ICU · Oncology
Tumour lysis syndrome
Also known as Tumour lysis syndrome (TLS) · Hyperuricaemia · Rasburicase · Acute tumour lysis syndrome (ATLS) · Cairo-Bishop classification · Urate nephropathy · Tumor lysis syndrome
Tumour lysis syndrome (TLS) is a metabolic oncological emergency from rapid malignant cell lysis releasing intracellular contents: HYPERKALAEMIA (intracellular K+ dumped — most dangerous, causes fatal arrhythmia), HYPERPHOSPHATAEMIA (tumour cells carry ~4x normal phosphate), HYPOCALCAEMIA (secondary — Ca2+ precipitates with phosphate as calcium-phosphate crystals), and HYPERURICAEMIA (nucleic acid breakdown → purines → xanthine → uric acid via xanthine oxidase). Uric acid and calcium-phosphate precipitate in renal tubules → acute kidney injury (AKI), which then reduces K+ and phosphate excretion → a self-amplifying vicious cycle. Onset 12-72h after starting chemotherapy/radiotherapy/corticosteroids/targeted therapy for high-turnover tumours (ALL, Burkitt lymphoma, lymphoblastic lymphoma, high-grade NHL, AML with high WBC); spontaneous TLS can precede therapy in bulky disease. Cairo-Bishop definition: laboratory TLS (≥2 abnormal values — urate ≥475 µmol/L/8 mg/dL, K+ ≥6.0 mmol/L, phosphate ≥1.45 mmol/L, Ca2+ ≤1.75 mmol/L, or 25% change within 3 days before to 7 days after therapy) vs clinical TLS (LTLS PLUS AKI, arrhythmia/sudden death, or seizure). Prevention is the cornerstone: aggressive IV hydration 3 L/m2/day (goal urine output 100 mL/m2/h) starting 24-48h BEFORE chemo + rasburicase 0.15-0.2 mg/kg IV for HIGH risk (recombinant urate oxidase — converts EXISTING uric acid → soluble allantoin; CONTRAINDICATED in G6PD deficiency) or allopurinol 300 mg/day for INTERMEDIATE risk (xanthine oxidase inhibitor — prevents NEW uric acid only). Treatment: aggressive hydration, rasburicase, treat hyperkalaemia per protocol (calcium gluconate → insulin-dextrose → salbutamol → binders → RRT), do NOT routinely treat asymptomatic hypocalcaemia, CRRT for refractory electrolyte disturbance or AKI. Do NOT alkalinise urine (worsens calcium-phosphate precipitation).
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Pathophysiology — why a dying tumour kills the host
Rapid lysis of a large number of malignant cells overwhelms the body's homeostatic capacity. Each lysed cell empties its intracellular contents into the extracellular fluid. Malignant cells carry an unusually large intracellular load of potassium (intracellular K+ is ~140 mmol/L vs ~4 mmol/L in extracellular fluid), phosphate (~4x normal cells, reflecting high nucleic acid and phosphometabolite content), and nucleic acids (DNA/RNA from a rapidly dividing cell). When cytotoxic therapy kills these cells en masse over hours, the released solutes exceed renal and extrarenal clearance capacity, producing the four defining metabolic disturbances.[6][1]
The 4 metabolic disturbances of TLS — mechanism and consequence
| Disturbance | Mechanism (what the dying tumour cell releases) | Consequence |
|---|---|---|
| HYPERKALAEMIA (#1 danger) | Intracellular K+ is ~140 mmol/L. Massive tumour lysis dumps K+ into extracellular fluid faster than the (already injured) kidney and Na+/K+-ATPase can compensate. | Fatal arrhythmia — peaked T waves → PR prolongation → QRS widening → sine wave → VF/asystole. The usual mode of death in TLS. |
| HYPERPHOSPHATAEMIA | Malignant cells carry ~4x the phosphate of normal cells (high nucleic acid and phosphometabolite content). Lysis releases this load acutely. | Drives hypocalcaemia (Ca-P precipitation) and direct calcium-phosphate nephropathy (nephrocalcinosis → AKI). |
| HYPOCALCAEMIA (secondary) | NOT a release phenomenon — Ca2+ precipitates as insoluble calcium-phosphate (and calcium-urate) crystals in the setting of hyperphosphataemia. Ionised/corrected calcium falls. | Symptomatic: perioral paraesthesia, tetany, carpopedal spasm, Chvostek/Trousseau signs, laryngospasm, seizures, QT prolongation → torsades de pointes. |
