Overview
- Patients with haematological malignancies represent an increasing proportion of ICU admissions.
- The combination of the underlying disease process, myelosuppressive chemotherapy, and immunosuppressive agents creates a uniquely vulnerable population.
- Three life-threatening complications demand fluency at the CICM Final level: febrile neutropenia (FN), tumour lysis syndrome (TLS), and leukaemic blast crisis.
- Each carries distinct pathophysiology, time-critical recognition criteria, and management strategies that differ meaningfully from the general sepsis or metabolic emergency approach.
Febrile Neutropenia
Definition and Risk Stratification
Febrile neutropenia is defined as a single oral temperature ≥38.3°C, or a sustained temperature ≥38.0°C for more than one hour, in a patient with an absolute neutrophil count (ANC) $< 0.5 \times 10^9/L$, or an ANC $< 1.0 \times 10^9/L$ predicted to fall below $0.5 \times 10^9/L$ within 48 hours.
Risk stratification guides the intensity of management:
| Risk Category | Criteria | Mortality Risk |
|---|---|---|
| Low risk | Expected neutropenia < 7 days, no comorbidities, MASCC score ≥ 21 | < 5% |
| High risk | Expected neutropenia ≥ 7 days, haematological malignancy, AML/BMT, organ dysfunction | 10-30% |
| ICU-level | Septic shock, respiratory failure, end-organ dysfunction | > 40% |
- ICU patients by definition fall into high-risk categories.
- The MASCC score and equivalent tools are of limited utility once organ support is required.
Pathophysiology
- Myelotoxic chemotherapy ablates the granulocyte pool.
- Without neutrophil-mediated containment, commensal gut flora, particularly gram-negative bacilli, translocate across a damaged mucosal barrier.
- Gram-positive organisms (coagulase-negative staphylococci, viridans streptococci) from central venous lines account for a growing proportion of bacteraemias.
- Invasive fungal infection (principally Aspergillus spp. and Candida spp.) emerges as a dominant concern when neutropenia extends beyond 7-10 days or with repeated antibacterial exposure.
- Classical signs of infection, localised erythema, purulence, peritonism, are attenuated or absent without granulocytes.
- Fever may be the sole indicator.
- Radiological infiltrates may not appear until counts recover.
- This demands broad diagnostic casting and early empiric therapy.
Antibiotic Strategy
Empiric therapy should commence within one hour of recognition.
| Scenario | First-line | Modifications |
|---|---|---|
| Standard FN, no shock | Meropenem 1 g IV q8h | , |
| Septic shock | Meropenem 1 g IV q8h + vancomycin 25-30 mg/kg loading dose | Target AUC/MIC vancomycin monitoring |
| Prior MRSA/VRE colonisation | Add vancomycin or teicoplanin empirically | Review at 48-72 h |
| Persistent fever > 72 h | Add antifungal: micafungin 100 mg IV daily, or liposomal amphotericin B 3 mg/kg/day | Consider CT chest, galactomannan, beta-D-glucan |
| Suspected mucositis / enterocolitis | Consider metronidazole cover for anaerobes | Neutropenic enterocolitis (typhlitis) on CT: add metronidazole |
| Haematological malignancy with prolonged neutropenia | Early liposomal amphotericin or mould-active azole | Risk of Aspergillus very high beyond 10 days |
Meropenem is preferred over ceftazidime or piperacillin-tazobactam in the ICU setting because of its superior activity against AmpC-producing Enterobacterales and Pseudomonas aeruginosa at higher inoculum loads. De-escalation must follow culture-directed therapy; broad-spectrum coverage should not be maintained indefinitely.
Antifungal prophylaxis (fluconazole for low-risk; posaconazole for high-risk AML/myelodysplasia) may have already been prescribed prior to ICU admission, document pre-existing antifungal exposure to avoid unnecessary treatment gaps.
