Level 2 of 6Must-remember

Febrile neutropenia and neutropenic sepsis

Assess, manage and stay safe — enough on its own

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The card — assess, manage, caution

Assessment— look, ask, measure

The definition to work from: after cytotoxic chemotherapy, neutropenic fever is a single oral temperature of at least 38.3°C, or a temperature of 38°C or above sustained for more than one hour, in a patient with a neutrophil count below 0.5 × 10⁹/L — or below 1.0 × 10⁹/L if the nadir is anticipated to fall below 0.5 × 10⁹/L within the next 48 hours.
The wider NICE definition that catches the sickest: neutropenic sepsis is fever above 38°C lasting over one hour with neutrophils below 0.5 × 10⁹/L, or a neutropenic patient with any other signs or symptoms of significant sepsis — the hypotensive, rigoring, confused, tachypnoeic or hypothermic patient with no recorded fever satisfies the definition and carries a higher mortality.
The safest operating rule: treat fever, or unexplained deterioration, in any patient within about six weeks of chemotherapy as febrile neutropenia until the differential count says otherwise; Harrison's casts the net at fever with under 1500 granulocytes/μL (1.5 × 10⁹/L).
History to ask for: which regimen and which cycle, the date of the last dose (the nadir is usually days 7–14, with recovery by days 21–28), prior febrile neutropenia, central venous catheter, mucositis, prophylactic antibiotics or antifungals, corticosteroids, and whether anyone at home is unwell.
Remember functional neutropenia: in acute leukaemia or myelodysplasia the count may be numerically adequate but the neutrophils qualitatively defective, and the risk is comparable despite a reassuring blood count — and in acute leukaemia a white cell count as high as 300 × 10⁹/L commonly conceals neutropenia with blast cells predominating.
Measure at once: temperature, pulse, blood pressure, respiratory rate, oxygen saturation, conscious level, capillary refill, urine output and a lactate — a lactate above 2 mmol/L defines a high-risk episode and above 4 mmol/L predicts high mortality.Not available at your setup — Arterial blood gas.
The danger signs of established or impending septic shock: systolic blood pressure below 90 mmHg or a fall of over 40 mmHg from baseline; heart rate above 120/min; respiratory rate above 24/min; new oxygen requirement; new confusion; lactate above 2 mmol/L; mottled peripheries with prolonged capillary refill; urine output below 0.5 mL/kg/h; hypothermia below 36°C; and profound neutropenia below 0.1 × 10⁹/L.Not available at your setup — Arterial blood gas.
Population-specific red flags: new abdominal pain or bloody diarrhoea (neutropenic enterocolitis / typhlitis), spontaneous bleeding with thrombocytopenia, oozing from puncture sites (DIC), new headache or focal deficit in a thrombocytopenic patient, and a white cell count in the hundreds with breathlessness or confusion (leukostasis).Not available at your setup — Coagulation (PT/INR).
Examine the places infection hides: mouth and pharynx (mucositis, ulceration, thrush, herpetic vesicles or crusting at the vermilion border); skin including the back; every catheter exit site and tunnel; the perineum and perianal region, inspected with a light and the patient rolled; chest; abdomen; and the central nervous system, since new headache, confusion or neck stiffness demands imaging and consideration of lumbar puncture.Not available at your setup — CT scan.
Rigors occurring reproducibly a few minutes after a central line is flushed point fairly specifically to catheter-related bloodstream infection; right iliac fossa pain with diarrhoea and distension is neutropenic enterocolitis until excluded; breathlessness with a clear chest and clear radiograph is respiratory infection until proved otherwise.Not available at your setup — Central venous access.
Fever is often the only feature — in perhaps half of episodes no source is ever identified, and the absence of a source is not evidence against infection, it is the expected finding.
The classical signs of infection are made of neutrophils: pneumonia may produce no consolidation and a near-normal chest radiograph, an abscess no pus and no fluctuance, peritonitis little guarding, urinary infection no pyuria, and meningitis minimal neck stiffness — a normal examination does not lower the probability of serious infection.
The afebrile presentation is the most dangerous: hypotension, isolated rigors, new confusion, unexplained tachycardia or tachypnoea, vomiting, abdominal pain, or hypothermia below 36°C may occur without any recorded fever, and hypothermia here is a worse sign than fever.
Age and drugs blunt the picture: the elderly present with delirium, falls, incontinence, immobility or simply being off legs, frequently with a blunted febrile response, and beta-blockade means a heart rate of 90 may represent profound stress; patients on corticosteroids may not mount a fever at all, and the anti-inflammatory effect suppresses whatever localising signs remain.
Children compensate then decompensate abruptly — hypotension in a child is a pre-terminal sign, so act on tachycardia, rising respiratory rate (often the first sign of metabolic acidosis), prolonged capillary refill, cool or mottled peripheries, irritability or drowsiness, reduced urine output, and a parent reporting the child is not themselves.
Grade the neutropenia: mild 1.0–1.5 × 10⁹/L (little excess risk); moderate 0.5–1.0 (risk rising — treat as neutropenic if falling or within 7–14 days of chemotherapy); severe below 0.5 (meets the standard definition, substantial risk of bacteraemia); profound below 0.1 (highest risk, expect rapid deterioration and occult infection).

