Critical Care Nephrology · Two-Week Intensive · Lecture 6 of 9

Potassium, Calcium, Phosphorus & Magnesium

Electrolyte emergencies in the ICU — the mechanism, the dose, the onset, and the thing each drug does not do

40 minutes Nephrology Fellows Week 2

Based on Koyner, Handbook of Critical Care Nephrology (2021) · NTUH Yunlin Branch

Learning objectives

By the end of this session you will be able to…

Separate internal from external potassium balance, and use that split to sequence hyperkalaemia therapy by onset, duration and mechanism.
Prescribe calcium, insulin, β₂-agonist, binder and dialysate doses from memory — and state the evidence for and against each.
Interpret ionised calcium against albumin, pH and citrate, and decide when hypo- or hypercalcaemia deserves a drug at all.
Replace phosphate and magnesium at the right rate, and recognise magnesium as the gatekeeper of potassium and calcium correction.
Manage rhabdomyolysis and tumour lysis syndrome, and pre-empt the electrolytes that continuous therapy removes.

Koyner Ch 21–24, 49–50 · Ronco Ch 41, 57–58 · UKKA acute hyperkalaemia guideline 2023 · Cairo–Bishop 2004 · NICE CG32

Potassium

The only electrolyte that kills within minutes — and the one where the reflex to treat most often outruns the duty to verify.

Koyner Ch 21 · Ronco Ch 57 · UKKA 2023

Two balances, two clocks — and the switch that links them

Internal balance — minutes

98% of body K⁺ is intracellular. Insulin and β₂ stimulation drive K⁺ in; rising tonicity drives it out. Necrosis empties the pool.

External balance — hours to days

Net excretion is set in the aldosterone-sensitive distal nephron by aldosterone and distal Na⁺ delivery. ICU hyperkalaemia is multifactorial.

The pH-to-potassium myth

There is no usable pH–K⁺ conversion factor. In DKA, hyperkalaemia is insulin deficiency and hypertonicity, not pH.

Koyner Ch 21 · Palmer BF. Clin J Am Soc Nephrol. 2015;10:1050 · Terker AS et al. Cell Metab. 2015;21:39 · Ronco Ch 57

The Na⁺/K⁺-ATPase gradient is the resting potential; α-adrenergic tone also drives K⁺ out; the necrosis list is rhabdomyolysis, tumour lysis, haemolysis and burns. Potassium is freely filtered and ~90% reabsorbed, with ROMK and BK doing the distal secretion, and adaptation holds the potassium until GFR is very low. On the pH myth: mineral (hyperchloraemic) acidosis shifts potassium out substantially, organic and respiratory acidosis far less. WNK–SPAK switch: aldosterone answers volume depletion and hyperkalaemia oppositely — WNK1/WNK4–SPAK/OSR1 resolves the paradox: hyperkalaemia → NCC falls → more distal Na⁺ delivery → K⁺ secreted; volume depletion → NCC active → K⁺ spared. Calcineurin inhibitors activate it (tacrolimus pseudohypoaldosteronism type II). Timing cue: 90 s.

Before you treat: is the potassium real, and why is it high?

Mechanism	ICU examples
Reduced renal excretion	AKI, AKI on CKD, oliguria
Hypoaldosteronism / blockade	ACEi/ARB, MRAs, heparin, calcineurin inhibitors
Cellular release	Rhabdo, tumour lysis, haemolysis, ischaemic gut
Shift out of cells	Mineral acidosis, insulin deficiency, hypertonicity
Load	Stored blood, TPN, feeds, salt substitutes

Mechanism predicts trajectory: ongoing lysis needs a catheter, not another ampoule.

Pseudohyperkalaemia — repeat before you treat

In-tube haemolysis — commonest
Fist clenching raises K⁺ by up to 1–2
Leucocytosis — serum high, plasma normal
Familial — temperature-dependent red-cell leak

If gas and serum disagree by >0.5 with no ECG change, believe the gas.

Koyner Ch 21 · Palmer BF, Clegg DJ. JAMA. 2015;314:2405 · Ronco Ch 57 · UKKA acute hyperkalaemia guideline 2023

The ECG: useful when abnormal, worthless when normal

Peaked T wavesTall, narrow, symmetrical, short QT — earliest, least specific.

→

P-wave lossPR prolongs, P flattens, then vanishes.

→

QRS wideningSlowed phase-0 conduction. Danger zone — treat now.

→

Sine waveQRS merges with T; then VF or asystole.

MONTAGUE 2008 · retrospective ECG review

90 patients with K⁺ ≥6.0, ECGs read blind: the ECG was insensitive, and no potassium threshold reliably produced changes.

Common pitfall — treating the ECG instead of the potassium

A normal ECG never makes a potassium of 7 safe. Arrhythmia tracks the rate of rise. Give calcium for any ECG change.