G-CSF in the ICU Setting
Granulocyte colony-stimulating factor (G-CSF, filgrastim) accelerates neutrophil recovery but does not demonstrably reduce mortality in most FN scenarios.
| Indication | G-CSF Use |
|---|---|
| Afebrile neutropenia | No evidence of benefit |
| Febrile neutropenia, clinically stable | Not routinely indicated |
| Septic shock, pneumonia, fungal infection with clinical deterioration | May be considered; benefit unproven but reasonable in extremis |
| Primary prophylaxis (chemo regimens with ≥ 20% FN risk) | Recommended preventively, not in crisis |
| Secondary prophylaxis (prior FN episode) | Reduces subsequent cycle neutropenia |
- Dose: Filgrastim 5 mcg/kg/day SC, commencing 24-72 hours after chemotherapy completion; not administered concurrently with chemotherapy.
- In the ICU, G-CSF may be justified in severe, deteriorating sepsis with protracted neutropenia, though it can exacerbate capillary leak and worsen ARDS in some cases.
Tumour Lysis Syndrome
Pathophysiology and Diagnostic Criteria
- Tumour lysis syndrome (TLS) results from the rapid release of intracellular contents, potassium, phosphate, nucleic acids (metabolised to uric acid), and lactate dehydrogenase, into the systemic circulation following massive cell death.
- This may occur spontaneously in high-burden disease or following cytotoxic therapy.
Cairo-Bishop diagnostic criteria for laboratory TLS (two or more of the following, within 3 days before or 7 days after cytotoxic therapy):
| Parameter | Threshold |
|---|---|
| Uric acid | $\geq 476\ \mu mol/L$ ($\geq 8\ mg/dL$) or 25% increase from baseline |
| Potassium | $\geq 6.0\ mmol/L$ or 25% increase |
| Phosphate | $\geq 1.45\ mmol/L$ (paediatric $\geq 2.1\ mmol/L$) or 25% increase |
| Calcium (corrected) | $\leq 1.75\ mmol/L$ or 25% decrease |
Clinical TLS = Laboratory TLS plus one of: creatinine $\geq 1.5 \times$ upper limit of normal, cardiac arrhythmia, seizure, or death.
- High-risk malignancies include Burkitt lymphoma, ALL, AML with high WBC, and any rapidly proliferating tumour with large cell mass.
- Renal insufficiency at baseline substantially elevates risk.
Metabolic Consequences and Organ Impacts
| Electrolyte Disturbance | Consequence |
|---|---|
| Hyperkalaemia | Ventricular arrhythmia, cardiac arrest |
| Hyperphosphataemia | Calcium-phosphate precipitation → acute kidney injury, hypocalcaemia |
| Hypocalcaemia (secondary) | Tetany, laryngospasm, seizures, arrhythmia |
| Hyperuricaemia | Urate crystal deposition in renal tubules → oliguric AKI |
- The uric acid pathway is central: nucleic acid purines are catabolised via hypoxanthine → xanthine → uric acid, mediated by xanthine oxidase (XO).
- Humans lack functional uricase; uric acid is the terminal product with limited solubility in acidic urine.
$$\text{Xanthine} \xrightarrow{XO} \text{Uric Acid} \xrightarrow{\text{Uricase (absent in humans)}} \text{Allantoin}$$
Pharmacological Management
Rasburicase is the cornerstone of treatment for high-risk or established clinical TLS:
- Recombinant uricase that directly converts uric acid to the highly soluble allantoin
- Dose: 0.2 mg/kg IV daily (single or repeated doses based on uric acid levels); some centres use fixed low-dose strategies (3-6 mg flat dose) in adults
- Onset: uric acid falls within hours (4-24 hours); dramatically superior to allopurinol for rapid reduction
- Critical contraindication: G6PD deficiency, rasburicase generates hydrogen peroxide as a by-product; in G6PD-deficient patients this causes severe haemolysis and methaemoglobinaemia. Screen or assume risk and withhold in high-risk populations (Mediterranean, African, Southeast Asian ancestry)
- Blood samples must be collected in pre-chilled tubes and assayed immediately to avoid ex vivo enzymatic degradation falsely lowering measured uric acid
Allopurinol (XO inhibitor) is used for prophylaxis in intermediate-risk patients or when rasburicase is contraindicated:
- Dose: 300 mg/day orally (reduce to 100 mg/day in renal impairment)