| HYPERURICAEMIA | Massive nucleic acid (DNA/RNA) release → purine (guanine, adenine) breakdown → xanthine → uric acid (catalysed by xanthine oxidase). Uric acid is poorly soluble at urinary pH. | Urate nephropathy — uric acid precipitates as crystals in the distal renal tubules/collecting ducts → tubular obstruction → AKI. |
The kidney: victim and amplifier — the vicious cycle
The kidney is the central organ in TLS pathology. Acute kidney injury arises from four converging insults: (1) uric acid nephropathy — intratubular crystallisation of uric acid (most important early mechanism; uric acid solubility is pH-dependent and falls in concentrated acidic urine); (2) calcium-phosphate nephropathy — crystallisation and intrarenal deposition (nephrocalcinosis), which dominates later (after 48-72h as phosphate accumulates); (3) volume depletion — vomiting, poor oral intake, and obligate urinary solute losses reduce renal perfusion, and concentrated acidic urine favours further uric acid crystallisation; and (4) cytokine-mediated renal vasoconstriction and inflammatory tubular injury. Once AKI develops, renal K+ and phosphate excretion fall, worsening the very hyperkalaemia and hyperphosphataemia that define TLS — a self-amplifying vicious cycle that is why established TLS is so dangerous and why dialysis is so often required.[6][1]
The arrhythmia mechanism — hyperkalaemia meets hypocalcaemia
Hyperkalaemia depolarises the cardiac myocyte resting membrane potential (makes it less negative) → inactivates fast sodium channels → slows phase-0 depolarisation and conduction → PR prolongation, QRS widening, conduction block, re-entrant ventricular arrhythmias (VF), and ultimately asystole. Hypocalcaemia compounds this by prolonging the action potential plateau and the QT interval → torsades de pointes. The two disturbances are synergistic: the hyperkalaemic heart with a long QT from hypocalcaemia is exquisitely arrhythmogenic. This is why ECG monitoring is mandatory and why calcium gluconate is given for ECG changes — it raises extracellular Ca2+, raising the threshold for depolarisation and transiently restoring membrane stability without lowering potassium.[1]
Spontaneous (pre-treatment) TLS
In very high-burden, high-turnover disease (Burkitt lymphoma, lymphoblastic lymphoma, T-cell ALL with a large mediastinal/abdominal mass), tumour cells can undergo spontaneous necrosis before any therapy is given. These patients may already have hyperuricaemia, hyperphosphataemia, and AKI at diagnosis. Spontaneous TLS is a marker of extreme tumour burden and carries a worse prognosis because the kidney is injured before prophylaxis can begin.[1]
Clinical presentation — recognise the pattern
TLS presents as acute metabolic decompensation in a patient with a high-turnover malignancy, typically 12-72h after starting cytotoxic therapy (chemotherapy, radiotherapy, corticosteroids, or targeted/biological agents such as rituximab, venetoclax, or bortezomib). The clinical features map directly to the four metabolic disturbances plus the AKI.[6]
TLS clinical features — by metabolic disturbance
| Disturbance | Clinical features | Severity marker |
|---|---|---|
| Hyperkalaemia | Often asymptomatic until ECG changes; muscle weakness, paraesthesia. ECG: peaked (tented) T waves → flattened/disappearing P waves → PR prolongation → QRS widening → sine wave → VF → asystole. | Sine wave / VF / asystole = peri-arrest. ECG changes = give calcium gluconate immediately. |
| Hyperphosphataemia | Largely asymptomatic itself — manifests through hypocalcaemia and AKI. | Rising phosphate drives worsening hypocalcaemia and Ca-P nephropathy. |
| Hypocalcaemia | Perioral/finger paraesthesia, muscle cramps, carpopedal spasm, Chvostek sign (facial nerve twitch on tapping), Trousseau sign (carpal spasm with BP cuff inflated above systolic), laryngospasm, seizures. ECG: QT prolongation → torsades. | Seizure, laryngospasm, torsades = severe — treat with calcium gluconate. |