Management— do this, in order

High-dose broad-spectrum intravenous antibiotics ideally within one hour of admission, without awaiting test results — the blood count confirms the diagnosis, it does not license the delay, and time to effective antibiotic is the most modifiable determinant of survival.Doctor / Nurse
Take cultures first, but 'first' means within minutes: two peripheral blood culture sets plus one from every lumen of any central catheter, urine, stool if diarrhoea, swabs of line site, wounds and ulcers, sputum, and respiratory viral PCR.Not available at your setup — Blood culture, Central venous access.
Cover *Pseudomonas* and other Gram-negative bacilli — this is not negotiable, since *Escherichia coli*, *Pseudomonas* and *Klebsiella* from a mucositic gut cause rapid clinical deterioration; follow local bacteriological resistance patterns rather than a textbook.
Standard first-line monotherapy: piperacillin–tazobactam 4.5 g IV every 6–8 hours (paediatric 90 mg/kg of the combination every 6–8 hours, maximum 4.5 g per dose).Doctor / Nurse
Meropenem 1 g IV every 8 hours (paediatric 20 mg/kg every 8 hours, maximum 1 g per dose) if the patient is shocked, was recently exposed to piperacillin–tazobactam, or is known to be colonised with ESBL organisms.Doctor / Nurse
Alternatives: cefepime or ceftazidime 2 g IV every 8 hours (paediatric 50 mg/kg every 8 hours, maximum 2 g per dose) — cefepime is CMDT's baseline agent, while ceftazidime is antipseudomonal but has poor Gram-positive cover.Doctor / Nurse
Add an aminoglycoside only for the shocked patient or where local resistance demands it: gentamicin 5–7 mg/kg IV once daily by ideal body weight (paediatric 7 mg/kg once daily) or amikacin 15 mg/kg, monitoring levels and creatinine, then reassess daily.Doctor / NurseNot available at your setup — Renal function (creatinine/urea).
Add a glycopeptide only for a specific reason — not routinely: vancomycin 15–20 mg/kg IV every 8–12 hours (load 25–30 mg/kg if severe; paediatric 15 mg/kg every 6 hours) or teicoplanin 400 mg IV every 12 hours for 3 doses then 400 mg daily (paediatric 10 mg/kg every 12 hours for 3 doses, then 10 mg/kg daily), for an infected catheter exit site or tunnel, known MRSA colonisation, severe mucositis, a skin source, haemodynamic instability, or a Gram-positive isolate pending sensitivities — and stop at 48–72 hours if none emerges.Doctor / NurseNot available at your setup — Central venous access.
Severe penicillin allergy: carbapenem cross-reactivity is low (well under 1% with meropenem) but not zero, so in documented anaphylaxis use aztreonam 2 g IV every 8 hours (paediatric 30 mg/kg every 6–8 hours) or ciprofloxacin 400 mg IV every 8–12 hours (paediatric 10 mg/kg every 8 hours, maximum 400 mg per dose) combined with a glycopeptide — but a history of rash alone should not deprive a shocked patient of a beta-lactam.Doctor / Nurse
Resuscitate in parallel: oxygen to a saturation of 94–98% (88–92% if at risk of hypercapnic respiratory failure), and balanced crystalloid or 0.9% sodium chloride 500 mL over 15 minutes in an unstable adult (250 mL if frail, elderly or cardiac) or 10–20 mL/kg in a child, repeated against blood pressure, heart rate, conscious level and urine output.
Hypotension persisting after 20–30 mL/kg needs vasopressors, with noradrenaline first choice; target urine output of at least 0.5 mL/kg/h in adults and at least 1 mL/kg/h in children.Doctor / NurseNot available at your setup — Infusion pump.
Antipyresis: paracetamol 1 g orally or intravenously up to four times daily (children 15 mg/kg per dose, maximum 60 mg/kg in 24 hours), documenting the temperature first — and avoid NSAIDs and aspirin, since these patients are frequently thrombocytopenic and often have incipient kidney injury.
Support the counts: platelet transfusion for thrombocytopenic bleeding unless trivial, prophylactic platelets to maintain the count above 10 × 10⁹/L in acute leukaemia, red cell concentrate for anaemia, and irradiated cellular components for immunosuppressed and transplant recipients.Doctor / NurseNot available at your setup — Blood & blood products.
Treat oral candidiasis with fluconazole 50–100 mg orally daily in adults (3–6 mg/kg daily in children); hand hygiene and a single room where available are worthwhile.
Reassess at 48–96 hours against cultures, clinical trajectory and neutrophil recovery: if improving and afebrile, continue the same agent and narrow if a pathogen is isolated; if febrile but stable, re-examine head to toe, repeat cultures from every lumen, review the drug chart for drug fever and image — do not change antibiotics reflexively.Not available at your setup — Blood culture, CT scan.
Persistent fever with clinical instability: broaden from cefepime to meropenem 1 g every 8 hours IV, with an additional Gram-negative agent (ciprofloxacin or tobramycin) if critically ill, add Gram-positive cover if not already given, and search hard for an undrained source.Doctor / Nurse
Think fungus at day 3–5, not day 1: if fever has not resolved after 3–5 days with CT or sensitive blood-test evidence of disseminated fungal infection, add liposomal amphotericin B, voriconazole or caspofungin — treatment of confirmed or suspected systemic *Candida* or *Aspergillus* infection runs for up to three weeks, and in systemic candidaemia the intravenous catheter must be removed.Doctor / NurseNot available at your setup — CT scan, Central venous access, Blood culture.
Anticipate the concurrent emergencies: tumour lysis 1–5 days after chemotherapy — treat hyperkalaemia with ECG change immediately using calcium gluconate 10%, 10 mL IV over 5–10 minutes (paediatric 0.5 mL/kg, maximum 20 mL), insulin with glucose and nebulised salbutamol — plus neutropenic enterocolitis, thrombocytopenic haemorrhage, DIC and leukostasis.Doctor / NurseNot available at your setup — Serum electrolytes.