Montague BT et al. Clin J Am Soc Nephrol. 2008;3:324 · Koyner Ch 21 · Ronco Ch 57 · UKKA 2023

The hyperkalaemia prescription — five jobs, six drugs, one that removes

Job	Agent · dose	Onset	What it does not do
Protect the membrane	Calcium gluconate 10–30 mL	1–3 min	No effect on K⁺
Shift into cells	Insulin 10 U + dextrose	15 min	Removes nothing; K⁺ returns
Shift into cells	Salbutamol 10–20 mg neb	~30 min	Not monotherapy
Buffer the acidosis	Bicarbonate 50–100 mmol	Hours	No acute shift
Excrete renally	Furosemide 40–120 mg	30–60 min	Useless in anuria

The organising principle

Rungs 1–3 are a loan against time. Only a kidney, a binder or a circuit subtracts.

Koyner Ch 21 · UKKA acute hyperkalaemia guideline 2023 · Blumberg A et al. Am J Med. 1988;85:507 and Kidney Int 1992;41:369 · Allon M, Shanklin N. Am J Kidney Dis. 1996;28:508 · Allon M et al. Ann Intern Med. 1989;110:426

Calcium salts: which one, and when calcium is the wrong drug

Calcium gluconate 10%

90 mg (2.2 mmol) elemental Ca per 10 mL; safe peripherally. "Needs hepatic activation" is wrong. Effect wanes at 30–60 min — redose if the QRS widens.

Calcium chloride 10%

272 mg (6.8 mmol) per 10 mL — three times the elemental calcium. Reserve for arrest; extravasation necroses.

COCA 2021

Calcium chloride vs saline in arrest: sustained ROSC 19% vs 27%, 30-day survival 5.2% vs 9.1% — stopped early.

Pitfall — calcium in digoxin toxicity

Intracellular calcium is already high, and IV calcium may precipitate "stone heart". Treat with digoxin-specific Fab.

Vallentin MF et al. JAMA. 2021;326:2268 (COCA) · Koyner Ch 21–22, 27 · Levine M et al. J Emerg Med. 2011;40:41 · Ronco Ch 57

Insulin: the best shifter and the commonest iatrogenic harm on the ward

10 U regular insulin with 25 g dextrose — onset 15 min, ΔK⁺ 0.6–1.2
The insulin outlasts the dextrose: hypoglycaemia appears at 1–3 h
Highest risk: eGFR <30, low body weight, glucose <7
Mitigation: 5 U or 0.1 U/kg, then 10% dextrose 75 mL/h

MOUSSAVI 2021 · reduced-dose insulin

3,437 patients: hypoglycaemia OR 0.55, with no loss of K⁺ lowering. Retrospective only.

Write the monitoring into the order

Glucose at 30 min, 1, 2, 4, 6 h; K⁺ at 1 and 4 h.

Insulin and salbutamol act on the same pump — additive, not synergistic.

Moussavi K et al. Pharmacotherapy. 2021;41:598 · Kelley D et al. Pharmacotherapy. 2025;45:794 · Allon M, Copkney C. Kidney Int. 1990;38:869 · Apel J et al. Clin Kidney J. 2014;7:248 · UKKA 2023 · Koyner Ch 21

Actually removing potassium: the gut and the circuit

Binder	Dose	Onset	Niche	Cautions
Sodium polystyrene sulfonate	15–30 g PO/PR	Hours; unreliable	None	GI events HR 1.94
Sodium zirconium cyclosilicate	10 g TDS ≤48 h	~1 h	The only acute data	Na⁺ load
Patiromer	8.4 g daily	~7 h	Chronic — enables RAASi	Hypomagnesaemia

Binder trials

ZS-003: ΔK⁺ 0.7 vs 0.3. OPAL-HK: ΔK⁺ −1.01. ENERGIZE (ED): missed its acute endpoint.

Dialysis — the only fast subtraction

Charytan 2025: a 3.0 K bath plus SZC vs 2.0 — modelled AF rate ratio 0.52

And the rebound

K⁺ rebounds within ~6 h; ongoing lysis needs CKRT

Packham DK et al. N Engl J Med. 2015;372:222–231 · Kosiborod M et al. JAMA. 2014;312:2223 · Weir MR et al. N Engl J Med. 2015;372:211–221 · Butler J et al. Eur Heart J. 2022;43:4362 · Peacock WF et al. Acad Emerg Med. 2020;27:475 (ENERGIZE) · Noel JA et al. JAMA Intern Med. 2019;179:1025 · Charytan DM et al. Kidney Int. 2025;107:169 · Geldermann N et al. Emerg Med J. 2026;43:305 · Koyner Ch 21

Hypokalaemia: locate the leak, then replace at the right rate

K⁺ <3.5; weakness ~2.5; respiratory failure below 2.0. ECG: U waves

Urine K⁺/Cr

<13 = conservation; higher = renal wasting

TTKG — retired

Urea recycling breaks it.