| Hyperuricaemia / AKI | Oliguria, anuria, fluid overload (pulmonary oedema), uraemic features (nausea, confusion, pericarditis), metabolic acidosis. | Oligoanuria + rising creatinine = dialysis likely. |
| Systemic | Lethargy, nausea, vomiting, reduced GCS (uraemia, hypocalcaemia). | Hypotension from volume overload or uraemia is late. |
Cairo-Bishop classification and grading — the exam-defining framework
The Cairo-Bishop system (2004, refined by Howard 2011 and the 2010 international expert panel) defines and grades TLS. Every CICM/FFICM/EDIC candidate must know it cold.[2][3][6]
Cairo-Bishop — Laboratory TLS (LTLS) vs Clinical TLS (CTLS)
| Laboratory TLS (LTLS) | Clinical TLS (CTLS) | |
|---|---|---|
| Timing window | Within 3 days BEFORE to 7 days AFTER cytotoxic therapy | Same window |
| Diagnostic criterion | ≥2 of the following four (present simultaneously per Howard 2011 refinement): | LTLS (as left) PLUS ≥1 clinical complication: |
| • Uric acid ≥475 µmol/L (8.0 mg/dL) OR 25% rise from baseline | (a) Acute kidney injury — creatinine >1.5× the upper limit of normal (or 1.5× baseline in children) | |
| • Potassium ≥6.0 mmol/L OR 25% rise from baseline | (b) Cardiac arrhythmia or sudden death | |
| • Phosphate: adults ≥1.45 mmol/L (4.5 mg/dL); children ≥2.1 mmol/L (6.5 mg/dL) OR 25% rise from baseline | (c) Seizure | |
| • Corrected calcium ≤1.75 mmol/L (7.0 mg/dL) OR 25% fall from baseline | ||
| Note | Howard 2011 modification: abnormal values present SIMULTANEOUSLY; symptomatic hypocalcaemia alone qualifies even without the numerical threshold | A patient with CTLS by definition has LTLS |
Cairo-Bishop severity grading (0-5)
| Grade | Definition |
|---|---|
| 0 | No TLS |
| I / II / III | LTLS or CTLS with complications of mild / moderate / severe intensity (grade III = severe/serious) |
| IV | Life-threatening complication (e.g., VF, status epilepticus, severe AKI requiring RRT) |
| V | Death attributable to TLS |
Practical point for the intensivist: the ICU patient with TLS almost always has CTLS — they are in ICU precisely because they have AKI, an arrhythmia, or a seizure. The role of the LTLS criteria at the bedside is to confirm the diagnosis and to quantify the metabolic load you must reverse. [1]
Risk factors and risk stratification — who gets prophylaxis with what
TLS risk is determined by tumour-related factors (type, bulk, proliferative rate, sensitivity to therapy), patient-related factors (baseline renal function, hydration, age), and treatment-related factors (potency and speed of the cytotoxic regimen). The 2010 international expert panel consensus stratifies patients into low, intermediate, and high risk.[3][7]
TLS risk factors
| Domain | High-risk features |
|---|---|
| Tumour type | Burkitt lymphoma / lymphoblastic lymphoma; ALL (especially WBC ≥100 ×10⁹/L in children, ≥25 ×10⁹/L in adults, or high tumour burden); AML with WBC ≥25-50 ×10⁹/L; bulky high-grade / aggressive NHL (especially with LDH >2× ULN); high-burden solid tumours (neuroblastoma, germ-cell tumours, small-cell lung cancer, advanced medulloblastoma) — solid-tumour TLS is rarer but increasingly recognised with high-burden disease |
| Tumour burden / proliferation | Bulky disease (lymph node mass ≥10 cm, or ≥3 masses ≥3 cm); LDH elevated, particularly ≥2× ULN (surrogate for tumour bulk and turnover); extensive marrow infiltration; high proliferative fraction (Ki-67); large abdominal/mediastinal mass (Burkitt) |
| Treatment sensitivity | Tumours expected to respond RAPIDLY (Burkitt to rituximab + chemo; CLL to venetoclax; ALL to steroids). A tumour that lyses fast releases contents faster than the kidney can clear them. |
| Baseline renal function | Pre-existing CKD/AKI, uraemia at diagnosis, oliguria, pre-existing hyperuricaemia — reduces clearance reserve |
| Patient factors | Dehydration / hypovolaemia (concentrated acidic urine favours uric acid crystallisation); acidic urine pH; concurrent nephrotoxins (NSAIDs, contrast, aminoglycosides); advanced age |
Risk-stratified prophylaxis — the BCSH / Coiffier framework