- Prevents new uric acid formation but does not reduce existing uric acid load; therefore inferior for established hyperuricaemia
- Critical drug interaction: Allopurinol and febuxostat both inhibit XO, co-administration with azathioprine or mercaptopurine causes dramatic accumulation of these immunosuppressants, potentially causing fatal myelosuppression. Dose reduction to 25-33% of mercaptopurine/azathioprine dose is mandatory if combination unavoidable
| Agent | Mechanism | Role | Key Caution |
|---|---|---|---|
| Rasburicase | Uricase: converts uric acid → allantoin | Treatment of established TLS / high-risk prophylaxis | G6PD deficiency; ex vivo sample degradation |
| Allopurinol | XO inhibitor: blocks uric acid synthesis | Prophylaxis in intermediate risk | Interaction with azathioprine/6-MP |
| Febuxostat | Non-purine XO inhibitor | Alternative to allopurinol (not TLS first-line) | Same XO interaction; cardiovascular risk |
Fluid, Electrolyte, and Renal Management
Aggressive IV hydration is the cornerstone of TLS prevention and treatment:
- Target urine output $\geq 2\ mL/kg/hour$; IV crystalloid 2-3 L/m² /day in adults without fluid overload
- Urinary alkalinisation is no longer routinely recommended: it promotes calcium-phosphate precipitation in tubules and offers no proven benefit over rasburicase
- Avoid potassium and phosphate in IV fluids
- Treat hyperkalaemia with standard measures (calcium gluconate for membrane stabilisation, insulin-dextrose, salbutamol, resonium, CRRT)
- Hyperphosphataemia: restrict dietary phosphate, phosphate binders if able to take orally; CRRT removes phosphate effectively
- Hypocalcaemia: do not treat asymptomatically, calcium administered in setting of hyperphosphataemia worsens organ precipitation
Renal Replacement Therapy in TLS
CRRT (continuous veno-venous haemodiafiltration, CVVHDF) is preferred over intermittent haemodialysis:
| Indication | Threshold |
|---|---|
| Oliguria/anuria refractory to fluid | Persisting despite adequate hydration |
| Potassium ≥ 6.5 mmol/L refractory | Unresponsive to medical management |
| Uric acid rising despite rasburicase | Rare; very high cell burden |
| Phosphate ≥ 3.0 mmol/L with AKI | Symptomatic or compounding hypocalcaemia |
| Fluid overload | Preventing adequate hydration strategy |
CVVHDF at higher effluent rates (35-40 mL/kg/hour) removes uric acid, phosphate, and potassium simultaneously and maintains haemodynamic stability.
Leukaemic Blast Crisis and Hyperleukocytosis
Definition and Pathophysiology
Hyperleukocytosis is defined as a WBC $> 100 \times 10^9/L$, though symptoms typically emerge at WBC $> 100 \times 10^9/L$ in AML and $> 400 \times 10^9/L$ in CML/ALL (blast cells in CML crisis behave differently from AML blasts).
- Leukaemic blasts are large, poorly deformable cells.
- At extreme WBC counts, they physically obstruct the microvasculature, a phenomenon termed leucostasis.
- Blasts also aggregate, trigger local inflammatory cytokine release, consume oxygen, and generate thrombin, leading to a prothrombotic and paradoxically haemorrhagic state (concurrent DIC in ~10-20% of AML presentations).
$$\text{Blood viscosity} \propto \text{Haematocrit} \times \text{WBC (large rigid blasts)}$$
Target organs: brain (confusion, stupor, coma, focal deficits, intracranial haemorrhage) and lungs (respiratory failure, pulmonary infiltrates mimicking ARDS or haemorrhage).
Clinical Features of Leucostasis
| System | Manifestation |
|---|---|
| CNS | Confusion, headache, blurred vision, papilloedema, focal deficits, coma |
| Pulmonary | Dyspnoea, hypoxaemia, bilateral infiltrates (leukaemic pneumonitis) |
| Renal | Acute tubular necrosis from blast micro-occlusion |
| Cardiac | Myocardial infarction despite non-obstructed coronaries |
| Priapism | Microvascular obstruction |
Concurrent DIC, thrombocytopenia, and coagulopathy make haemorrhagic complications equally likely as thrombotic ones, avoid red cell transfusion if haematocrit permits, as increasing viscosity worsens leucostasis.
