosis, and kidney transplant.
• Bartter and Gitelman syndromes (the latter gives hypokalemia, hypomagnesemia, hypocalciuria and alkalosis).
• Familial renal Mg wasting disorders (CLDN16/19, CNNM2, EGF, KCNA1 and others).

4. Redistribution or shift

• Hungry bone syndrome (after parathyroidectomy or thyroidectomy).
• Refeeding syndrome.
• Insulin therapy, catecholamine excess, and acute pancreatitis.
• Massive transfusion (citrate binding).
• Burns and heavy sweating.
• Cardiopulmonary bypass.

How to separate renal from non-renal loss

• 24-hour urine Mg above 24 mg, or fractional excretion of Mg above 2% (some use 4%), despite low serum Mg indicates renal wasting.
• FEMg below 2% points to GI loss, poor intake, or redistribution.

Clinical relevance to your patient

• Diuretics and PPI use.
• Osmotic diuresis from poor glucose control.
• Poor intake and malnutrition.
• GI or biliary losses and possible pancreatitis.
• Nephrotoxic antibiotics.

1. Start: serum Mg below 1.7 mg/dL, or refractory low K and Ca with normal PTH and phosphate.
2. Step 1 (exclude pseudo-causes): albumin or ionized Ca, creatinine, glucose and ketones, ABG, phosphate, lipase, 25-OH vitamin D, ECG for QTc, and the drug chart.
3. Step 2 (look for an obvious cause): PPI, diuretics, aminoglycosides, amphotericin B, cisplatin, alcohol, diarrhea or drain output, poor intake, diabetic osmotic diuresis.
4. Step 3 (urine Mg and fractional excretion):
   • FEMg above 2% (or 24-hour urine Mg above 24 mg) means renal wasting. Look at drugs, metabolic causes (diabetes, hypercalcemia, post-ATN diuresis), then genetic tubular disorders (Gitelman, Bartter and others).
   • FEMg below 2% means an extrarenal cause. That covers poor intake or malabsorption, GI loss (diarrhea, NG suction, fistula, pancreatitis), and redistribution (refeeding, hungry bone, insulin, citrate).
5. Step 4 (secondary effects): hypokalemia, hypocalcemia, QT prolongation, arrhythmia, tetany and seizures.
6. Step 5 (treat):
   • For symptomatic or severe cases, give MgSO4 1 to 2 g IV over 10 to 60 minutes, then 4 to 8 g over 12 to 24 hours.
   • Replace K and Ca together with Mg.
   • Reduce the dose 25 to 50% in renal impairment, and monitor reflexes, respiratory rate and Mg levels.
7. Step 6 (treat the cause): stop or swap offending drugs, control glucose, restore nutrition carefully (watch refeeding), and control the gallbladder empyema source.