| Risk category | Hydration | Urate-lowering therapy | Monitoring |
|---|---|---|---|
| HIGH risk (Burkitt, lymphoblastic lymphoma, ALL high WBC, bulky high-grade NHL with LDH >2× ULN, AML high WBC, established/spontaneous TLS) | IV fluids 3 L/m2/day (or ~2-3 L/day adults), goal urine output >100 mL/m2/h (>2 mL/kg/h); start 24-48h before chemo | RASBURICASE 0.15-0.2 mg/kg IV (single dose, may repeat in 24h). Screen for G6PD deficiency first. Allopurinol is an ADD-ON or alternative only if rasburicase unavailable/contraindicated. | U&E, uric acid, phosphate, calcium, creatinine every 6-12h for 48-72h; continuous cardiac monitoring |
| INTERMEDIATE risk (intermediate-grade NHL, AML moderate WBC, multiple myeloma, low-burden ALL/CLL) | Same aggressive hydration | ALLOPURINOL 300 mg/day PO (start 24-48h before chemo). Rasburicase if uric acid rises or LTLS develops. | Same, every 12h |
| LOW risk (indolent lymphomas, low-burden solid tumours) | Maintain hydration; oral fluids | None routinely | U&E, urate, phosphate, calcium daily |
Prevention — the cornerstone
Prevention is far more effective than treatment. Most TLS is predictable and preventable with risk assessment, hydration, and the correct urate-lowering agent. The intensivist's job is often to oversee prophylaxis of a high-risk patient on the haematology ward, and to escalate to ICU the moment laboratory TLS appears.[1][7]
TLS prevention strategy
Identify high-risk tumours
HIGH risk: ALL (high WBC), Burkitt lymphoma, lymphoblastic lymphoma, high-grade NHL (high tumour burden), AML (high WBC), tumours with high cell turnover or large burden. MODERATE risk: intermediate-grade lymphoma, AML (moderate WBC), multiple myeloma. LOW risk: indolent lymphomas, low-burden solid tumours. Risk-stratify using tumour type, bulk (LDH, size, marrow involvement), proliferative rate, baseline renal function, and expected treatment sensitivity.
Aggressive hydration — ALL patients, the single most important intervention
IV fluids: 3 L/m2/day (or 2-3x maintenance) starting 24-48h BEFORE chemotherapy. Goal: urine output >100 mL/m2/h. Normal saline. High urinary flow dilutes uric acid and phosphate, reducing tubular crystallisation. Add a loop diuretic (furosemide) ONLY if urine output falls below target despite euvolaemia, or to manage volume overload. Do NOT alkalinise urine — routine alkalinisation is NOT recommended (worsens calcium-phosphate precipitation).
Allopurinol — moderate/intermediate risk
Allopurinol 300 mg/day PO (100 mg/m2/day in children). Xanthine oxidase inhibitor — prevents NEW uric acid formation. Does NOT lower existing uric acid (so ineffective for established hyperuricaemia/AKI). Start 24-48h before chemotherapy. Caution: reduces clearance of azathioprine and 6-mercaptopurine (both metabolised by xanthine oxidase) — reduce azathioprine/6-MP dose by 75% to avoid fatal myelosuppression. Also potentiates warfarin.
Rasburicase — high risk
Rasburicase 0.15-0.2 mg/kg IV (single dose, may repeat in 24h). Recombinant urate oxidase — converts EXISTING uric acid to soluble allantoin. Rapidly lowers uric acid within 4h. Screen for G6PD deficiency BEFORE giving (rasburicase generates H2O2 that causes haemolysis and methaemoglobinaemia in G6PD deficiency). Preferred over allopurinol for high-risk prophylaxis and all established TLS. Sample handling: uric acid samples after rasburicase MUST be transported on ice and processed immediately — rasburicase degrades uric acid in the tube at room temperature (falsely low results).
Monitor closely (12-72h post-chemo)
Check U&E, uric acid, phosphate, calcium, creatinine every 4-6h for the first 72h (every 6-12h thereafter through day 7). Continuous cardiac monitoring (hyperkalaemia risk). Monitor urine output hourly (AKI risk). Escalate (rasburicase, hyperkalaemia treatment, ICU, RRT) the moment LTLS appears.
Avoid nephrotoxins
Stop NSAIDs, aminoglycosides, iodinated contrast, and ACE inhibitors/ARBs during the at-risk window to protect renal perfusion and tubular function.