Then branch

Wasting + acidosis → RTA; + alkalosis → mineralocorticoid excess

Route	Dose	Rules
Oral KCl (preferred)	40–60 mmol/dose	Raises K⁺ by 1–1.5
IV KCl peripheral	10 mmol/h, ≤40 mmol/L	Dilute in saline, not dextrose
IV KCl central	Up to 20 mmol/h	More in extremis
Potassium phosphate	15 mmol PO₄ ≈ 22 mmol K⁺	—

Pitfall — the hypokalaemia that will not correct

Intracellular Mg²⁺ plugs ROMK; depleted, the duct wastes K⁺ — replace magnesium first.

Koyner Ch 21, 24 · Lin SH et al. Arch Intern Med. 2004;164:1561 · Kamel KS, Halperin ML. Curr Opin Nephrol Hypertens. 2011;20:547 · Huang CL, Kuo E. J Am Soc Nephrol. 2007;18:2649

Calcium

One number matters in the ICU, the formula everyone quotes does not work there, and most low calcium needs no drug at all.

Koyner Ch 22, 50 · Ronco Ch 58

Ionised calcium, the sensor that guards it, and why correction fails

Corrected Ca (mg/dL) = measured Ca + 0.8 × (4.0 − albumin g/dL) Payne 1973, ambulatory patients with isolated hypoalbuminaemia; in the ICU it misclassifies both directions.

Why arithmetic cannot fix it

pH: alkalaemia drops ionised Ca with an unchanged total; hyperventilation can cause tetany at a normal total. Sepsis changes albumin concentration and binding affinity.

The CaSR sets the target

Falling ionised Ca releases PTH within seconds; rising Ca inactivates NKCC2 — an endogenous loop diuretic. Septic hypocalcaemia resists topping up.

Citrate — the ICU's commonest cause of a low ionised calcium

Citrate chelates ionised Ca by design. The tell is a total-to-ionised ratio >2.5. Answer: more systemic calcium, less citrate.

Payne RB et al. Br Med J. 1973;4:643 · Slomp J et al. Crit Care Med. 2003;31:1389 · Hendy GN, Canaff L. Semin Cell Dev Biol. 2016;49:37 (CaSR, cytokines and calcium homeostasis) · Koyner Ch 22 · Ronco Ch 58

Hypocalcaemia: usually a marker, occasionally a diagnosis, rarely a prescription

Causes worth chasing

Citrate · hyperphosphataemia · pancreatitis, rhabdo · hypomagnesaemia (blocks PTH) · hungry bone · denosumab, foscarnet

The ICU reality

Ionised Ca²⁺ is abnormal in >50% of ICU patients
The mortality association attenuates after severity adjustment

Symptomatic

Tetany, seizure, arrhythmia: 100–200 mg elemental Ca²⁺.

Then

Infusion 0.5–1.5 mg elemental Ca/kg/h; recheck at 1 h. Replace magnesium.

The case for restraint in sepsis

Cochrane: no clear evidence of outcome benefit — the trials never measured mortality or organ failure. Don't top up an asymptomatic septic patient.

Forsythe RM et al. Cochrane Database Syst Rev. 2008;CD006163 · Collage RD et al. Crit Care Med. 2013;41:e352 · Zivin JR et al. Am J Kidney Dis. 2001;37:689 · Egi M et al. Crit Care Med. 2011;39:314 · Aberegg SK. Chest. 2016;149:846 · Koyner Ch 22

Hypercalcaemia: three malignant mechanisms and a volume problem

PTHrP · ~80% of malignant cases

Squamous, renal cell, breast. PTHrP drives bone resorption and distal Ca reabsorption. PTH suppressed, phosphate low.

Osteolysis

Direct invasion and RANKL-driven osteoclast activation — myeloma, breast.

Extrarenal 1,25-(OH)₂D

Unregulated 1-α-hydroxylase in macrophages — lymphoma, sarcoid, TB. The only glucocorticoid-responsive subgroup.

Check PTH first: non-suppressed = hyperparathyroidism, lithium, or FHH
Other: immobilisation, thiazides, vitamin D excess, thyrotoxicosis
Severity: mild <12 · moderate 12–14 · severe >14; symptoms track the rate of rise

Why the kidney amplifies it

Calcium activates the TAL CaSR, inactivating NKCC2 — a nephrogenic DI. The patient becomes volume-depleted. Volume is the first drug.

Koyner Ch 22, 50 · Rosner MH, Dalkin AC. Clin J Am Soc Nephrol. 2012;7:1722 · Ronco Ch 58

Hypercalcaemia: the ladder, with real doses and real onsets

Isotonic saline — 200–300 mL/h until replete; lowers Ca 1–2; never alone

Stop Ca, vitamin D and thiazides. Loops only if hypervolaemic.

Calcitonin 4 IU/kg q12h; onset 4–6 h — the only fast drug; stop at 48–72 h.

Zoledronic acid 4 mg IV. Avoid in severe AKI.

Denosumab 120 mg SC — not renally cleared; ES 2023 suggests it over IV bisphosphonate.

Glucocorticoids — 1,25-D-mediated disease only; ineffective in PTHrP.