Leucapheresis
Leucapheresis (therapeutic leukapheresis) is the rapid extracorporeal reduction of circulating blast count using apheresis technology:
- Indication: Symptomatic leucostasis (neurological or pulmonary compromise) with WBC typically $> 100 \times 10^9/L$ in AML, or $> 300-400 \times 10^9/L$ in ALL/CML
- Mechanism: Continuous-flow centrifugal separation removes the white cell fraction; reduces WBC by 30-60% per procedure
- Frequency: Once or twice daily until WBC falls below symptomatic threshold; definitive treatment is chemotherapy
- Limitations: Leucapheresis is a temporising bridge, it does not treat the underlying disease. Cell rebound occurs rapidly (within hours) without concurrent chemotherapy. It does not reliably prevent TLS, which may be precipitated by the cytoreduction itself
- Complications: Hypocalcaemia (citrate chelation in apheresis circuit), coagulopathy (factor removal), haemodynamic instability, air embolism, central line complications
- Large-bore central venous access (dialysis-type catheter) is required; peripheral access is insufficient for adequate flow rates
Concurrent ICU Measures
- Do not transfuse red cells unless haematocrit critically low (Hb < 70 g/L), increases viscosity
- Platelet threshold for transfusion: maintain $> 20 \times 10^9/L$ prophylactically; $> 50 \times 10^9/L$ if active bleeding or planned procedure
- Hydroxyurea 1-4 g orally can provide rapid chemical debulking while awaiting leucapheresis or chemotherapy initiation
- Correct coagulopathy: cryoprecipitate for fibrinogen < 1.5 g/L; FFP for active haemorrhage with elevated PT/APTT
- Avoid aspirin/anticoagulation unless compelling indication, DIC with haemorrhage dominates over thrombosis in many presentations
- Ophthalmology review for fundoscopic assessment of retinal leucostasis
- CT brain to exclude haemorrhage before any anticoagulation decision
- Definitive chemotherapy (e.g. cytarabine-based induction) should commence as soon as safely feasible
CICM Final Implications
Hot Case / Viva Approach
In the CICM hot case or viva, the examiner is testing your ability to systematically recognise these complications, articulate the underlying mechanism, and deliver time-critical, evidence-informed management. Key exam traps include:
| Trap | Correct Response |
|---|---|
| Using G-CSF routinely in established FN | Not indicated unless severe sepsis with deterioration; not standard practice |
| Giving allopurinol for acute established TLS | Rasburicase is required for acute treatment; allopurinol is prophylactic only |
| Transfusing packed RBCs for anaemia in hyperleukocytosis | Worsens viscosity and leucostasis; avoid unless critical |
| Alkalinising urine in TLS | Not currently recommended; promotes calcium-phosphate precipitation |
| Ignoring G6PD status before rasburicase | Potentially fatal haemolysis, always address in viva |
| Co-prescribing standard-dose azathioprine with allopurinol | Fatal myelosuppression; reduce AZA/6-MP dose by 75% |
Monitoring Targets in TLS
| Parameter | Target / Action Threshold |
|---|---|
| Uric acid | $< 360\ \mu mol/L$ ($< 6\ mg/dL$) |
| Potassium | $< 6.0\ mmol/L$; treat ≥6.5 mmol/L urgently |
| Phosphate | $< 1.45\ mmol/L$ |
| Corrected calcium | $> 2.0\ mmol/L$ (treat symptoms, not numbers) |
| Urine output | $\geq 2\ mL/kg/hour$ |
| Creatinine trend | Any rising trend warrants early nephrology/CRRT discussion |
Communication and Multidisciplinary Coordination
These patients require close collaboration between intensivist, haematologist, nephrology, and transfusion medicine. Anticipate:
- Early haematology involvement for chemotherapy timing, prognosis, and transplant eligibility
- Transplant-specific infection risks if bone marrow transplant has occurred (CMV, PCP, EBV)
- Goals-of-care conversations: many of these patients have aggressive underlying malignancy; ICU admission should have clear objectives, reversibility assessment, and time-limited trials articulated early with the patient, family, and haematology team
Fluency in the pharmacology, metabolic complications, and organ-support strategies for these three conditions is expected at the CICM Final level, the examiner will probe mechanism, dosing rationale, and critical safety considerations rather than accepting protocol recitation.