Treatment of established TLS — the ICU protocol
The patient with established (clinical) TLS in ICU needs simultaneous, aggressive management of all four metabolic disturbances, with hyperkalaemia taking immediate priority.[1][7]
Established TLS management
Continuous cardiac monitoring + 12-lead ECG
Look for hyperkalaemic changes (peaked T waves, PR prolongation, QRS widening, sine wave) and QT prolongation from hypocalcaemia. ECG changes = hyperkalaemic emergency.
Treat hyperkalaemia FIRST (it kills first) — staged protocol
CALCIUM GLUCONATE 10% 10 mL IV over 2-5 min if ANY ECG change (membrane stabilisation, does NOT lower K+, onset 1-3 min, lasts 30-60 min — repeat if ECG changes recur). Then INSULIN/DEXTROSE 10 units soluble insulin + 25-50 g glucose IV (shifts K+ intracellular, onset 15-30 min, lasts 4-6h — monitor glucose). SALBUTAMOL 10-20 mg nebulised (beta-2 agonist, additive K+-lowering — caution in tachyarrhythmia/ischaemia). POTASSIUM BINDERS (sodium zirconium cyclosilicate — fastest onset; patiromer; calcium resonium/sodium polystyrene sulfonate — actually REMOVE potassium). RENAL REPLACEMENT THERAPY if refractory, or if AKI/oliguria means K+ will keep rising.
Rasburicase for hyperuricaemia
Rasburicase 0.15-0.2 mg/kg IV (may repeat in 24h). Converts EXISTING uric acid to soluble allantoin (renally excreted). Rapid effect (within 4h) — the definitive treatment for TLS hyperuricaemia (allopurinol does NOT lower existing uric acid). MUST confirm G6PD status / exclude haemolysis first. Sample on ice (see prevention).
Aggressive hydration — continue IV fluids 3 L/m2/day
Goal urine output >100 mL/m2/h. The kidney must be flushed to clear uric acid, phosphate, and potassium. Use loop diuretics to maintain urine output if euvolaemic/hypervolaemic. If oliguric despite volume → prepare for RRT.
Hyperphosphataemia
Oral phosphate binders (sevelamer preferred — avoid calcium-based binders as they add calcium load and worsen Ca-P deposition). Aggressive hydration. RRT if refractory — the only definitive way to remove phosphate rapidly is dialysis.
Do NOT routinely treat hypocalcaemia
Hypocalcaemia is secondary to hyperphosphataemia (Ca-P precipitation). Giving calcium acutely worsens calcium-phosphate deposition in renal tubules (nephrocalcinosis) and tissues, worsening AKI. Treat ONLY if SYMPTOMATIC (tetany, carpopedal spasm, laryngospasm, seizure, or QT prolongation with arrhythmia/torsades): calcium gluconate 10% 10-20 mL IV slowly with ECG monitoring. Once phosphate is lowered and AKI resolves, calcium normalises.
Renal replacement therapy
Indications: refractory hyperkalaemia; refractory hyperphosphataemia/hypocalcaemia; symptomatic volume overload/pulmonary oedema; AKI with uraemia/acidosis/oliguria. CRRT (continuous) is PREFERRED — smooth solute clearance without the rapid shifts and rebound of intermittent haemodialysis, and better tolerated haemodynamically. Intermittent haemodialysis if very rapid correction needed (peri-arrest hyperkalaemia). Dialysate composition matters — use a low-calcium, phosphate-free/low-phosphate regimen guided by serum values.