Haemodialysis, low-calcium bath — for coma or arrhythmia; temporising.

El-Hajj Fuleihan G et al. Endocrine Society guideline, J Clin Endocrinol Metab. 2023;108:507 · Chen CL et al. Eur J Cancer. 2015;51:1467 · Major P et al. J Clin Oncol. 2001;19:558 · Hu MI et al. J Clin Endocrinol Metab. 2014;99:3144 · Camus C et al. Intensive Care Med. 1996;22:116 · Koyner Ch 22, 50

Phosphate & Magnesium

The two electrolytes nobody calls about: one keeps the patient on the ventilator, the other silently blocks every correction you are attempting.

Koyner Ch 23–24 · Ronco Ch 57–58 · NICE CG32

Hypophosphataemia: the mechanism, the causes, the cost

The regulatory axis

Proximal NaPi-IIa/IIc; PTH and FGF23 internalise them → phosphaturia
FGF23 needs α-klotho, suppresses 1-α-hydroxylase
AKI: high-FGF23, low-klotho
Serum PO₄ mirrors stores poorly

Causes in the ICU

CRRT — dominant; >50% incidence
Refeeding, DKA insulin
Respiratory alkalosis
Diuretics, sepsis, alcohol
Hungry bone, IV iron

Consequences

Diaphragmatic weakness (weaning failure 34% vs 10%)
Prolonged respiratory failure — CRRT ≈ 2× tracheostomy
Reduced cardiac index
Rhabdomyolysis and haemolysis

Pitfall — the phosphate that is not really low (or high)

High-dose mannitol causes factitious hypophosphataemia by assay interference — think twice before KPO₄ in a neurocritical patient.

Koyner Ch 23 · Aubier M et al. N Engl J Med. 1985;313:420 · Demirjian S et al. Nephrol Dial Transplant. 2011;26:3508 · Zazzo JF et al. Intensive Care Med. 1995;21:826 · Leaf DE et al. Clin Kidney J. 2023;16:1555

Replacing phosphate: weight-based, slow, and counted

Serum PO₄	IV dose	Time	Notes
2.3–3.0 mg/dL	0.16 mmol/kg	6 h	Oral if the gut works
1.6–2.2 mg/dL	0.32 mmol/kg	6 h	Recheck 2–4 h after
≤ 1.5 mg/dL	0.64 mmol/kg	6 h	Expect to repeat
Haemolysis/rhabdomyolysis	15 mmol	2 h	The only faster setting

Four prescribing rules

1. Count the cation: KPO₄ 15 mmol ≈ 22 mmol K⁺. 2. Never share a line with calcium. 3. Don't chase the number. 4. On CRRT, prevent rather than replace — phosphate-containing fluid abolishes the problem.

Taylor BE et al. J Am Coll Surg. 2004;198:198 · Geerse DA et al. Crit Care. 2010;14:R147 · Broman M et al. Acta Anaesthesiol Scand. 2011;55:39 · Koyner Ch 23

Refeeding syndrome: the predictable emergency

Carbohydrate after starvation triggers an insulin surge that drives PO₄, K⁺ and Mg²⁺ into cells of an already depleted body.

High risk — any one

BMI <16 · weight loss >15% · low K⁺/PO₄/Mg²⁺ before feeding

High risk — any two

BMI <18.5 · weight loss >10% · no intake >5 d · alcohol

Controversy

An ICU RCT found better survival with hypocaloric feeding.

The prescription

Thiamine 200–300 mg before calories
Start at 10 kcal/kg/day
Supplement from day 0: PO₄, K⁺ and Mg²⁺
Slow the feed, don't stop it, when PO₄ falls

NICE CG32, Nutrition support for adults (2006, updated 2017) · Doig GS et al. Lancet Respir Med. 2015;3:943 · Koyner Ch 15, 23 · Marinella MA. J Intensive Care Med. 2005;20:155

Hyperphosphataemia: mostly a kidney problem, occasionally a lab artefact

Retention

AKI and CKD dominate — phosphaturia compensates only until GFR falls. Hypoparathyroidism raises phosphate.

Release

Tumour lysis, rhabdo, haemolysis, DKA — these carry the nephrotoxin too, so phosphate keeps rising.

Load

Sodium-phosphate enemas and bowel preps: ~32 g phosphorus per 250 mL — plus sodium. Never in renal impairment, worst in the elderly.