Caution— what harms

Never wait for the blood count, the culture result or the ward round before giving antibiotics — Davidson's instruction is treatment within one hour, without awaiting test results, and mortality rises measurably with each hour of delay.Not available at your setup — Blood culture.
Never accept a normal examination as reassurance: no pus, a normal chest radiograph, a soft abdomen and clear urine microscopy carry almost no negative predictive value, because the signs of infection are made of neutrophils.
Never rely on a chest radiograph to exclude pneumonia — it may be normal in established neutropenic pneumonia, and a normal film in a breathless or hypoxic patient is an indication for CT, not for reassurance.Not available at your setup — CT scan.
Never use ceftriaxone or any agent without antipseudomonal cover as sole empirical therapy, since Gram-negative organisms from a mucositic gut kill fastest.
Do not add vancomycin routinely: trials have not shown a survival benefit from empirical glycopeptide cover, and it drives resistance and nephrotoxicity — add it only for a defined indication and stop at 48–72 hours if no Gram-positive isolate emerges.Not available at your setup — Renal function (creatinine/urea).
Never perform a digital rectal examination, take a rectal temperature or give a suppository, and avoid intramuscular injections in the thrombocytopenic patient — instrumenting a mucosa that cannot defend itself risks seeding a bacteraemia.
Avoid NSAIDs and aspirin for fever or pain: these patients are frequently thrombocytopenic and often have incipient kidney injury; naproxen is classically used for tumour fever but is hazardous here for exactly those reasons.Not available at your setup — Renal function (creatinine/urea).
Do not give anti-motility agents for diarrhoea until *Clostridioides difficile* and typhlitis have been excluded.
Do not be reassured by a MASCC or qSOFA score: qSOFA is insensitive in early neutropenic sepsis and a score of 0 must not reassure; SIRS criteria are non-specific because fever and tachycardia are near-universal; track-and-trigger scores under-call the patient on beta-blockers or steroids; and MASCC should justify de-escalation of care in an already-observed patient, never withholding antibiotics.
A normal or high white cell count does not exclude neutropenia — it is the neutrophil count that matters, and in acute leukaemia a white cell count as high as 300 × 10⁹/L commonly masks profound neutropenia with blasts predominating; functional neutropenia carries comparable risk with a numerically adequate count.
Do not treat hypotension in a child as the first sign of shock — it is pre-terminal; and do not treat a normal temperature in an elderly or steroid-treated patient as evidence against infection, since hypothermia below 36°C is a worse sign than fever.
Do not change antibiotics reflexively for persistent fever in a stable patient: persistent fever during profound neutropenia is common and often resolves only with count recovery — re-examine, re-culture and image instead.Not available at your setup — Blood culture.
Do not escalate antifungals on fever alone in a patient already on posaconazole prophylaxis (standard for AML induction and reinduction): the regimen should not be modified on the basis of persistent or recurrent neutropenic fever alone.
Expect the toxicity of your own treatment: nephrotoxicity and ototoxicity from aminoglycosides and amphotericin, antibiotic-associated diarrhoea and *C. difficile*, resistance selection, and the oncological cost of a dose reduction or delay of the next cycle where chemotherapy is curative in intent.Not available at your setup — Renal function (creatinine/urea).

Refer / escalate

Escalate to critical care immediately for systolic blood pressure below 90 mmHg or a fall of over 40 mmHg, heart rate above 120/min, respiratory rate above 24/min, a new oxygen requirement, new confusion, lactate above 2 mmol/L, urine output below 0.5 mL/kg/h, hypothermia below 36°C, or hypotension persisting after 20–30 mL/kg of fluid — and discuss every episode with the treating oncology or haematology team the same day.

The card — assess, manage, caution

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