Rasburicase vs allopurinol — head to head
| Feature | Rasburicase | Allopurinol |
|---|---|---|
| Mechanism | Recombinant urate oxidase → converts EXISTING uric acid → allantoin (soluble) | Xanthine oxidase inhibitor → prevents NEW uric acid formation |
| Effect on existing uric acid | YES — destroys it (the key difference) | NO — does not lower pre-existing uric acid |
| Onset | Hours (uric acid falls within 4h) | Days (no acute effect on existing load) |
| Role | HIGH-risk prophylaxis; TREATMENT of established TLS / hyperuricaemia | INTERMEDIATE-risk prophylaxis |
| Dose | 0.15-0.2 mg/kg IV (single dose, repeat in 24h if needed) | 300 mg/day PO (100 mg/m2/day children) |
| Key contraindication / caution | G6PD deficiency (haemolysis, methaemoglobinaemia) — screen first; pregnancy | Azathioprine / 6-mercaptopurine interaction (reduce dose 75%); warfarin potentiation; pregnancy |
| Cost | Very expensive | Cheap |
| Sample handling | Uric acid sample on ice, process immediately | Routine |
Monitoring — the at-risk window
The metabolic disturbances of TLS evolve over hours, not days. Close monitoring during the 12-72h post-chemotherapy window (and up to 7 days for slower agents) is what catches laboratory TLS before it becomes clinical TLS. The intensivist sets the monitoring frequency by risk.[1][7]
Monitoring schedule by risk and phase
| Phase / risk | Bloods frequency | What to watch | Action threshold |
|---|---|---|---|
| 0-72h post-chemo (HIGH risk) | U&E, uric acid, phosphate, calcium, creatinine every 4-6h | K+, phosphate trend, uric acid, urine output, ECG | K+ ≥6.0 or ECG change → hyperkalaemia protocol; uric acid rising → rasburicase; phosphate ≥1.45 → binders, consider RRT |
| 72h-7 days (HIGH risk) | Every 6-12h | Same — phosphate may continue to rise after 48-72h | Escalate to ICU if LTLS → CTLS |
| 0-72h (INTERMEDIATE risk) | Every 6-12h | Same | Switch allopurinol → rasburicase if uric acid rises or LTLS develops |
| Continuous (all at-risk) | Hourly urine output; continuous cardiac monitoring (high risk) | Oliguria (<100 mL/m2/h), arrhythmia | Oliguria despite volume → furosemide if euvolaemic, else RRT prep |
Key principle: the trend matters more than any single value. A potassium that climbs 1 mmol/L over 6h in an oliguric patient is heading for arrhythmia even if the absolute number is not yet alarming. Anticipate, do not react. [1]
Exam practice
SAQ — Hyperkalaemic peri-arrest in tumour lysis syndrome
10 minutes · 10 marks
A 34-year-old man with newly diagnosed Burkitt lymphoma (large abdominal mass, LDH 4500 U/L) develops weakness and palpitations 18 hours after starting chemotherapy. ECG shows widened QRS (160 ms) with a sine-wave trend. Potassium 7.8 mmol/L, phosphate 3.1 mmol/L, corrected calcium 1.55 mmol/L, uric acid 620 µmol/L, creatinine 220 µmol/L.
SAQ — Risk stratification and prophylaxis before chemotherapy
10 minutes · 10 marks
A 19-year-old woman is admitted for induction of T-cell acute lymphoblastic leukaemia with a large mediastinal mass and white cell count 180 × 10⁹/L. She is currently well-hydrated. The haematology team asks for ICU input on tumour lysis prophylaxis before starting induction.
Clinical pearls
Red flags
Prognosis
TLS outcomes and prognostic factors
| Factor | Outcome | Notes |
|---|---|---|
| Overall mortality (established TLS) | Up to 5-20% in severe cases | Death usually from hyperkalaemic arrhythmia or AKI complications; dramatically lower with effective prophylaxis |
| Pre-existing / baseline AKI | Worse outcomes | Reduced clearance reserve — more likely to need RRT and refractory electrolyte disturbance |
| Underlying tumour | Burkitt / high-grade NHL / ALL with high WBC = highest risk | Risk correlates with tumour bulk (LDH), proliferative rate, treatment sensitivity |
| Need for RRT | 5-20% of high-risk patients | Usually temporary (days); renal function typically recovers as the tumour-lysis load clears; some have residual CKD |
| Time to intervention | Early prophylaxis = excellent; late CTLS = high mortality | Prevention is far more effective than treatment — risk stratification before therapy is paramount |
| Spontaneous TLS | Poorer prognosis | Presents late with established AKI/metabolic derangement before therapy begins |
Key trials and evidence
Cairo & Bishop 2004 — TLS classification (Cairo-Bishop criteria) (PMID 15384972)
Source
British Journal of Haematology — the seminal classification paper
What it established
The Cairo-Bishop system: laboratory TLS (≥2 of uric acid ≥475 µmol/L/8 mg/dL, K+ ≥6.0 mmol/L, phosphate ≥1.45 mmol/L adult, calcium ≤1.75 mmol/L, or 25% change within the at-risk window) vs clinical TLS (LTLS PLUS AKI / arrhythmia / sudden death / seizure)