Treatment, in order

Preserve GFR, expand volume
Enteral binders for chronic control
KRT if severe and symptomatic — continuous > intermittent
Watch the Ca × PO₄ product

Pseudohyperphosphataemia

Paraproteinaemia — up to 32 mg/dL
Hyperlipidaemia, liposomal ampho-B
Haemolysed sample
Treat only with hypocalcaemia, a mechanism or AKI

Koyner Ch 23 · Ronco Ch 103 · Haider DG et al. PLoS One. 2015;10:e0133426 · Ori Y et al. Arch Intern Med. 2012;172:263 · Tan HK et al. Int J Artif Organs. 2001;24:186

Hypomagnesaemia: the gatekeeper of potassium and calcium

Causes — and why the serum level under-reads them

Only ~0.3% of body Mg is in serum
Renal wasting: loops/thiazides, hyperglycaemia
Drugs: PPIs, aminoglycosides, ampho-B
GI loss: diarrhoea, fistulae, pancreatitis
Alcohol use disorder — ~⅓ hypomagnesaemic

Consequences — two of them are why you are failing

Refractory hypokalaemia — loss of intracellular Mg²⁺ unblocks ROMK
Refractory hypocalcaemia — reduced PTH secretion
Twitching, tetany
ECG: widened QRS, long QT → torsades

Situation	Regimen
Torsades, with a pulse	MgSO₄ 2 g over 15 min, then 1 g/h
Severe symptomatic	2 g over 5–10 min, then 4–6 g/day ×3–5 d
Mild-moderate, gut working	Magnesium oxide 400 mg TDS
Cardiac arrest, non-torsades	Not recommended

Koyner Ch 24 · Tzivoni D et al. Circulation. 1988;77:392 · Gu WJ et al. Trials. 2012;13:41 · Panchal AR et al. Circulation. 2018;138:e740 · Huang CL, Kuo E. J Am Soc Nephrol. 2007;18:2649

Hypermagnesaemia: iatrogenic, graded and reversible

Serum Mg²⁺ (mg/dL)	Clinical picture
1.7–2.4	Normal
≥4.8	Loss of deep tendon reflexes — the first sign
5–8	Nausea, vomiting, flushing
12–15	AV block, bradycardia, QRS widening
> 15	Complete heart block, arrest

Who gets it

Obstetric magnesium — toxicity follows a GFR fall
Mg-containing antacids and laxatives in CKD
Any exogenous load with AKI
Tumour lysis and rhabdo release Mg

Treatment

Stop the magnesium — including the laxative nobody charted. 1 g IV calcium gluconate antagonises the membrane effect but removes none. Dialysis for kidney failure.

Koyner Ch 24 · Clark BA, Brown RS. Am J Nephrol. 1992;12:336 · Bokhari SR et al. Am J Med Sci. 2018;355:390

Rhabdomyolysis & tumour lysis

Two lysis syndromes, one physiology: cells empty into plasma faster than the kidney can clear them. Fluid given early is worth more than any drug given later.

Koyner Ch 49–50 · Ronco Ch 38, 41

Rhabdomyolysis: CK is a marker, not a predictor — and how myoglobin injures

Classic triad present in fewer than half of patients
Threshold: CK >5× ULN; peaks 24–72 h
Dipstick blood without red cells
AKI 13–50%

Third-spacingNecrotic muscle sequesters litres.

→

VasoconstrictionMyoglobin scavenges NO.

→

Cast nephropathyMyoglobin precipitates with Tamm–Horsfall.

→

Haem toxicityFree iron, ATP depletion.

McMahon risk score

Age, sex, Cr, aetiology, Ca <7.5, CK >40,000, HCO₃⁻ <19, phosphate. Score <5 → 2.3% KRT or death; >10 → 61.2%.

K⁺ ↑Earliest lethal complication

PO₄ ↑With hyperuricaemia

Ca²⁺ ↓Deposited into muscle

DIC· compartment syndrome

Koyner Ch 49 · McMahon GM et al. JAMA Intern Med. 2013;173:1821 · Bosch X et al. N Engl J Med. 2009;361:62 · Clarkson PM et al. Med Sci Sports Exerc. 2006;38:623 · Zager RA. Kidney Int. 1996;49:314

Rhabdomyolysis management: volume early, and honesty about the rest

Stop the muscle injury — release the crush, stop the statin. Correct hypophosphataemia and hypokalaemia.

Isotonic crystalloid, immediately — in crush injury start during extrication. Target UO >200 mL/h

Saline while K⁺ is high, balanced after.

Once anuria is established, fluid harms.

Sodium bicarbonate — no difference in AKI. Reserve it for acidaemia.

Mannitol — no benefit over volume, nephrotoxic at high dose.

KRT for the usual indications — never prophylactically to clear myoglobin.

Koyner Ch 49 · Sever MS, Vanholder R. Clin J Am Soc Nephrol. 2013;8:328 · Brown CV et al. J Trauma. 2004;56:1191 · Zeng X et al. Cochrane Database Syst Rev. 2014;CD008566 · Cho YS et al. Emerg Med J. 2007;24:276

Two traps in the rhabdomyolysis patient

Pitfall 1 — replacing the early calcium

Calcium deposits into damaged muscle; as it heals it rebounds, producing hypercalcaemia in ~20–30% of severe cases. Do not treat early hypocalcaemia unless symptomatic — or as membrane protection.

Pitfall 2 — missing compartment syndrome

Fluid makes injured muscle swell, so the syndrome often appears after good care. A tense limb with CK still rising needs compartment pressures measured and a same-hour surgical opinion.

Akmal M et al. J Clin Endocrinol Metab. 1986;63:137 · Bosch X et al. N Engl J Med. 2009;361:62 · Koyner Ch 49 · Ronco Ch 38

Cairo–Bishop: laboratory versus clinical TLS — and where it fails

Laboratory TLS (≥2, day −3 to +7)	Threshold
Uric acid	≥8 or 25% rise
Potassium	≥6.0 or 25% rise
Phosphate	≥4.5 (≥6.5 children) or 25% rise
Calcium	≤7.0 or 25% fall

Clinical TLS (lab + one)	Definition
Kidney	Cr ≥1.5× ULN
Cardiac	Arrhythmia/sudden death
Neurological	Seizure

Where the definition breaks down

A 25% rise within the normal range is meaningless. Cr ≥1.5× ULN is a poor AKI definition — use KDIGO. Rasburicase destroys urate ex vivo.

Who is at high risk

Burkitt, ALL, high-grade lymphoma, AML
Bulky disease, high LDH
Hyperuricaemia, oliguria, CKD
Newer triggers: venetoclax, rituximab, CAR-T

Cairo MS, Bishop M. Br J Haematol. 2004;127:3 · Cairo MS et al. Br J Haematol. 2010;149:578 · Howard SC et al. N Engl J Med. 2011;364:1844 · Koyner Ch 50

TLS: what to give, and what to stop giving

Prevent

Volume is the cornerstone
Allopurinol: prevents new urate, not existing; dose-reduce in CKD
Febuxostat if allopurinol is contraindicated
Monitor K⁺, PO₄, Ca²⁺ and urate q6–12h

Rasburicase — the specifics

Urate oxidase → allantoin, 5–10× more soluble. 0.2 mg/kg IV
Contraindicated in G6PD deficiency — test first
Active ex vivo: send the urate on ice

CORTES 2010

Urate response 87% vs 66%; time to control 4 vs 27 h.

Two things not to do

Don't alkalinise the urine. Don't routinely replace calcium — the Ca × PO₄ product is already high.

Cortes J et al. J Clin Oncol. 2010;28:4207 · Mackie T et al. J Oncol Pharm Pract. 2026 (online) · Howard SC et al. N Engl J Med. 2011;364:1844 · Coiffier B et al. J Clin Oncol. 2008;26:2767 · Ronco Ch 41 · Koyner Ch 50

The bill for continuous therapy — what it removes, and what to give back

Lost	Why it matters	What to prescribe
Phosphate	Hypophosphataemia in >50%; 2× tracheostomy	Phosphate-containing fluid
Potassium	The hyperkalaemic patient is hypokalaemic within 24 h	Use a K⁺-containing bag
Magnesium	Deficiency perpetuates hypokalaemia	Scheduled IV MgSO₄
Calcium	Citrate lowers ionised Ca by design	Systemic calcium per protocol
Amino acids, vitamins	10–15 g/day amino acids removed	Protein 1.5–2.5 g/kg/day

Key point

Electrolyte replacement is prophylaxis, not rescue. Write it into the order set on day 0.

Koyner Ch 15, 23–24, 30 · Demirjian S et al. Nephrol Dial Transplant. 2011;26:3508 · Yang Y et al. Crit Care. 2013;17:R205 · Ronco Ch 57–58

Cases, polls & wrap-up

Four bedside decisions where the physiology above becomes an order you have to sign.

Koyner Ch 21–24, 49–50

Case 1 · K⁺ 7.2 mmol/L with a wide QRS

78 M, day 3 of urinary sepsis; oliguric AKI, on lisinopril and spironolactone.

K⁺ 7.2HCO₃⁻ 15QRS 148Glu 5.1

Shift-and-observe, or catheter?

Protect · 0–3 minCalcium gluconate 10–30 mL IV; repeat if the QRS stays wide.

→

Shift · 15–30 minInsulin 5 U with dextrose; salbutamol.

→

Subtract · same hourStop the ACEi and spironolactone; audit K⁺ fluids.

→

Remove · <2 hCall for a dialysis catheter.

Why not bicarbonate at HCO₃⁻ 15?

Bolus bicarbonate does not shift K⁺ acutely. Treat the acidosis once the catheter is in.

Koyner Ch 21 · UKKA 2023 · Blumberg A et al. Am J Med. 1988;85:507 · Ronco Ch 57

Case 2 · Crush injury, CK 85,000 U/L

34 M, trapped 5 h, extricated 90 min ago; both thighs tense. Dipstick 3+ blood, no red cells.

CK 85,000K⁺ 5.9iCa²⁺ 0.88PO₄ 6.8HCO₃⁻ 16UO 25 mL/h

Hypocalcaemic and asymptomatic — replace calcium?