Key contribution
The classification system every intensivist and haematologist uses to define and grade TLS — the exam framework
Clinical bottom line
Know the numerical thresholds and the LTLS vs CTLS distinction cold for the exam
Cairo 2010 — International expert TLS panel consensus (PMID 20331465)
Source
British Journal of Haematology — international consensus of paediatric + adult oncology TLS experts
What it established
A formal medical-decision-tree risk model assigning LOW / INTERMEDIATE / HIGH TLS risk based on laboratory TLS, tumour proliferation/bulk/stage, and renal impairment — with matched prophylaxis recommendations
Key contribution
Standardised pre-therapy risk stratification: hydration alone (low), hydration + allopurinol (intermediate), or hydration + rasburicase (high)
Clinical bottom line
The risk-stratification backbone that drives prophylaxis decisions
Coiffier 2008 — JCO TLS management guidelines (PMID 18509186)
Source
Journal of Clinical Oncology — evidence-based review and guidelines
What it established
Reinforced aggressive hydration, rasburicase for high-risk/treatment, allopurinol for prophylaxis, and recommended AGAINST routine urine alkalinisation
Key contribution
The definitive anti-alkalinisation stance underpinning all modern practice
Clinical bottom line
Hydrate aggressively; do NOT alkalinise the urine
Cortes 2010 — Rasburicase Phase III trial in adults (PMID 20713865)
Source
Journal of Clinical Oncology — multicentre randomised Phase III, 275 adults with haematological malignancies at risk of TLS
Arms
Rasburicase 0.20 mg/kg/day d1-5 vs rasburicase d1-3 then allopurinol vs allopurinol alone d1-5
Key result
Uric acid control (≤7.5 mg/dL, days 3-7): 87% (rasburicase) vs 78% (rasburicase→allopurinol) vs 66% (allopurinol), p=0.001. Time to control in hyperuricaemic patients: 4h (rasburicase) vs 27h (allopurinol)
Clinical bottom line
Definitive adult evidence that rasburicase controls uric acid faster and more effectively than allopurinol — established rasburicase as first-line for high-risk prophylaxis and established TLS
Howard 2011 — NEJM TLS review (PMID 21561350)
Source
New England Journal of Medicine — the definitive narrative review
Key modifications
Howard refined Cairo-Bishop: laboratory TLS requires the abnormal values present SIMULTANEOUSLY, and symptomatic hypocalcaemia alone qualifies even without meeting the numerical threshold
Clinical guidance
Comprehensive pathophysiology, risk stratification, management — hydration + rasburicase (high) / allopurinol (intermediate), no alkalinisation, RRT for refractory disturbance
Clinical bottom line
The single most-cited TLS reference — read it for the exam
Jones 2015 — BCSH TLS guidelines (PMID 25876990)
Source
British Journal of Haematology — British Committee for Standards in Haematology
What it established
Practical UK risk-stratified prophylaxis algorithm; confirmed rasburicase for high-risk, allopurinol for intermediate-risk; reinforced against routine alkalinisation; highlighted G6PD screening before rasburicase
Key contribution
The practical bedside decision framework used across the UK and ANZ ICUs
Clinical bottom line
The operational guideline — pair with the 2010 expert consensus for risk stratification
Howard 2024 — Nature Reviews Disease Primers TLS primer (PMID 39174582)
Source
Nature Reviews Disease Primers — comprehensive disease primer
What it established
Updated authoritative synthesis of TLS pathophysiology, the four converging renal insults, spontaneous TLS, risk stratification, and contemporary management including CRRT and newer urate-lowering strategies
Key contribution
The current definitive reference integrating a decade of evidence since the 2011 NEJM review
Clinical bottom line
The 2024 state-of-the-art reference for pathophysiology and risk-adapted prevention
References
- [1]Howard SC, Avagyan A, Workeneh B, et al. Tumour lysis syndrome Nat Rev Dis Primers, 2024.PMID 39174582
- [2]Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification Br J Haematol, 2004.PMID 15384972
- [3]Cairo MS, Coiffier B, Reiter A, Younes A; TLS Expert Panel. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus Br J Haematol, 2010.PMID 20331465
- [4]Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review J Clin Oncol, 2008.PMID 18509186
- [5]Cortes J, Moore JO, Maziarz RT, et al. Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study J Clin Oncol, 2010.PMID 20713865
- [6]Howard SC, Jones DP, Pui CH. The tumor lysis syndrome N Engl J Med, 2011.PMID 21561350
- [7]Jones GL, Will A, Jackson GH, Webb NJ, Rule S; British Committee for Standards in Haematology. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology Br J Haematol, 2015.PMID 25876990