Do

Isotonic crystalloid now, titrated to UO >200
Calcium here is membrane protection, not repletion
Measure compartment pressures (delta <30 → theatre)
Score him; ICU

Do not

Replace the ionised calcium of 0.88 — he is asymptomatic
Give mannitol, or bicarbonate except for acidaemia
Dialyse to "wash out myoglobin"
Keep pushing fluid once anuric

Koyner Ch 49 · Sever MS, Vanholder R. Clin J Am Soc Nephrol. 2013;8:328 · McMahon GM et al. JAMA Intern Med. 2013;173:1821

Case 3 · Burkitt lymphoma, 12 hours after the first cycle

26 M, bulky abdominal disease, LDH 3,400 U/L. Received allopurinol and IV saline before chemotherapy. Now confused, with a rising creatinine and a falling urine output.

Uric acid 11.4 mg/dLK⁺ 6.1 mmol/LPO₄ 8.2 mg/dLCa²⁺ 6.6 mg/dLCr 1.2 → 2.6 mg/dLUO 20 mL/h

Does he meet criteria for clinical TLS? What do you give, what one test must precede the drug, and what do you deliberately withhold despite an abnormal number?

Hands up — then name the test, and the reason his allopurinol did not prevent this

Koyner Ch 50 · Cairo MS, Bishop M. Br J Haematol. 2004;127:3 · Cortes J et al. J Clin Oncol. 2010;28:4207 · Howard SC et al. N Engl J Med. 2011;364:1844

Case 4 · Falling calcium on citrate CRRT

61 F, alcoholic hepatitis and septic shock, hour 30 of CVVHDF with regional citrate anticoagulation. Nurse reports she keeps increasing the systemic calcium infusion; the patient is now cramping and the QT is 510 ms. Bicarbonate is rising and the anion gap is widening.

Patient iCa 0.92 mmol/LCircuit iCa 0.28 mmol/LTotal Ca 10.4 mg/dLTotal:iCa 2.8HCO₃⁻ 31Lactate 4.1Mg²⁺ 0.58 mmol/L

The fork: is this simply under-replacement of calcium, or citrate accumulation? Which number decides it, and what do you change first?

Discuss in pairs · one number, one action

Koyner Ch 21–22, 33 · Ronco Ch 57 · Lecture 09 — KRT II

Model answer: citrate accumulation ("citrate lock"). The decisive number is the total-to-ionised calcium ratio > 2.5, both in the same units (here 2.60 ÷ 0.92 mmol/L = 2.8) — the total calcium is normal or high while the ionised is low, because calcium is chelated, not absent. Supporting features: liver failure impairing citrate metabolism, rising bicarbonate (citrate is metabolised to bicarbonate) alongside a widening anion gap from unmetabolised citrate, and a rising lactate. The wrong move is to keep escalating calcium — that raises total calcium and the ratio without fixing the ionised level. Correct actions: reduce the citrate dose (lower blood flow, so lower citrate delivery), accept a higher circuit ionised calcium target, consider switching to heparin or no anticoagulation, and replace the magnesium (0.58 mmol/L) which is both chelated by citrate and blocking PTH release. Timing cue: 2 minutes — this is the case fellows most often get wrong on first pass.

Poll 1

A 62-year-old on furosemide and a proton pump inhibitor has K⁺ 3.0 mmol/L with U waves. You give 40 mmol of KCl centrally over 2 hours. The repeat potassium is 3.1 mmol/L. Magnesium has not been checked.

A. Give another 40 mmol of KCl and recheck in 2 h · B. Check and replace magnesium before any further potassium · C. Add spironolactone to reduce distal secretion · D. Switch to oral KCl and accept a 24-hour correction · E. Send a urine K⁺/creatinine ratio and wait for it before acting.

Hands up — then say which of his two drugs is the bigger culprit, and by what mechanism

Koyner Ch 21, 24 · Huang CL, Kuo E. J Am Soc Nephrol. 2007;18:2649 · Ronco Ch 57

Answer B. Intracellular Mg²⁺ physically plugs ROMK from the cytosolic side; when depleted, the plug is lost, ROMK conductance rises and the collecting duct wastes potassium obligately — so the potassium you gave was excreted. A is the common wrong answer and risks an eventual overshoot once magnesium is finally replaced. C is a real strategy in chronic refractory hypokalaemia but is far too slow here and does nothing about the magnesium. D wastes 24 hours in a patient with U waves. E is the trap for the physiologically minded: the urine ratio is a useful test but you do not need it to justify giving magnesium, and waiting delays the fix. Culprits: the loop diuretic is the bigger one (it abolishes the lumen-positive potential in the thick ascending limb that drives paracellular Mg²⁺ reabsorption), while PPIs impair TRPM6-mediated intestinal absorption over months. Give MgSO₄ 2 g IV then continue 3–5 days, because serum magnesium says nothing about intracellular stores. Timing cue: 1 minute.

Poll 2

Day 2 after subtotal parathyroidectomy for tertiary hyperparathyroidism in a haemodialysis patient. She has perioral paraesthesia and a positive Trousseau sign. Ionised Ca 0.78 mmol/L, phosphate 1.9 mg/dL (0.61 mmol/L), Mg²⁺ 0.55 mmol/L, alkaline phosphatase 1,180 U/L, intact PTH 42 pg/mL.

A. Surgical hypoparathyroidism — start calcium and expect a short course · B. Hungry bone syndrome — high-dose calcium infusion plus calcitriol and magnesium, for weeks · C. Citrate effect from the dialysis circuit · D. Vitamin D deficiency — give cholecalciferol · E. Reduce dialysate calcium to stimulate residual parathyroid tissue

Hands up — then name the one laboratory value that separates A from B

Koyner Ch 22 · Ronco Ch 58 · El-Hajj Fuleihan G et al. J Clin Endocrinol Metab. 2023;108:507

Answer B. The discriminator is the phosphate: hungry bone drives calcium AND phosphate AND magnesium into remineralising bone, so phosphate is LOW; surgical hypoparathyroidism removes phosphaturic PTH, so phosphate would be HIGH. The detectable PTH of 42 confirms residual parathyroid function, excluding A. The very high alkaline phosphatase is the classic predictor — along with large gland mass, younger age, high preoperative PTH and severe preoperative bone disease. Treatment is aggressive: continuous IV calcium (often 1–2 mg/kg/h of elemental calcium), oral calcium carbonate with meals, calcitriol started preoperatively where possible, magnesium replacement (0.55 mmol/L here is blocking both PTH release and PTH action), and a higher dialysate calcium — for weeks, not days. C is wrong because standard bicarbonate dialysis does not cause this picture and the timing is off. D is too slow and does not explain the low phosphate. E is exactly backwards and would deepen the hypocalcaemia. Timing cue: 1 minute.

Key takeaways

Repeat the potassium before treating it; never let a normal ECG reassure you.
Calcium protects the membrane and removes nothing — only a kidney, binder or circuit subtracts.
Insulin 5 U or 0.1 U/kg when eGFR <30 — it halves hypoglycaemia without losing effect.
Binders are a bridge and a RAASi-enabler; SPS has no acute role.
Ionised calcium is the only calcium that counts; total:ionised >2.5 means citrate.
Replace magnesium before K⁺, thiamine before calories, phosphate before weaning.
In tumour lysis: check G6PD before rasburicase, and chill the urate sample.

References & further reading

Where to go deeper

UKKA. Acute hyperkalaemia guideline 2023.
Moussavi K, et al. Pharmacother. 2021;41:598.
Packham D. ZS-003. NEJM. 2015;372:222–231.
Weir M. OPAL-HK. NEJM. 2015;372:211–221.
Vallentin M, et al. COCA. JAMA. 2021;326:2268.
Slomp J, et al. Crit Care Med. 2003;31:1389 · El-Hajj Fuleihan G, et al. JCEM. 2023;108:507.
Taylor B, et al. J Am Coll Surg. 2004;198:198.
McMahon G, et al. JAMA Intern Med. 2013;173:1821 · Cairo M, Bishop M. Br J Haematol. 2004;127:3.

Full list: (1) UKKA acute hyperkalaemia guideline 2023 + Montague (CJASN 2008;3:324–330); (2) Moussavi (Pharmacotherapy 2021;41:598–607), Kelley (Pharmacotherapy 2025;45:794–800), Allon & Copkney (Kidney Int 1990;38:869–872); (3) ZS-003 (NEJM 2015;372:222–231), HARMONIZE (JAMA 2014;312:2223–2233), ENERGIZE (Acad Emerg Med 2020;27:475–486), Geldermann (Emerg Med J 2026;43:305–311); (4) OPAL-HK (NEJM 2015;372:211–221), DIAMOND (Eur Heart J 2022;43:4362–4373), Noel SPS GI events (JAMA Intern Med 2019;179:1025–1033), Charytan (Kidney Int 2025;107:169–179); (5) COCA (JAMA 2021;326:2268–2276); (6) Slomp (Crit Care Med 2003;31:1389–1393), Collage (Crit Care Med 2013;41:e352–e360), Forsythe Cochrane (2008;CD006163), Endocrine Society hypercalcaemia (JCEM 2023;108:507–528); (7) Taylor (J Am Coll Surg 2004;198:198–204), Doig (Lancet Respir Med 2015;3:943–952), NICE CG32; (8) McMahon (JAMA Intern Med 2013;173:1821–1828), Sever & Vanholder (CJASN 2013;8:328–335), Brown (J Trauma 2004;56:1191–1196); (9) Cairo & Bishop (Br J Haematol 2004;127:3–11), Cortes (J Clin Oncol 2010;28:4207–4213), Mackie (J Oncol Pharm Pract 2026), Howard (NEJM 2011;364:1844–1854); (10) Koyner Handbook Ch 15, 21–24, 30, 49–50; Ronco Critical Care Nephrology 3e Ch 38, 41, 57–58; Palmer (CJASN 2015;10:1050–1060).

Critical Care Nephrology · Two-Week Intensive

Thank you

Questions & discussion — bring the worst potassium you have ever treated, and the one you nearly missed.

Next: Lecture 07 — Acid-Base Disorders & DKA